231 results on '"Jacqueline C. Barrientos"'
Search Results
152. Patterns of hepatitis B reactivation and liver test abnormalities in patients with chronic lymphocytic leukemia (CLL) treated with idelalisib plus an anti-CD20 antibody
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Tadeusz Robak, Jennifer R. Brown, Julia Li, Marco Montillo, Ronald L. Dubowy, Guan Xing, John M. Pagel, Jacqueline C. Barrientos, Peter Hillmen, Thomas J. Kipps, Andrew D. Zelenetz, Anthony R. Mato, and Jeffrey A. Jones
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Hepatitis B virus ,Cancer Research ,HBsAg ,business.industry ,Chronic lymphocytic leukemia ,virus diseases ,Hepatitis B ,medicine.disease ,medicine.disease_cause ,digestive system diseases ,03 medical and health sciences ,0302 clinical medicine ,Anti cd20 antibody ,Oncology ,Antigen ,030220 oncology & carcinogenesis ,Immunology ,medicine ,In patient ,business ,Idelalisib ,030215 immunology - Abstract
7533Background: Hepatitis B reactivation can occur after hepatitis B virus (HBV) surface antigen (HBsAg) loss, especially in immunocompromised patients (pts).1,2A high rate of reactivation has been...
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- 2016
153. Outcomes with ibrutinib by line of therapy in patients with CLL: Analyses from phase III data
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Paul M. Barr, Susan O'Brien, John C. Byrd, Jan A. Burger, Joi Ninomoto, Steven Coutre, Jennifer R. Brown, Tadeusz Robak, Jacqueline C. Barrientos, Danelle F. James, Alessandra Tedeschi, Peter Hillmen, Stephen Devereux, Stephen Chang, Nishitha Reddy, Thomas J. Kipps, Florence Cymbalista, and Paolo Ghia
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Line of therapy ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Prior Therapy ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,Ibrutinib ,medicine ,In patient ,Once daily ,business ,030215 immunology - Abstract
7520Background: Ibrutinib (ibr) is the first-in-class once daily Bruton’s tyrosine kinase inhibitor FDA approved for patients (pts) with CLL with ≥ 1 prior therapy. We evaluated outcomes with ibr b...
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- 2016
154. Results of a randomized, double-blind placebo-controlled phase 3 study evaluating idelalisib in combination with bendamustine and rituximab in patients with relapsed/refractory CLL and adverse prognostic features
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Adeboye H. Adewoye, Christopher Pocock, Ann Janssens, Jacqueline C. Barrientos, Mazyar Shadman, Javier Loscertales, Ehab Atallah, Charles M. Farber, Javier de la Serna, Maria Aiello, Stephan Stilgenbauer, Steven Coutre, Yeonhee Kim, Lyndah Dreiling, Andrew D. Zelenetz, Herbert Eradat, and Jennifer R. Brown
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0301 basic medicine ,Oncology ,Bendamustine ,Cancer Research ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Standard treatment ,Population ,Phases of clinical research ,Subgroup analysis ,Placebo ,Surgery ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,Rituximab ,business ,Idelalisib ,education ,medicine.drug - Abstract
7514Background: Patients (pts) with relapsed CLL and adverse prognostic features respond poorly to standard treatment. Here we present a subgroup analysis from a phase 3 randomized double-blind placebo-controlled study. We evaluated progression-free survival (PFS) in this pt population enrolled between June 2012 and August 2014. Methods: All 416 pts (207/209 on the idelalisib (IDELA)/placebo [plb] arms, respectively) had BR for 6 cycles Q 28 days (B = 70 mg/m2 D1, D2 of each cycle; R = 375 mg/m2 C1 and 500 mg/m2 C2-6) and IDELA 150 mg BID or plb. IDELA/plb continued until independent review committee confirmation of disease progression, death, intolerable toxicity, or withdrawal of consent. Mutational analysis was centrally performed. Median time on study was 12 months. Results: Improvement in PFS was observed on the IDELA vs plb arm in all adverse-risk categories evaluated (Table). Conclusions: IDELA with BR consistently increased PFS in all risk categories evaluated. The safety profile was consistent wi...
