91 results on '"Jacqueline C. Barrientos"'
Search Results
2. Initiating First-Line (1L) Ibrutinib (Ibr) in Patients (pts) with Chronic Lymphocytic Leukemia (CLL) Improves Overall Survival (OS) Outcomes to Rates Approximating an Age-Matched Population of ≥65 Years
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Paolo Ghia, Carolyn Owen, Jacqueline C. Barrientos, Paul M. Barr, Anthony R. Mato, Chunxue Shi, Anita Szoke, Chris Abbazio, Gabriel S. Krigsfeld, and Jan A. Burger
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. Final Results of the Phase 1/2 Study of Acalabrutinib Monotherapy in Treatment-Naive Chronic Lymphocytic Leukemia with >6 Years of Follow-up
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John C. Byrd, Jennifer A. Woyach, Richard R. Furman, Peter Martin, Susan O'Brien, Jennifer R. Brown, Deborah M. Stephens, Jacqueline C. Barrientos, Piers EM Patten, Talha Munir, Krish Patel, Anna Butturini, Marianne de Borja, Min Hui Wang, Nitin Jain, and William G. Wierda
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
4. Identification of Three Unique Clusters of Serum Proteins with Distinctive Functionalities in IGHV-Mutated MBL
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Gonzalo Blanco, Florencia Palacios, Kamala Vanarsa, Poojitha Dugyala, Pui Yan Chiu, Steven L Allen, Yasmine Kieso, Anna Puiggros, Jacqueline C. Barrientos, Xavier Calvo, Jonathan E. Kolitz, Eva Gimeno, Joanna M. Rhodes, Ana Ferrer, Kanti R Rai, Barbara Sherry, Blanca Espinet, Chandra Mohan, and Nicholas Chiorazzi
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
5. Phase 1/2 Study of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Results with >4 Years of Follow-up
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Richard R. Furman, William G. Wierda, Anna Schuh, Piers EM Patten, Jorge M. Chaves, Jennifer R. Brown, Talha Munir, Peter Martin, Farrukh T. Awan, Deborah M. Stephens, Paolo Ghia, Jacqueline C. Barrientos, Krish Patel, Jennifer A. Woyach, Anna Butturini, Marianne de Borja, Min Hui Wang, Susan O'Brien, and John C. Byrd
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
6. Real-World Outcomes with First-Line Ibrutinib (Ibr) Versus Chemoimmunotherapy (CIT) in Patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): Final Analysis Results from the InformCLL Registry
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Nilanjan Ghosh, Jeff P. Sharman, Jacqueline C. Barrientos, Danielle Brander, Meghan Gutierrez, Linda Wu, Zaina P. Qureshi, Sandhya Upasani, Maoko Naganuma, and Anthony R. Mato
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
7. Acalabrutinib in treatment-naive chronic lymphocytic leukemia
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Jacqueline C. Barrientos, William G. Wierda, Raquel Izumi, Ahmed Hamdy, Nitin Jain, Min Hui Wang, John M. Pagel, Jennifer R. Brown, Peter Hillmen, Peter Martin, John C. Byrd, Richard R. Furman, Stephen Devereux, Susan O'Brien, Jennifer A. Woyach, Deborah M. Stephens, and Priti Patel
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Adult ,Male ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,Immunology ,Biochemistry ,Internal medicine ,Humans ,Medicine ,Dosing ,Adverse effect ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Chemotherapy ,business.industry ,Atrial fibrillation ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Confidence interval ,Discontinuation ,Pyrazines ,Benzamides ,Mutation ,Cohort ,Female ,Tumor Suppressor Protein p53 ,business - Abstract
Acalabrutinib has demonstrated significant efficacy and safety in relapsed chronic lymphocytic leukemia (CLL). Efficacy and safety of acalabrutinib monotherapy were evaluated in a treatment-naive CLL cohort of a single-arm phase 1/2 trial (ACE-CL-001). Adults were eligible for enrollment if chemotherapy was declined or deemed inappropriate due to comorbidities (N = 99). Patients had a median age of 64 years and 47% had Rai stage III/IV disease. Acalabrutinib was administered orally 200 mg once daily, or 100 mg twice daily until progression or intolerance. A total of 99 patients were treated; 57 (62%) had unmutated immunoglobulin heavy-chain variable gene, and 12 (18%) had TP53 aberrations. After median follow-up of 53 months, 85 patients remain on treatment; 14 discontinued treatment, mostly because of adverse events (AEs) (n = 6) or disease progression (n = 3). Overall response rate was 97% (90% partial response; 7% complete response), with similar outcomes among all prognostic subgroups. Because of improved trough BTK occupancy with twice-daily dosing, all patients were transitioned to 100 mg twice daily. Median duration of response (DOR) was not reached; 48-month DOR rate was 97% (95% confidence interval, 90-99). Serious AEs were reported in 38 patients (38%). AEs required discontinuation in 6 patients (6%) because of second primary cancers (n = 4) and infection (n = 2). Grade ≥3 events of special interest included infection (15%), hypertension (11%), bleeding events (3%), and atrial fibrillation (2%). Durable efficacy and long-term safety of acalabrutinib in this trial support its use in clinical management of symptomatic, untreated patients with CLL.
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- 2021
8. Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy
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Alan P Skarbnik, Paul M. Barr, Danielle M. Brander, Hanna Weissbrot, Ian W. Flinn, Peter Sportelli, Suman Kambhampati, Patricia Y. Tsao, Jeffrey Pu, Lindsey E. Roeker, Dana Paskalis, Nicole Lamanna, Stephen J. Schuster, Anthony R. Mato, James A. Reeves, Frederick Lansigan, Bruce D. Cheson, Michael S. Weiss, Nicole LaRatta, Gustavo Fonseca, Hari P. Miskin, Issam Hamadeh, Colleen Dorsey, Andrea Sitlinger, Nilanjan Ghosh, John M. Pagel, Eline T. Luning Prak, Kanti R. Rai, Jakub Svoboda, and Jacqueline C. Barrientos
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medicine.medical_specialty ,education.field_of_study ,business.industry ,Immunology ,Population ,Phases of clinical research ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Gastroenterology ,Rash ,Discontinuation ,hemic and lymphatic diseases ,Internal medicine ,Clinical endpoint ,medicine ,Progression-free survival ,Leukocytosis ,medicine.symptom ,education ,business - Abstract
Purpose Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in CLL. Umbralisib a novel, highly selective PI3Kδ/CK1e inhibitor, is active and well tolerated in CLL patients. This phase 2 trial evaluated umbralisib in CLL patients who are intolerant to prior BTK or PI3K inhibitor therapy. Patients and methods In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg oral daily in CLL patients requiring therapy per investigator discretion who were intolerant to prior BTK or PI3K inhibitor therapy, until progression or toxicity. Primary endpoint was progression-free survival (PFS). Secondary endpoints included time to treatment failure and umbralisib safety profile. DNA isolated from buccal swabs was genotyped for polymorphisms in CYP3A4, CYP3A5 and CYP2D6. Results Fifty-one patients were enrolled (44 BTKi and 7 PI3Kδi intolerant). Median age was 70 years (range 48-96), median of 2 prior lines of therapy (1-7), 24% had del17p and/or TP53 mutation, and 65% were IGHV unmutated. Most common AEs leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median progression free survival (PFS) was 23.5 months (95% CI 13.1-not estimable). 58% of patients were on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib due to an AE. Eight patients (16%) had dose reductions and were successfully re-challenged. Conclusions Umbralisib is safe and effective in this BTK and alternate PI3K inhibitor intolerant CLL population. These are the first prospective data to confirm that switching from a BTK or alternate PI3K inhibitor to umbralisib can result in durable, well tolerated responses.
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- 2021
9. CD8+ T Cells from Patients with CLL Show Evidence of Granzyme B and Perforin Cytotoxic Capacity, Which Is Enhanced upon Exposure to Exogenous IL2 and/or IL21
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Cristina Paraschivescu, Shivani Chhabra, Rukhsana Aslam, Byeongho Jung, Gerardo Ferrer, Jacqueline C. Barrientos, Joanna M. Rhodes, Jonathan E. Kolitz, Steven L Allen, Kanti R Rai, Barbara Sherry, and Nicholas Chiorazzi
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
10. Waveline-001: Updated Results from a Phase 1 Dose Escalation and Cohort Expansion Study of Zilovertamab Vedotin (MK-2140) in Non-Hodgkin Lymphoma
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Stephen E. Spurgeon, Matthew Mei, Paul M. Barr, Jacqueline C. Barrientos, Sven de Vos, Richard R. Furman, Krish Patel, Philip A. Thompson, Michael Y. Choi, Avyakta Kallam, Sirou Wang, Uzor C. Ogbu, Akash Nahar, and Michael L. Wang
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
11. Integrin Signaling Pathway Is Crucial for the Recently Divided Fraction of CLL Cells and Facilitates Cell Migration in a Disease Progressive Manner
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Xiao J. Yan, Florencia Palacios, Shih-Shih Chen, Wentian Li, Joanna M. Rhodes, Jacqueline C. Barrientos, Steven L Allen, Jonathan E. Kolitz, Kanti R Rai, and Nicholas Chiorazzi
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
12. Venetoclax Re-Treatment of Chronic Lymphocytic Leukemia (CLL) Patients after a Previous Venetoclax-Based Regimen
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Andre Goy, Manali Kamdar, Paul M. Barr, Anthony R. Mato, Beenish S Manzoor, Alison J. Moskowitz, Kavita Sail, Alan P Skarbnik, Jacqueline C. Barrientos, Martin Simkovic, Richard R. Furman, Catherine C. Coombs, John N. Allan, Joanna M Rhodes, Lindsey E. Roeker, Jeffrey J. Pu, Andrew D. Zelenetz, Brittany Jane Hale, Kurt S. Bantilan, Michael Y. Choi, Stephen J. Schuster, Tatyana Feldman, Lori A. Leslie, Celina J. Komari, Meghan C. Thompson, and Frederick Lansigan
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Oncology ,medicine.medical_specialty ,Venetoclax ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,Regimen ,chemistry ,Internal medicine ,medicine ,business - Abstract
BACKGROUND: Treatment of chronic lymphocytic leukemia (CLL) with a fixed-duration venetoclax (Ven)-based regimen is now a standard of care (SOC) option for both frontline and relapsed refractory (R/R) disease based on results of the CLL14 and MURANO trials (Fischer et al NEJM 2019, Seymour et al NEJM 2018). As fixed-duration Ven regimens are now a SOC, it is expected that an increasing number of patients (pts) will ultimately progress after Ven exposure and require additional CLL-directed therapy. While many discuss re-treatment with Ven as a subsequent treatment option, the current literature contains response data on an extremely limited number of evaluable pts (11 pts MURANO, overall response rate (ORR) 55%; 3 pts VEN 365, ORR 100%). Whether re-treatment with Ven is an acceptable option remains an important unanswered clinical question. METHODS: We conducted a multicenter, retrospective study of CLL pts treated with a Ven-based regimen (Ven1) and then re-treated with a second Ven-based regimen (Ven2) in a later line of therapy (LOT). Data were collected from 13 centers and the CLL Collaborative Study of Real-World Evidence database. CLL pts were eligible for inclusion if they were treated with a Ven-based regimen in any LOT and then re-treated with a Ven-based regimen as a later LOT. Collected data included demographics, prognostic disease characteristics, tumor lysis syndrome (TLS) risk and incidence, clinical response and reasons for treatment discontinuation (dc). The primary study endpoint was investigator-assessed ORR (CR: complete response, PR: partial response, SD: stable disease, PD: progression of disease, iwCLL 2018). Kaplan-Meier method was used to estimate progression free survival (PFS). All other analyses were descriptive. RESULTS: We identified 25 pts who were re-treated with Ven. Pt characteristics prior to treatment with Ven1 are summarized in Table 1. In 24% of pts (n=6), Ven1 was administered as part of a clinical trial. Median prior LOT was 2 (range 0-10) with 12.0% treatment naïve and 60% with prior BTKi exposure. The majority of pts had ≥1 high-risk prognostic marker: del17p (39%), TP53 mut (27%), complex karyotype ≥5 abnormalities (30%) and unmutated IGHV (84%). For Ven1, treatment regimens, TLS risk, and dose are summarized in Table 2. With a median duration of exposure of 15 months (mos) (64% pts > 12 mos) for Ven1, the ORR was 88% (CR: 48%, PR: 40%, Figure 1A). Ten pts had minimal residual disease (MRD) assessments by flow cytometry; 8 pts (80%) achieved undetectable MRD (10^-4). Most common reasons for Ven1 dc included: toxicity (28%), completion of planned therapy (24%), MD/pt preference (24%), other (12%), alloHSCT (4%) and cost (4%). There was a median of 8.7 mos (36% > 12 mos) between Ven1 and the initiation of Ven2, and 88% did not receive another LOT between Ven1 and Ven2. Reasons for Ven2 initiation were either CLL progression (87.5%) or MRD-positive relapse (12.5%). For Ven2, TLS risk, TLS incidence and dose information are outlined in Table 2. TLS was a rare event during Ven re-treatment (4.5%, lab only). For Ven2, Ven monotherapy was the most common regimen (52%). Standard Ven dose-escalation was used for re-initiation in 17 of 19 pts with available data, however 1 pt started Ven2 at 400 mg daily (no TLS) and another underwent a prolonged ramp-up period. At the time of this analysis, 18 pts had available response assessments for Ven2: ORR is 72.2% (CR: 4, PR: 9, SD: 4 and PD: 1, Figure 1B). Median time from Ven2 to progression or last follow up is 8 mos (0.2-29 mos). Median PFS has not been reached. Estimated 12-month PFS is 69.1%. For pts with a CR to Ven2, median follow up time is 14.5 mos vs 7 mos for pts with PR or SD. Of 25 pts re-treated with Ven, 68% remain on Ven2 presently and 32% have discontinued Ven2, including due to CLL progression (n=4), completion of planned therapy (n=1), unrelated death (n=1), MD/pt preference (n=1). CONCLUSIONS: To our knowledge, this is the largest reported cohort of CLL pts re-treated with Ven after a prior Ven-based regimen. The high ORR in this pt population (median 2 prior therapies) suggests that re-treatment is a promising strategy and should be considered in treatment sequencing algorithms. Notably, pts with a CR to Ven2 had a longer median follow up than those with a PR or SD, suggesting a likelihood of deeper responses with time. Given the promising ORR, further research to prospectively validate Ven re-treatment is warranted. Updated data will be presented. Disclosures Allan: Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria; Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy. Sail:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Manzoor:Abbvie: Current Employment, Other: may hold stock or stock options. Pu:Takeda Pharmaceuticals: Consultancy. Barr:Gilead: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Morphosys: Consultancy; TG therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy. Coombs:LOXO Oncology: Honoraria; MEI Pharma: Honoraria; Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. Schuster:AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria; Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding. Skarbnik:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy; Beigene: Speakers Bureau; Verastem: Speakers Bureau; Novartis: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rhodes:Verastem: Consultancy; Abbvie/Genentech: Consultancy; Pharmacyclics: Consultancy; AstraZeneca: Consultancy. Barrientos:Janssen: Honoraria; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding; Bayer: Consultancy; Genentech: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy. Roeker:American Society of Hematology: Research Funding; Abbott Laboratories: Other: spouse with minority ownership interest ; AbbVie: Other: spouse with minority ownership interest . Leslie:Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kamdar:Roche: Research Funding. Choi:Pharmacyclics/Abbvie: Research Funding; Genentech: Consultancy. Simkovic:Abbvie: Consultancy, Other: travel expenses. Lansigan:Seattle Genetics: Consultancy; BMS: Consultancy; BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding. Zelenetz:Novartis: Consultancy; Gilead: Research Funding; Janssen: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Roche: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Consultancy; MorphoSys: Research Funding; Amgen: Consultancy; Sandoz: Research Funding; Celgene: Research Funding; MEI Pharma: Research Funding. Moskowitz:Merck: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Miragen Therapeutics: Consultancy; Incyte: Research Funding; Merck: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Seattle Genetics: Consultancy. Goy:Morphosys: Research Funding; AbbVie: Research Funding; MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Infinity Verastem: Research Funding; Infinity: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; CALBG: Research Funding; Constellation: Research Funding; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Xcenda: Consultancy; Hackensack UMC and University of Nebraska: Research Funding. Feldman:Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Trillium: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Viracta: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Furman:Verastem: Consultancy; Genentech: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy; Pharmacyclics: Consultancy; Oncotarget: Consultancy; Loxo Oncology: Consultancy; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy. Mato:Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BeiGene: Consultancy; LOXO: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Adaptive: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding.
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- 2020
13. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab
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Jacqueline C. Barrientos, Susan O'Brien, Ulrich Jaeger, Nishitha Reddy, Jennifer R. Brown, Steven Coutre, Constantine S. Tam, Peter Hillmen, Danelle F. James, John C. Byrd, Richard R. Furman, John M. Pagel, Patrick Thornton, Remus Vezan, Paul M. Barr, Jan A. Burger, Sandra Dai, Jennifer A. Woyach, Carol Moreno, Thomas J. Kipps, Stephen P. Mulligan, and Marco Montillo
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Clinical Trials and Observations ,Immunology ,Antibodies, Monoclonal, Humanized ,Ofatumumab ,Biochemistry ,Time ,law.invention ,chemistry.chemical_compound ,Antineoplastic Agents, Immunological ,Piperidines ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,Progression-free survival ,Aged ,business.industry ,Adenine ,Hazard ratio ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Progression-Free Survival ,Clinical trial ,Pyrimidines ,chemistry ,Ibrutinib ,Pyrazoles ,Female ,Rituximab ,business ,Progressive disease ,Follow-Up Studies ,medicine.drug - Abstract
Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with
- Published
- 2019
14. Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib
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Martin S. Tallman, Paul M. Barr, Jacqueline C. Barrientos, Mark R. Litzow, Anthony R. Mato, Elisabeth Paietta, Jose F. Leis, Renee C. Tschumper, Curtis A. Hanson, Richard Stone, Neil E. Kay, Victoria Wang, Harry P. Erba, Amanda F. Cashen, Cong Christine Zhang, Tait D. Shanafelt, Susan O'Brien, Esteban Braggio, Avina K. Singh, Steven Coutre, Michael P Mullane, and Connie Lesnick
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Male ,medicine.medical_specialty ,Neoplasm, Residual ,Cyclophosphamide ,Immunology ,Disease ,Biochemistry ,Gastroenterology ,chemistry.chemical_compound ,Piperidines ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Progression-free survival ,Protein Kinase Inhibitors ,Lymphoid Neoplasia ,business.industry ,Surrogate endpoint ,Adenine ,Hazard ratio ,Cell Biology ,Hematology ,Middle Aged ,Flow Cytometry ,Prognosis ,Leukemia, Lymphocytic, Chronic, B-Cell ,Progression-Free Survival ,Fludarabine ,body regions ,Treatment Outcome ,chemistry ,Ibrutinib ,Rituximab ,Female ,business ,Vidarabine ,medicine.drug - Abstract
E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (
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- 2020
15. Quality of Life in Patients <=70 Years of Age with Chronic Lymphocytic Leukemia Treated Frontline with Ibrutinib-Rituximab Versus Fludarabine Cyclophosphamide Rituximab: Analysis from ECOG-ACRIN E1912
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Priyanka A. Pophali, Amanda F. Cashen, Anthony R. Mato, Mark R. Litzow, Steven Coutre, Lynne I. Wagner, Cong Christine Zhang, Neil E. Kay, Fengmin Zhao, Mary L. Thomas, Jose F. Leis, Richard Stone, Paul M. Barr, Martin S. Tallman, Tait D. Shanafelt, Jacqueline C. Barrientos, Richard F. Little, Susan O'Brien, Elisabeth Paietta, Avina K. Singh, Harry P. Erba, Xin Victoria Wang, and Curtis A. Hanson
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Oncology ,medicine.medical_specialty ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Cyclophosphamide/Rituximab ,Fludarabine ,chemistry.chemical_compound ,Quality of life ,chemistry ,Internal medicine ,Ibrutinib ,Medicine ,Rituximab ,In patient ,business ,medicine.drug - Abstract
Background: The ECOG-ACRIN randomized phase 3 clinical trial E1912 established ibrutinib-rituximab (IR) as the standard of care for CLL patients Methods: Patients enrolled on E1912 completed the Functional Assessment of Cancer Therapy-General (FACT-G) and Leukemia subscale at randomization (baseline), 3, 6, and 12 months post-randomization, and every 6 months for 2 years regardless of disease status. The primary outcome was the 31-item FACT-Leukemia Trial Outcome Index (FACT-Leu TOI), calculated by summing items from the FACT-G physical wellbeing (PWB), functional well-being (FWB), and leukemia subscales (score range: 0-124). The primary endpoint was defined as the difference in FACT-Leu TOI change scores from randomization to 12 months (at response evaluation) between patients treated with continuous therapy Arm A (IR) vs time-limited therapy Arm B (FCR). Mean change scores from baseline to each time point were calculated using all cases with data at baseline and the corresponding time point. Comparisons between treatment arms were performed using two-sample t tests. Linear mixed effects models were used to estimate the trajectories of PRO scores. Results: PRO data was extracted on 3/8/2021. PRO data was provided at baseline and 12 months for 233/354 (65.8%) patients on the IR arm and 118/175 (67.4%) patients on the FCR arm. At enrollment, there were no significant differences in the baseline FACT-Leu TOI scores (mean ± SE) between the two arms: IR (93.27 ± 1.03) vs FCR (92.68 ± 1.38; p=0.73). The FACT-Leu TOI score improved from baseline to 12 months in both arms (Table 1 and Figure 1). The change scores from baseline to 12 months, the primary outcome, were not significantly different between IR (7.59 ± 1.09) vs FCR (8.22 ± 1.44; p=0.73). Change in FACT-Leu TOI from baseline to 3 months was 5.77 ± 0.77 and 4.06 ± 1.18 (p=0.22); and from baseline to 6 months was 6.87 ± 0.87 and 8.01 ± 1.44 (p=0.50) in the IR and FCR arms, respectively. After the first 6 months of treatment, the improvement in FACT-Leu TOI scores was maintained in both treatment arms. There was no significant difference in total FACT-Leu TOI score in the continuous therapy (IR) vs time-limited therapy (FCR) arms over the first 36 months post registration. Analysis of FACT subscales showed PWB improved in the IR arm (0.37 ± 0.22) and declined in the FCR arm (-0.92 ± 0.39) from baseline to 3 months (p=0.004 for difference in PWB change between arms) but there was no significant difference between the two arms for change in PWB scores from baseline to 6 and 12 months. There were no significant differences between the two arms for change in FWB and FACT-Leu subscales from baseline to 3, 6 and 12 months. Conclusions: QOL improves in CLL patients age 70 and younger when treated in the frontline setting with IR or FCR. The improvement in QOL is maintained during continuous therapy with ibrutinib and there is no significant decline in QOL over time. Given the improvement in PFS and OS with IR over FCR seen in E1912, the results of this QOL analysis support the use of frontline ibrutinib in previously untreated younger CLL patients. Acknowledgement: This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under award numbers: U10CA180794, U10CA180820, UG1CA189863, UG1CA190140, UG1CA232760, UG1CA233180, UG1CA233230, UG1CA233253, UG1CA233277, UG1CA233290, UG1CA233339, UG1CA189859, UG1CA233332. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Figure 1 Figure 1. Disclosures Kay: Oncotracker: Membership on an entity's Board of Directors or advisory committees; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Research Funding; Acerta Pharma: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Sunesis: Research Funding; Genentech: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding. O'Brien: Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy; Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding. Coutre: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Other: Data Safety Monitoring Committee, Research Funding. Barr: AstraZeneca: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Beigene: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Abbvie/Pharmacyclics: Consultancy. Cashen: Secura Bio, ADC Therapeutics: Consultancy. Mato: Adaptive Biotechnologies: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; MSKCC: Current Employment; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; Janssen: Consultancy, Research Funding; Genmab: Research Funding. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee; AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau. Stone: Onconova: Consultancy; AbbVie: Consultancy; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Takeda: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Innate: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Celgene: Consultancy; Macrogenics: Consultancy. Litzow: Actinium: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Tallman: NYU Grand Rounds: Honoraria; Kura: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Shanafelt: Genentech, Pharmacyclics: Research Funding. Wagner: Eli Lilly, Johnson & Johnson: Other: Spouse, previously held individual stocks;; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Athenex Inc: Consultancy.