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- 2016
155. Ibrutinib for Transformed Lymphoma; A Report of 4 Patients
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Amy Sharma, Jacqueline C. Barrientos, Sadia Riaz, Jonathan E. Kolitz, and Steven L. Allen
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Oncology ,medicine.medical_specialty ,business.industry ,Large cell ,Immunology ,Large-cell lymphoma ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Surgery ,Lymphoma ,chemistry.chemical_compound ,chemistry ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Ibrutinib ,medicine ,Rituximab ,Primary effusion lymphoma ,business ,Diffuse large B-cell lymphoma ,Progressive disease ,medicine.drug - Abstract
Introduction Large cell lymphoma transformed from an indolent lymphoproliferative disorder typically carries a worse prognosis than de novo diffuse large B cell lymphoma. When transformation to large cell lymphoma occurs in CLL (Richter's syndrome), traditional anthracycline or platinum based therapy is associated with a median survival of Cases: Patient A, age 68 at transformation, was a 64 year old male at diagnosis with CLL Rai stage 1. He was initially asymptomatic with a performance status of 0. 4 years later he developed dyspnea on exertion after one block and was found to have a left pleural effusion with diffuse lymphadenopathy with increased PET avidity. Biopsy of a supraclavicular node was positive for extracavitary primary effusion lymphoma, HHV8+, CD5-, CD10-. Patient was given R-CHOP x 6 cycles; he relapsed after 18 months and was given ibrutinib 560mg daily with monthly rituximab x 6 and achieved a PR with reversion to CLL. He is currently continuing ibrutinib in this remission for 10+ months. Patient B, age 90 at transformation, was a 68 year old female at diagnosis of CLL, Rai stage 0. She developed stage III CLL 18 years after diagnosis, was treated with BR x 6 cycles. 2 years later she developed Richter's transformation which was CD10+. Although she achieved a PR after 4 months of ibrutinib 560mg with monthly rituximab, her PS was 4 and she was transferred to hospice and expired 4.5 months after initiating ibrutinib/rituximab. Patient C, age 87 at relapse, was a 73 year old male at diagnosis when he originally presented with stage 1 DLBCL transformed from marginal zone lymphoma. He had 3 cycles of R-CHOP and RT to involved area and was disease free for 14 years until he had worsening thrombocytopenia. This was monitored for 3 years until age 87 when CT/PET showed increasing SUV in multiple lymph nodes and the spleen. Biopsy showed diffuse large B cell lymphoma, CD10-. He was started on ibrutinib 560mg with monthly rituximab x 6. He achieved a CR by CT/PET except for persistent splenic disease. He underwent splenectomy and continues in CR on ibrutinib at 9+ months. Patient D is an 83 year old female with large cell transformation from marginal zone lymphoma at diagnosis. She had stage IV disease with large cells involving pleural fluid and bone marrow. She was CD10-. She received R-CHOP x 3 with progressive disease. At that time ibrutinib 560mg alone was initiated. She has a CR based on recent CT/PET findings and is continuing ibrutinib at 18+ months. Conclusion: All of the above patients responded to ibrutinib given with or without rituximab with symptomatic and objective remissions; all of the CD10 negative cases are alive and still responding 9-18 months after initiating therapy. Studies examining the efficacy of ibrutinib in diffuse large B cell lymphoma are underway. This report supports the need for further study of ibrutinib in the transformed setting, particularly in the elderly where patients may not be appropriate for aggressive therapies. Disclosures Off Label Use: Ibrutinib was used to treat transformed large cell lymphoma.. Kolitz:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Barrientos:Gilead: Research Funding; NIH/NCATS: Research Funding; ASH-AMFDP: Research Funding. Allen:Millennium: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Equity Ownership; Onconova: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees.