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- 2021
16. Ibrutinib Combined with Obinutuzumab and CHOP (I-OCHOP) for Richter Transformation
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Carlos López, Joanna Rhodes, Kanti R. Rai, Vernon Wu, and Jacqueline C. Barrientos
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Oncology ,medicine.medical_specialty ,Richter transformation ,business.industry ,Immunology ,Cell Biology ,Hematology ,CHOP ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Obinutuzumab ,Internal medicine ,Ibrutinib ,medicine ,business - Abstract
Background: The development of Richter Transformation (RT) in patients (pts) with chronic lymphocytic leukemia (CLL) while on targeted agents has been reported to have a median survival of 2.3-3.5 months (mo). Treatment is usually anthracycline-based combination regimens, though responses are short-lived. Phase 2 trial of combined venetoclax-REPOCH achieved a median progression free survival (PFS) of 16 mo. We studied the use of ibrutinib in combination with obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone (I-OCHOP) JUN2017-SEP2018 (ClinicalTrials.gov: NCT03145480). During the conduct of the study, ibrutinib plus RCHOP in untreated diffuse large B cell lymphoma (NCT01855750) reported more treatment-emergent serious adverse events when compared to RCHOP, leading to higher rates of treatment discontinuation with toxicity more prominent in elderly pts. Since the majority of pts with CLL are elderly, enrollment was stopped. We report the outcomes of 3 participants. Methods: Informed consent was provided through IRB-approved protocol. Subjects were enrolled in an open-label phase II trial combining ibrutinib with O-CHOP. Ibrutinib 560mg was taken daily starting cycle 1 day 1 (C1D1) continuously until progression or start of new anticancer treatment. Obinutuzumab was given per prescription insert starting on C1D1 with CHOP for up to 6 cycles. Pts were allowed to discontinue study drugs to pursue allogeneic stem cell transplant (allo-SCT). Pts aged 18-80 years old with adequate organ function, Eastern Cooperative Oncology Group performance status ≤ 2, and histologically confirmed evidence of RT from CLL were eligible to participate. Prior targeted agent use was allowed until 24 hours prior to dosing. Chemo- or immuno-therapy was not allowed within 21 and 10 days of C1D1 respectively. The primary endpoint was investigator-assessed overall response rate (ORR) per revised response criteria for malignant lymphoma. Secondary outcomes included hematological improvement, PFS, overall survival (OS), and quality of life. Pts were allowed to pursue allo-SCT after achieving a response and were followed for PFS/OS. Descriptive analyses were utilized, and PFS/OS was calculated from initial treatment to death or last follow-up. Results: Three pts consented and started therapy: two women and one man with a median [range] age of 53 [36-73] years, all had high-risk disease (Figure 1). Median Cumulative Illness Rating Scale at baseline 2 [0-4]. No large cell lymphoma involved the bone marrow. All pts developed RT while on a novel agent (ibrutinib, acalabrutinib, or venetoclax monotherapy respectively). All enrolled immediately after RT diagnosis and received I-OCHOP. Participants had overall good adherence to ibrutinib therapy (mean missed doses per 28-day treatment cycle was 0.88 doses) while on trial. Two pts developed neutropenia (n=1, grade 3 and n=1, grade 4; neither febrile) that resolved by time of withdrawal from study. 2 pts had anemia (grade 1 and 2), and one participant had thrombocytopenia (grade 2), neither requiring transfusion support. All 3 pts reported fatigue (all grade 2 or less) that on average improved during treatment as assessed by FACIT questionnaire (mean Δ from baseline to end of treatment: -5). Figure 1 lists other adverse events. Of 3 enrolled pts, 2 pts achieved remission (1 complete, 1 partial) and undetectable minimal residual disease (detection sensitivity 0.01%) in the bone marrow post 4 cycles I-OCHOP and underwent allo-SCT and were followed for progression. Figures 2 and 3 show the PET responses after 2 cycles of I-OCHOP in 2 participants with bulky lymphadenopathy. Time to allo-SCT for the 2 pts was 3.7 and 3.9 mo from C1D1. After transplant, one pt relapsed with RT in the central nervous system after 20 mo and died from pneumonia 5 mo later; the other pt is alive 49.5 mo later with no evidence of disease. The third pt had rapid progression and came off study. Median PFS for the 3 pts was 23.5 mo [1.9-NR] and OS 29.1 mo [6.7-NR] as of datacut July 30, 2021. Conclusions: Despite historically poor outcomes reported after RT while on a targeted agent, ibrutinib addition to anthracycline-based regimen seemed well tolerated. Two patients achieved a rapid and deep responses irrespective of prior BTK inhibitor use and were able to pursue allo-SCT which correlated with durable PFS/OS. Figure 1 Figure 1. Disclosures Rhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant.
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- 2021
17. Phase 1b/2 Study of Cirmtuzumab and Ibrutinib in Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL)
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Gina G Chung, Catriona Jamieson, Joseph Tuscano, Jean L. Koff, Alec Goldenberg, James B. Breitmeyer, Lori A. Leslie, Thomas J. Kipps, Michael Wang, Salim Yazji, Michael Y. Choi, Tanya Siddiqi, Jacqueline C. Barrientos, Hun Ju Lee, Iris Isufi, Nicole Lamanna, Yao Wang, William G. Wierda, and Suki Subbiah
- Subjects
Cirmtuzumab ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Ibrutinib ,Cancer research ,Medicine ,Mantle cell lymphoma ,business - Abstract
Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and has demonstrated additive/synergistic activity with many anticancer agents, including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment-naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr). MCL Part 1 is closed, and Part 2 is open for enrollment. CLL Parts 1, 2 & 3 are closed for enrollment. Results: As of 18Jun2021 data cutoff, 28, 34 and 28 pts were treated in MCL Parts 1 & 2, CLL Parts 1 & 2, and CLL Part 3 (Cirm/Ibr (n=18) or Ibr (n=10)). In Parts 1 & 2 MCL, the median number (#) of prior systemic regimens was 1.5 (1-4) including pts relapsing after Ibr (n=4), auto-SCT (n=6), auto-SCT/allo-SCT (n=1), or auto-SCT/CAR-T (n=1). Ki-67 ≥30% and extra-nodal disease was present in 54% and 68% of pts, respectively. The median # of prior systemic regimens for CLL Parts 1 & 2 and CLL Part 3 (RR), was 2 (1-15) including auto-SCT (n=1), and 2 (1-6). Pts entered with Rai staging ≥ Grade 2 in 71% and 64%. Safety (MCL and CLL): Most frequent treatment emergent (TEAEs) (≥30%) for both MCL and CLL pts treated with Cirm/Ibr (N=80), (all grades; regardless of causality) included contusion & fatigue (both 40.0%), and diarrhea (37.5%). Most frequent (≥5%) Grade ≥3 TEAEs, regardless of causality included hypertension (10.0%), fatigue, neutropenia, pneumonia, and atrial fibrillation (all 6.3%), leukocytosis and anemia (both 5.0%). Grade ≥3 TEAEs of myelosuppression, regardless of causality, include anemia (5.0%), thrombocytopenia (1.3%), and neutropenia (6.3%). Most TEAEs in MCL or CLL pts were considered related by Investigator to Ibr alone 64% or 84% vs. Cirm alone 14.3% or 16%. Efficacy (MCL): The best response of 20 evaluable pts in Parts 1 & 2 included CR 35%, PR 45%, SD 10%, and 10% PD. At a median follow-up of 14.9 mos., the objective response rate (ORR), clinical benefit rate (CBR) and median duration of response (DOR) for overall, ≥30% Ki-67, and >1 prior systemic regimen subgroups, were 80%, 90% and (not reached) NR (95% CI: 11.9, NR), 81.8%, 81.8% and 13.8 (95% CI: 8.7, NR), and 90%, 100% and NR (95% CI: 8.7, NR). Responses occurred in all evaluable pts who received prior SCT+/- CAR-T (4CR, 2PR) or prior Ibr (2CR, 2PR). The median PFS (mPFS) for overall, pts achieving CR, and >1 prior systemic regimen subgroups were all NR with varying 95% CI: (16.5, NR), (0.03, NR), and (0.03, NR). Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 & 2 included 94.1% ORR, 11.8% CR, 82.3% PR/PR-L, and 5.9% SD for a CBR of 100%. In Part 3, evaluable Cirm/Ibr TN (n=8) or RR (n=7) and Ibr TN (n=4) or RR (n=3) arms achieved 100% or 85.7% and 100% or 100% ORR, 12.5% or 0% and 0% or 0% CR, 87.5% or 85.7% and 100% or 100% PR/PR-L, 0% or 14.3% and 0% or 0% SD. No pts had PD as best response. All pts had a CBR of 100%. For Parts 1 & 2, at a median follow-up of 24.8 mos., the DOR for overall and >1 prior systemic regimen subgroups, was NR (8.3, 35.9) and NR (12.0, 29.6). In Part 3, at a median follow-up of 14.7 mos., the DOR for TN or RR Cirm/Ibr and Ibr arms is NR (7.7, 18.6) or NR (9.2, 14.8) and NR (11.2, 18.5) or NR (8.3, 14.2). The mPFS (Parts 1 & 2) for overall, pts achieving CR, and >1 prior systemic regimen subgroups were NR (9.1, 35.8), NR (95% CI: 22.5, NR), and NR (9.1, 35.2). In Part 3, mPFS for TN or RR Cirm/Ibr and Ibr arms is all NR. Conclusions: Cirm/Ibr is well-tolerated. ORR, CR, DOR, and mPFS were similar across all subgroups of MCL and CLL pts regardless of number of prior systemic regimens or poor risk factors. Striking responses were observed in patients with MCL as evidenced by a mPFS that was NR (95% CI: 16.5, NR), CR of 35%, and a DOR of NR (95% CI: 11.9, NR) within the study period. These data compare very favorably to the mPFS of 12.8 mos, CR of 20%, and a DOR of 18.6 mos., reported for Ibr alone (Rule 2017). For CLL pts treated with Cirm/Ibr, results continue to be encouraging as they mature. The study is ongoing, with MCL enrollment expanded to include Cirm + Ibr in pts who have had an inadequate response to an Ibr regimen, or who are refractory to approved BTKi agents. Figure 1 Figure 1. Disclosures Lee: Oncternal: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Seagen: Research Funding; BMS: Honoraria, Research Funding; Aptitude Health: Honoraria; Guidepoint: Honoraria; Century Therapeutics: Consultancy; Pharmacyclics: Research Funding; Janssen: Honoraria. Choi: Abbvie: Other: Institution: Research Grant/Funding; Pharmacyclics: Other: Institution: Research Grant/Funding; Oncternal: Other: Institution: Research Grant/Funding; Velosbio: Other: Institution: Research Grant/Funding; Merck: Other: Institution: Research Grant/Funding; Geron: Other: Institution: Research Grant/Funding. Siddiqi: Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Speakers Bureau; Oncternal: Research Funding; TG Therapeutics: Research Funding. Wierda: Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Karyopharm: Research Funding; Xencor: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; KITE Pharma: Research Funding; Miragen: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; Genentech: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; Loxo Oncology, Inc.: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Tuscano: BMS: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Acrotech: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding. Leslie: Abbvie: Consultancy, Honoraria; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy. Breitmeyer: Oncternal Therapeutics: Current Employment, Membership on an entity's Board of Directors or advisory committees. Yazji: Oncternal Therapeutics: Current Employment. Wang: Oncternal Therapeutics: Current Employment. Wang: OMI: Honoraria; Moffit Cancer Center: Honoraria; Chinese Medical Association: Honoraria; Newbridge Pharmaceuticals: Honoraria; DTRM Biopharma (Cayman) Limited: Consultancy; InnoCare: Consultancy, Research Funding; Scripps: Honoraria; Mumbai Hematology Group: Honoraria; VelosBio: Consultancy, Research Funding; BioInvent: Research Funding; Hebei Cancer Prevention Federation: Honoraria; Epizyme: Consultancy, Honoraria; Anticancer Association: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Lilly: Research Funding; Physicians Education Resources (PER): Honoraria; Dava Oncology: Honoraria; Clinical Care Options: Honoraria; Molecular Templates: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Imedex: Honoraria; Juno: Consultancy, Research Funding; Celgene: Research Funding; Genentech: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Bayer Healthcare: Consultancy; BGICS: Honoraria; CAHON: Honoraria; Oncternal: Consultancy, Research Funding; CStone: Consultancy. Jamieson: Forty Seven Inc.: Patents & Royalties. Kipps: Genentech-Roche: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other, Speakers Bureau; Janssen: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Roche: Honoraria, Other; MD Anderson Cancer Center: Research Funding; Velos: Research Funding; CRIM: Research Funding; Indy Hematology Review: Other; TG Therapeutics: Other; Verstem: Other, Speakers Bureau; University of California, San Diego: Current Employment; Pharmacyclics/AbbVie: Honoraria, Research Funding; Breast Cancer Research Foundation: Research Funding; SCOR - The Leukemia and Lymphoma Society: Research Funding; National Cancer Institute/NIH: Honoraria, Research Funding; Genentech/Roche: Honoraria; European Research Initiative on CLL (ERIC): Honoraria; Genetech: Honoraria, Other; Celgene: Consultancy, Honoraria, Other, Research Funding; Bionest Partner: Other; DAVA Pharmaceuticals: Speakers Bureau; DAVAOncology: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other, Speakers Bureau; Oncternal Therapeutics, Inc.: Current holder of stock options in a privately-held company, Other: Stock or other ownership, Patents & Royalties: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory., Research Funding; Moores Cancer Center: Current Employment; MedImmune Inc: Research Funding; GlaxoSmithKline: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an Abbvie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbott Laboratories: Consultancy, Research Funding.
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- 2021
18. Efficacy of Ibrutinib Monotherapy in Pre-Clinical Mouse Models of Richter Transformation: Ibrutinib Effectively Reduces the Incidence of Richter Transformation but Fails in Treating Transformed Lymphoma, Especially in Primary Lymphoid Tissue
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Kanti R. Rai, Jacqueline C. Barrientos, Uwe Wirtz, Shih-Shih Chen, Xiao-Jie Yan, Nicholas Chiorazzi, and Edith Szafer-Glusman
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Richter transformation ,business.industry ,Incidence (epidemiology) ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Transformed Lymphoma ,chemistry.chemical_compound ,Lymphatic system ,chemistry ,Ibrutinib ,Cancer research ,Medicine ,business - Abstract
Richter's transformation (RT) is a complication of chronic lymphocytic leukemia (CLL) characterized by the development of an aggressive lymphoma, typically diffuse large B cell lymphoma (DLBCL). RT is associated with high expression of activation-induced cytidine deaminase (AID) and aberrant somatic hypermutation of non-immunoglobulin genes. Current frontline therapy of CLL, ibrutinib, eliminates AID + CLL cells and alters tissue microenvironment to Th1-biased niches; however approximately 10-20% of CLL patients develop RT upon ibrutinib treatment. In addition, ibrutinib leads to a clinical response in only ~40% of RT patients. Thus, RT remains an important unmet challenge for CLL patients and the mechanism of RT development during ibrutinib treatment is poorly understood. To determine the contributions of AID and T cells in RT development, and to understand the efficacy of ibrutinib in the treatment of RT, we first created patient-derived xenografts (PDXs) with samples from three RT patients who were refractory to (immuno)chemotherapy but had not previously received ibrutinib. In each case, the B-lymphocytes were larger in size and expressed lower levels of CD5 but higher levels of activation markers compared with the CLL cell counterpart. In PDXs, ibrutinib treatment led to significantly less RT cells in spleen with percentage of inhibition ranging from 28-60% for all three cases. Notably, AID levels were similar in RT cells residing in spleen of ibrutinib-treated and control mice. The numbers of T cells were also similar, although Th1:Th2 ratios were significantly increased by ibrutinib (control vs ibrutinib group: 33% vs 42%, P=0.01). Interestingly, the growth and survival of RT cells located in bone marrow (BM) were not affected by ibrutinib. We then investigated the efficacy of ibrutinib in the prevention and treatment of RT in a novel strain of TCL-1 mice, TCL1/Igκ-AID mice, that have AID overexpressed solely in B lymphocytes. These mice develop accelerated CLL disease, have shorter overall survival (OS), and bear increased numbers of AID signature mutations in genes that are drivers in CLL and DLBCL. First we injected primary splenocytes from a TCL1/Igκ-AID mouse (A-31) into wild-type C57BL/6 mice. A week later, mice were treated with vehicle or ibrutinib continuously for 3 weeks (N=5 per group, duplicated experiments). At the end of treatment, RT cells were found in 25% of recipients in the control group and only in 10% of ibrutinib-treated recipients. Ibrutinib-treated animals had overall smaller spleens and lymph nodes (LNs) filled with significantly less CLL or RT cells. Importantly, the balance of Th1/Th2 cytokines was also significantly changed by ibrutinib (Th1/Th2 in control vs ibrutinib: 25% vs 47%, P=0.01). However, again RT cells in BMs of treated and control animals were similar. We then repeated the experiment to determine overall survival by giving the mice vehicle or ibrutinib continuously. Compared to the TCL1/Igκ-AID (A-31) donors, recipients treated with control vehicle developed more aggressive CLL with shorter OS. However, Ibrutinib did not change the OS; both control and ibrutinib treated recipients had similar OS with all the mice developed and died from RT eventually. Finally, to determine the efficacy of ibrutinib in the treatment of RT in TCL1/Igκ-AID mice, we sorted A-31-derived RT cells collected from LNs, and injected these into C57BL/6 mice. Mice then received treatment for 3 weeks. Notably, ibrutinib did not change the numbers or sizes of LNs or spleens. The numbers of RT cells at all sites, including BM, remained the same. In both groups, the number of T cells and the Th1:Th2 were not altered by ibrutinib. In summary, our data suggest that ibrutinib is somewhat effective against primary RT cells in the spleen in PDX models but not at all in the aggressive TCL1/IgK-AID mouse model. This might be because ibrutinib does not reduce AID levels in tissue-resident RT cells. Notably, although RT cells in spleens and LNs respond to ibrutinib, those residing in BM are resistant in both PDX and TCL1/IgK-AID models. This suggests different clones or different ibrutinib-responsiveness of RT cells in primary versus secondary lymphoid tissues. Overall, these results suggest that ibrutinib does not prevent or cure RT. Additionally, TCL1/Igκ-AID mice might provide a model to study the development, prevention, and treatment of RT without the influence of prior chemo- or other therapies. Disclosures Wirtz: Abbvie: Current Employment. Szafer-Glusman: AbbVie: Current Employment, Other: Stock or other ownership.
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- 2021
19. Serum Proteomic Analyses Suggest That the HMGB1 and Other Inflammatory Pathways Are Operational in MBL and Are Less in Overt CLL
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Kamala Vanarsa, Steven L. Allen, Anna Puiggros, Jonathan E. Kolitz, Eva Gimeno, Chandra Mohan, Nicholas Chiorazzi, Xavier Calvo, Ana Ferrer, Kanti R. Rai, Gonzalo Blanco, Jacqueline C. Barrientos, Florencia Palacios, Blanca Espinet, Poojitha Dugyala, Yasmine Kieso, and Joanna M Rhodes
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biology ,business.industry ,Immunology ,chemical and pharmacologic phenomena ,Cell Biology ,Hematology ,HMGB1 ,Biochemistry ,immune system diseases ,hemic and lymphatic diseases ,biology.protein ,Medicine ,Inflammatory pathways ,business - Abstract
Background. CLL-like monoclonal B-ceII lymphocytosis (MBL) is considered a requisite precursor of CLL, with 1-2% of subjects annually progressing to CLL requiring therapy. The role of immune alterations leading to and operating in MBL and controlling progression to CLL is not well characterized. Since an increased frequency of immune-related conditions associated with immune dysfunction exists prior to CLL diagnosis (Landgren et al, Br J Haematol 2007 and Blood 2007; Andersen et al, Leukemia 2020), immune alterations likely exist in MBL. We have examined the serum protein profiles of MBL and CLL in search of clues linking immune dysfunction with malignant transformation. Objectives. 1. Characterize the serum proteomic profiles of MBL individuals, IGHV-mutated CLL (M-CLL) and IGHV-unmutated CLL (U-CLL) patients, and age-matched healthy controls (HC). 2. Compare the serum proteomic profiles between the groups. 3. Assess the effect of IGHV mutation status on serum proteomic profiles in CLL. Methods. A total of 12 MBL, 12 M-CLL, 12 U-CLL and 12 age-matched HC were studied. Patients were cared for at Northwell Health, New York (n=25) and Hospital del Mar, Barcelona (n=11). All patients were treatment naive except for one U-CLL patient who was treated one year beforehand. Serum samples were collected, and their protein levels measured employing SOMAmers (modified single-stranded DNA aptamers; SomaLogic) to quantify relative levels of 1,310 proteins. P-values Results. Overall, the levels of 862 proteins differed significantly between groups: MBL vs. HC: 10 downregulated (d) and 24 upregulated (u); M-CLL vs. HC: 206d and 6u; U-CLL vs. HC: 54d and 40u; M-CLL vs. MBL: 384d and 5u; U-CLL vs. MBL: 74d and 24u; and M-CLL vs. U-CLL: 35d and 0u. IPA highlighted a role for the pro-inflammatory HMGB1 pathway in several comparisons. First, an activated HMGB1 pathway was predicted in MBL compared to HC, together with activation of phagocytes, and an inhibition of the systemic immune suppressor TGF-β. Second and consistent with the former, U-CLL patients displayed an activated HMGB1 pathway compared to HC, along with other signs of immune stimulation (activated NFkB and Th1 pathways, maturation of dendritic cells, and inhibition of TGF-β) and leukemic progression (activated progression of tumor, and leukocyte extravasation). Third and contrary to the above, the HMGB1 pathway was inhibited when comparing M-CLL to HC, in line with a global immune suppression signature (inhibited PRR, GM-CSF, FcεRI, IL1, IL8, TNF, Th1, STAT3 and NFkB pathways, in addition to inhibited cell movement, viability and activation). Notably, inhibition of immune pathways was predicted for both M-CLL and U-CLL compared to MBL (diminished TNF and IL6 signaling, and reduced cell movement), although the greatest differences were seen for M-CLL vs. MBL comparison, including blockade of the HMGB1 pathway in M-CLL. Finally, the M-CLL vs. U-CLL comparison suggested inhibited INFγ, IL2, IL3, IL4, NFkB, and decreased T lymphocyte stimulation and movement of tumor cells in M-CLL patients. Conclusions. An increased pro-inflammatory signature with involvement of the HMGB1 pathway was identified in MBL and U-CLL compared with HC, whereas the opposite was seen for M-CLL. Since MBL most often exhibit mutated IGHV (91% of cases in our cohort), these findings suggest immune stimulation as a characteristic feature in the pre-leukemic and U-CLL leukemic stage that surprisingly is not operative in M-CLL. Consistent with this, M-CLL displayed a global immune suppression (HMGB1 pathway inhibition), whereas U-CLL exhibited signs of immune stimulation (HMGB1 pathway activation) compared to HC which may relate to distinct capabilities of the two subtypes to interact with the microenvironment. Lastly, the increased inflammatory signature identified in MBL, which are mainly IGHV-mutated, was lessened in CLL, mainly in M-CLL patients. This is consistent with a decreased influence of immune imbalance and the HMGB1 pathway associated with IGHV-mutated clonal expansions. Acknowledgments. GB is supported by a grant from Fundación Alfonso Martín Escudero. Disclosures Allen: Alexon: Research Funding; Bristol Myers Squibb: Other: Equity Ownership; C4 Therapeutics: Other: Equity Ownership; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees. Rhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant.
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- 2021
20. Clinical Outcomes of Low Histologic Grade Follicular Lymphoma with High Proliferation Index
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Jacqueline C. Barrientos, Vernon Wu, Muhammed A Salyana, Steven L. Allen, Kristin Lynn Sticco, Jonathan E. Kolitz, Joanna Rhodes, and Mohammed Abdelwahed
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Pathology ,medicine.medical_specialty ,Proliferation index ,business.industry ,Histologic grade ,Immunology ,Follicular lymphoma ,Medicine ,Cell Biology ,Hematology ,business ,medicine.disease ,Biochemistry - Abstract
Background: Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma (NHL) accounting for ~35% of NHL and often have a clinically indolent course. PET/CT max SUV ≥10 and high proliferative index are associated with FL at high risk for transformation to aggressive lymphoma (Schöder, 2005; Rossi, 2020). A subset of patients (pts) with low histologic grade and high proliferation index (LG-HPI) have a more aggressive clinical course with inferior overall survival (OS) compared to low grade, low proliferation index (LG-LPI) FL patients (Wang, 2005). The aim of our study was to identify outcomes for patients with LG-HPI FL at our institution. Methods: We conducted a single center, retrospective study of FL diagnosed from 1/1/2015-1/1/2021. Demographic information, diagnoses, laboratory results, medications, pathology, and radiology reports were collected from pts' electronic medical records. Pathology specimens were de-identified and retrospectively reviewed by two pathologists. Review included comprehensive evaluation of histologic grade, proliferation index by Ki-67 percentage (Ki-67%), immunohistochemical staining, and c-MYC immunohistochemical staining. Biopsies were classified as LG-LPI if Grade 1-2 and Ki-67 was Results: 152 pts were diagnosed with FL and included for analysis. Patient characteristics are summarized in Table 1. Median age at diagnosis for all pts was 65.9 years. Sixty-three pts had LG-LPI, 61 LG-HPI, and 28 HG pts. Ten pts transformed to DLBCL (2 LG-LPI, 5 LG-HPI, 3 HG). Treatment regimens included initial observation (n = 44), anti-CD20 therapy alone (n = 24), chemo-immunotherapy (n = 53), and other (n = 31). Median TTFT was 1.27 mo (range 0-115.2 mo). There was moderate correlation between SUV of biopsied lesion ≥10 and Ki-67 percentage (ROC Area 0.6175). Median PFS was longer for LG-LPI compared to LG-HPI (78.6 vs 57.8 mo, p = 0.04, HR 2.37) but not between LG-HPI and HG (57.8 vs 61.3 mo respectively, p = 0.32) (Figure 1A). Median OS was not reached in any cohort with median follow up of 29.5 mo. There was no difference in OS between LG-LPI vs LG-HPI (p = 0.53) (Figure 1B). Histologic grade, proliferation index, Ann Arbor Staging, FLIPI score, PET/CT SUV intensity (max or of biopsied lesion), presence of c-Myc staining, or initial treatment regimen were not associated with median PFS or OS in either subgroup on univariate analysis. Conclusions: In our cohort, PFS was shorter for LG-HPI compared to LG-LPI but with a similar trajectory to that of HG FL, consistent with prior reports. No differences were seen in OS between LG-HPI and LG-LPI, and no covariates of interest including histologic grade, proliferation index, Ann Arbor Staging, FLIPI score, PET/CT SUV intensity, presence of c-Myc staining, or initial treatment regimen were associated with differences in PFS or OS. Our study is limited by a short follow up time compared to prior published cohorts (29.5 vs 98.4 mo). PET/CT SUV values of ≥10 have moderate predictive value for higher proliferative disease and can aid in identifying patients with higher proliferative disease. Longer follow up is needed to determine if LG-HPI impacts OS. References: 1. SchöderH, et al. Intensity of 18fluorodeoxyglucose uptake in positron emission tomography distinguishes between indolent and aggressive non-Hodgkin's lymphoma. J Clin Oncol 2005;23:4643-51. 2. Rossi C, et al. Baseline SUVmaxis related to tumor cell proliferation and patient outcome in follicular lymphoma. Haematologica 2020;Online ahead of print. 3. Wang SA, et al. Low histologic grade follicular lymphoma with high proliferation index: morphologic and clinical features. Am J Surg Pathol2005;29:1490-6. Figure 1 Figure 1. Disclosures Allen: Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Other: Equity Ownership; Bristol Myers Squibb: Other: Equity Ownership; Alexon: Research Funding. Rhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant.