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- 2015
156. The Correlation of APOBEC Gene Family Member Expression with Worse CLL Patient Outcome Suggests a Role in CLL Mutational Evolution
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Kanti R. Rai, Jonathan E. Kolitz, Charles C. Chu, Arvind Dhayalan, Jacqueline C. Barrientos, Steven L. Allen, Thomas MacCarthy, Nicholas Chiorazzi, Chaohui Yuan, Piers E.M. Patten, and Xiao-Jie Yan
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APOBEC ,APOBEC1 ,Immunology ,Cell Biology ,Hematology ,APOBEC-3G Deaminase ,Cytidine deaminase ,Biology ,Biochemistry ,Helsinki declaration ,Germline mutation ,Cancer research ,IGHV@ ,Gene - Abstract
A mutational signature consistent with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide) activity has been identified in somatic mutations found in large-scale surveys of ultra-deep sequencing data from many human cancers including chronic lymphocytic leukemia (CLL). APOBEC is a cytidine deaminase family made up of eleven genes, including AID (activation-induced cytidine deaminase) and APOBEC3B, both of which have been implicated in somatic mutation in various cancers, including CLL. These observations have led to the hypothesis that APOBEC cytidine deaminases may be driving somatic mutations leading to the development of more aggressive cancers. Therefore, we examined APOBEC gene family member RNA expression levels in CLL to test for correlations with expression levels and patient outcome. We further examined if CLL cells generated de novo APOBEC family member mutational patterns in the immunoglobulin variable region gene (IGHV) after implantation in a mouse xenograft model of CLL. CLL peripheral blood mononuclear cells (PBMCs) and associated clinical data were collected from patients after informed consent as approved by the Institutional Review Board at the North Shore-Long Island Jewish Health System and in accordance with the Helsinki Declaration. CLL samples were chosen based on availability with no pre-established inclusion/exclusion criteria. CLL RNA expression levels were examined by microarray or quantitative real-time PCR (qPCR). For microarray studies, CLL B cells were purified prior to RNA isolation and acquisition of microarray expression data using Illumina Human WG6 and HT12 bead chips, followed by quantile normalization using GenomeStudio software (Illumina). For qPCR, RNA expression from CLL PBMCs was measured relative to glyceraldehyde 3-phosphate dehydrogenase gene expression by Taqman assay with Roche UPL probes and LightCycler 480. To examine de novo mutations in CLL, the IGHV region was ultra-deep sequenced (Roche 454 FLX system) from human CLL cells recovered from the NOD/Shi-scid,γcnull (NSG) xenograft mouse model of CLL as approved by the Institutional Animal Care and Use Committee at the North Shore-Long Island Jewish Health System. CLL patient (N = 65) RNA expression by microarray showed very low levels of APOBEC1, 2, 3A, 3B, 3D, 4, and AID, modest levels of APOBEC3C and 3H, and high levels of APOBEC3F and 3G. Higher AID expression levels significantly correlated (P To test if CLL cells can acquire de novo mutations indicative of APOBEC gene family member activity, human CLL cells were transferred into NSG mice. After CLL cells proliferated for 4-14 weeks in this xenograft model, the IGHV region was amplified, ultra-deep sequenced, and analyzed for specific mutational characteristics of various APOBEC gene family members. The results of these ongoing analyses will be presented. In conclusion, the expression levels of the APOBEC gene family members AID, APOBEC3B, and potentially APOBEC3F and 3H, correlate with worse patient outcome. These data are consistent with the hypothesis that APOBEC gene family member activity may promote new mutations at sites outside the IG gene loci leading to the evolution of aggressive CLL. Disclosures Barrientos: Pharmacyclics, Celgene, and Genentech: Membership on an entity's Board of Directors or advisory committees; Gilead, Pharmacyclics, and AbbVie: Research Funding.