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- 2021
21. First-Line Treatment with Ibrutinib (Ibr) Plus Venetoclax (Ven) for Chronic Lymphocytic Leukemia (CLL): 2-Year Post-Randomization Disease-Free Survival (DFS) Results from the Minimal Residual Disease (MRD) Cohort of the Phase 2 Captivate Study
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Jacqueline C. Barrientos, James P. Dean, Constantine S. Tam, Ian W. Flinn, Edith Szafer-Glusman, Tanya Siddiqi, Ryan Jacobs, John M. Pagel, William G. Wierda, Paolo Ghia, Alessandra Tedeschi, Thomas J. Kipps, Cathy Zhou, Stephen Opat, Eva González-Barca, Bryone J. Kuss, Joi Ninomoto, Xavier C. Badoux, and John N. Allan
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Oncology ,medicine.medical_specialty ,Randomization ,business.industry ,Venetoclax ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Minimal residual disease ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Ibrutinib ,Ven ,Cohort ,medicine ,business ,Distributed File System - Abstract
Background : Ibr, an established standard of care in CLL, is a once-daily Bruton tyrosine kinase inhibitor with significant progression-free survival (PFS) and overall survival benefit shown in multiple randomized phase 3 studies in first-line CLL. Ven, an oral BCL-2 inhibitor approved as a single agent or combined with rituximab or obinutuzumab for CLL treatment, achieves high rates of undetectable MRD (uMRD). Ibr and Ven, with distinct and complementary mechanisms of action, work synergistically to mobilize CLL cells from lymph nodes and lymphoid niches, enhance cell killing, and eliminate distinct CLL cell populations. CAPTIVATE (PCYC-1142; NCT02910583) is an international, multicenter phase 2 study evaluating first-line Ibr + Ven in 2 cohorts: MRD and Fixed-Duration (FD). Patients (pts) first received 3 cycles of Ibr followed by 12 cycles of combined Ibr + Ven. In the primary analysis of the MRD cohort, pts with Confirmed uMRD who after fixed duration treatment were randomized to placebo or continued Ibr had similar post-randomization 1-year DFS rates (95% and 100%, respectively) (Wierda, ASH 2020). Two-year post-randomization results are presented. Methods : Pts aged Results : 164 pts were enrolled. Median age was 58 years (range, 28-69). High-risk features included unmutated IGHV (60% of pts), del(17p)/TP53 mutation (20%), complex karyotype (19%), and del(11q) without del(17p) (17%). After 12 cycles of Ibr + Ven, 149 pts were randomized: Confirmed uMRD to placebo (n=43) or Ibr (n=43); without Confirmed uMRD to Ibr (n=31) or Ibr + Ven (n=32). Median overall follow-up was 38.2 mo (range, 15.0-47.9); median post-randomization follow-up was 24.0 mo (range, 5.8-33.1). In pts with Confirmed uMRD randomized to placebo versus Ibr, no new DFS events occurred since the primary analysis; 2-year DFS rates post-randomization remained unchanged at 95% (placebo) vs 100% (Ibr), for a 4.7% difference (95% CI -1.6-10.9) and overall log-rank P=0.1573 (Figure 1). In the placebo and Ibr arms post-randomization, modest improvements were observed in complete response (CR) rates, including CR with incomplete bone marrow recovery (CRi) (Figure 2). Estimated 36-mo PFS rates were 95% with placebo and 100% with Ibr. In pts without Confirmed uMRD randomized to Ibr vs Ibr + Ven, greater improvements in best uMRD rates and CR/CRi rates were observed with Ibr + Ven than with Ibr post-randomization (Figure 2). Estimated 36-mo PFS rates were 97% with both Ibr and Ibr + Ven. Median treatment duration was 36.8 mo (range, 0.5-47.9) in all pts (N=164). Modest differences in AEs were observed across treatment arms post-randomization. During the overall study period across all-treated pts, the most frequent grade 3/4 AEs were neutropenia (36%), hypertension (10%), thrombocytopenia (5%), and diarrhea (5%). With up to 48 mo of treatment, AEs led to discontinuation of Ibr or Ven in 13% of pts; no new safety signals emerged. Conclusions : First-line Ibr + Ven is an all-oral, once-daily, chemotherapy-free regimen that provides deep responses in pts with CLL. With an additional year of follow-up and no new MRD relapses, PDs or deaths in pts with confirmed uMRD, the 2-year DFS rate in the MRD-guided placebo arm remained high at 95% while 3-year PFS rates were ≥95% across all randomized treatment arms. The results in pts with Confirmed uMRD support the potential for treatment-free remission with fixed-duration treatment, including in pts with high-risk features. High rates of uMRD were achieved; the safety profile of Ibr + Ven was consistent with known safety profile for each agent. Figure 1 Figure 1. Disclosures Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding. Allan: Celegene: Research Funding; AstraZeneca Pharmaceuticals LP, Genentech, a member of the Roche Group, Janssen Biotech Inc, TG Therapeutics Inc.: Research Funding; AbbVie: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; TG Therapeutics: Research Funding; Epizyme: Consultancy; AbbVie Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Janssen Biotech Inc, Pharmacyclics LLC: Consultancy; AbbVie Inc, Ascentage Pharma, Epizyme, Genentech, a member of the Roche Group, Janssen Biotech Inc, Pharmacyclics LLC: Other: Advisory Committee. Siddiqi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Kipps: Janssen: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Roche: Honoraria, Other; MD Anderson Cancer Center: Research Funding; Velos: Research Funding; CRIM: Research Funding; Indy Hematology Review: Other; TG Therapeutics: Other; Verstem: Other, Speakers Bureau; University of California, San Diego: Current Employment; Pharmacyclics/AbbVie: Honoraria, Research Funding; Breast Cancer Research Foundation: Research Funding; SCOR - The Leukemia and Lymphoma Society: Research Funding; National Cancer Institute/NIH: Honoraria, Research Funding; Genentech/Roche: Honoraria; European Research Initiative on CLL (ERIC): Honoraria; Bionest Partner: Other; Celgene: Consultancy, Honoraria, Other, Research Funding; Genetech: Honoraria, Other; Genentech-Roche: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other, Speakers Bureau; DAVA Pharmaceuticals: Speakers Bureau; DAVAOncology: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other, Speakers Bureau; Oncternal Therapeutics, Inc.: Current holder of stock options in a privately-held company, Other: Stock or other ownership, Patents & Royalties: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory., Research Funding; Moores Cancer Center: Current Employment; MedImmune Inc: Research Funding; GlaxoSmithKline: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an Abbvie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbott Laboratories: Consultancy, Research Funding. Kuss: Commonwealth Serum Laboratories: Other: Stock or other ownership; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria; Roche Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen: Speakers Bureau. Opat: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Monash Health: Current Employment; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GIlead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Flinn: Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Badoux: Janssen: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses. Tedeschi: Beigene: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Gonzalez-Barca: Kiowa: Consultancy, Speakers Bureau; Eusapharma: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Speakers Bureau; Roche: Other: Travel, Accommodations, Expenses; AbbVie: Other: Travel, Accommodations, Expenses, Speakers Bureau. Pagel: Pharmacyclics/AbbVie: Consultancy; Gilead: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; BeiGene: Consultancy; Epizyme: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy; Incyte/MorphoSys: Consultancy. Jacobs: AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; MEI Pharma: Research Funding; TeneoBio: Research Funding; SecuraBio: Consultancy, Speakers Bureau; Verastem: Consultancy; TG Therapeutics: Research Funding, Speakers Bureau; Jannsen: Speakers Bureau; Genentech: Consultancy; AbbVie: Consultancy, Speakers Bureau. Szafer-Glusman: AbbVie: Current Employment, Other: Stock or other ownership. Zhou: AbbVie: Current Employment, Other: Stock and other ownership. Ninomoto: AbbVie: Current Employment, Other: Stock or other ownership. Dean: Pharmacyclics: Current Employment, Other: Stock or other ownership; AbbVie: Other: Stock Ownership. Tam: Pharmacyclics: Honoraria; BeiGene: Consultancy, Honoraria; Loxo: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria. Wierda: Janssen: Research Funding; AstraZeneca: Research Funding; GSK/Novartis: Research Funding; Acerta Pharma Inc.: Research Funding; Karyopharm: Research Funding; Xencor: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Loxo Oncology, Inc.: Research Funding; Genentech: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Cyclacel: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; KITE Pharma: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. OffLabel Disclosure: Ibrutinib in combination with venetoclax is not approved in any indication.
- Published
- 2021
22. Phase 1 Dose Escalation and Cohort Expansion Study of the Anti-ROR1 Antibody-Drug Conjugate Zilovertamab Vedotin (MK-2140) for the Treatment of Non-Hodgkin Lymphoma
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Stephen E. Spurgeon, Ying Zhu, Michael Y. Choi, Paul M. Barr, Richard R. Furman, Philip A. Thompson, Avyakta Kallam, Michael Wang, Sven de Vos, Matthew Mei, Jacqueline C. Barrientos, Patricia Marinello, Krish Patel, and Samhita Chakraborty
- Subjects
Oncology ,Drug ,medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Anti-ROR1 Antibody ,Internal medicine ,Cohort ,Dose escalation ,Medicine ,Hodgkin lymphoma ,business ,health care economics and organizations ,media_common ,Conjugate - Abstract
Introduction: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transmembrane protein that is overexpressed in multiple cancers, including hematological malignancies. Zilovertamab vedotin (MK-2140) is an antibody -drug conjugate comprising a humanized IgG1 monoclonal antibody, a proteolytically cleavable linker, and the antimicrotubule cytotoxic agent monomethyl auristatin E (MMAE). Preclinical evidence demonstrated the cytotoxicity of zilovertamab vedotin in hematologic cell lines. This first human phase 1 dose escalation study (NCT03833180) evaluated the safety and efficacy of zilovertamab vedotin at various doses in patients with relapsed/refractory hematologic malignancies. Methods: Eligible patients aged ≥18 years with an Eastern Cooperative Oncology Group Performance Status of 0-2 and histological diagnosis of chronic lymphocytic leukemia/small lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, acute lymphoid leukemia, acute myeloid leukemia, or non-Hodgkin lymphoma (NHL; mantle cell lymphoma [MCL], follicular lymphoma, marginal zone lymphoma, diffuse large B-cell lymphoma [DLBCL], Richter transformation, Burkitt lymphoma, and T-cell-NHL) were enrolled. Participants received zilovertamab vedotin intravenously at starting doses of 0.50 mg/kg (up to 2.5 mg/kg) on day 1 every 3 weeks (Q3W) (Schedule 1), 1.0 mg/kg (planned up to 2.25 mg/kg) on day 1 and 8 Q3W (Schedule 2), or 1.0 mg/kg (planned up to 2.25 mg/kg) on days 1, 8, and 15 Q4W (Schedule 3) using an accelerated plus 3+3 dose escalation design. The primary end point was determination of the maximum tolerated dose (MTD). Secondary end points included safety, objective response rate (ORR), and duration of response (DOR). We present data for participants with NHL enrolled in Schedule 1. Results: A total of 51 patients were enrolled in Schedule 1 (starting dose 0.5 [n=1], 1.00 [n=3], 1.50 [n=3], 2.00 [n=3], 2.25 [n=11], or 2.50 [n=30] mg/kg) as of the data cutoff of May 18, 2021. Median (range) age of patients was 70 (44-91) years, 54.9% of patients were male, 49.0% had an ECOG PS of 0, and 41/51 (80%) were diagnosed with NHL; 13/51 (25.5%) were diagnosed with DLBCL and 17/51 (33.3%) were diagnosed with MCL. Enrollment in Schedules 2 and 3 is currently ongoing. The MTD for Schedule 1 was determined to be 2.5 mg/kg. Any-cause adverse events (AEs) occurred in 48 patients (94.1%), most commonly (≥30%) nausea (45.1%), fatigue (45.1%), peripheral neuropathy (41.2%), diarrhea (37.3%), dizziness (35.3%), and neutrophil count decrease (33.3%). Grade ≥3 AEs occurred in 33 (64.7%) patients, most commonly (≥5%) neutrophil count decrease (29.4%), hemoglobin decrease (15.7%), febrile neutropenia (7.8%), peripheral neuropathy (7.8%), platelet count decrease (7.8%), diarrhea (5.9%), lipase increase (5.9%), and pneumonia (5.9%). One patient died due to acute respiratory failure; however, it was not considered treatment-related by the investigator. A total of 7 (13.7%) patients permanently discontinued due to an AE and 18 (35.3%) had treatment interrupted or reduced due to an AE. Treatment-related AEs occurred in 36 patients (70.6%), most commonly (≥20%) peripheral neuropathy (41.2%), fatigue (37.3%), neutrophil count decrease (29.4%), nausea (27.5%), and diarrhea (21.6%); 24 patients (47.1%) experienced a grade ≥3 treatment-related AE. For Schedule 1, ORR was 36.6% (15/41 [95% CI: 22.1%-53.1%]) among all participants with NHL, with 5 having a complete response (CR) and 10 having a partial response (PR). ORR was 38.5% (95% CI: 13.9%-68.4%) for the 13 patients in the NHL group who had DLBCL; 3 patients had a CR and 2 patients had a PR. ORR was 52.9% (95% CI: 27.8%-77.0%) for the 17 patients in the NHL group who had MCL; 2 patients had a CR and 7 patients had a PR. Median (range) DOR was 7.8 months (2.1-17.6+ months) among all participants in Schedule 1 with NHL who achieved a response. Conclusion: These data suggest that targeting the ROR1 pathway with zilovertamab vedotin is associated with a tolerable safety profile and promising antitumor activity in patients with relapsed/refractory NHL. Disclosures Wang: Anticancer Association: Honoraria; Dava Oncology: Honoraria; BioInvent: Research Funding; Bayer Healthcare: Consultancy; Hebei Cancer Prevention Federation: Honoraria; Lilly: Research Funding; Scripps: Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Research Funding; CAHON: Honoraria; InnoCare: Consultancy, Research Funding; Molecular Templates: Research Funding; Pharmacyclics: Consultancy, Research Funding; Oncternal: Consultancy, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Genentech: Consultancy; Newbridge Pharmaceuticals: Honoraria; VelosBio: Consultancy, Research Funding; Celgene: Research Funding; Physicians Education Resources (PER): Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; OMI: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; Chinese Medical Association: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Clinical Care Options: Honoraria; Mumbai Hematology Group: Honoraria; Moffit Cancer Center: Honoraria; BGICS: Honoraria; CStone: Consultancy; Imedex: Honoraria; Epizyme: Consultancy, Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding. Mei: Janssen: Honoraria; EUSA: Honoraria; Sanofi-Genzyme: Honoraria; Morphosys: Honoraria; TG Therapeutics: Other: Institution: Research Grant/Funding; Epizyme: Other: Institution: Research Grant/Funding; BMS: Other: Institution: Research Grant/Funding; Beigene: Other: Institution: Research Grant/Funding; Incyte: Other: Institution: Research Grant/Funding. Barr: Beigene: Consultancy; Gilead: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Abbvie/Pharmacyclics: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy. Furman: Acerta/AstraZeneca: Consultancy; Janssen: Consultancy, Honoraria; Beigene: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Loxo Oncology: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; AstraZeneca: Honoraria; Sunesis: Consultancy; Oncotracker: Consultancy; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Morphosys: Consultancy; Sanofi: Consultancy; X4 Pharmaceuticals: Consultancy. Patel: TG Therapeutics: Consultancy, Speakers Bureau; Abbvie: Consultancy; Sunesis Pharmaceuticals: Research Funding; Juno Pharmaceuticals: Consultancy; MEI Pharma: Consultancy, Research Funding; Kite: Consultancy, Research Funding, Speakers Bureau; Millenium/Takeda: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; Trillium Therapeutics: Research Funding; BeiGene: Consultancy; Aptevo Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Xencor: Research Funding; Velos Bio: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Curis, Inc: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau. Thompson: AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Choi: Abbvie: Other: Institution: Research Grant/Funding; Pharmacyclics: Other: Institution: Research Grant/Funding; Oncternal: Other: Institution: Research Grant/Funding; Velosbio: Other: Institution: Research Grant/Funding; Merck: Other: Institution: Research Grant/Funding; Geron: Other: Institution: Research Grant/Funding. Zhu: Merck & Co., Inc.: Current Employment. Chakraborty: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Marinello: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Spurgeon: Ionis: Other: Institution: Research Grant/Funding; Gilead Sciences: Other: Institution: Research Grant/Funding; Bristol Myers Squibb: Other: Institution: Research Grant/Funding; BeiGene: Other: Institution: Research Grant/Funding; AstraZeneca: Other: Institution: Research Grant/Funding; Acerta Pharma: Other: Institution: Research Grant/Funding; Pharmacyclics: Consultancy; Janssen: Consultancy, Other: Institution: Research Grant/Funding; Genentech: Consultancy, Other: Institution: Research Grant/Funding; Karyopharm: Consultancy; Velos Bio: Consultancy, Other: Institution: Research Grant/Funding; Merck & Co., Inc.: Other: Institution: Research Grant/Funding; Fred Hutchinson Cancer Research Center: Other: Data Safety Monitoring Board.
- Published
- 2021
23. Cirmtuzumab, an Anti-ROR1 Antibody, in Combination with Ibrutinib: Clinical Activity in Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL) from a Phase 1/2 Study
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Hun Ju Lee, Iris Isufi, Xen Ianopulos, James B. Breitmeyer, Joseph Tuscano, Catriona Jamieson, William G. Wierda, Alec Goldenberg, Nicole Lamanna, Jean L. Koff, Michael Y. Choi, Suki Subbiah, Frank J. Hsu, Elizabeth Weihe, Lori A. Leslie, Thomas J. Kipps, Tanya Siddiqi, Jacqueline C. Barrientos, Gina G Chung, and Michael Wang
- Subjects
business.industry ,Cirmtuzumab ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Anti-ROR1 Antibody ,chemistry.chemical_compound ,chemistry ,Ibrutinib ,medicine ,Cancer research ,Mantle cell lymphoma ,business - Abstract
Introduction: Cirmtuzumab (Cirm) is a high-affinity humanized monoclonal antibody designed to inhibit the tumor promoting activity of ROR1. In this study, we examined the safety and efficacy of Cirm in combination with ibrutinib (Ibr) in patients (pts) with MCL or CLL. ROR1 is an onco-embryonic tyrosine kinase-like receptor that is found at high levels on the cell surface of many hematologic and solid cancers. Activation of ROR1 by binding its ligands such as Wnt5a results in increased intracellular signaling, tumor growth and survival, enhanced cancer cell stemness and epithelial mesenchymal transition. Methods: Pts with relapsed or refractory (RR) MCL or treatment naïve (TN) or RR CLL were enrolled and treated in separate groups. In Part 1 Dose Escalation (DE), groups of MCL and CLL pts received Cirm IV q2wks x5 doses then q4wks at assigned doses of 2-16 mg/kg, and in CLL, additional fixed dose levels of 300 or 600 mg were evaluated. The safety and PK of single-agent Cirm was assessed during the first 28 days, and then Ibr was started at 560 mg/day PO for MCL or 420 mg/day PO for CLL. After reviewing the safety and PK data from Part 1, a recommended regimen of fixed dose Cirm 600 mg IV q2wks x3 then q4wks plus Ibr starting D0 was chosen for use in Parts 2 and 3. In Part 3, CLL pts (only) were randomized to either Cirm/Ibr vs. Ibr alone Results: As of April 30, 2020, 12 evaluable MCL pts were enrolled into Part 1 DE. Of these pts, 83% (10) had received ≥ 2 separate prior treatment regimens. In CLL, 34 pts (12 TN and 22 RR pts) enrolled into Part 1 DE (n= 18) or Part 2 Expansion (n= 16). At least 79% of CLL pts in Parts 1 and 2 were high risk as determined by unmutated IGHV, del17p, and/or del11q. Safety: For both MCL and CLL, the most common adverse events (AEs) considered at least possibly related to Cirm alone were grade 1/2 (e.g. fatigue, 6%) with no dose limiting toxicities or discontinuations. The combination of Cirm plus Ibr was well tolerated, with no new or accentuated AEs compared to the known safety profile of Ibr alone. Cirm may be lowering the rates of certain AEs normally seen with Ibr; for example, neutropenic events were 8 mos after stopping all therapy. At a median follow-up of 12.8 mos, 100% of CLL pts were free of disease progression and 82% remained on study. CLL cells collected after the first 28 days of treatment showed a decrease in stemness signature (Choi et al, Cell Stem Cell 2019), with similar reductions seen with single agent Cirm or Cirm + Ibr. Additional pts have been enrolled into Part 2 Expansion MCL and into Part 3 CLL. Early data from these arms are not yet available and will be reported later. Conclusions: Cirmtuzumab in combination with ibrutinib is a well-tolerated and active regimen for RR MCL and TN or RR CLL. The 58% CR/CMR rate for MCL compares favorably to published data with single agent Ibr of 27% (Rule, et al. Haematologica 2019) and it is encouraging that responses occurred in heavily pretreated pts, including those with high Ki-67 expression. In CLL, the high ORR and interim PFS are encouraging; the significance of these observations will be determined with longer follow-up. These data support the continued investigation of this regimen in ROR1-expressing hematologic and solid malignancies. This study is ongoing, and due to the high CR rate in MCL pts, the number of pts to be enrolled in the Part 2 Expansion will be increased to further characterize the safety and efficacy of this combination. Disclosures Lee: Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau; Celgene: Research Funding; Guidepoint Blogal: Consultancy; Oncternal Therapeutics: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding. Choi:Pharmacyclics/Abbvie: Research Funding; Genentech: Consultancy. Siddiqi:Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; BeiGene: Other: DMC member; AstraZeneca: Other: Travel/accommodations/expenses; Astrazenca: Membership on an entity's Board of Directors or advisory committees; PCYC: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding. Barrientos:Oncternal Therapeutics: Research Funding; Gilead: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Sandoz: Consultancy; Janssen: Honoraria; Genentech: Consultancy. Lamanna:Octapharma: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Juno: Other: Institutional research grants, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MingSight: Other: Institutional research grants, Research Funding; Oncternal, Verastem, TG Therapeutics: Other: Institutional research grants, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Columbia University Medical Center: Current Employment; Loxo: Research Funding. Tuscano:Abbvie: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Seattle Genetics: Honoraria; Novartis: Research Funding; Spectrum: Research Funding; Takeda: Research Funding; Genentech: Research Funding. Leslie:KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ianopulos:Oncternal Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Breitmeyer:Oncternal Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Hsu:Oncternal Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Immune Design: Ended employment in the past 24 months. Wang:Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria; MoreHealth: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Targeted Oncology: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; Guidepoint Global: Consultancy; Dava Oncology: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; OncLive: Honoraria; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding. Jamieson:Bristol-Myers Squibb: Other; Forty Seven Inc: Patents & Royalties. Kipps:VelosBio: Research Funding; Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Research Funding; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding.