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- 2015
157. Characterization of Atrial Fibrillation and Bleeding Risk Factors in Patients with Chronic Lymphocytic Leukemia (CLL): A Population-Based Retrospective Cohort Study of Administrative Medical Claims Data in the United States (US)
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Jacqueline C. Barrientos, Nicole Meyer, Kanti R. Rai, and Xue Song
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medicine.medical_specialty ,Antiplatelet drug ,Framingham Risk Score ,business.industry ,medicine.drug_class ,medicine.medical_treatment ,Incidence (epidemiology) ,Immunology ,Anticoagulant ,Salvage therapy ,Retrospective cohort study ,Atrial fibrillation ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Surgery ,Internal medicine ,Concomitant ,Medicine ,business - Abstract
Background: CLL is the most common form of adult leukemia in the Western World. It primarily affects the elderly with ~70% of patients diagnosed ≥65 years of age. Therapy is reserved until symptoms occur, when most patients have multiple chronic comorbidities including hypertension, arrhythmias, and other conditions that require the use of anticoagulants and/or antiplatelet agents. Understanding the frequency of use of these agents and bleeding events in routine clinical practice could provide additional insights on the real-world burden of the use of these drugs in patients with an underlying predisposition to bleeding due to CLL-related thrombocytopenia and other comorbidities. This is particularly relevant as several chemoimmunotherapy regimens used in CLL may have direct cardiotoxic and antiplatelet effects. Most importantly, emerging evidence suggests that some of the recently approved targeted agents may be associated with risk of cardiac arrhythmias or bleeding events. The mechanisms behind these events and the relations between them are largely unclear but affect the quality of life of CLL patients. The aim of this retrospective database study was to characterize the outcomes of newly diagnosed CLL patients in terms of: [1] incidence of atrial fibrillation (AFIB), [2] incidence of AFIB risk factors, [3] bleeding risk factors as measured by the 5-variable Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score (which quantifies the risk of drug-associated hemorrhage), and [4] anticoagulant/antiplatelet drug usage over the course of their treatment. Methods: Based on administrative medical claims from the MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Databases in the US, we identified adults diagnosed with CLL between 1/1/2004 - 4/30/2015. Patients selected for this study were required to have at least two treatment lines where the 2nd line treatment represented a change in initial therapy (index date = start of 1st line treatment). anticoagulant/antiplatelet use, incidence of AFIB (per 10,000 patient days), and ATRIA bleeding risk score were assessed during 1st and 2nd line treatment. Patients were continuously enrolled for ≥ 6 months (baseline) before index date, and followed until disenrollment from the health plan or 4/30/2015, whichever came first. Results: Of approximately 67 million adults (per year) in the database, we identified 2,335 adults with newly diagnosed CLL (mean age: 62 years; 66% male; 46% Medicare as primary payer) treated with antineoplastic therapy and followed for a mean of 35.3 months. The mean duration of first line treatment was 3.3 months, and 4.1 months for 2nd line treatment. Anticoagulant/antiplatelet use at baseline was common (25%), and use increased during 1st line (31%) and 2nd line (32%) treatment. During follow-up, the incidence of AFIB during 1st line and 2nd line treatment was 4.57 and 5.70/10,000 person days (95% CI: 3.7-5.5 and 4.8-6.6), respectively. The proportion of patients with ATRIA scores indicating moderate (ATRIA score 4) to high (ATRIA score ≥ 5) risk of bleeding increased from initial therapy (1st line treatment = 18%) to salvage therapy (2nd line treatment = 22%) [see Figure]. Conclusions: We provide the first real-world estimates of anticoagulant/antiplatelet use, AFIB, AFIB risk, and bleeding risk factors in adult patients newly diagnosed with CLL in the US. In our study, the use of anticoagulant/antiplatelet agents at diagnosis was common (25%) and increased over time from 1st to 2nd line treatment. Similarly, AFIB incidence and the ATRIA bleeding risk score also increased over the course of the natural disease progression. Since ATRIA scores of ≥ 5 correlate with a 5.8% annual risk of major hemorrhage, understanding the characteristics of the CLL patients at diagnosis and relapse will ultimately help optimize treatment selection based on the potential risks and benefits of each individual treatment regimen. These data, an evaluation of cardiac status, use of concomitant medications, and potential risk factors should be considered in the management of CLL. Disclosures Barrientos: Gilead: Research Funding; NIH/NCATS: Research Funding; ASH-AMFDP: Research Funding. Meyer:Truven Health Analytics: Employment. Song:Truven Health Analytics: Employment. Rai:Leon Levy Foundation: Research Funding; Nash Family Foundation: Research Funding; Nancy Marks Family Foundation: Research Funding; Karches Family Foundation: Research Funding.