- Published
- 2020
24. Real-World Prognostic Biomarker Testing, Treatment Patterns and Dosing Among 1461 Patients (pts) with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) from the informCLL Prospective Observational Registry
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Sandhya Upasani, Jacqueline C. Barrientos, Nilanjan Ghosh, Anthony R. Mato, Jeff P. Sharman, Israel Arango-Hisijara, Meghan Gutierrez, Qing Huang, Karen Kadish, Danielle M. Brander, Jennifer Han, and Reethi Iyengar
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Lymphocytic lymphoma ,Internal medicine ,medicine ,Observational study ,Prognostic biomarker ,Dosing ,business - Abstract
Background: Treatment options, together with guidelines, for pts with CLL have evolved and expanded with the introduction of novel agents. The informCLLTM registry is the largest US-based prospective, observational registry of pts who received treatment for CLL/SLL in the post-novel agent era. This prospective real-world registry is uniquely positioned to examine the impact of the dynamic treatment landscape, treatment practices, and outcomes in routine clinical setting. Here we present baseline characteristics, prognostic biomarker testing, and treatment patterns for the fully enrolled pt population. Methods: From Oct 2015 to June 2019, informCLL (PCYC-1134; NCT02582879) enrolled eligible pts with CLL/SLL who were ≥18 years (y), initiated FDA-approved treatment for CLL/SLL within ±45 days of enrollment and provided consent. Pts were classified into 5 groups based on treatment received at enrollment (index): ibrutinib (single agent or combination), chemoimmunotherapy (CIT), chemotherapy (CT), immunotherapy (IT), and other novel agents. Descriptive analyses are presented. Results: The registry fully enrolled with 1461 pts: 855 (59%) previously untreated and 606 (41%) relapsed/refractory (R/R) pts. Community-based practices enrolled 93% of pts. The median age was 71 y (33% ≥75 y), the majority were male (64%), and 88% had ECOG performance status of 0/1. For pts with staging performed at enrollment (n=852), 51% had Rai stage III/IV. Median (range) time from diagnosis to initial treatment on study was 18.6 months (mos, FISH testing was performed in 28% (n=415) of pts and was more frequent in previously untreated vs R/R pts (33% vs 21%). TP53 mutation testing was performed in 11% (n=162) of pts (previously untreated: 13%; R/R: 9%). IGHV mutational status testing was performed in 12% (n=171) of pts (previously untreated: 13%; R/R 10%). Of pts with prognostic biomarker testing, 24% (100/415) had del(17p), 27% (43/162) had TP53 mutation, and 71% (121/171) had unmutated IGHV. Prognostic biomarker testing by treatment group is shown in Figure 1. Table 1 shows the distribution of pts receiving different treatments on study. Across lines of therapy, the most common treatment was ibrutinib (46%); the majority (87%) started ibrutinib treatment at the recommended daily dose of 420 mg, and pts continuing ibrutinib therapy largely did not require dose modifications (75%). At 12 or 24 mos, 77% (307/401) and 68% (126/184) of pts continued on ibrutinib treatment, respectively. For pts who completed the most common CIT regimens (bendamustine + rituximab [BR] and fludarabine + cyclophosphamide + rituximab), 80% and 85%, respectively, received Conclusions: The informCLL registry provides an opportunity to prospectively assess CLL treatment patterns in the era of novel agents. The most common index treatment was ibrutinib and the majority of ibrutinib-treated pts remained on therapy at 2 y follow-up; CIT (primarily BR) was also used for one-third of patients. Prognostic biomarker testing rates were poor, especially for TP53 and IGHV mutational status. Data from informCLL also indicate a 'knowledge gap' in terms of prognostic marker testing and selection of therapies for pts with high-risk disease. Data from the now complete pt population and with continued follow up will allow for the ongoing evaluation of real-world treatment decisions and pt care that cannot be addressed by data from randomized clinical trials. Disclosures Mato: Janssen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding; BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; LOXO: Consultancy, Research Funding. Barrientos:Janssen: Honoraria; Oncternal Therapeutics: Research Funding; Sandoz: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy. Sharman:AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BeiGene: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Brander:BeiGene: Other, Research Funding; MEI Pharma: Other, Research Funding; DTRM: Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ArQule: Consultancy, Other, Research Funding; Pfizer: Consultancy, Other; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; Ascentage: Other, Research Funding; Teva: Consultancy, Honoraria; Tolero: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Verastem: Consultancy, Honoraria, Other, Research Funding; NCCN: Other; Novartis: Consultancy, Other; NCCN: Other; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding. Kadish:Bluebird Bio: Current equity holder in publicly-traded company; Blueprint Medicines: Current equity holder in publicly-traded company; Teva Pharmaceutical: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; Editas Medicine: Current equity holder in publicly-traded company; Johnson & Johnson: Current equity holder in publicly-traded company; Sarepta Therapeutics: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; Agios: Current equity holder in publicly-traded company; Celgene: Current equity holder in publicly-traded company, Speakers Bureau; Takeda: Speakers Bureau. Arango-Hisijara:Bristol-Myers Squibb: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Upasani:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment; Protagonist Therapeutics: Current Employment. Han:Johnson and Johnson: Current equity holder in publicly-traded company; Janssen: Current Employment, Other: Travel expenses. Huang:Janssen Scientific Affairs, LLC: Current Employment; Johnson & Johnson: Current equity holder in publicly-traded company. Iyengar:Express Scripts: Patents & Royalties; AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Ghosh:Karyopharm: Consultancy; Genmab: Consultancy, Speakers Bureau; SGN: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; Juno/Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Forty Seven Inc: Consultancy, Other: Research Bureau, Research Funding; Celgene/Bristol-Myers Squibb: Speakers Bureau; AbbVie: Speakers Bureau; AstraZeneca: Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Roche/Genentech: Research Funding.
- Published
- 2020
25. VLS-101, a ROR1-Targeting Antibody-Drug Conjugate, Demonstrates a Predictable Safety Profile and Clinical Efficacy in Patients with Heavily Pretreated Mantle Cell Lymphoma and Diffuse Large B-Cell Lymphoma
- Author
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Elizabeth M. Schmidt, Katti Jessen, Richard R. Furman, Avyakta Kallam, Paul M. Barr, Sven de Vos, Lydia B King, Stephen E. Spurgeon, Peter C. Riebling, Langdon L. Miller, Brian Lannutti, Matthew Mei, David W. Johnson, Michael Wang, Krish Patel, Simon Rule, Patricia Graham, Kate Flanders, Jacqueline C. Barrientos, and Michael Y. Choi
- Subjects
Antibody-drug conjugate ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Safety profile ,ROR1 ,Cancer research ,medicine ,Mantle cell lymphoma ,In patient ,Clinical efficacy ,business ,Diffuse large B-cell lymphoma - Abstract
Introduction: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is physiologically expressed during embryogenesis, largely disappears by birth, but can be reexpressed pathologically in transformed tissues of many hematological and solid cancers. VLS-101 is an antibody-drug conjugate (ADC) comprising a rapidly internalizing, humanized monoclonal antibody (UC-961) that recognizes extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin, monomethyl auristatin E (MMAE). Methods: This first-in-human, Phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and efficacy of VLS-101 in patients unselected for tumor ROR1 expression who had previously treated chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Richter transformation lymphoma (RTL). VLS-101 was infused over 30 min every 3 wk until cancer progression or intolerable toxicity. After accrual of 1 patient at the first dose level, cohorts were enrolled by 3+3 dose escalation with additional patients accrued and intrapatient dose escalation permitted to refine estimates of maximum tolerated dose and recommended dosing regimen (RDR). Results: 32 patients were enrolled, including 19 males and 13 females with median (range) ages of 70 (54-84) ys; ECOG performance status (n) of 0 (18), 1 (10), or 2 (4); and tumor types (n) of MCL (15), CLL (7), DLBCL (5), FL (3), MZL (1), and RTL (1). Patients had received a median (range) of 4 (1-24) prior systemic therapies including hematopoietic stem cell transplantation (5) and/or chimeric antigen receptor (CAR)-T or -natural killer (NK) cells (6). Among patients with MCL, 15/15 (100%) had received a Bruton tyrosine kinase inhibitor (BTKi), 13/15 (87%) discontinued the BTKi due to progressive disease, and 2/15 (13%) discontinued for atrial fibrillation after 15.6 or 68.5 months of BTKi therapy. Patients (n) by VLS-101 starting dose were 0.5 (1), 1.0 (3), 1.5 (3), 2.25 (11), and 2.5 (14) mg/kg. With intrapatient dose escalation, many patients (n) received a maximum of 2.25 mg/kg (12) or 2.5 mg/kg (17) during VLS-101 therapy (range: 1 to 13 cycles). Cycle 1 DLTs (n/N) by mg/kg dose level were 0.5 (0/1), 1.0 (0/3), 1.5 (0/3), 2.25 (1/11 [9%] Gr 4 neutropenia), and 2.5 (2/14 [14%]; one Gr 4 neutropenia; one Gr 3 diarrhea of uncertain cause). Gr 4 neutropenia occurred in 9/32 (28%) patients; 1/32 (3%) had neutropenic fever. Granulocyte colony-stimulating factor successfully ameliorated neutropenia. Baseline Gr 1 neuropathy was present in 10/32 (31%) patients. On-study reversible Gr 3 neuropathy occurred in 3/32 (9%) patients; no Gr 4 neuropathy occurred. Except for Gr ≤2 alopecia in 3/32 (9%) patients, other adverse events were not obviously drug-related. Considering all 175 infusions administered, drug-related infusion reactions, vomiting, tumor lysis syndrome, rash, hepatic or renal abnormalities, or QT prolongation were not observed. PK showed changes in ADC and MMAE exposures proportional with VLS-101 dose and a mean ADC half-life of ~2.5 d. PD indicated exposure-dependent ROR1 occupancy on circulating CLL cells. No neutralizing anti-drug antibodies were detected. Objective tumor responses were not seen in patients with other tumor types but were observed in 7/15 (47%) of patients with MCL (4 partial; 3 complete) and in 4/5 (80%) of patients with DLBCL (2 partial; 2 complete). From start of therapy, 6/7 patients with responding MCL have responses ongoing at 35, 38, 45, 47, 50, and 58 wk and 2/4 patients with responding DLBCL have responses ongoing at 23 and 47 wk of follow-up. Conclusions: In heavily pretreated patients, VLS-101 infusions were well tolerated and demonstrated a predictable safety profile consistent with an MMAE-containing ADC. Tumor selectivity was confirmed, with no evidence of ROR1-mediated toxicities or non-MMAE toxicities that would suggest normal tissue binding. Considering all data, the VLS-101 RDR was 2.5 mg/kg every 3 wk. Efficacy results provide clinical proof of concept for targeting ROR1 with VLS-101 and demonstrate durable objective responses in patients with advanced MCL or DLBCL, including those with prior BTKi or cellular therapies. Phase 1-2 studies of VLS-101 monotherapy and combination therapy in patients with hematological cancers and solid tumors are planned. Figure Disclosures Wang: Nobel Insights: Consultancy; Lu Daopei Medical Group: Honoraria; Oncternal: Consultancy, Research Funding; MoreHealth: Consultancy; Juno: Consultancy, Research Funding; Loxo Oncology: Consultancy, Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; OncLive: Honoraria; Guidepoint Global: Consultancy; VelosBio: Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Targeted Oncology: Honoraria. Barrientos:Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Oncternal Therapeutics: Research Funding; Sandoz: Consultancy; Janssen: Honoraria; AstraZeneca: Consultancy. Furman:Verastem: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Speakers Bureau; Loxo Oncology: Consultancy; Oncotarget: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Genentech: Consultancy. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Barr:AstraZeneca: Consultancy, Research Funding; Verastem: Consultancy; Abbvie/Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy; Morphosys: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; TG therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Genentech: Consultancy. Choi:Genentech: Consultancy; Pharmacyclics/Abbvie: Research Funding. de Vos:Bayer: Consultancy; Verastem: Consultancy. Patel:Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Kite: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Rule:Janssen: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy. Flanders:VelosBio: Current Employment, Current equity holder in private company. Jessen:VelosBio: Current Employment, Current equity holder in private company; eFFECTOR: Current equity holder in private company. Riebling:VelosBio: Current Employment, Current equity holder in private company. Graham:Ce3: Current Employment. King:Ce3: Current Employment; VelosBio: Consultancy; AI Therapeutics: Consultancy. Schmidt:VelosBio: Current Employment, Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company. Lannutti:VelosBio: Current Employment, Current equity holder in private company; Gilead Sciences: Current equity holder in publicly-traded company. Johnson:Zentalis: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Current equity holder in publicly-traded company; Neoleukin: Current equity holder in publicly-traded company; Oncternal: Divested equity in a private or publicly-traded company in the past 24 months; Appelis: Divested equity in a private or publicly-traded company in the past 24 months; Acerta: Patents & Royalties; VelosBio: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Miller:Cleveland BioLabs: Consultancy, Current equity holder in publicly-traded company; Gilead Sciences: Current equity holder in publicly-traded company; Cancer Genetics: Current equity holder in publicly-traded company; Incuron: Consultancy; Zentalis: Consultancy, Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; EpiThany: Current equity holder in private company; AstraZeneca: Current equity holder in publicly-traded company; VelosBio: Consultancy, Current Employment, Current equity holder in private company; AI Therapeutics: Consultancy, Current equity holder in private company; Catalys Pacific: Consultancy. Spurgeon:Cardinal Health: Honoraria; VelosBio: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Acerta: Research Funding; AstraZeneca: Research Funding; Genmab: Research Funding; Beigene: Research Funding; Verastem: Research Funding.
- Published
- 2020
26. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL
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John C. Byrd, Paul M. Barr, Richard R. Furman, Jennifer R. Brown, Jan A. Burger, Jacqueline C. Barrientos, Tadeusz Robak, Juthamas Sukbuntherng, Susan O'Brien, George Cole, Marco Montillo, Steven Coutre, Claire Dearden, Samuel Suzuki, Danelle F. James, Stephen P. Mulligan, Peter Hillmen, John M. Pagel, Nishitha Reddy, Ulrich Jaeger, Carol Moreno, and Florence Cymbalista
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Clinical Trials and Observations ,Chronic lymphocytic leukemia ,Immunology ,Antineoplastic Agents ,Biochemistry ,Disease-Free Survival ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Pharmacokinetics ,Internal medicine ,Agammaglobulinaemia Tyrosine Kinase ,medicine ,Humans ,Bruton's tyrosine kinase ,Dosing ,neoplasms ,Protein Kinase Inhibitors ,Dose-Response Relationship, Drug ,biology ,business.industry ,Adenine ,Cell Biology ,Hematology ,Protein-Tyrosine Kinases ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Surgery ,Clinical trial ,Dose–response relationship ,Leukemia ,Pyrimidines ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Mutation ,biology.protein ,Patient Compliance ,Pyrazoles ,Female ,Tumor Suppressor Protein p53 ,business ,030215 immunology - Abstract
Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), at a once-daily dose of 420 mg achieved BTK active-site occupancy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that was maintained at 24 hours. It is unknown if intermittent interruption of ibrutinib therapy contributes to altered clinical outcomes. We therefore evaluated the effect of ibrutinib dose adherence on patient outcomes in the phase 3 RESONATE trial. The overall mean dose intensity (DI) was 95% with median treatment duration of similar to 9 months. Pharmacokinetic assessment of ibrutinib exposure at 420-mg dose suggested similar exposure regardless of patient weight or age. As assessed by independent review committee, patients with higher DI experienced longer median progression-free survival (PFS) compared with those with lower DI regardless of del17p and/or TP53 status. Of 79 patients requiring a drug hold, treatment was restarted at the original dose in 73 (92%) patients. Mean duration of a missed-dose event was 18.7 days (range, 8-56). Patients missing >= 8 consecutive days of ibrutinib had a shorter median PFS vs those missing
- Published
- 2017
27. Ventricular arrhythmias and sudden death in patients taking ibrutinib
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Renata Walewska, Jeffrey A. Jones, Versha Banerji, Robert J. Glynn, Kerry J. Savage, Gregory F. Michaud, Jennifer R. Brown, Javid Moslehi, Lijian Yu, Eric D. Jacobsen, Benjamin L. Lampson, and Jacqueline C. Barrientos
- Subjects
medicine.medical_specialty ,Immunology ,030204 cardiovascular system & hematology ,Pharmacology ,Biochemistry ,Sudden death ,Food and drug administration ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Bruton's tyrosine kinase ,In patient ,Letter to Blood ,biology ,business.industry ,Atrial fibrillation ,Cell Biology ,Hematology ,medicine.disease ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,biology.protein ,Cardiology ,business - Abstract
To the editor: Ibrutinib, approved by the US Food and Drug Administration (FDA), is an inhibitor of Bruton tyrosine kinase (BTK).[1][1][⇓][2][⇓][3][⇓][4]-[5][5] Ibrutinib use is associated with atrial fibrillation (AF), with an incidence of 5% to 6% after 18 months on therapy[4][4][⇓][5]-[6
- Published
- 2017
28. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma
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Sven de Vos, Jacqueline C. Barrientos, Brian Munneke, Franck Morschhauser, Isaiah Dimery, Alina Smith, Peter Martin, Ariela Noy, Stephen C. Smith, Christopher R. Flowers, Catherine Thieblemont, Shachar Peles, Morton Coleman, Robert T. Chen, Graham P. Collins, Shuo Ma, and Darrin M. Beaupre
- Subjects
Male ,0301 basic medicine ,medicine.medical_treatment ,Phases of clinical research ,Biochemistry ,Gastroenterology ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Recurrence ,Agammaglobulinaemia Tyrosine Kinase ,Medicine ,Fatigue ,Aged, 80 and over ,B-Lymphocytes ,Standard treatment ,Anemia ,Hematology ,Middle Aged ,Protein-Tyrosine Kinases ,Chemotherapy regimen ,030220 oncology & carcinogenesis ,Ibrutinib ,Female ,Immunotherapy ,Adult ,medicine.medical_specialty ,Immunology ,Antineoplastic Agents ,Disease-Free Survival ,Drug Administration Schedule ,03 medical and health sciences ,Chemoimmunotherapy ,Internal medicine ,Humans ,Protein Kinase Inhibitors ,Aged ,Chemotherapy ,business.industry ,Adenine ,Lymphoma, B-Cell, Marginal Zone ,Pneumonia ,Cell Biology ,medicine.disease ,Surgery ,Regimen ,Pyrimidines ,030104 developmental biology ,chemistry ,Pyrazoles ,Marginal zone B-cell lymphoma ,business - Abstract
Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically confirmed MZL of all subtypes who received ≥1 prior therapy with an anti-CD20 antibody–containing regimen were treated with 560 mg ibrutinib orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee–assessed overall response rate (ORR) by 2007 International Working Group criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ≥1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% confidence interval [CI], 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7 to not estimable), and median progression-free survival was 14.2 months (95% CI, 8.3 to not estimable). Grade ≥3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit–risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL. This study is registered at www.clinicaltrials.gov as #NCT01980628.
- Published
- 2017
29. Ibrutinib and Rituximab Provides Superior Clinical Outcome Compared to FCR in Younger Patients with Chronic Lymphocytic Leukemia (CLL): Extended Follow-up from the E1912 Trial
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Curtis A. Hanson, Amanda F. Cashen, Harry P. Erba, Susan O'Brien, Esteban Braggio, Paul M. Barr, Michael P Mullane, Victoria Wang, Steven Coutre, Tait D. Shanafelt, Avina K. Singh, Martin S. Tallman, Diane F. Jelinek, Mark R. Litzow, Neil E. Kay, Cong Christina Zhang, Anthony R. Mato, Jose F. Leis, Richard Stone, Jacqueline C. Barrientos, and Richard F. Little
- Subjects
Oncology ,medicine.medical_specialty ,Cytopenia ,Cyclophosphamide ,business.industry ,FCR Regimen ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Fludarabine ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Ibrutinib ,medicine ,Rituximab ,business ,health care economics and organizations ,medicine.drug - Abstract
BACKGROUND: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has been the standard therapy for younger patients with CLL. FCR therapy is particularly effective in patients with immunoglobulin heavy chain variable region (IGHV) mutated CLL. Approximately half of IGHV mutated patients are progression free 8 years after FCR therapy. At the ASH 2018 meeting, we reported the initial results of the ECOG 1912 (E1912) trial, a phase 3 trial comparing the FCR regimen to the combination of ibrutinib and rituximab (IR) for previously untreated CLL patients age 70 or younger who required therapy. With median follow-up of approximately 34 months, the trial demonstrated both a progression-free survival (PFS) and an overall survival (OS) benefit relative to FCR. On sub-set analysis by IGHV mutation status, the difference in PFS was statistically significant for IGHV unmutated patients but, with current follow-up, not IGHV mutated patients. Here, we present updated results for PFS in the E1912 trial. METHODS: As previously reported, eligible patients were treatment-naive individuals with CLL age 70 or younger. Patients with deletion 17p- were excluded from participating in the E1912 trial given their known poor response to FCR therapy. Patients were randomly assigned in a two-to-one ratio to receive ibrutinib (420 mg/day until disease progression or unacceptable toxicity) and rituximab (50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, and then 500 mg/m2 on day 1 of cycles 3-7) or six courses of intravenous fludarabine (25 mg/m2 days 1-3), cyclophosphamide (250 mg/m2 days 1-3) and rituximab (50 mg/m2 on day 1 of cycle 1, 325 mg/m2 on day 2 of cycle 1, and then 500 mg/m2 on day 1 of cycles 2-6) every 28-days. Adverse events (AEs) were graded according to the NCI Common Toxicity Criteria (version 4). Dose adjustments for cytopenias were based on the IWCLL CLL Working Group grading scale. The primary endpoint of the trial was PFS with OS a secondary endpoint. Analysis was by intention to treat. RESULTS: With median follow-up of 45 months, 257 (73%) of 354 patients randomized to IR remain on ibrutinib. With extended follow-up, grade 3 and above treatment-related AEs were observed in 70% of IR and 80% of FCR treated patients (OR=0.56; 95% CI 0.34 - 0.90; p=0.013). Among IR-treated patients, the median time on treatment is currently 43 months (range=0.2-61). Among the 95 patients who have discontinued ibrutinib, the reason for discontinuation was progression or death in 23 (7% of patients who started IR; 24% of those who discontinued treatment), AE or complication in 48 (14% of patients who started IR; 51% of those who discontinued treatment), and withdrawal of consent or other reasons in 24 (7% of patients who started IR; 25% of those who discontinued treatment). On multivariable Cox regression adjusting for Timed Up and Go test score, Cumulative Illness Rating Scale (CIRS) score, age, gender, ECOG performance status, creatinine clearance, and baseline anemia/thrombocytopenia, only CIRS score (range 0 - 14) predicted discontinuation of ibrutinib for a reason other than progression or death (HR=1.13 per unit increase; 95% CI 1.03 - 1.23; p=0.009). Among the 72 patients who discontinued ibrutinib for a reason other than progression or death, the median time on ibrutinib was 15.1 months (range 0.2-58.2 months). The median time from ibrutinib discontinuation to disease progression or death was 23 months. With current follow-up, we observed 110 PFS events. The hazard ratio (HR) for PFS favored IR over FCR (HR=0.39; 95% CI 0.26-0.57; p CONCLUSIONS: Although less than 7% of ibrutinib treated patients progressed while on therapy, roughly 1 in 5 patients have discontinued ibrutinib for a reason other than progression or death. The only parameter significantly associated with discontinuation for a reason other than progression was increased baseline CIRS score. With extended follow-up, the combination of ibrutinib and rituximab continues to provide superior PFS compared to FCR for younger patients with previously untreated CLL. Disclosures Shanafelt: Pharmacyclics: Research Funding; Patent: Patents & Royalties: US14/292,075 on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia; Polyphenon E International: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Glaxo-SmithKline: Research Funding; Hospira: Research Funding; Cephalon: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; Acerta: Research Funding; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Verastem: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; Kite: Research Funding. Barrientos:AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding. Coutre:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Gilead: Research Funding; BeiGene: Other: Travel, Accommodations, Expenses & Data Safety Monitoring Committee; Genentech: Consultancy. Barr:Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; Gilead: Consultancy; Verastem: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Celgene: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Astra Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Cashen:Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy. Erba:Amgen: Consultancy; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; Astellas Pharma: Consultancy; Astellas Pharma: Consultancy; Amgen: Consultancy; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Pfizer: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding. Stone:Arog Pharmaceuticals: Consultancy, Honoraria, Research Funding; Otsuka-Astex Pharmaceuticals: Consultancy; Fujifilm: Consultancy; AstraZeneca: Consultancy; Celator Pharmaceuticals: Consultancy; Abbvie: Consultancy, Research Funding; Ono Pharmaceutical-Theradex Oncology: Consultancy; Cornerstone Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Other: Fees for serving on a data and safety monitoring board ; Orsenix: Consultancy; MacroGenics: Consultancy; Jazz Pharmaceuticals: Consultancy; Agios: Consultancy, Research Funding; Stemline Therapeutics: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Fees for serving on a steering committee, and fees for serving on a data and safety monitoring board; Novartis: Consultancy, Research Funding; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees; Argenx: Other: Fees for serving on a data and safety monitoring board ; Roche: Consultancy. Tallman:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees.
- Published
- 2019
30. Efficacy of Therapies Following Venetoclax Discontinuation in CLL: Focus on B-Cell Receptor Signal Transduction Inhibitors and Cellular Therapies
- Author
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Amber C. King, Michael Y. Choi, Guilherme Fleury Perini, Sirin Khajavian, Mazyar Shadman, Kentson Lam, Jason C. Lee, Bita Fakhri, Jeffrey J. Pu, Danielle M. Brander, Pratik Shah, Colleen Dorsey, Bruce D. Cheson, Kayla Bigelow, Talha Munir, Neil Bailey, Ryan Jacobs, Stephen J. Schuster, Thomas D. Rodgers, Hanna Weissbrot, Satyen H. Gohil, Lindsey E. Roeker, Andrew D. Zelenetz, Andrea Sitlinger, Pallawi Torka, Kate J Whitaker, Chaitra S. Ujjani, Nicolas Martinez-Calle, Christopher P. Fox, Brian T. Hill, Alan P Skarbnik, Paul M. Barr, Chadi Nabhan, Javier Pinilla Ibarz, Anthony R. Mato, Krista Isaac, Christine A. Garcia, Ariel F Grajales-Cruz, Allison M. Winter, Maryam Sarraf Yazdy, Toby A. Eyre, John M. Pagel, Jacqueline C. Barrientos, John N. Allan, Erica B. Bhavsar, Othman S. Akhtar, Julie Goodfriend, Helen Parry, Nicole Lamanna, Craig A. Portell, Timothy J Voorhees, Catherine C. Coombs, Rachael Pocock, and Joanna Rhodes
- Subjects
business.industry ,Venetoclax ,Immunology ,B-cell receptor ,Cell Biology ,Hematology ,Signal transduction inhibitor ,Biochemistry ,Discontinuation ,Cell therapy ,chemistry.chemical_compound ,chemistry ,Ibrutinib ,Cancer research ,Medicine ,Signal transduction ,business ,Idelalisib - Abstract
Introduction: Venetoclax (VEN) based therapy has become a standard of care in front line and relapsed-refractory (R/R) CLL based on favorable efficacy and toxicity. Whereas prospective data regarding activity of therapies following ibrutinib (IBR) or idelalisib (IDE) are available in the settings of progression (VEN, non-covalent BTKi) and intolerance (acalabrutinib), how best to manage patients (pts) who discontinue (dc) VEN remains a key unanswered question. With the increased use of VEN in early lines of therapy (LOT; CLL 14, MURANO), the activity of BTK inhibitors (BTKi) and cellular therapies following VEN becomes a critical issue. No prospective study has addressed this question, and currently reported VEN clinical trials have limited information about subsequent treatments. While recent data describe VEN resistance mechanisms (Guieze 2018, Blombery 2019), the impact of VEN resistance on efficacy of post VEN therapies is unknown. To address this gap, we conducted an international study to identify a large cohort of pts who dc VEN and have been subsequently treated. Methods: We conducted an IRB approved multicenter (31 US, EU, South American sites, in partnership with UK CLL Forum and CORE registry), retrospective cohort study of CLL pts who dc VEN for any reason. We examined demographics, dc reasons, responses, survival, adverse events (AEs) and activity of post VEN therapies. Primary endpoints were overall response rate (ORR) and progression free survival (PFS) for the post VEN treatments stratified by treatment type (BTKi, PI3Ki and cellular therapy: CAR-T or alloHSCT). ORR was defined by iwCLL criteria and PFS was defined from VEN dc to disease progression (PD), death, or last follow up for next treatment. Pts were further stratified by BTKi (resistant / intolerant) and PI3Ki exposure prior to VEN. PFS-2 was defined as time from VEN start to tumor progression on IBR or death from any cause. Results: 326 CLL pts who dc VEN in the front line (4%) and R/R settings (96%) were identified. The cohort was 69% male, 87% white, median (med) age 66 (38-91) at VEN start, 27% treated with VEN based combinations (n=88, med 6 cycles anti-CD20 abs). Pre VEN prognostic features: 82% IGHV unmutated (n tested=166), 47% del17p (n=306), 45% TP53 mut (n=217), 39% complex karyotype (n=273), 23% BTK mut (n=79), 18% NOTCH1 mut (n=103), 10% PLCγ2 mut (n=74). Pts received med 3 therapies (0-11) prior to VEN; 40% were BTKi naïve (n=130), 60% were BTKi exposed (196) and 81% were IDE naïve (n=263). Most common reasons for VEN dc were PD (38%), AE (20%), Richter's transformation (RT, 14%), 8% pt preference, and HSCT 5%. Of 326 pts who dc VEN, 188 (58%) were treated with a subsequent LOT, 61 are alive and untreated and 77 died prior to a subsequent LOT. Post VEN sequencing analyses focused on BTKi, PI3Ki and cellular therapy (CAR-T or alloHSCT) activities following VEN dc (Table1). ORR to BTKi was 84% (n=44) vs. 54% (n=30, p Conclusions: In the largest experience of therapies following VEN dc in CLL, we demonstrated that therapy selection following VEN requires consideration of prior novel agent exposure and reasons for discontinuation. For BTKi naïve pts, selection of a covalently binding BTKi results in high ORR and durable remissions. PFS-2 data provide reassurance for using VEN prior to IBR. For BTKi exposed pts, BTK inhibition is not effective in the setting of BTKi resistance but should be considered if prior BTKi intolerance. PI3K inhibition following VEN does not appear to result in durable remissions even in PI3Ki naïve pts, suggesting possible overlap in resistance mechanisms (BTK or VEN with PI3K). We conclude that BTKi in naïve or previously responsive pts and alloHSCT following VEN appear to be the most effective strategies with durable responses. These data suggest that a number of effective regimens exist for post VEN pts, providing support for VEN use earlier in the course of CLL. Disclosures Mato: Acerta: Consultancy; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Janssen: Consultancy; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Consultancy. Roeker:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Eyre:Gilead: Consultancy, Other: Research support, Speakers Bureau; Roche: Honoraria; Abbvie: Honoraria, Other: Travel to Conferences; Janssen: Honoraria, Other: Travel to Conferences ; Takeda: Other: Travel to Conferences . Jacobs:Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; JUNO: Consultancy; Gilead: Consultancy; TG Therapeutics: Honoraria, Research Funding. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. Lamanna:Celgene: Consultancy; Infinity/ Verastem: Research Funding; Ming: Research Funding; TG Therapeutics: Research Funding; Oncternal: Research Funding. Brander:Tolero: Research Funding; MEI: Research Funding; BeiGene: Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Acerta: Research Funding. Shadman:AbbVie: Consultancy, Research Funding; Astra Zeneca: Consultancy; BeiGene: Research Funding; TG Therapeutic: Research Funding; ADC Therapeutics: Consultancy; Atara Biotherapeutics: Consultancy; Verastem: Consultancy; Acerta Pharma: Research Funding; Sunesis: Research Funding; Mustang Bio: Research Funding; Celgene: Research Funding; Pharmacyclics: Consultancy, Research Funding; Sound Biologics: Consultancy; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Ujjani:AstraZeneca: Consultancy; Genentech: Consultancy; Rigel: Consultancy; Gilead: Consultancy; Abbvie: Research Funding; Pharmacyclics: Research Funding. Perini:Janssen: Other: Advisory Board; Abbvie: Other: Advisory Board; AstraZeneca: Other: Advisory Board. Pinilla Ibarz:Sanofi: Speakers Bureau; Bayer: Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy; TG Therapeutics: Consultancy. Barrientos:Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy; Gilead: Consultancy; Genentech: Consultancy. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Choi:Abbvie: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; Oncternal: Research Funding. Coombs:H3 Biomedicine: Research Funding. Barr:Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Merck: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; AbbVie: Consultancy. Portell:Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding. Schuster:AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Loxo Oncology: Honoraria; Pfizer: Honoraria; Nordic Nanovector: Honoraria; Pharmacyclics: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; Merck: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Martinez-Calle:ABBVIE: Other: Travel support. Munir:AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees. Nabhan:Aptitude Health: Employment. King:Astrazeneca: Other: Advisory board; Genentech: Other: Advisory Board ; Incyte: Other: Advisory Board. Zelenetz:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cheson:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding. Fox:Gilead: Consultancy; Janssen: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Allan:Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Consultancy.
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- 2019
31. Curriculum in Chronic Lymphocytic Leukemia Narrows the Educational Gaps of the Oncology Healthcare Team
- Author
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Farrukh T. Awan, Patrick Kugel, Katie S. Lucero, Lauren Willis, Jacqueline C. Barrientos, John N. Allan, Emily S Van Laar, Lisa Brauer, Danielle M. Brander, and Jonathon B. Cohen
- Subjects
Further education ,Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Pharmacist ,Cell Biology ,Hematology ,Certification ,Correct response ,Biochemistry ,Internal medicine ,Health care ,medicine ,Video lecture ,business ,Competence (human resources) ,Curriculum - Abstract
Introduction: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. Treatment selection in CLL is dependent upon a number of factors, such as patient age and genetic mutations, and can be challenging. A number of novel therapies and combination treatment approaches are now available, making treatment selection and management of adverse events increasingly complex. We sought to determine if a curriculum of online continuing professional education (CPE) activities could improve hematologists/oncologists (hem/onc, H/O), pathologists (path), nurse/NP, and pharmacist knowledge, competence, and confidence related to clinical decision making in patients with CLL. Methods: An expert panel identified educational gaps related to the treatment of patients with CLL. Based on the educational needs identified, the curriculum included 4 activities that were posted online between March 2019-June 2019. The first activity was a 30 minute video lecture (1 faculty) about measurable residual disease (MRD) analysis in CLL. The second activity was 30 minute video roundtable discussion (3 faculty) about treatment initiation and selection in newly diagnosed CLL. The third activity was a text activity focused on relapsed/refractory (R/R) CLL with 2 patient cases. The final activity was a video discussion between a nurse and pharmacist about mitigating side effects and optimizing compliance with oral therapies in CLL. Three activities were certified for physicians and the fourth activity was certified for nurses and pharmacists. Multiple-choice questions were asked before and after participation in each activity A repeated-pairs analysis was conducted where individual learners served as their own controls. Improved indicates an incorrect response pre-activity and a correct response post-activity. Reinforced indicates a correct answer pre- and post-activity. Improved confidence indicates a higher level of confidence post-activity. Results: As of July 2019, there were 356 hem/oncs, 154 pathologists, 178 nurses/NPs, and 504 pharmacists included in this analysis. The curriculum had a large impact on the knowledge and competence of hem/oncs and pathologists. MRD is an indicator of improved progression free survival: 13% H/O and path improved their knowledge, 58% H/O and 36% path reinforced their knowledge. The role for MRD measurement in CLL: 24% H/O and 15% of path improved their knowledge, 51% H/O and 39% path reinforced their knowledge. Selecting therapy for treatment-naïve CLL: 13% H/O and 30% path improved their competence, 57% H/O and 36% path reinforced their competence. Selecting therapy for relapsed/refractory (R/R) CLL: 39% H/O and 42% path improved their competence, 26% H/O and 11% path reinforced their competence. Managing treatment-related side effects in CLL: 11% H/O and 33% path improved their competence, 72% H/O and 31% path reinforced their competence. 10% of nurses/NPs and 11% of pharmacists improved and 30% of nurses/NPs and 38% of pharmacists reinforced their skills counseling patients about adverse event management and drug-drug interactions in R/R CLL. Tailoring frontline therapy in treatment-naïve CLL: 26% H/O and 15% path improved their confidence. Tailoring therapy in R/R CLL: 34% H/O and 31% path improved their confidence. Using MRD in CLL management: 31% H/O and 21% path improved their confidence. Improving patient engagement by using effective interprofessional communication: 25% nurses/NPs and 36% pharmacists improved their confidence. Conclusions: This analysis shows that an online CPE curriculum, utilizing many different formats (video, text, panel discussions) can improve and reinforce the knowledge, competence, and confidence of hem/oncs, pathologists, nurses/NPs, and pharmacists in multiple areas surrounding the treatment of patients with CLL. Results also suggest the following areas warrant further education: knowledge of the role for MRD in CLL management, individualizing therapy selection for treatment-naïve and R/R CLL, and managing treatment-related adverse events of CLL therapies. Acknowledgements: Sameer Bhagavatula contributed to data analysis for this research. Figure Disclosures Allan: Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy, Honoraria; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy; Genentech: Consultancy; Sunesis: Consultancy; Gilead: Consultancy. Brander:AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Tolero: Research Funding; DTRM Biopharma: Research Funding; BeiGene: Research Funding; MEI: Research Funding; Acerta: Research Funding; Novartis: Consultancy; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding. Cohen:Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding. Barrientos:Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy; Gilead: Consultancy; Genentech: Consultancy.
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- 2019
32. Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: 42-Month Follow-up of a Phase 2 Study
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Raquel Izumi, Ahmed Hamdy, John M. Pagel, Min Hui Wang, Todd Covey, Jennifer A. Woyach, Jacqueline C. Barrientos, Paolo Ghia, Kathleen A. Burke, Susan O'Brien, Richard R. Furman, Anna Schuh, William G. Wierda, John C. Byrd, Priti Patel, Jennifer R. Brown, Peter Hillmen, Farrukh T. Awan, Melanie M. Frigault, Peter Martin, Michael Gulrajani, Jorge Chaves, Wayne Rothbaum, Stephen Devereux, and Deborah M. Stephens
- Subjects
Bendamustine ,medicine.medical_specialty ,Lymphocytosis ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Gastroenterology ,Internal medicine ,medicine ,Acalabrutinib ,Rituximab ,medicine.symptom ,Idelalisib ,business ,medicine.drug - Abstract
Background: Targeted inhibition of Bruton tyrosine kinase (BTK) has improved clinical outcomes for patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a highly selective, covalent BTK inhibitor. A recently completed phase 3 trial showed acalabrutinib improved progression-free survival (PFS) vs idelalisib or bendamustine + rituximab in relapsed/refractory (R/R) CLL patients (ASCEND: Ghia et al. EHA 2019;273259:LB2606). This is an updated analysis with extended follow-up of a phase 1-2 multicenter study (NCT02029443) in patients with R/R CLL/small lymphocytic lymphoma (SLL), to demonstrate the durability of response and long-term tolerability of acalabrutinib. Methods: Patients with CLL or SLL were eligible if they were R/R after ≥1 prior treatment. Eligible patients were ≥18 years of age with an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Oral acalabrutinib 100 mg was administered twice daily. All patients were treated until progressive disease or unacceptable toxicity occurred. Study endpoints included overall response rate (ORR), PFS, duration of response (DOR) and safety, with post hoc analysis of event-free survival (EFS). Response rates were based on the International Workshop on Chronic Lymphocytic Leukemia 2008 criteria (Hallek et al., 2008) with modification for lymphocytosis (Cheson et al., 2012). Nine patients had longitudinal peripheral blood mononuclear cell samples from pre-treatment baseline, during treatment and at progression analyzed for whole exome sequencing, to assess acquired mechanisms of treatment resistance. Results: In total, 134 patients with R/R CLL/SLL received ≥ 1 dose of acalabrutinib. The median age was 66 years (range, 42-85 years). Baseline characteristics included ECOG PS ≤1 (97%), bulky lymph nodes ≥5 cm (39%), unmutated immunoglobulin heavy chain variable region (IGHV; 73%), chromosome 17p13.1 deletion (23%), chromosome 11q22.3 deletion (18%), and complex karyotype (≥3 abnormalities; 35%). The median number of prior therapies was 2 (range, 1-13). Patients received acalabrutinib for a median of 41 months (range, 0.2-58 months). Most adverse events (AEs) were mild to moderate, and most commonly were diarrhea (52%), headache (46%), and upper respiratory tract infection (36%). Grade ≥3 AEs occurred in 66% of patients; most commonly (≥5% of patients) neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%) and diarrhea (5%). AEs of interest included atrial fibrillation (7% all grades; 3% Grade ≥3) and major bleeding events (5% all grades; 3% Grade ≥3). Most patients (56%) remained on treatment. The most common reasons for discontinuing treatment were progressive disease (21%) and AEs (11%). AEs leading to discontinuation occurring in ≥1 patient included pneumonia (4 events), anemia, neutropenia, and thrombocytopenia (2 events each). The ORR (partial response with lymphocytosis or above) was 94% (95% confidence interval [CI]: 89-97%); with 4% of patients having complete response, 84% having partial response and 6% having partial response with lymphocytosis (Table). The median DOR, PFS and EFS were not reached; the estimated 42-month DOR was 61% (95% CI: 49-71%), PFS was 68% (95% CI: 59-76%) and EFS was 64% (95% CI: 54-71%). Responses were similar regardless of genomic features, including unmutated IGHV, chromosomal deletions and complex karyotype (Table). Upon relapse during acalabrutinib treatment, whole exome sequencing detected BTK mutations in 6 of 9 (67%) tested patients that were not detectable at baseline. Of the 6 patients with detectable BTK C481X mutations, 4 had expansion to high allele frequency of the BTK mutation at progression (up to 58%). In a longitudinal analysis of patients who had a sample after 6 months of treatment, the BTK mutation was not detectable. No PLCG2 gene mutations were detected using exome analysis in the 9 patients analyzed. Conclusions: These updated results confirm the earlier reports of acalabrutinib efficacy for the treatment of CLL and provide additional data on DOR and long-term tolerability. Reported AEs indicate a tolerable and consistent safety profile, with a low rate of major bleeding events. Genomic profiling in a small subset of patients indicated that acquired mutation of BTK was the most frequent mechanism of acalabrutinib resistance. Disclosures Furman: Genentech: Consultancy. Wierda:Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding. Schuh:Roche: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Devereux:Servier: Speakers Bureau; Roche: Consultancy, Other: Travel expenses, Speakers Bureau; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; MSD: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau. Brown:Pfizer: Consultancy; Sun: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pharmacyclics: Consultancy; Morphosys: Other: Data safety monitoring boards ; Sun Pharmaceuticals, Inc: Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Martin:Karyopharm: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy. Awan:Sunesis: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Innate Pharma: Research Funding; Gilead: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Stephens:Acerta: Research Funding; Gilead: Research Funding; Karyopharm: Research Funding. Ghia:Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy. Barrientos:Bayer: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Genentech: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Burke:AstraZeneca: Employment, Equity Ownership. Covey:Acerta Pharma: Employment, Equity Ownership; AstraZeneca: Equity Ownership. Gulrajani:AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership. Hamdy:Acerta Pharma: Employment, Equity Ownership. Izumi:Acerta Pharma: Employment, Equity Ownership. Frigault:Acerta Pharma: Employment; AstraZeneca: Employment, Equity Ownership. Patel:Acerta Pharma: Employment, Equity Ownership. Rothbaum:Acerta Pharma: Employment, Equity Ownership. Wang:AstraZeneca: Equity Ownership; Acerta Pharma: Employment. O'Brien:Eisai: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; Verastem: Consultancy; Vaniam Group LLC: Consultancy; Astellas: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Regeneron: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding. Byrd:Ohio State University: Patents & Royalties: OSU-2S; BeiGene: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau. OffLabel Disclosure: This is a Phase 1/2 investigational study of acalabrutinib in chronic lymphocytic leukemia
- Published
- 2019
33. CLL B Cells Develop Resistance to Ibrutinib By Reinvigorating the IL-4R - IL-4 Axis Blocked By Bruton's Tyrosine Kinase Inhibitors Including Acalabrutinib and Zanubrutinib
- Author
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Constantine S. Tam, He Zhou, Alan G. Ramsay, Jacqueline C. Barrientos, Priyadarshini Ravichandran, Gerardo Ferrer, Nicholas Chiorazzi, Shih-Shih Chen, Michael Ibrahim, Kanti R. Rai, Steven L. Allen, Jonathan E. Kolitz, and Natalia C. Couto-Francisco
- Subjects
0301 basic medicine ,T cell ,Immunology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Interleukin-4 receptor ,medicine ,Bruton's tyrosine kinase ,Interleukin 4 ,B cell ,CD40 ,biology ,business.industry ,Cell Biology ,Hematology ,Interleukin 10 ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Ibrutinib ,Cancer research ,biology.protein ,business ,030215 immunology - Abstract
Bruton's tyrosine kinases inhibitors (BTKis) represent major advances in CLL therapy. However resistance to this form of therapy is emerging, and such patients often progress more rapidly. Hence there is an important need for therapies that address resistance. Microenvironmental input like IL-4 is critical for CLL disease progression. Compared with normal B cells, CLL cells exhibit significantly higher levels of surface membrane (sm) IL-4 receptor (IL4-R) and contain increased amounts of pSTAT6, a downstream mediator of IL-4R signaling. IL-4 stimulation of CLL B cells suppresses smCXCR4 and increases smIgM, thus promotes CLL cell retention and expansion. In this study, we aimed to examine if smIL-4R expression, IL4R signaling, and IL-4-producing cells are altered in patients sensitive or resistant to BTKis. To do so, T and B cell subset changes were studied overtime in 12 acalabrutinib-treated CLL patients, 6 zanubrutinib-treated CLL patients, 30 ibrutinib-sensitive and 5 ibrutinib-resistant CLL patients, 4 of which exhibited BTK mutations. Consistent with only ibrutinib inhibiting T-cell kinase (ITK), T-cell subset analyses revealed no changes in Th1, Th2, Th17, Th9, and Th22 cells after zanubrutinib or acalabrutinib treatment. In contrast, a Th1-biased T-cell immunity was observed in patients responsive to ibrutinib. In patients progressing on ibrutinib, significantly reduced Th2 T cells were found during the resistant as well as sensitive periods. In an in vitro T-cell function assay using T cells collected before and after the treatment with each BTKi, only ibrutinib treated patients exhibited a reduced ability of T cells to support CLL B cell survival. We next studied changes in CLL B cells, including numbers of IL-4, -10 and -13 producing B cells after BTKi treatment. IL-13 producing CLL B cells were not changed. IL-10 producing CLL B cells were reduced in both ibrutinib sensitive and resistant patients, but not in zanubrutinib or acalabrutinib treated patients. Importantly, IL-4 producing CLL B cells were significantly decreased in patients treated with all 3 BTKi. Significantly reduced smIL-4R levels, impaired IL-4R signaling, decreased smIgM and increased smCXCR4 were also seen in patients treated with each BTKi. To understand the mechanism responsible for inhibition of IL-4 production in CLL cells treated with BTKis, we stimulated CLL cells through IgM, Toll-like receptor and CD40L, finding that only anti-IgM stimulation significantly increased IL-4 production and p-STAT6 induction. We then explored the function of IL-4. IL-4 enhanced CLL B cell survival in vitro and this action was blocked by all 3 BTKis. Moreover, adhesion of CLL B cells to smIL-4R expressing stromal cells was decreased by IL-4 and IL-4R neutralizing antibodies, especially in M-CLL cases. In in vivo studies transferring autologous T cells and CLL PBMCs into alymphoid mice, we found less CLL B cells in mouse spleens post ibrutinib than zanubrutinib or acalabrutinib treatment. This might be due to the suppressed Th2 cells found only in ibrutinib, while IL-4 producing B cells were reduced in all 3 BTKi treated mice. These results support the idea that IL-4 promotes CLL B cell adhesion and growth in tissues. Finally, we investigated the IL-4/IL-4R axis in ibrutinib-resistant patients. Although IL-4 producing T cells remain reduced during the sensitive and resistant phases, CLL B cell production of IL-4 and expression of and signaling through smIL-4R returned when patients developed ibrutinib-resistance. When comparing paired ibrutinib-sensitive and -resistant CLL B cells collected from 3 patients in a xenograft model that requires T cell help, we found ibrutinib-resistant CLL B cells grew in vivo with only minimal (~15%) numbers of autologous T cells compared to B cells collected from ibrutinib-sensitive phase; this suggested a reduced requirement for T-cell help for growth of ibrutinib-resistant CLL cells. In summary, we found IL-4 is a key survival factor in the CLL microenvironment that also improves leukemia cell adhesion to stromal cells expressing smIL-4R. IL-4 production and signaling can be stimulated in CLL B cells through the B-cell receptor, and are consistently blocked by BTKis. Moreover, the recovered ability of ibrutinib-resistant CLL B cells to produce and respond to IL-4 leads to disease progression, suggesting blocking the IL-4/IL-4R axis is a potential treatment for ibrutinib-resistant CLL patients. Disclosures Chen: Pharmacyclics: Research Funding; Beigene: Research Funding; Verastem: Research Funding; ArgenX: Research Funding. Tam:Abbvie, Janssen: Research Funding; Abbvie, Janssen, Beigene, Roche, Novartis: Honoraria. Ramsay:Celgene Corporation: Research Funding; Roche Glycart AG: Research Funding. Kolitz:Boeringer-Ingelheim: Research Funding; Roche: Research Funding; Astellas: Research Funding. Zhou:BeiGene: Employment. Barrientos:Genentech: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Rai:Pharmacyctics: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees.
- Published
- 2019
34. Dual Inhibition of PI3K-δ and PI3K-γ By Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Patient-Derived Xenograft Model
- Author
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Priyadarshini Ravichandran, Kanti R. Rai, Shih-Shih Chen, Michael Ibrahim, Jonathan A. Pachter, Yasmine Kieso, Nicholas Chiorazzi, Jeffery L. Kutok, Gerardo Ferrer, Jacqueline C. Barrientos, and David T. Weaver
- Subjects
0301 basic medicine ,Macrophage colony-stimulating factor ,Severe combined immunodeficiency ,biology ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Duvelisib ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Ibrutinib ,Cancer research ,biology.protein ,medicine ,Bruton's tyrosine kinase ,Idelalisib ,Interleukin 4 - Abstract
Novel agents targeting the B-cell receptor signaling pathway, such as ibrutinib and idelalisib, are effective in patients with chronic lymphocytic leukemia (CLL), but complete responses are infrequent and residual disease often remains. Patients may discontinue ibrutinib because of unacceptable adverse events or if they develop ibrutinib resistance due to Bruton tyrosine kinase (BTK) or phospholipase C gamma 2 (PLCG2) mutations or other less-well-defined mechanisms. Therefore, alternative therapies that can overcome ibrutinib intolerance and resistance are needed. Duvelisib (DUV) is an oral dual phosphatidylinositol 3-kinase (PI3K)-δ and -γ inhibitor with activity in patients with relapsed/refractory CLL and a manageable safety profile. Preclinical studies point to distinct roles of PI3K-δ and -γ in CLL biology, suggesting that dual isoform inhibition may enhance efficacy by targeting both CLL and CLL-supporting cells. Importantly, DUV potently inhibits PI3K-δ and -γ in human peripheral blood mononuclear cells and CLL cells. Here, we further characterize the distinct functions of PI3K-δ and -γ in CLL and examine the mechanisms of action of DUV in vitro and in a patient-derived xenograft (PDX) model, highlighting the ability of DUV to overcome ibrutinib resistance. We first assessed the in vivo efficacy of PI3K-δ and/or PI3K-γ inhibition on CLL B cells using a PDX mouse model in which activated patient-derived T cells and CLL B cells were injected into alymphoid NOD-scid IL-2Rγnull (NSG) mice. Cells from 4 patients were transferred and allowed to expand for 2 weeks, after which mice were treated with DUV, a PI3K-δ inhibitor, or a PI3K-γ inhibitor for 3 weeks. DUV and the PI3K-δ inhibitor, but not the PI3K-γ inhibitor, significantly decreased the number of CLL B cells in the spleens of mice. In another set of experiments, combination treatment with the PI3K-δ and -γ inhibitors more potently impaired CLL B-cell survival than the PI3K-δ inhibitor alone. Next, the effects of PI3K-δ or -γ inhibition on CLL-supporting cells, ie, autologous T cells and murine macrophages, were examined in the PDX model using the same 4 patient samples. Significant decreases in both patient-derived T cells and murine macrophages were observed in the spleens of mice treated with DUV or the PI3K-γ inhibitor but not with the PI3K-δ inhibitor. Therefore, the function of PI3K-δ and -γ in macrophages and macrophage-supported CLL cell survival were examined in vitro. Murine bone marrow-derived macrophages were polarized via interleukin 4 and macrophage colony stimulating factor in the presence of DUV, a PI3K-δ inhibitor, or a PI3K-γ inhibitor. Both DUV and the PI3K-γ inhibitor impaired M2 polarization, assessed by arginase 1 (ARG1) mRNA expression. Culture with M2 macrophages increased CLL B-cell viability, and the addition of DUV inhibited this survival-promoting activity more than the PI3K-δ or -γ inhibitors alone. To assess whether DUV could inhibit CLL B cells from ibrutinib-unresponsive patients, activated T cells and CLL B cells from 2 patients who progressed on ibrutinib (1 with a BTK C481S mutation and 1 without a BTK mutation) were transferred into NSG mice and allowed to expand for 2 weeks, and then mice were treated with DUV or ibrutinib for 3 weeks. For both patient samples, there was a > 10-fold reduction in the number of CLL B cells recovered from the spleens of mice treated with DUV, as well as a significant reduction in the percentage of proliferating CLL B cells. In contrast, ibrutinib did not have significant impact on CLL B-cell numbers or proliferation in the spleen. In conclusion, DUV inhibits the in vivo survival and proliferation of leukemic B cells from CLL patients, including those who have progressed on ibrutinib. Dual PI3K-δ and -γ inhibition is more effective at inhibiting CLL B cells in vivo than PI3K-δ inhibition alone. Moreover, PI3K-γ inhibition shifts macrophage polarization away from a CLL-supportive M2 phenotype. Thus, DUV exerts inhibitory effects on CLL B cells and on CLL-supporting T and myeloid cells. Overall, these findings elucidate the non-redundant roles of PI3K-δ and -γ in CLL and demonstrate the potent antitumor activity of dual PI3K isoform inhibition by DUV in ibrutinib-resistant patient CLL cells in vivo. Further investigation of DUV as a therapeutic option for patients who are refractory to or intolerant of ibrutinib or other BTK inhibitors is ongoing in a phase 2 clinical trial (BRIO; NCT03370185). Disclosures Chen: Janssen: Research Funding; ArgenX: Research Funding; Beigene: Research Funding; Pharmacyclics: Research Funding; Verastem: Research Funding. Kutok:Infinity Pharmaceuticals: Employment, Equity Ownership. Barrientos:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weaver:Verastem Oncology: Employment, Other: Stockholder; Agios Pharmaceuticals: Employment; Femto Dx: Equity Ownership. Pachter:Verastem: Employment, Other: Stockholder. Rai:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees. Chiorazzi:AR Pharma: Equity Ownership; Janssen, Inc: Consultancy.