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- 2015
158. Outcomes of Patients with Chronic Lymphocytic Leukemia (CLL) after Idelalisib Therapy Discontinuation
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Nancy Driscoll, Jacqueline C. Barrientos, Alexis Mark, Jaewon Chung, Alison Bender, Manmeen Kaur, and Kanti R. Rai
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Bendamustine ,medicine.medical_specialty ,business.industry ,Immunology ,Salvage therapy ,Cell Biology ,Hematology ,Ofatumumab ,medicine.disease ,Biochemistry ,Discontinuation ,Surgery ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Ibrutinib ,medicine ,Rituximab ,Idelalisib ,business ,Pneumonitis ,medicine.drug - Abstract
Objective Idelalisib is a first-in-class oral PI3Kd inhibitor approved for use in combination with rituximab in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). We describe the characteristics, causes of discontinuation, and outcomes in patients who discontinued treatment after idelalisib therapy. Methods 38 R/R CLL patients participated in 5 idelalisib combination trials at the North Shore-LIJ Cancer Institute and were included in this analysis. The patients were enrolled from 2011 until 2014, and data were locked in March 1st, 2015. Patients were evaluated for time to therapy discontinuation and reasons for discontinuation. The majority of the patients had been heavily pretreated and 39% of the patients had a high risk prognostic marker including deletion of 11q or 17p. 21 R/R CLL patients participated in the Phase Ib trial of idelalisib in combination with several agents including Rituximab (R), Bendamustine (B) ± R, Fludarabine, Chlorambucil ± R, and Ofatumumab. The trial was designed for 48 weeks and patients were allowed to continue on an extension trial with idelalisib if still deriving benefit. Patients on the parent trial were on therapy a median of 335 days. 42% (11/21) continued in the extension trial at the end of the parent trial. Causes of discontinuation from initial 48-week trial included: grade 4 transaminitis (1) on day 64 with failed rechallenge at lower doses; Richter's transformation (1) on day 161; grade 3/4 diarrhea/colitis (4) on days 52, 231, 255, and 365; refractory/progressive CLL (2) on days 8 and 170; aplastic anemia (1) on day 172; and septic shock in a patient with uncontrolled autoimmune hemolytic anemia (1) on day 271. Of the patients on the extension trial, the median time on drug was 412 days with 27% (3/11) discontinuing due to grade 3/4 diarrhea/colitis; 36% (4/11) due to progression, 9% (1/11) due to pneumonia and subsequent progression 2 months later. Of the 3 patients that remain on study, their median time on therapy is 1072 days without evidence of toxicities. Of the 17 patients that participated in placebo-controlled phase III studies, 11 participated in R +/- idelalisib (study 116) and 6 on BR+/-idelalisib (study 115). Study 116 was unblinded during the trial: 35% (4/11) received idelalisib + R upfront. Of these, only 2 patients (50%) were able to continue on extension study as the other 2 patients developed pneumonitis and were taken off study early. One patient is continues on study at day 1011 whereas the second patient developed progressive multifocal leukoencephalopathy on day 714 and died days after being taken off drug. 86% (6/7) of the remaining patients initially randomized to placebo crossed over to idelalisib at the time of confirmed progression. Of these, 14% (1/6) developed both colitis and later pneumonitis, 14% (1/6) withdrew consent, and 14% (1/6) had progression of disease. For blinded study 115 (BR+/-idelalisib), 6 patients participated: 33% (2/6) developed grade 3/4 diarrhea/colitis, 16% (1/6) developed pneumonitis, and 16% (1/6) has progressed. In our experience, none of the patients with severe diarrhea/colitis were able to maintain lower doses for a prolonged period of time without recurrent colitis or the development of pneumonitis. Since the start of these trials, 31% (12/38) of the patients have died: the overall survival after discontinuation for these patients varies widely from 0 to 303 days with a median overall survival of 64 days after discontinuation. Most patients with relapsed/refractory CLL who discontinued idelalisib early were difficult to treat and had poor outcomes. Over the course of the trials, the Bruton's tyrosine kinase inhibitor ibrutinib was approved and used as salvage therapy in 10 patients with confirmed progression; except for 1 patient, all patients successfully achieved a prolonged response with ibrutinib suggesting salvage therapy with a targeted agent may be a reasonable therapeutic approach for patients after idelalisib failure. Interestingly, the rate of Richter's transformation was extremely rare in this study (2%). Conclusions This single-institution experience with idelalisib identifies baseline factors associated with therapy discontinuation, mainly grade 3/4 diarrhea/colitis and progression of disease as a reason for discontinuation from therapy. Our data suggest the use of ibrutinib may be a reasonable choice in patients after idelalisib failure. Disclosures Barrientos: ASH-AMFDP: Research Funding; Gilead: Research Funding; NIH/NCATS: Research Funding. Off Label Use: idelalisib is approved in combination with rituximab only. I will discuss our experience of idelalisib in combination with other agents.