- Published
- 2018
35. A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912)
- Author
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Jacqueline C. Barrientos, Susan O'Brien, Victoria Wang, Mark R. Litzow, Curtis A. Hanson, Martin S. Tallman, Tait D. Shanafelt, Richard Stone, Harry P. Erba, and Neil E. Kay
- Subjects
Oncology ,medicine.medical_specialty ,Cyclophosphamide ,Chronic lymphocytic leukemia ,Immunology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Chemoimmunotherapy ,Internal medicine ,medicine ,Chlorambucil ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Fludarabine ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Conventional PCI ,Rituximab ,business ,030215 immunology ,medicine.drug - Abstract
BACKGROUND: Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies, accounting for ~11% of all hematologic neoplasms. Over the last 15 years, a series of phase 3 trials have established that chemoimmunotherapy (CIT) with fludarabine, cyclophosphamide, and rituximab (FCR) improves both progression free survival (PFS) and overall survival (OS) compared with chemotherapy alone. FCR is the gold standard for young fit patients with treatment naïve CLL. In parallel with the advances in CIT, a profound increase in the understanding of CLL B-cell biology led to new therapeutic approaches.1 Among these, ibrutinib (an irreversible inhibitor of Bruton's Tyrosine Kinase [BTK]) has had the largest impact on clinical practice to date. Initial trials of ibrutinib demonstrated robust and durable efficacy in patients with relapsed/refractory disease. Subsequent phase 3 trials showed improved PFS and OS with ibrutinib relative to chlorambucil in previously untreated, older CLL patients. Despite these advances, the efficacy of ibrutinib as a first-line treatment for younger CLL patients (i.e. METHODS: Eligible patients were treatment-naive individuals with CLL who were age Hematologic toxicity was graded according to the 2008 IWCLL Working Group scale. All other adverse events were graded according to the NCI Common Toxicity Criteria (version 4). The primary endpoint was PFS with a secondary endpoint of overall survival (OS). Analysis was by intention to treat. The first planed interim analysis for PFS was scheduled to occur 24-27 months after full accrual with the first interim analysis for OS scheduled to occur if the boundary for PFS was crossed. The primary analysis was a stratified logrank test applied to all patients as randomized. Treatment effect p-values are one-sided. The study was approved by the Central Institutional Review Board for the National Cancer Institute, conducted in accordance with the principles of the Declaration of Helsinki, and registered with ClinicalTrials.gov (NCT02048813). RESULTS: A total of 529 patients were accrued between January 31, 2014 and June 9, 2016. 354 patients were assigned to ibrutinib and rituximab (IR) and 175 to FCR. Nineteen patients did not start protocol therapy. The first interim analysis was performed September 2018. With median follow-up of 33.4 months, we observed 77 PFS events and 14 deaths. The hazard ratio (HR) for PFS favored IR over FCR (HR=0.352; 95% CI 0.223-0.558; p In subgroup analysis for PFS, IR was superior to FCR independent of age, sex, performance status, disease stage or the presence/absence of del11q23. With current follow-up, IR was also superior to FCR for IGHV unmutated patients (HR=0.262; 95% CI 0.137-0.498; p Grade 3 and 4 treatment-related adverse events were observed in 58% of IR and 72% of FCR treated patients (p=0.0042). Specifically, FCR was more frequently associated with grade 3 and 4 neutropenia (FCR: 69 [44%] of 158 vs. IR: 80 [23%] of 352; p CONCLUSIONS: The combination of ibrutinib and rituximab provides superior PFS and OS relative to FCR for patients with previously untreated CLL age Disclosures Shanafelt: Mayo Clinic: Patents & Royalties: Physician Well-being Index, Medical Student Well-being Index, Well-being index; Celgene: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Kay:Janssen: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees. O'Brien:Amgen: Consultancy; Astellas: Consultancy; Celgene: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Vaniam Group LLC: Consultancy; Abbvie: Consultancy; Alexion: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding. Barrientos:Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Erba:Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Pfizer: Consultancy, Other: grant; Incyte: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; Janssen: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Astellas: Research Funding; Incyte: Consultancy, Speakers Bureau; Astellas: Research Funding; Pfizer: Consultancy, Other: grant; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; MacroGenics: Consultancy; MacroGenics: Consultancy; Amgen: Research Funding; Takeda/Millenium: Research Funding; Amgen: Research Funding; Takeda/Millenium: Research Funding; Seattle Genetics: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Immunogen: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; MacroGenics: Consultancy; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Daiichi Sankyo: Consultancy, Research Funding; Juno: Research Funding; Juno: Research Funding; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Daiichi Sankyo: Consultancy, Research Funding. Stone:Juno: Consultancy; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; FujiFilm: Consultancy; Sumitomo: Consultancy; Ono/Theradex: Consultancy; Otzuka/Astex: Consultancy; Pfizer: Consultancy; Roche: Consultancy; AbbVie: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Celator / Jazz: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cornerstone: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Tallman:ADC Therapeutics: Research Funding; Daiichi-Sankyo: Other: Advisory board; BioSight: Other: Advisory board; AbbVie: Research Funding; Cellerant: Research Funding; AROG: Research Funding; Orsenix: Other: Advisory board.
- Published
- 2018
36. Prognostic Testing and Treatment Approaches in Patients with Chronic Lymphocytic Leukemia: Clinical Experience from an Interim Analysis of the informCLLTM Real-World Registry
- Author
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Nilanjan Ghosh, John M. Pagel, Sandhya Upasani, Meghan Gutierrez, Jacqueline C. Barrientos, Lucille Ferrante, David Ipe, Anthony R. Mato, Danielle M. Brander, Nick Giafis, Karen Kadish, Carlos I. Amaya-Chanaga, Brian Tomlinson, Jeff P. Sharman, Murali Sundaram, and Reethi Iyengar
- Subjects
030213 general clinical medicine ,medicine.medical_specialty ,business.industry ,Immunology ,Immediate family member ,Cell Biology ,Hematology ,Tp53 mutation ,Interim analysis ,Biochemistry ,Clinical trial ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Family medicine ,Charlson comorbidity index ,Ibrutinib ,medicine ,In patient ,business ,IGHV@ - Abstract
Background : Prior to the approvals of ibrutinib (ibr), idelalisib, and venetoclax, data from the Connect CLL registry showed that across 199 US centers only 65% of patients (pts) had FISH testing and 6% had IGHV testing performed prior to the first chronic lymphocytic leukemia (CLL)-directed treatment (tx), and 40% had repeat FISH testing prior to a subsequent therapy (Mato, Br J Haematol 2016). In today's era, molecular-genetic testing should be universally performed to guide tx decisions for pts with CLL, particularly for pts with 17p deletion (del[17p]), TP53 mutation, and/or unmutated IGHV (U-CLL), as recommended by several guidelines. Whether the widespread availability of novel agents has improved prognostic testing patterns and if those results are appropriately utilized in selecting therapies remain important unanswered questions. InformCLL (NCT02582879) is a US, multicenter, prospective, observational real-world registry of pts with CLL receiving various lines of tx across 150 centers (96% community, 4% academic). This analysis describes rates of prognostic testing in pts with CLL stratified by line of therapy, proportions of pts with specific abnormalities, and current tx patterns in clinical practice in this registry. Methods : Enrollment began in Oct 2015. Eligible pts had to be ≥18 years (y), start approved anti-CLL tx within 30 days of enrollment, and provide consent. First tx at enrollment was classified into 5 groups: chemoimmunotherapy (CIT), chemotherapy (CT), immunotherapy (IT), ibr, and other novel agents. For this interim analysis (data cut: Feb 2018), the number of pts with CLL who had testing performed for FISH, TP53 mutational status, and IGHV mutational status, as well as CLL tx for subgroups of pts stratified by abnormality, was summarized as frequency counts and percentages. Results : At the time of this analysis, the registry had enrolled 840 pts (459 previously untreated; 381 relapsed or refractory [R/R]). The majority of pts were male (64%) and Caucasian (92%); median (range) age was 70y (34-95), and median (range) Charlson Comorbidity Index was 2 (0-9). Overall, prognostic biomarker testing was performed infrequently. Among all pts (N=840), 262 (31%) had FISH testing, 89 (11%) had testing performed for TP53 mutation, and 94 (11%) had testing for IGHV mutational status (Table 1). Among 459 pts tested prior to first-line tx, 164 (36%) had testing for FISH, 54 (12%) for TP53, and 55 (12%) for IGHV; among 381 R/R pts, 98 (26%) had testing for FISH, 35 (9%) for TP53, and 39 (10%) for IGHV. For tested pts, 70/262 (27%) pts had del(17p), 23/89 (26%) had mutated TP53, and 69/94 (73%) had U-CLL. For previously untreated tested pts, 47/164 (29%) had del(17p), 14/54 (26%) had mutated TP53, and 35/55 (64%) had U-CLL; for tested R/R pts, 23/98 (23%) had del(17p), 9/35 (26%) had mutated TP53, and 34/39 (87%) had U-CLL. Among 70 pts with del(17p), the most common tx was ibr (n=38; 54%); however, a considerable proportion of pts received CT/CIT (n=24; 34%) (Table 2). In 47 previously untreated pts with del(17p), 27 (57%) received ibr and 16 (34%) received CT/CIT; in 23 R/R pts with del(17p), 11 (48%) received ibr and 8 (35%) CT/CIT. Among 23 pts with mutated TP53, 15 (65%) were treated with ibr, while 7 (30%) with CT/CIT. Of 14 previously untreated pts with mutated TP53, 9 (64%) received ibr and 5 (36%) CT/CIT; of 9 R/R pts with mutated TP53, 6 (67%) received ibr and 2 (22%) CT/CIT. Among 69 pts with U-CLL, 30 (43%) were treated with ibr and 32 (46%) with CT/CIT. In 35 previously untreated pts with U-CLL, CT/CIT was more common (n=20; 57%) than ibr (n=13; 37%), while in 34 R/R pts with U-CLL, ibr was more common (n=17; 50%) than CT/CIT (n=12; 35%). Conclusions : There remains a considerable lack of prognostic marker testing among pts with CLL in the modern era. These findings, as compared to prior registry results, suggest that the advent of novel agents and specific testing guidelines (eg, iwCLL) have not improved prognostic testing patterns in the real-world setting. Moreover, of pts tested who had abnormalities such as del(17p), TP53 mutation, or U-CLL, approximately one-third still received CIT. These results underscore a need to educate on how to utilize these markers to guide CLL tx decisions for optimal clinical outcomes. Additional evaluations (eg, regression analyses) to identify factors associated with failure to perform FISH, TP53, and IGHV testing are planned. Disclosures Mato: Portola: Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Prime Oncology: Honoraria; Regeneron: Research Funding; Johnson & Johnson: Consultancy; Acerta: Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding. Barrientos:Janssen: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding. Brander:BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Kadish:Pharmacyclics, an AbbVie Company: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau. Ghosh:Celgene: Consultancy; PCYC: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Pharmacyclics, an Abbvie Company: Consultancy, Research Funding, Speakers Bureau; SGN: Consultancy, Research Funding, Speakers Bureau; Forty seven Inc: Research Funding; TG Therapeutics: Honoraria, Research Funding; F. Hoffman-La Roche Ltd: Research Funding; Genentech: Research Funding; Spectrum: Consultancy; Abbvie: Consultancy, Speakers Bureau; Juno: Consultancy, Research Funding. Giafis:Pharmacyclics, an AbbVie Company: Employment, Other: Travel; AbbVie: Equity Ownership. Ipe:AbbVie: Equity Ownership; Pharmacyclics, an AbbVie Company: Employment, Other: Travel. Upasani:Pharmacyclics, an AbbVie Company (self and immediate family member): Employment; AbbVie (self and immediate family member): Equity Ownership. Sundaram:AbbVie: Employment, Equity Ownership, Other: Travel; Johnson & Johnson: Employment, Equity Ownership, Other: Travel. Ferrante:Janssen: Employment, Equity Ownership. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Iyengar:Pharmacyclics, an AbbVie company: Employment; AbbVie: Equity Ownership; Express Scripts: Patents & Royalties. Sharman:Acerta: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding.
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- 2018
37. Extended Survival in CLL Patients Who Discontinued Idelalisib Because of Colitis Correlates with Higher Th17 Levels in Blood and Colon Tissue
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Pui Yan Chiu, Barbara Sherry, Nicholas Chiorazzi, Jacqueline C. Barrientos, Rukhsana Aslam, Gerardo Ferrer, and Kanti R. Rai
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medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Internal medicine ,Colon tissue ,medicine ,Colitis ,business ,Idelalisib - Abstract
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western countries. Despite significant clinical and molecular advances, CLL remains an incurable disease. In CLL there is ongoing communication between leukemic B cells and non-leukemic cells in the tissue microenvironment. Idelalisib, a PI3Kδ inhibitor, is efficacious in CLL although side effects like inflammatory reactions in different tissues (e.g., colitis, transaminitis and pneumonitis) and progression of disease can lead to discontinuation of the drug. We previously presented an intriguing finding that a cohort of patients who discontinued idelalisib therapy due to colitis had extended survival compared to other patients who discontinued drug but did not have colitis. Of note, the colon tissues from patients with ulcerative colitis (UC) often contain elevated levels of Th17 cells and decreased levels of Treg (Foxp3+) cells. Moreover, Th17 cells from humans and mice have been shown to promote autoimmune B-cell maturation. In this regard, we have previously published that circulating Th17 levels are elevated in CLL patients and Th17 numbers correlate with extended survival. For these reasons, we have now quantified the numbers of Th17 and Treg cells in the blood and colon tissues of a cohort of CLL patients with drug-associated colitis and extended survival and have investigated the effects of in vitro exposure to idelalisib on Th17 generation. Circulating Th17A levels were quantified in a cohort of patients (n=11) before starting idelalisib-treatment and at the time the drug was discontinued due to colitis by flow cytometric analysis of intracellular IL-17A in CD4+ T cells. In addition, colon tissues from those CLL patients who developed colitis during idelalisib treatment taken at the time of drug discontinuation and patients with UC were examined to quantify the infiltration of T (CD3+) cells, Th17 (IL17A+) cells and Treg (Foxp3+) cells by immunohistochemistry (IHC). As negative control tissues (CT) for these studies we used colectomy samples from patients with inactive diverticulosis. FACS analysis of peripheral blood mononuclear cells from the CLL patients treated with idelalisib and having extended survival showed significantly higher circulating Th17A levels (P < 0.01) at the time of drug discontinuation compared to pre-treatment levels. In addition, IHC analyses on tissues from a subset of these same patients indicated that the ratio of % IL-17A+ to CD3+ cells was significantly higher in CLL than in CT (P = 0.0002). It was also significantly higher in CLL than UC (P = 0.001), even though the average number of CD3+ cells in UC was higher than in CLL (P = 0.0001). We also determined the ratio of % FoxP3+ to CD3+ cells in the colon tissues of 12 CT, 16 UC and 6 CLL patients from the cohort studied above. This revealed the average percentage of FoxP3+ cells within the total number of infiltrating T cells was significantly higher in CLL than CT (P = To examine the effect of idelalisib on Th17-cell generation, naïve CD4+ CLL T cells from 6 patients (3 M-CLL + 3 U-CLL) were activated in vitro by anti-CD3/28 ligation plus IL-2 in the presence or absence of idelalisib. After 7 days, T helper subset profiling was performed by intracellular cytokine staining. Significantly higher percentages of Th17A cells and significantly lower percentages of Th1 cells (IFNg+) (P= 0.006) were found in cultures containing idelalisib. The percentages of Tregs were unchanged in the same cultures. These findings suggest that the higher numbers of Th17s in blood and tissue of patients after idelalisib treatment may reflect the action of idelalisib on Th17 generation. In conclusion, CLL patients who discontinued idelalisib due to colitis and yet had extended survival have increased circulating and tissue-resident Th17 cells and decreased levels of Treg cells. These findings suggest that an immune imbalance between Th17 and Treg cell numbers and function promotes colitis and at the same time favors improved clinical outcome. This is consistent with the known action of Th17 cells enhancing autoimmune B-cell responses. Disclosures Barrientos: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rai:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees. Chiorazzi:Janssen, Inc: Consultancy; AR Pharma: Equity Ownership.
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- 2018
38. Ibrutinib Treatment Reduces Myeloid Derived Suppressor Cell Numbers and Function in Chronic Lymphocytic Leukemia
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Jacqueline C. Barrientos, Pui Yan Chiu, Gerardo Ferrer, Kanti R. Rai, Florenca Palacios, Jan A. Burger, Barbara Sherry, Jonathan E. Kolitz, Nicholas Chiorazzi, Andrea Nicola Mazzarello, Shih-Shih Chen, Byeongho Jung, Xiao J. Yan, Aslam Rukhsana, and Steven L. Allen
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0301 basic medicine ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,T cell ,Immunology ,B-cell receptor ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Medicine ,business.industry ,FOXP3 ,Cell Biology ,Hematology ,medicine.disease ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Myeloid-derived Suppressor Cell ,Cancer research ,business ,CD8 - Abstract
In chronic lymphocytic leukemia (CLL), bidirectional interactions of leukemic B cells with components of a complex, yet incompletely defined tumor microenvironment (TME) are critical for leukemic cell survival and proliferation. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, blocks signals that are crucial for survival of CLL cells which are delivered by the B cell receptor (BCR) and certain other receptors. However since BTK and its family members are expressed by other cell types, ibrutinib can also affect non-leukemic cells, thereby altering their function. Here, we focused on understanding how myeloid-derived suppressor cells (MDSCs), a non-leukemic cell type within the TME, and their main target, T cells, are affected by ibrutinib therapy. Using blood cells from a set of 20 previously untreated patients receiving ibrutinib, we analyzed circulating MDSCs and their subsets 15 days before and 1, 2 and 3 months after treatment initiation. As anticipated, at the first month time point the absolute CLL B-cell count increased significantly (P=0.024), followed by a progressive reduction at consecutive time points (P We also observed differences in T-cell subpopulations shortly after ibrutinib treatment began. T cell counts increased significantly at the second month compared to pre-treatment (P=0.024); this was the case for both CD4+ and CD8+ cells (P = 0.022 and 0.010, respectively). In addition, CD8+ T cells maintained significance through the third month (P = 0.033). When exploring T cell subsets defined by cytokine production, we observed a spike at the second month of CD4+IL17F+ and of CD8+IL17F+, CD8+IL17A+ and CD8+FoxP3+ T cells. However, by the 3rd month, only the IFNγ-producing subset of CD4+ and CD8+ T cells were significantly higher (P = 0.049 and 0.042, respectively). Next we analyzed the function of gMDSCs and mMDSCs in the presence of ibrutinib in vitro, addressing the two main effects of these cells on T lymphocytes: suppression of T-cell proliferation and modulation of T-cell differentiation. Specifically, ibrutinib did not directly reduce T-cell expansion in the absence of MDSCs and did not alter the effect of CLL gMDSCs nor mMDSCs on T-cell proliferation, since the significant reduction induced by gMDSCs (P=0.047) and the insignificant, variable effect of mMDSCs were unchanged by the drug. However when we analyzed the influence of gMDSCs, mMDSCs and monocytes on naïve CD4+ T-cell differentiation in the presence or absence of ibrutinib, to our surprise the only T cell subpopulation directly compromised by ibrutinib was the Th1/IFNγ-producing subset. This was opposite that observed in co-cultures with gMDSCs, mMDSCs or normal monocytes in the presence of ibrutinib where Th1 cells expanded significantly (P= 0.021, 0.010, and 0.005, respectively). In the latter co-cultures not containing ibrutinib, more IL-4-producing (Th2) cells were found. Additionally, ibrutinib had a positive effect on IL-22+ (Th22) and FoxP3+ (Treg) cell numbers in the presence of MDSCs and monocytes. In summary, opposite to what we observed for CLL B and T cells, MDSC counts fell progressively after initiating ibrutinib therapy, possibly due to a direct effect of ibrutinib on BTK in MDSCs or an indirect effect mediated by diminishing signals from CLL B cells that would normally be delivered after BCR engagement. Ibrutinib did not directly alter the T cell suppressive ability of MDSCs, but it did skew T-cell differentiation to Th1 cells when MDSCs were present, in line with our finding higher Th1 cells in the blood after 3 months of treatment. Thus over time, ibrutinib shifts the CLL TME from an immunosuppressive to a more immune effective one. Disclosures Chen: Beigene: Research Funding; Verastem: Research Funding; Pharmacyclics: Research Funding. Barrientos:Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy. Kolitz:Magellan Health: Consultancy, Honoraria. Rai:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees. Chiorazzi:Janssen, Inc: Consultancy; AR Pharma: Equity Ownership.
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- 2018
39. Musashi 2 Is Overexpressed in Poor Outcome CLL Patients and Their Proliferative Fraction and Silencing This Gene Induces Apoptosis and Increases Cell Adhesion and Movement
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Gerardo Ferrer, Jonathan E. Kolitz, Xiao-Jie Yan, Nicholas Chiorazzi, Jacqueline C. Barrientos, Florencia Palacios, R Rai Kanti, and Steven L. Allen
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Cell type ,Stromal cell ,VAV1 ,Immunology ,Cell ,Cell Biology ,Hematology ,Biology ,Actin cytoskeleton ,Biochemistry ,medicine.anatomical_structure ,medicine ,Cancer research ,CD5 ,Stem cell ,Clone (B-cell biology) - Abstract
The growth of CLL cells stems from a small fraction of dividing CD5+B cells. The size and rate of growth of this proliferative fraction (PF) correlates directly with poor outcome prognostic markers and inversely with time-to-first-treatment. Furthermore, since dividing cells upregulate DNA mutators (AID and APOBEC), the PF can acquire new DNA abnormalities that can lead to more lethal disease. Hence, cells of the PF are important targets for therapy. By gene expression profile analysis, we found that Musashi 2 (MSI2) is highly expressed in the PF (CXCR4DimCD5Bright) compared with the resting fraction (RF) that expresses the reciprocal phenotype (CXCR4BrightCD5Dim). In normal cells, MSI2 binds to mRNA and blocks or enhances protein translation. MSI2 levels are higher in proliferating normal and malignant stem cells and during tumorigenesis. In CLL, high MSI2 mRNA levels associate with poor outcome. Nevertheless, nothing is known about the function of MSI2 in CLL cells. Therefore, we studied the biological role of MSI2 in CLL B cells. We found that CLL B cells express higher levels of MSI2 protein than those of healthy donors (HD). MSI2 levels were higher in U-CLL than M-CLL, and M-CLL B cells expressed more than HD cells, consistent with MSI2 associating with poor prognosis. Within a CLL clone, MSI2 was higher in PF than RF. Also, microenvironment signals that induce B cell proliferation also increased MSI2 protein levels. Consistent with these observations in patients, in vitro experiments showed that dividing cells contain more MSI2 protein than undivided cells. Next, we investigated the importance of MSI2 on CLL survival. In primary CLL cells, we knocked down MSI2 levels using MSI2 siRNA and co-cultured CLL cells with stromal cells (HS5) or stimulated them with CpG ODN + IL15, with or without HS5 cells. In the three conditions tested, knock-down of MSI2 resulted in a significant decrease in tumor-cell survival compared with the control (P = 0.0342, 0.0079, and 0.0274, respectively). In addition, down regulation of MSI2 led to an upregulation of cleaved caspase3 (1.3 fold change;P= 0.029), p27kip1 (1.10 fold change; P= 0.0026) and phospho p53 (1.16 fold change; P= 0.017) compared with siRNA control (siCTR). Collectively, the results highlight the importance of MSI2 in primary CLL-cell survival and suggest that these are mediated by caspase 3, p27kip1 and p53 signaling pathways. Reported comparisons of the RNAs that MSI2 binds in different cell types suggest that MSI2 regulates both common and unique mRNA targets in a cell type-specific manner. Hence to study the role of MSI2 in CLL, we analyzed the proteomes of MSI2 knockdown B cells from 12 CLL patients and controls. This showed that MSI2 knock down significantly increased the levels of 12 proteins (P ≤ 0.01 and fold change ≤ -1.2 ≥ 1.2). Since Ingenuity Pathway Analysis of these proteins suggested an increase cellular movement, we confirmed protein levels by flow cytometry of proteins involved in migration: Fer (non-tyrosine-protein kinase receptor), VAV1 (guanine nucleotide exchange factors) and its active form (phosphorY174 VAV, pVAV). Since Fer and VAV1 play a role in actin cytoskeleton regulation, we next knocked down MSI2 in B cells from the same 12 CLL patients and evaluated by microscopy cytoskeleton rearrangement of cells bound to fibronectin-coated slides. We used an established method to classify round cells as having a non-modified cytoskeleton and elongated cells as having undergone cytoskeleton rearrangement. Also, we counted the number of cells with an accumulation of polarized actin and others with multiple protrusions. MSI2 downregulation increased the number of elongated, polarized and cells with multi protrusions. Thus, MSI2 levels are higher in B cells from poor outcome patients and also in the dividing/divided cells of the PF before and after stimulation. Also, MSI's downregulation induces apoptosis of CLL cells and increases adhesion and migration. Therefore, we propose that MSI2 is a valuable target for therapeutic intervention since inhibiting its functions will likely abort clonal evolution and disease progression, making CLL an even more chronic and manageable condition. Disclosures Barrientos: Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kolitz:Magellan Health: Consultancy, Honoraria. Chiorazzi:Janssen, Inc: Consultancy; AR Pharma: Equity Ownership.