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- 2015
159. Deep and Durable Responses Following Venetoclax (ABT-199 / GDC-0199) Combined with Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results from a Phase 1b Study
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Ming Zhu, Mary Ann Anderson, Jacqueline C. Barrientos, Wijith Munasinghe, Shuo Ma, Danielle M. Brander, Michael Y. Choi, Constantine S. Tam, Su Young Kim, Betty Prine, Rod A. Humerickhouse, Matthew S. Davids, Thomas J. Kipps, John F. Seymour, Tanita Mason-Bright, and Andrew W. Roberts
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Bendamustine ,medicine.medical_specialty ,Venetoclax ,business.industry ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Transplantation ,chemistry.chemical_compound ,chemistry ,Chemoimmunotherapy ,Internal medicine ,Ven ,medicine ,Rituximab ,business ,Febrile neutropenia ,medicine.drug - Abstract
Introduction: Venetoclax (VEN) is a selective, orally bioavailable BCL-2 inhibitor. This is a phase 1b, study of VEN plus rituximab (R) to determine safety, PK and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). The recommended phase 2 dose for VEN plus R was previously reported to be 400mg/day. The aims of this analysis were to evaluate progression-free survival (PFS), overall survival (OS), and the durability of responses off all therapy in pts achieving CR. We also assessed minimal residual disease (MRD) status, which has previously been shown to be strongly predictive of PFS and OS after chemoimmunotherapy. Methods: Pts began once daily VEN (20 or 50 mg) to final cohort doses (200-600 mg/day) followed by R, given every 4 weeks for a total of 6 doses. VEN dosing was continuous. Responses were assessed by iwCLL criteria with CT scan and bone marrow (BM) biopsy after combination therapy (Month 7). MRD was assessed on BM aspirates in local laboratories using ≥4 color flow cytometry (minimum sensitivity of 0.01%). Results: 49 pts (48 CLL/1 SLL) were enrolled in 5 dose escalation cohorts (n=41; 200-600mg/day) and a safety expansion cohort (n=8; 400mg/day); results herein combine data from all cohorts. Median (range) age was 68 (50-88) years. The median (range) number of prior regimens was 2 (1-5). 45 (92%) received prior R and 14 (29%) had R-refractory disease; 29 (59%) received prior fludarabine and 9 (18%) had fludarabine-refractory disease. Of pts with available data, 9/46 (20%) had del(17p); 19/27 (70%) expressed unmutated IGHV. As of June 4, 2015, 12 pts have discontinued the study: 6 due to PD (5 were Richter's transformation), 3 due to AEs (neuropathy, TLS, and myelodysplasia [heavily pretreated and hypocellular marrow at study entry; pt achieved MRD-negative CR with incomplete marrow recovery, CRi, and proceeded to transplant]), and 3 withdrew consent (1 after achieving MRD-negative CR). The investigator-assessed ORR was 86% (42/49) with 20 (41%) CR/CRi, 1 (2%) nPR and 21 (43%) PR. 4 had SD, 2 had PD, and 1 died before assessment (fatal TLS). 9 with PR or SD at the 7 month assessment achieved CR after a median (range) additional time of VEN monotherapy of 6 (2-9) months. BM MRD was evaluated in 40 pts. MRD-negativity was achieved in 15/20 (75%) pts who achieved a CR/CRi and 26/49 (53%) overall. Disease has progressed in 5/42 (12%) responders; 89% are free from progression at 12-months. The median PFS has not been reached. At 12 and 24 months, actuarial PFS is 87% and 84%, respectively, with a median (range) follow-up for pts without events of 17.5 (0.03-32) months. 94% were alive at 12 months; the median OS has not been reached. Although the numbers are small, the ORR, CR rates, PFS, and OS were not significantly impacted by high-risk subgroups. 8 pts stopped VEN after achieving CR/CRi, 6 of whom were MRD-negative at the time. 2 withdrew from the study after achieving CR/CRi without evidence of progression; 6 remain in follow-up with a median (range) of 15 (4-24) months off VEN. The 2 MRD-positive pts had asymptomatic progression with rising lymphocytosis after 19 and 24 months off VEN; both are eligible for retreatment with VEN when clinically appropriate. Treatment-emergent AEs in >25% of pts were neutropenia (55%), diarrhea (53%), nausea (49%), upper respiratory tract infection (45%), fatigue and pyrexia (each 37%), cough (35%), and headache (33%). Grade 3/4 AEs in >10% were neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (10%). 1 treatment-emergent AE (TLS) led to death; no other fatal TLS events occurred after a protocol modification aimed at TLS risk management and prophylaxis. 2 deaths occurred after PD. Key efficacy data are summarized in the table. Conclusions: VEN plus R induces a high rate of deep and durable responses, independent of adverse prognostic factors, with a tolerable safety profile. 41% of pts achieved CR/CRi and 53% achieved BM MRD-negativity. Remission off all therapy has been maintained in pts achieving MRD-negative CR. The median PFS and OS have not yet been reached; 24-month PFS is estimated to be 84%. The high rate of MRD-negativity is an encouraging step towards prolonged PFS and durable elimination of CLL/SLL. VEN plus R versus bendamustine plus R is being evaluated in a phase 3 trial in pts with previously treated CLL (MURANO; NCT02005471). Table 1. Table 1. Disclosures Ma: Genentech, Pharmacyclics/Janssen and Gilead: Speakers Bureau; Genentech, Pharmacyclics/Janssen and Gilead: Consultancy; NCCN, AbbVie, Pharmacyclics, Novartis, Gilead, Celgene, and Xeme: Research Funding. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Seymour:Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kipps:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria. Barrientos:Gilead, Pharmacyclics, and AbbVie: Research Funding; Pharmacyclics, Celgene, and Genentech: Membership on an entity's Board of Directors or advisory committees. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Anderson:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Choi:AbbVie: Consultancy, Other: Advisory Board, Research Funding; Gilead: Consultancy, Other: Advisory Board, Speakers Bureau. Tam:Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Mason-Bright:AbbVie: Employment, Equity Ownership. Prine:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Kim:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Roberts:Walter and Eliza Hall Institute of Medical Research: Employment; Genentech: Research Funding; AbbVie: Research Funding; Servier: Research Funding.
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- 2015
160. Chronic Lymphocytic Leukemia Patients and Eµ-TCL1 Mice Share a Phenotype of Functional Granulocyte-like and Dysfunctional Monocyte-like Myeloid Derived Suppressor Cells
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Jacqueline C. Barrientos, Kanti R. Rai, Gerardo Ferrer, Brendan Franca, Jonathan E. Kolitz, Steven L. Allen, Xiao-Jie Yan, and Nicholas Chiorazzi
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education.field_of_study ,Monocyte ,Chronic lymphocytic leukemia ,Immunology ,Population ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Leukemia ,medicine.anatomical_structure ,Granulocyte macrophage colony-stimulating factor ,Monocyte differentiation ,medicine ,Myeloid-derived Suppressor Cell ,CD5 ,education ,medicine.drug - Abstract
Immune imbalance is a common characteristic of patients with chronic lymphocytic leukemia (CLL). This feature is shared with Eμ-TCL1 transgenic mice that, like CLL patients, exhibit an expansion of CD5+ B cells with associated non-B-cell defects. In patients and in mice, T-cell responses are often ineffective. This alteration is generally considered due to the direct effects of the leukemic cells. The expansion of myeloid derived suppressor cells (MDSCs), which play a major role in helping tumor cells escape immune surveillance by inhibiting T-cell responses, is promoted by many cancers. MDSCs are a heterogeneous population of cells that are subdivided into monocyte-like (m-MDSC) and granulocyte-like (g-MDSC) subsets, both in humans and mice. There we have investigated the extent that patients with CLL have expansions of MDSCs, what are their types and functions, and how these correlate with the Eμ-TCL1 mice model. Using flow cytometry on cryopreserved PBMCs, we found that the absolute numbers of MDSCs (HLA-DRlo/CD11b+/CD33+) in 49 untreated CLL patients were significantly higher than 15 healthy controls (HCs) (966 446 vs. 163 578 cells/ml, P When we evaluated the ability of MDSCs to inhibit autologous T-cell proliferation in CLL patients (n=7), we observed a consistent reduction of proliferation only when co-culturing with g-MDSCs(P=0.034). In contrast, the effects of m-MDSCs on T-cell expansion were varied and insignificant statistically. In 5 CLL samples, we induced m-MDSCs (im-MDSCs) from purified CD33+ cells in vitro with GM-CSF, IL10, and IL6; the im-MDSCs effectively suppressed T-cell proliferation in 4 of 5 cases at an average inhibition of 33% (range: 10-79%). Thus, dysfunctional m-MDSC suppression was not inherent and functional suppression could be achieved by stimulation of CLL precursor cells. Similarly in 3 independent experiments performed with MDSCs from Eμ-TCL1 mice (12-14 months of age), we observed a reduction of in vitro proliferation with g-MDSCs (P=0.049) and not with m-MDSCs. In addition, for those Eμ-TCL1 animals for which sufficient sample was available, we subdivided the g-MDSC population into the two subpopulations based on CD11b density; the CD11blo subset present less nuclear segmentation and higher suppressive activity. In summary, absolute numbers of MDSCs in the blood of CLL patients and Eμ-TCL1 mice are elevated and correlate with the levels of expansion of the leukemia. The major subtype in both situations was g-MDSCs.These g-MDSCs were functionally competent suppressors, whereas m-MDSCs were impaired in this function. In CLL patients, this m-MDSC suppressor defect could be corrected by in vitro stimulation with growth factors that support monocyte differentiation. The high similarity between CLL patients and Eμ-TCL1 mice in relation to MDSC number and function suggest that an imbalance in g-MDC vs. m-MDSC function may affect CLL development and expansion, altering interactions with members of the microenvironment such as T cells. Disclosures No relevant conflicts of interest to declare.