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- 2018
40. Chronic Lymphocytic Leukemia Treatment Patterns, Dosing, and Sequencing in the Era of Novel Targeted Therapies: Interim Analysis Results from the Prospective informCLLTM Real-World Registry
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David Ipe, Anthony R. Mato, Lucille Ferrante, Jeff P. Sharman, Murali Sundaram, Brian Tomlinson, Nick Giafis, Reethi Iyengar, Karen Kadish, Carlos I. Amaya-Chanaga, Sandhya Upasani, Danielle M. Brander, Meghan Gutierrez, Jacqueline C. Barrientos, Nilanjan Ghosh, and John M. Pagel
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Oncology ,medicine.medical_specialty ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Interim analysis ,Biochemistry ,Internal medicine ,medicine ,Dosing ,business - Abstract
Background : Chronic lymphocytic leukemia (CLL) treatment (tx) has changed dramatically with the emergence of novel targeted therapies, and real-world data from observational studies continue to improve our understanding of tx patterns/outcomes. Beginning enrollment Oct 2015, informCLL (NCT02582879) began as a US, multicenter, prospective, observational real-world registry of patients (pts) with CLL who received CLL tx. From registry data, we describe demographic and clinical characteristics of pts with CLL, as well as tx patterns, dosing, and sequencing in clinical practice. Methods : In the informCLL registry, 96% of recruiting sites across the US were community hematology-oncology sites. For this planned interim analysis (data cut: Feb 2018), txs were classified into 5 groups based on first tx at enrollment: chemoimmunotherapy (CIT), chemotherapy (CT), immunotherapy (IT), ibrutinib (ibr), and other novel agents. Eligible pts had to be ≥18 years (y), initiate tx of approved anti-CLL therapy within 30 days of enrollment, and provide consent. Categorical variables were summarized as frequency counts and percentages. Continuous variables were summarized as median, range, mean, and standard deviation. Results : 840 pts (previously untreated, n=459; relapsed or refractory [R/R], n=381) were enrolled. Median age was 70y (previously untreated=69y; R/R=71y). Most pts were male (64%), Caucasian (92%), and presented with ECOG PS 0/1 (previously untreated: 88%; R/R: 86%) (Table 1). 45% of previously untreated and 57% of R/R pts presented with Rai stage III/IV. Hypertension and type 2 diabetes were the most common comorbidities. At enrollment, the 3 most common txs were ibr (44%), CIT (34%), and IT (15%). In previously untreated pts, CIT was the most common tx (overall=42%; bendamustine+rituximab [BR]=20%, fludarabine+cyclophosphamide+rituximab [FCR]=10%, obinutuzumab+chlorambucil [GC]=9%) and single-agent ibr was the most common novel agent (38%). In R/R pts, single-agent ibr was the most common tx (48%). In pts Conclusions : The most common agent used across all lines of tx was ibr. Most ibr-treated pts started at the FDA-recommended once-daily dose of 420 mg, with few dose interruptions/reductions. Most pts who received BR, FCR, or GC did not receive 6C of tx. Of pts who initiated subsequent tx, ibr was commonly used in pts who received IT, CIT, or CT. Few pts who received ibr switched to subsequent therapy. Continued follow up will further inform tx practices and enhance our understanding of CLL tx in the real-world setting. Disclosures Sharman: Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Acerta: Consultancy, Research Funding. Barrientos:Janssen: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding. Brander:Teva: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding. Pagel:Gilead: Consultancy; Pharmacyclics, an AbbVie Company: Consultancy. Kadish:Janssen: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Pharmacyclics, an AbbVie Company: Speakers Bureau. Ghosh:Celgene: Consultancy; PCYC: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; F. Hoffman-La Roche Ltd: Research Funding; Pharmacyclics, an Abbvie Company: Consultancy, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Honoraria, Research Funding; Spectrum: Consultancy; Forty seven Inc: Research Funding; SGN: Consultancy, Research Funding, Speakers Bureau; Juno: Consultancy, Research Funding. Giafis:Pharmacyclics, an AbbVie Company: Employment, Other: Travel; AbbVie: Equity Ownership. Ipe:AbbVie: Equity Ownership; Pharmacyclics, an AbbVie Company: Employment, Other: Travel. Upasani:AbbVie (self and immediate family member): Equity Ownership; Pharmacyclics, an AbbVie Company (self and immediate family member): Employment. Sundaram:AbbVie: Employment, Equity Ownership, Other: Travel; Johnson & Johnson: Employment, Equity Ownership, Other: Travel. Ferrante:Janssen: Employment, Equity Ownership. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Iyengar:AbbVie: Equity Ownership; Pharmacyclics, an AbbVie company: Employment; Express Scripts: Patents & Royalties. Mato:Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AstraZeneca: Consultancy; Portola: Research Funding; Johnson & Johnson: Consultancy; Acerta: Research Funding; AbbVie: Consultancy, Research Funding; Prime Oncology: Honoraria; Celgene: Consultancy; Regeneron: Research Funding; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding.
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- 2018
41. IGHV-unmutated and IGHV-mutated chronic lymphocytic leukemia cells produce activation-induced deaminase protein with a full range of biologic functions
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Jonathan E. Kolitz, Matthew D. Scharff, Patricia K. A. Mongini, Thomas MacCarthy, Lu Zhang, Kanti R. Rai, Rajendra N. Damle, Sergio Roa, Amanda R. Magli, Steven L. Allen, Piers E.M. Patten, Charles C. Chu, Emilia Albesiano, Xiao-Jie Yan, Dorothy Kim, Jacqueline C. Barrientos, and Nicholas Chiorazzi
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Chronic lymphocytic leukemia ,Molecular Sequence Data ,Immunology ,Immunoglobulin Variable Region ,Kaplan-Meier Estimate ,medicine.disease_cause ,Biochemistry ,Somatic evolution in cancer ,Gene Expression Regulation, Enzymologic ,immune system diseases ,Cytidine Deaminase ,Sequence Homology, Nucleic Acid ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,medicine ,Activation-induced (cytidine) deaminase ,Humans ,DNA Breaks, Double-Stranded ,RNA, Messenger ,neoplasms ,Cells, Cultured ,Mutation ,Microscopy, Confocal ,Lymphoid Neoplasia ,Base Sequence ,biology ,Gene Expression Regulation, Leukemic ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Biology ,Hematology ,Cytidine deaminase ,Flow Cytometry ,medicine.disease ,Immunoglobulin Class Switching ,Leukemia, Lymphocytic, Chronic, B-Cell ,Molecular biology ,Leukemia ,Microscopy, Fluorescence ,Immunoglobulin class switching ,Leukocytes, Mononuclear ,biology.protein ,Immunoglobulin Heavy Chains ,IGHV@ ,Cell Division - Abstract
Clonal evolution occurs during the course of chronic lymphocytic leukemia (CLL) and activation-induced deaminase (AID) could influence this process. However, this possibility has been questioned in CLL because the number of circulating AID mRNA+ cells is exceedingly low; synthesis of AID protein by blood CLL cells has not been demonstrated; the full range of AID functions is lacking in unmutated CLL (U-CLL), and no prospective analysis linking AID expression and disease severity has been reported. The results of the present study show that circulating CLL cells and those within secondary lymphoid tissues can make AID mRNA and protein. This production is related to cell division because more AID mRNA was detected in recently divided cells and AID protein was limited to the dividing fraction and was up-regulated on induction of cell division. AID protein was functional because AID+ dividing cells exhibited more double-stranded DNA breaks, IGH class switching, and new IGHV-D-J mutations. Each of these actions was documented in U-CLL and mutated CLL (M-CLL). Furthermore, AID protein was associated with worse patient outcome and adverse cytogenetics. We conclude that the production of fully functional AID protein by U-CLL and M-CLL cells could be involved in clonal evolution of the disease.
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- 2012
42. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results
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Michael E. Williams, Stephen E. Spurgeon, Ewa Chmielowska, Michael L. Wang, Dana Lee, John Radford, Darrin M. Beaupre, Andre Goy, Jorge E. Romaguera, Liang Zhang, Kristie A. Blum, Peter Johnson, Linda Baher, Martin Dreyling, Simon Rule, Jacqueline C. Barrientos, Peter Martin, Stephan Stilgenbauer, Wiesław Wiktor Jędrzejczak, Brad S. Kahl, Mei Cheng, Rebecca Auer, Ranjana H. Advani, and Wojciech Jurczak
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Adult ,Diarrhea ,Male ,medicine.medical_specialty ,Neutropenia ,Nausea ,Anemia ,Clinical Trials and Observations ,Immunology ,Administration, Oral ,Antineoplastic Agents ,Lymphoma, Mantle-Cell ,Biochemistry ,Gastroenterology ,Drug Administration Schedule ,chemistry.chemical_compound ,Recurrence ,Internal medicine ,Clinical endpoint ,Agammaglobulinaemia Tyrosine Kinase ,Medicine ,Humans ,Adverse effect ,Protein Kinase Inhibitors ,Survival analysis ,Fatigue ,Aged ,Aged, 80 and over ,business.industry ,Cell Biology ,Hematology ,Middle Aged ,Protein-Tyrosine Kinases ,medicine.disease ,Survival Analysis ,Thrombocytopenia ,Surgery ,Dyspnea ,Treatment Outcome ,chemistry ,Ibrutinib ,Mantle cell lymphoma ,Female ,medicine.symptom ,business ,Follow-Up Studies - Abstract
Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Patients (N = 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was 8.3 months; 46% of patients were treated for >12 months, and 22% were treated for ≥2 years. The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. The 24-month progression-free survival and overall survival rates were 31% (95% confidence interval [CI], 22.3-40.4) and 47% (95% CI, 37.1-56.9), respectively. The most common adverse events (AEs) in >30% of patients included diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). The most frequent grade ≥3 infections included pneumonia (8%), urinary tract infection (4%), and cellulitis (3%). Grade ≥3 bleeding events in ≥2% of patients were hematuria (2%) and subdural hematoma (2%). Common all-grade hematologic AEs were thrombocytopenia (22%), neutropenia (19%), and anemia (18%). The prevalence of infection, diarrhea, and bleeding was highest for the first 6 months of therapy and less thereafter. With longer follow-up, ibrutinib continues to demonstrate durable responses and favorable safety in relapsed/refractory MCL. The trial is registered to www.ClinicalTrials.gov as #NCT01236391.
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- 2015
43. 11q Deletion (del11q) Is Not a Prognostic Factor for Adverse Outcomes for Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with Ibrutinib: Pooled Data from 3 Randomized Phase 3 Studies
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Graeme Fraser, Paul M. Barr, Charles Phelps, Asher Chanan-Khan, Mariya Salman, Stephan Stilgenbauer, Joi Ninomoto, Ann Janssens, Angela Howes, Sebastian Grosicki, Mei Cheng, Steven Coutre, Fatih Demirkan, Michael Hallek, Susan O'Brien, Thomas J. Kipps, Paula Cramer, Ulrich Jaeger, Danelle F. James, Peter Hillmen, Jacqueline C. Barrientos, John C. Byrd, and Isabelle G. Solman
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Prognostic factor ,medicine.medical_specialty ,business.industry ,Adverse outcomes ,Bulky Disease ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Lymphocytic lymphoma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Baseline characteristics ,Family medicine ,Ibrutinib ,medicine ,Pooled data ,business ,Complete response ,030215 immunology - Abstract
Background: Patients (pts) with CLL/SLL that have del11q tend to have relatively short remission durations and shorter overall survival (OS) with standard chemotherapy regimens. Ibrutinib (ibr), a first-in-class, oral, once-daily inhibitor of Bruton's tyrosine kinase (BTK) is indicated by the US FDA for the treatment of pts with CLL/SLL and allows for treatment without chemotherapy. In phase 3 studies, treatment with single-agent ibr was superior to treatment with ofatumumab (ofa) in relapsed/refractory (R/R) CLL/SLL (RESONATE; Byrd, N Engl J Med 2013) or chlorambucil (clb) in treatment-naïve (TN) CLL/SLL (RESONATE-2; Burger, N Engl J Med 2015); treatment with ibr + bendamustine/rituximab (BR) was also superior to treatment with BR in R/R CLL/SLL (HELIOS; Chanan-Khan, Lancet Oncol 2016). We examined the outcome of pts in these 3 studies who did or did not have del11q to determine the impact of del11q on clinical outcomes. Methods: In RESONATE, pts with R/R CLL/SLL received ibr 420 mg/day until progressive disease (PD) or unacceptable toxicity (tox) vs ofa for up to 24 weeks (300 mg week 1, 2000 mg weekly for 7 weeks, 2000 mg every 4 weeks for 16 weeks). In RESONATE-2, pts ≥65 years of age with TN CLL/SLL (excluding del17p) received ibr 420 mg/day until PD or tox vs clb 0.5 mg/kg (up to max of 0.8 mg/kg) on days 1 and 15 of each 28-day cycle (≤12 cycles). In HELIOS, pts with R/R CLL/SLL (excluding del17p) received BR (≤6 cycles) with or without ibr 420 mg/day (starting on day 2 of cycle 1) followed by single-agent ibr or placebo continued until PD or tox. Data from pts in the 3 studies were pooled (ibr pool, comparator pool) and analyzed based on whether or not their CLL/SLL had del11q. We performed a multivariate analysis to examine for risk factors prognostic for survival (del11q del17p, age, sex, race, current Rai stage, baseline ECOG PS, number of prior therapies, cytopenias; no multiplicity adjustment). Results: A total of 1210 pts with del11q data were included in the analysis: 609 in the ibr pool (179 with del11q, 430 without del11q) vs 601 in the comparator pool (149 with del11q, 452 without del11q). Demographics and baseline characteristics were generally similar in pts regardless of del11q status; differences of more than 10% included proportions with bulky disease ≥5 cm (63% vs 49%) and unmutated IGHV (88% vs 72%) in pts with or without del11q, respectively. Median lymphadenopathy and absolute lymphocyte counts were also higher in pts with del11q. At the time of the primary analysis, median treatment durations in the ibr pool were 20.0 mo with del11q and 18.7 mo without del11q; in the comparator pool 5.3 mo with del11q and 8.5 mo without del11q. Overall, ibr-treated pts had higher overall response rate (ORR) and complete response (CR) rates and longer progression-free survival (PFS, Figure) and OS than comparator-treated pts regardless of del11q status. In the ibr pool, the presence of del11q was associated with a trend of longer PFS and OS while in the comparator pool, pts with del11q had shorter PFS (Figure, Table), as compared to pts without del11q. Results were similar when excluding pts with del17p (10% of ibr pool [6%/11% with/without del11q] and 9% of comparator pool [8%/10% with/without del11q]; Table). By multivariate analysis, in the comparator pool, del11q, male sex, >1 prior therapy, presence of cytopenias, and unmutated IGHV (in R/R only) were associated with shorter PFS. However, these differences were not found in the ibr pool. The presence of del11q did not unfavorably impact the tempo of reductions in lymphadenopathy for ibr-treated pts, but did for comparator-treated pts. Adverse events leading to discontinuation were similar in ibr- and comparator-treated pts (12% [9% vs 13% with/without del11q] vs 13% [12% vs 13% with/without del11q]). Deaths within 30 days of last dose occurred in 31 pts (5% [3% vs 6% with/without del11q]) in the ibr pool and 28 pts (5% [6% vs 4% with/without del11q]) in the comparator pool. Conclusions: Treatment with ibr was superior to comparator regardless of del11q status; the benefit of ibr was most marked for pts with CLL/SLL with del11q. Presence of del11q was associated with a trend of longer PFS and OS in ibr-treated pts and shorter PFS and lower ORR in comparator-treated pts. By multivariate analysis, presence of del11q was a prognostic factor for shorter PFS for comparator-treated pts, but not for ibr-treated pts. Disclosures Kipps: Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Demirkan:Amgen: Consultancy. Coutre:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding. Barrientos:Gilead: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy, Research Funding. Barr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Fraser:Celgene: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau. Jaeger:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Cramer:Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Mundipharma: Other: Travel, Accommodations, Expenses; Astellas: Other: Travel, Accommodations, Expenses; Roche: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Other: Travel, Accommodations, Expenses, Research Funding. Stilgenbauer:Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding. Salman:Janssen Research & Development: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Solman:Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses; AbbVie: Equity Ownership. Cheng:Johnson & Johnson: Equity Ownership; AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Phelps:Johnson & Johnson: Employment, Equity Ownership. Ninomoto:Pharmacyclics LLC, an AbbVie Company: Employment; Amgen, Inc.: Equity Ownership; AbbVie: Equity Ownership. Howes:Janssen: Employment, Other: Leadership; Johnson & Johnson: Equity Ownership. James:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Hallek:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau.
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- 2016
44. Outcomes of Ibrutinib Therapy By Age in Patients with CLL/SLL: Analyses from Phase 3 Trial Data (RESONATE and RESONATE-2)
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John C. Byrd, Danelle F. James, Peter Hillmen, Steven Coutre, Cathy Zhou, Paul M. Barr, Jacqueline C. Barrientos, Joi Ninomoto, Susan O'Brien, Jennifer A. Woyach, Nishitha Reddy, Alessandra Tedeschi, Stephen Devereux, Neil E. Kay, Jennifer R. Brown, Jan A. Burger, and Stephen P. Mulligan
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Upper respiratory infections ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Small cell lymphoma ,Lymphocytic lymphoma ,Management ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Medicine ,In patient ,Once daily ,business ,030215 immunology - Abstract
Background: Chronic lymphocytic leukemia (CLL) is primarily a disease of the elderly, with the majority of patients (pts) older than 65 y at diagnosis (US SEER). Historically, younger, more fit pts were eligible for aggressive chemoimmunotherapy treatments, but older age and comorbid conditions can limit options due to tolerability concerns. Ibrutinib (ibr), a first-in-class, oral, once-daily inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA for the treatment of pts with CLL/small lymphocytic lymphoma (SLL) and allows for treatment without chemotherapy. Results from the phase 3 RESONATE (PCYC-1112) and RESONATE-2 (PCYC-1115) trials established ibr as a standard option in relapsed/refractory (R/R) and treatment-naïve (TN) CLL/SLL. This analysis examines safety and efficacy from these studies by age. Methods: RESONATE randomized 391 pts with R/R CLL/SLL to receive ibr (n=195; 420 mg once daily) until progressive disease (PD) or unacceptable toxicity or intravenous ofatumumab (n=196; 300 mg at week 1, 2000 mg weekly for 7 w and then every 4 w for 16 w). RESONATE-2 randomized TN pts aged ≥65 y to receive ibr (n=136; 420 mg once daily) until PD or chlorambucil (clb; n=133; 0.5 mg/kg to a maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Pt data from both studies were grouped by age (ibr and comparators [comp]) and analyzed for effect of age on outcome. Results: Ibr group included 136 TN pts: 65 to Conclusions: The PFS rate for TN ibr pts was similar regardless of age subgroup, whereas it was shorter for clb-treated pts ≥75 y compared with those 65 to Disclosures Woyach: Karyopharm: Research Funding; Morphosys: Research Funding; Acerta: Research Funding. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Brown:Pfizer: Consultancy, Honoraria, Other: travel, accommodations, expenses; Genentech: Consultancy, Honoraria; Roche: Honoraria; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Sun Biopharma: Honoraria, Other: travel, accommodations, or other expenses. Coutre:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding. Barr:AbbVie: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Devereux:Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy; Roche: Consultancy, Other: Travel, Accommodations, Expenses ; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Reddy:KITE: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees; INFINITY: Membership on an entity's Board of Directors or advisory committees. Mulligan:GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Zhou:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Ninomoto:AbbVie: Equity Ownership; Amgen: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. James:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Portola: Consultancy; Gilead: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Roche: Other: Travel, Accommodations, Expenses.
- Published
- 2016
45. Comparative Density Analyses of B Cell Receptor-Complex Components (Membrane IgM, Membrane IgD, and Stimulatory/Inhibitory Co-Receptors) on Intraclonal Subpopulations of CLL B Cells, before and during Ibrutinib Therapy
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Yun Liu, Stefano Vergani, Shih-Shih Chen, Sophia Yancopoulos, Kanti R. Rai, Gerardo Ferrer, Xiao-Jie Yan, Nicholas Chiorazzi, Jacqueline C. Barrientos, and Andrea Nicola Mazzarello
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biology ,Chemistry ,Immunology ,CD22 ,hemic and immune systems ,Cell Biology ,Hematology ,CD38 ,Biochemistry ,Molecular biology ,Immunoglobulin D ,CD19 ,chemistry.chemical_compound ,immune system diseases ,Immunoglobulin M ,hemic and lymphatic diseases ,Ibrutinib ,biology.protein ,IL-2 receptor ,CD5 - Abstract
B cell receptor signaling is a key factor in chronic lymphocytic leukemia (CLL), evinced by inhibitory drug ibrutinib's efficacy. Studies of normal and CLL B cells indicate surface membrane IgM or IgD engagement has diverse signaling consequences. But little is known about relative amounts of sIg/co-receptor components within intraclonal fractions and how their compositions affect signaling. We studied relative densities of IgM and IgD and Ig-associated stimulatory and inhibitory co-receptors in two subsets based on: [1] relative densities of IgM and IgD and [2] reciprocal expression of CXCR4/CD5 indicating activation state. Samples from 5 U and 5 M-CLL patients, pre and during (4-6 weeks) ibrutinib treatment, were tested by conventional and by imaging flow cytometry using an ISX Mark II providing multiple spectral images of individual cells in a flow setting. After subfractionating clones for IgM (IgMDim, IgMInt, IgMBright) or IgD (IgDDim, IgDInt, IgDBright) densities, we quantified relative densities of stimulatory/inhibitory molecules on the subsets. A directly proportional change was observed for CD5, CD19, CD20, Siglec10, CD25, HLA-DR, and CD38 as IgM moved from Dim to Bright. Exceptions were CXCR4, which dramatically decreased as IgM density increased, and CD22, that had a constant density in all fractions. Similar changes were seen for IgD except for CD22 which increased in IgDBright density. Again CXCR4 showed the opposite pattern. CD25 and HLADR remained constant within IgD increments. Stimulatory markers CD25 and HLADR changed upward only in the transition to IgMBright. Together these imply signaling through IgM heightens as IgM density increases, but does not through IgD, likely due to increased Siglec 10 and CD22. The reduced amounts of smCXCR4 suggest impaired ability of cells with high smIgM or smIgD to traffic. We examined subpopulations based on CXCR4 and CD5. IgD and IgM densities increased from resting (RF) CXCR4Bright/CD5Dim to intermediate (INT) CXCR4Int/CD5Int to proliferative (PF) CXCR4Dim/CD5Bright fractions, although the degree of upregulation was more marked for IgD than IgM. All stimulatory/inhibitory coreceptors also increased in density from RF to PF. Interestingly, CD22 and IgD retained a constantdensity from RF to INT but increased considerably at the PF. Although stimulatory molecules CD25, CD38 and HLADR had upward trends, peaking occurred in the PF. Collectively, this implies signaling capacity through smIgM amplifies toward the PF due to higher smIgM density and IgD upregulation. Finally, we evaluated CLL clones as a whole as well as based on the subsets above for ibrutinib treatment induced changes. Clonally, a density decrement occurred for smIgD and an increment for smIgM. Data for the other molecules fell into 3 categories based on relative density changes: Decreasing: CD5, CD20, CD38, CD25, HLA-DR; Increasing: CXCR4: Invariant: CD22, CD19, Siglec10. For subfractionating based on smIgs density, ibrutinib drastically reduced density differences for co-receptors and activation markers among IgM or IgD density subpopulations with IgMBright and IgDBright fractions more affected than the Dim and Intermediate density counterparts. Similarly for the CXCR4/CD5 subpopulations, lower differences in relative expression of coreceptors from RF to PF were found. As for IgM and IgD levels, the PF was the most reduced. The composite effect was a reduced slope of change among the original sets of density change categories (IgMDim -> IgMBright; IgDDim -> IgDBright; RF to PF), leading to more phenotypically homogenous subpopulations. In summary, prior to ibrutinib therapy, both the Ig and most of the associated molecules increase density in subsets marked by increased IgM and IgD densities and marked by decreasing CXCR4/CD5 densities. However, there was a major difference in density correlations for CXCR4 and CD22. CXCR4, levels were lowest on IgMBright and IgDBright cells which differs from published data using anti-IgM beads. For CD22 the highest levels were in IgDBright but not in IgMBright and in CXCR4/CD5 subset with the highest IgD and IgM (CXCR4Dim/CD5Bright). In contrast, ibrutinib treatment led to an overall change in coreceptor molecules altering considerably the density relationships with IgM and IgD. Concomitantly, these culminate in a downregulatory membrane stimulatory environment. Disclosures No relevant conflicts of interest to declare.
- Published
- 2016
46. The RNA-Binding Protein Musashi 2 Is Upregulated in the Proliferative Fraction of CLL Clones, Particularly in U-CLL Patients, and Its Silencing Induces Programmed Cell Death
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Jonathan E. Kolitz, Xiao J. Yan, Kanti R. Rai, Jacqueline C. Barrientos, Nicholas Chiorazzi, Florencia Palacios, and Steven L. Allen
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0301 basic medicine ,CD40 ,biology ,Cell growth ,Immunology ,Cell Biology ,Hematology ,CD38 ,Cell cycle ,Biochemistry ,CD19 ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,immune system diseases ,hemic and lymphatic diseases ,biology.protein ,Cancer research ,CD5 ,Stem cell ,Interleukin 4 - Abstract
CLL develops from a small fraction of dividing monoclonal CD5+ B cells. The size and rate of growth of this proliferative fraction (PF) correlates inversely with time-to-first-treatment and directly with poor outcome prognostic markers. Furthermore, since the dividing cells upregulate DNA mutators such as AID and APOBEC family members, the PF has a greater propensity for acquiring new DNA abnormalities that can lead to more lethal disease. Hence, cells of the PF are important targets for therapy for patients with worst outcome category. The PF (CXCR4DimCD5Bright) differs by more than 1000 genes from the resting fraction (RF, CXCR4Bright CD5Dim); these genes relate to replication, migration, and regulation of gene expression. Some of these genes are also preferentially expressed in the PF of U-CLL cases. One such gene is Musashi 2 (MSI2). MSI2 regulates gene expression by binding consensus sequences of mRNA and blocking protein translation. High MSI2 expression is involved in proliferation of normal and malignant stem cells, tumorigenesis, and poor outcome. In CLL, high MSI2 mRNA expression has been identified in patients with worse prognosis. Nevertheless, nothing is known about the function of MSI2 in CLL cells. Therefore, we report studies of the biological role of MSI2 in B-CLL cells and its possible association with B-cell proliferation and CLL disease progression. First, we evaluated MSI2 protein levels by flow cytometry in CD19+CD5- and CD19+CD5+ cells from healthy donors (HDs; n=25) and in CD19+CD5+ from CLL patients (n=55). Higher MSI2 expression was observed in CLL than HD B cells, whereas no differences were found in CD19+CD5+ and CD19+CD5- cells from HDs. Also, MSI2 protein levels were higher in U-CLL than M-CLL, and M-CLL B cells express more MSI2 than HDs. Finally, MSI2 protein levels correlated with CD38, a CLL poor prognosis marker, suggesting MSI2 associates with poor prognosis in CLL. Within the leukemic clone, we observed 25% more MSI2 in the PF than the Int (defined as CXCR4intCD5int) and 15% more in the Int than the RF (PF>Int >RF). The PF contains 40% more MSI2 than the RF, suggesting the highest amounts of MSI2 protein are in dividing and recently-divided cells. Since CLL B cell proliferation occurs in the microenvironment of lymphoid organs, presumably delivered by external signals, we tested whether such signals could stimulate MSI2 expression. Results indicate that CD40L+IL4 and Toll-like 9 stimulation plus IL15 (TLR9+IL5) increase MSI2 synthesis in vitro 1.4 and 1.8 fold, respectively. The increases are associated with the appearance of phospho ERK and AKT. Also, inhibition of AKT signaling by a PI3K inhibitor decreases MSI2 levels, suggesting AKT is involved in MSI2 synthesis. In this regard, signals from the microenvironment inducing cell growth and proliferation promote MSI2 synthesis in B cells from CLL patients. In addition, cells entering the cell cycle (Ki-67+ cells, those incorporating the thymidine analogue EdU, and cells in S, G2 and M cell cycle phases) express higher MSI2 levels than quiescent cells. Furthermore, dividing cells contain higher MSI2 levels than non-dividing cells as determined by CFSE dilution. These results suggest that cells entering the cell cycle or recently dividing have greater MSI2 expression. Since high MSI2 levels associate with cell proliferation and its inhibition is said to promote apoptosis, we studied the effect of MSI2 downregulation in the CLL MEC1 cell line to determine if MSI2 is a potential therapeutic target for CLL. Our findings show that siRNAs decrease MSI2 mRNA (80%) and protein (40%) levels compared to negative controls. Downregulation of MSI2 in MEC1 led to cleaved caspase 3, TRAIL R1 and R2, FADD, TNFR1, P21, P27, phosho-p53, and decreased levels of inhibitors of apoptosis such as cIAP2 and survivin. Hence these data suggest downregulation of MSI2 in CLL cells could induce apoptosis. Thus, MSI2 levels are higher in B cells from poor outcome patients and also in the dividing/divided cells of the PF before and after stimulation. Also, MSI's downregulation induces apoptosis of CLL cell line. Therefore, we propose that MSI2 is a valuable target for therapeutic intervention. Inhibiting its function and its role in cell proliferation will likely abort clonal evolution and disease progression, and make CLL an even more chronic and manageable condition. Disclosures No relevant conflicts of interest to declare.
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- 2016
47. In Vivo Evidence of in Situ Cell Death Preferentially Occurring in CLL Patients with Minimal Lymphocytosis By the Diminished BCL2 and Loss of T Cell Support after Ibrutinib Treatment
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Yasmine Kieso, Steven Ham, Kanti R. Rai, Shih-Shih Chen, Jacqueline C. Barrientos, Emily Kate Butera, Priyadarshini Ravichandran, Romi Lyallpuri, Jan A. Burger, Nicholas Chiorazzi, and Ileana D'Aloisio
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Lymphocytosis ,Venetoclax ,business.industry ,T cell ,Chronic lymphocytic leukemia ,Immunology ,T cell chemotaxis ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,immune system diseases ,hemic and lymphatic diseases ,Ibrutinib ,medicine ,Monoclonal B-cell lymphocytosis ,medicine.symptom ,business ,B cell - Abstract
Chronic lymphocytic leukemia (CLL) patients receiving the BTK inhibitor ibrutinib develop lymphocytosis. Prolonged lymphocytosis is associated with good prognosis in both treatment-naïve (TN) and relapsed/refractory (R/R) patients, although in general R/R cases have higher lymphocytosis peaks. Because the degree and duration of the elevations vary between patients, lymphocytosis is likely not caused solely by release of cells from tissue niches. Mathematical modeling suggests less profound lymphocytosis of shorter duration is due to loss of tissue resident cells in situ. To address contributions of local elimination and egress to the periphery, we performed phenotypic and functional analyses of cell migration, survival/growth and interactions of CLL B and T cells, and correlated these results with ibrutinib induced T and B cell lymphocytoses. Studies of CLL B cell lymphocytosis were performed with TN (17 U- and 11 M-CLL) and R/R (5 U-CLL) cases receiving single-agent ibrutinib therapy. Faster resolution of lymphocytosis was seen in TN U-CLL than in M-CLL cases (P = 0.008). Conversely, all 5 R/R U-CLL patients exhibited considerably longer lymphocytosis upon ibrutinib use (median time to normalization in TN vs R/R U-CLL: 17 vs 77 days, P = 0.01). Nevertheless, after treatment, all cases showed reduced surface levels of chemokine receptors (CXCR5, CXCR7, CCR7), integrins (CD11a, CD49d) and elevated numbers of CXCR4 molecules that were non-functional based on impaired receptor signaling and recycling/internalization. Also, CLL B cells collected after 2 cycles of ibrutinib treatment exhibited impaired chemotaxis to lymphoid tissues in alymphoid NSG mice. However, none of these changes differed between CLL cases with minimal or prolonged lymphocytosis. We next investigated ibrutinib induced changes in tissue resident cells in a xenograft mouse model. Activated autologous T cells and PBMC prepared from TN (2 U- and 3 M-CLL) and R/R (1 U-CLL) patients were injected into NSG mice. 14 days later, mice were given ibrutinib daily for 2 weeks. Ibrutinib significantly inhibited CLL B cell growth in spleens in all 5 TN cases but to a much greater extent in U-CLL than M-CLL (P = 0.01). The R/R case also had reduced CLL B cell numbers in spleens after treatment, but this was not statistically significant. Molecules controlling CLL B cell survival were then examined in 15 TN and 5 R/R cases. Ibrutinib reduced BCL2 protein levels in TN patients with minimal lymphocytosis but not those with prolonged lymphocytosis (P < 0.001) or R/R patients (P = 0.017). These data suggest those tissue resident cells that are lost after ibrutinib therapy have reduced BCL2 protein levels. In CLL T cells, ibrutinib targets ITK, an enzyme involved in T cell migration and function. Indeed, we found ibrutinib induced T cell lymphocytosis in the same cohort of patients described above. Shorter T cell lymphocytosis was seen in TN U- but not M-CLL or R/R cases (19.6±4 vs 44.3±13, P = 0.04). Ibrutinib blocked T cell chemotaxis in all the cases, but only significantly inhibited T cell growth of TN U-CLL cases in the same xenograft studies. The loss of T cells correlates with the greater inhibition of CLL B cells observed in TN U-CLL rather than in M-CLL cases. Supporting this finding, patients with minimal B cell lymphocytosis also had rapid resolution of T cell lymphocytosis. These data indicate ibrutinib blocked T cell growth in situ, especially in TN U-CLL patients. The loss of T cells further enhances CLL B cell death in tissues after ibrutinib treatment as autologous T cells can protect U-CLL cells from apoptosis by upregulating BCL2. Collectively, our findings suggest that although ibrutinib promotes T and B cell egress in almost all the CLL cases, patients with prolonged lymphocytosis after ibrutinib treatment have better cell survival in situ even after loss of tumor microenvironment contact. In situ cell death after ibrutinib treatment preferentially occurs in TN U-CLL but not in TN M-CLL and R/R cases, in part due to loss of BCL2 and of the support from non-neoplastic immune cells like T cells, documenting that these beneficial actions of ibrutinib are intimately involved in the numbers of lymphocytes that circulate after drug administration. Finally, our data are consistent with the previous report that ibrutinib increases leukemic cell sensitivity to venetoclax, providing a strong rationale for combination therapy of ibrutinib and venetoclax in CLL. Disclosures Barrientos: Janssen: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Burger:Gilead: Research Funding; Roche: Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Portola: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Research Funding.
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- 2016
48. A Distributed International Patient Data Registry for Hairy Cell Leukemia
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Robert J. Kreitman, Eric H. Kraut, Martin S. Tallman, Anthony D. Ho, Sascha Dietrich, James S. Blachly, Graeme R. Quest, Tamar Tadmor, Judit Demeter, Francesco Lauria, Michael R. Grever, Jacqueline C. Barrientos, Kanti R. Rai, Jeffrey A. Jones, Christopher Heckler, Aaron Polliack, Leslie A. Andritsos, Andrei Fagarasanu, Claire Dearden, Thorsten Zenz, Gunnar Juliusson, Julio Delgado, Enrico Tiacci, Alessandro Gozzetti, Jae H. Park, Monica Else, Mirela Anghelina, Sameer A. Parikh, Nicholas Chiorazzi, Constantine S. Tam, Omkar Lele, Tadeusz Robak, Jan A. Burger, Philip R. O. Payne, Brunangelo Falini, Daniel J. DeAngelo, James B. Johnston, Xavier Troussard, Loree Larratt, Versha Banerji, Pier Luigi Zinzani, Timothy G. Call, Emili Montserrat, Omar Abdel-Wahab, Gerard Lozanski, Farhad Ravandi, Francesco Forconi, Clive S. Zent, and Alan Saven
- Subjects
Disease specific ,business.industry ,media_common.quotation_subject ,Immunology ,Treatment outcome ,Library science ,Cell Biology ,Hematology ,Patient data ,Health records ,Biochemistry ,Health informatics ,Excellence ,Honorarium ,Medicine ,Source document ,business ,media_common - Abstract
BACKGROUND: The study of rare diseases is limited by the uncommon nature of the conditions as well as the widely dispersed patient populations. Current rare disease registries such as the National Organization of Rare Diseases utilize centralized platforms for data collection; however because of their broad nature, these do not always capture unique, disease specific elements. Hairy Cell Leukemia (HCL) is a rare leukemia globally with approximately 900 new cases diagnosed in the US each year. The HCL Foundation undertook creation of a Patient Data Registry that collects data from multiple HCL Centers of Excellence (COE) around the globe to better understand the complications, treatment outcomes, disease subtypes, comorbid conditions, epidemiology, and quality of life of patients with HCL. METHODS: Investigators at The Ohio State University Department of Biomedical Informatics and Division of Hematology in collaboration with the HCL Foundation developed a Patient Data Registry (PDR) for the longitudinal capture of high quality research data. This system differs from other registries in that it uses a federated( rather than centralized) architecture, wherein data is queried and integrated in an on-demand manner from local registry databases at each participating site. Further, the data collected for use in the registry combines both automated exports from existing electronic health records (EHRs) as well as additional data entered via a set of web-based forms. All manually entered data comes from source documents, and data provenance spanning electronic and manually entered data is maintained via multiple technical measures. Patients may be enrolled at HCL COE, or, if they do not have access to a COE they may enroll via a web-based portal (www.hairycellleukemia.org). At this time due to regulatory requirements the web-based portal is available to US patients only. All data are de-identified (see Figure 1: De-Identification Workflow) which reduces regulatory burden and increases opportunities for data access and re-use. End users have access to data via a project-specific query portal. RESULTS: The Patient Data Registry has been deployed at The Ohio State University, Royal Marsden Hospital, and MD Anderson Cancer Center, and is undergoing deployment at the University of Rochester. Up to 25 international HCL COE may participate. In addition, US patients are actively entering the registry via the web-based portal. To date, 227 patients have been consented to the registry with 119 of these being via the web-based entry point. CONCLUSION: We created an international and web-based patient data registry which will enable researchers to study outcomes in HCL in ways not previously possible given the rarity of the disease. This work was made possible by research funding from the Hairy Cell Leukemia Foundation. Figure De-Identification Workflow Figure. De-Identification Workflow Disclosures Andritsos: Hairy Cell Leukemia Foundation: Research Funding. Anghelina:Hairy Cell Leukemia Foundation: Research Funding. Lele:Hairy Cell Leukemia Foundation: Research Funding. Burger:Pharmacyclics: Research Funding. Delgado:Gilead: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Jones:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lozanski:Beckman Coulter: Research Funding; Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding. Montserrat:Morphosys: Other: Expert Testimony; Vivia Biotech: Equity Ownership; Gilead: Consultancy, Other: Expert Testimony; Pharmacyclics: Consultancy; Janssen: Honoraria, Other: travel, accommodations, expenses. Parikh:Pharmacyclics: Honoraria, Research Funding. Park:Genentech/Roche: Research Funding; Amgen: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tam:janssen: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heckler:Hairy Cell Leukemia Foundation: Research Funding. Payne:Hairy Cell Leukemia Foundation: Research Funding.
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- 2016
49. Integrated and Long-Term Safety Analysis of Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
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Steven Coutre, Paul M. Barr, Jacqueline C. Barrientos, Joi Ninomoto, Rudolph Valentino, Susan O'Brien, Michael O'Dwyer, Samuel Suzuki, Jan A. Burger, Danelle F. James, Paolo Ghia, Richard R. Furman, Peter Hillmen, Carol Moreno, Anna Schuh, John C. Byrd, Tadeusz Robak, Stephen Devereux, and Thomas J. Kipps
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030213 general clinical medicine ,medicine.medical_specialty ,business.industry ,Extension study ,Bulky Disease ,Treatment duration ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Lymphocytic lymphoma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,Ibrutinib ,medicine ,In patient ,Long term safety ,business ,Prolonged treatment - Abstract
Background: Ibrutinib (ibr), a first-in-class, oral once-daily inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA for the treatment of pts with CLL/SLL and allows for treatment without chemotherapy. Unlike chemotherapy that is given for a finite number of cycles, ibr is continued until progressive disease (PD) or unacceptable toxicity, leading to extended ibr treatment duration in many patients. The objective was to examine safety and tolerability of ibr therapy in pts with treatment-naïve (TN) or relapsed/refractory (R/R) CLL/SLL using an integrated safety analysis approach, and conduct an analysis of long-term safety. Methods: In study PCYC-1112 (RESONATE), pts with R/R CLL/SLL received ibr 420 mg orally once-daily vs. ofatumumab (Byrd, N Engl J Med 2015). In study PCYC-1115 (RESONATE-2), pts age ≥65 years with TN CLL/SLL received ibr 420 mg orally once-daily vs. chlorambucil (Burger, N Engl J Med 2015). Progressing pts could enroll in the extension study PCYC-1116 for next line therapy (including ibr). Data from ibr-treated pts from the above randomized controlled studies were pooled for an integrated safety analysis. In study PCYC-1102, pts with TN or R/R CLL/SLL received ibr 420 mg or 840 mg orally once-daily (Byrd, N Engl J Med 2013; O'Brien, Lancet Oncol 2014). Pts could continue receiving ibr in the long-term extension study PCYC-1103 where adverse event (AE) collection was limited to grade ≥3 AEs, major hemorrhage, or AEs leading to ibr dose modification. Only data from pts treated with ibr 420 mg daily were examined herein. Results: The integrated analysis included 330 pts; 51% Rai III/IV, 54% bulky disease ≥5 cm, 28% del11q, and 37% CrCl 1 year, 193 (58%) for >2-3 years, and 53 (16%) for >3 years. Concomitant medications included 50% antiplatelet agents, 28% anticoagulants, 3% granulocyte growth factors, and 2% IVIG. The most common AEs were diarrhea (53%) and fatigue (36%). Other AEs experienced by ≥25% of pts were upper respiratory tract infection (30%), nausea (29%), pyrexia (28%), and anemia (27%). Grade ≥3 AEs reported in ≥5% of pts were neutropenia (18%), pneumonia (12%), anemia (7%), and hypertension (HT, 6%). AEs of interest were primarily grade 1/2 (Table). AEs of any grade that led to dose reductions and discontinuation were reported in 13% and 19% of pts, respectively. AEs leading to discontinuation in >1 pt were pneumonia (n=4), anemia (n=3), atrial fibrillation (AFib, n=3), diarrhea (n=2), subdural hematoma (n=2), and thrombocytopenia (n=2). 29 pts died (9%), the most common causes of death were PD (n=8), and pneumonia/lung infection (n=7). In PCYC-1102/1103, 94 pts were treated with ibr for a median of 47.9 mo (max 67.4 mo). The most frequent grade ≥3 AEs were similar to those observed in PCYC-1112 or PCYC-1115/1116, and at times, reflect higher cumulative rates given the median 19 additional months of treatment and follow-up; grade ≥3 AEs reported in ≥5% of pts were hypertension (30%), pneumonia (17%), neutropenia (15%) atrial fibrillation (11%), diarrhea (9%), cellulitis (7%), thrombocytopenia (7%), hyperglycemia (7%), fatigue (6%), decrease in lymphocyte count (6%), and sepsis (5%). Most frequent malignancies included basal cell carcinoma (n=4), squamous cell carcinoma (n=4), and myelodysplastic syndromes (n=2). In 7 of 15 pts, the malignancy AE was diagnosed during the first year, while others occurred over time throughout the ongoing follow-up of >4 years. Overall survival for R/R pts was 74% at 36 mo in PCYC-1112, and 62% at 60 mo in PCYC-1102/1103. Survival of TN pts was 95% at 24 mo in PCYC-1115/1116, and 91% at 60 mo in PCYC-1102/1103 (Kaplan-Meier estimates). Conclusions: In these analyses, which included up to 5 years of follow up in TN and R/R CLL treated with single agent ibr, AEs were primarily grade 1/2 and were manageable with prolonged treatment. Disclosures Coutre: Janssen: Consultancy; Pharmacylics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Barr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Devereux:Roche: Consultancy, Other: Travel, Accommodations, Expenses ; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Kipps:Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria. Schuh:Roche: Consultancy, Honoraria; GSK: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Furman:Genentech: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Honoraria; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses; Gilead: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Portola: Consultancy. O'Dwyer:Roche: Other: Travel, accommodations, expenses; Novartis: Consultancy; Glycomimetics: Consultancy; Amgen: Consultancy, Other: Travel, Accommodations, Expenses ; BMS: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Equity Ownership, Honoraria, Research Funding; NUI Galway: Patents & Royalties. Ghia:Abbvie: Consultancy, Honoraria; Adaptive: Consultancy; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding. Valentino:Gilead: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Travel, accommodations, and expenses; AbbVie: Equity Ownership; Corvus: Equity Ownership; Johnson and Johnson: Equity Ownership, Other: Travel, accommodations, and expenses. Suzuki:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Leadership; Travel, Accommodations, Expenses. Ninomoto:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment; Amgen: Equity Ownership. James:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding.
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- 2016
50. Analysis of an Online Decision Support Tool for Chronic Lymphocytic Leukemia: Disparities in Treatment Selection Between Experts and Community Practitioners
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Jacqueline C. Barrientos, Kristen M Rosenthal, Farrukh T. Awan, Steven Coutre, Kevin L Obholz, and Andrew D. Zelenetz
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Decision support system ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Disease ,Biochemistry ,Clinical trial ,chemistry.chemical_compound ,Regimen ,chemistry ,Obinutuzumab ,Chemoimmunotherapy ,Ibrutinib ,Family medicine ,Medicine ,business ,Idelalisib - Abstract
Background. Rapid advances in clinical discovery and availability of new treatment options have increased the complexity of treatment decisions for patients with CLL. Guidelines list multiple agents and combinations as recommended therapeutic options for CLL but often do not provide specific treatment recommendations for individual patients. We developed an online treatment decision tool that provides treatment recommendations from CLL experts for specific patient cases. We hypothesized that these individualized recommendations from recognized experts would affect treatment plans. Here we report on an analysis of data entered into this CLL decision support tool, including variance between intended treatment of tool users and the recommendations made by the experts and the impact of the tool on subsequent therapy decisions. Methods. In December 2015, 5 experts provided treatment recommendations for 1380 case variations based on key factors that guide treatment choice. Expert-selected factors for newly diagnosed CLL included age, fitness (based on ECOG PS, CIRS, and renal function), and cytogenetic abnormalities (del[17p], del[11q], or other). Additional variables for patients with relapsed/refractory (R/R) disease after first-line treatment included previous treatment, response duration, and burden of comorbidities. To use the tool, drop-down menus allowed users to select from choices for each variable and their intended treatment for that patient. The corresponding treatment selection from 5 experts was then displayed and users were asked about the tool's impact on their planned treatment. Results. An analysis of 883 patient scenarios (67% treatment naive and 33% with R/R CLL) entered into the tool from February 2016 through July 2016 found substantial variation between the intended therapy choice among tool users and the recommendations from the experts.For example, in every patient case with del(17p), all 5 of the experts recommended ibrutinib as first-line therapy whereas only 49% of tool users planned to use ibrutinib for these patients. Of those users whose intended first-line therapy for del(17p) CLL did not match the experts' recommendation, 54% indicated that this tool would change their original treatment plan and 17% indicated a barrier to implementing this treatment. For either elderly or unfit patients without del(17p), 4 of 5 experts recommended obinutuzumab plus chlorambucil, but only 41% of tool users planned to use this regimen with 50% citing barriers to this treatment approach. For patients with del(17p) CLL and disease relapse or recurrence after chemoimmunotherapy, all 5 experts recommended ibrutinib for these cases with the exception of patients with a history of atrial fibrillation, anticoagulation, or difficult-to-control hypertension where 4 of 5 experts recommended idelalisib/rituximab. Again, the intended treatment plan of approximately 50% of tool users failed to match the experts' recommendation for these cases, and half of these users indicated that this tool would change their original treatment plan. At the time of tool development, all experts recommended either idelalisib/rituximab or clinical trial for patients with R/R CLL and del(17p) who previously received ibrutinib, but 61% of users indicated that they were unsure of the next appropriate treatment. All users who answered the impact question indicated that they now intended to use the expert-recommended treatment for these patients. For patients without del(17p) cytogenetics, treatment selection was more variable among experts and users and changed based on age, fitness, and previous therapy. For patients with del(11q) or other cytogenetics, approximately 20% of tool users were unsure of the appropriate treatment after progression on first-line therapy but 71% of those who answered the impact questions indicated that they remained unsure of their treatment approach despite viewing expert recommendations. Conclusions. Our analysis demonstrates that this interactive online therapy decision tool providing expert recommendations for specific case scenarios in CLL can support optimal decision making and change intended treatment for a majority of cases in which the planned therapy differed from the experts. Detailed comparisons of expert and user responses from the online tool will be presented. Disclosures Awan: Innate Pharma: Research Funding; Pharmacyclics: Consultancy; Novartis Oncology: Consultancy. Barrientos:AbbVie: Consultancy, Research Funding; Janssen: Consultancy; Gilead: Consultancy, Research Funding. Coutre:AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding. Zelenetz:Gilead Sciences: Research Funding.
- Published
- 2016
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