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- 2015
161. The Bruton Tyrosine Kinase (Btk) Inhibitor ACP-196: Marked Activity in Relapsed/Refractory CLL with a Favorable Safety Profile
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Ahmed Hamdy, Jacqueline C. Barrientos, William G. Wierda, Richard R. Furman, Jorge M. Chaves, Jane Huang, Deborah M. Stephens, Wayne Rothbaum, Raquel Izumi, S. Devereux, John C. Byrd, Susan O'Brien, Peter Hillmen, Tasheda Navarro, Jeffrey A. Jones, Todd Covey, Jennifer R. Brown, Paolo Ghia, Anna Schuh, and Min Hui Wang
- Subjects
medicine.medical_specialty ,Lymphocytosis ,Anemia ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Tumor lysis syndrome ,chemistry.chemical_compound ,chemistry ,Pharmacodynamics ,Internal medicine ,Ibrutinib ,medicine ,medicine.symptom ,Adverse effect ,Idelalisib ,business - Abstract
Introduction Btk is a kinase involved in B-cell receptor (BCR) signal transduction and a critical target in chronic lymphocytic leukemia (CLL). ACP-196-a potent, second generation Btk inhibitor that is more selective than the first-in-class Btk inhibitor, ibrutinib (Covey AACR2015)-has demonstrated antitumor activity in preclinical CLL models (Niemann AACR2014). Here, we present preliminary data from patients with relapsed/refractory (R/R) CLL/small lymphocytic lymphoma (SLL) enrolled in an ongoing Phase 1/2 study of single-agent ACP-196 (ClinicalTrials.gov NCT02029443). Methods and Patients This first-in-human study was designed to evaluate the safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics and efficacy of orally administered ACP-196 in patients with R/R CLL/SLL. Patients were continuously treated with ACP-196 at dosages ranging from 100 to 400 mg once daily (QD) as part of the dose-escalation portion of the study (4 cohorts of 6-8 patients per cohort), and 100 mg twice daily (BID) and 200 mg QD as part of the expansion portion of the study (2 cohorts). Of note, CLL patients with any degree of pancytopenia and prior exposure to PI3K inhibitors were allowed. CLL responses were investigator assessed per IWCLL criteria (modified Hallek 2008). SLL responses were investigator assessed per IWG criteria (Cheson 2007). Patients had a median age of 62 years (range 44-84), bulky lymph nodes ≥ 5 cm (47%) and median of 3 prior therapies (1-13). High-risk prognostic factors included del(17)(p13.1) 31% (18/58), del(11)(q22.3) 29% (17/58) and unmutated IGVH genes 75% (38/51). Results Results are presented through 01 June 2015 for the first 61 R/R patients, including 60 evaluable for response. The median time on study (N=61) was 10.3 (0.5-15.9) months. ACP-196 has been well tolerated with 93% (57/61) of patients continuing on study drug. Of the 4 patients who discontinued, 1 patient each discontinued due to withdrawal of consent, physician decision, unrelated AE (pre-existing, active autoimmune hemolytic anemia) and related AE (Grade 3 dyspnea). To date, no dose-related effect has been observed in frequency or severity of AEs or serious adverse events. No dose-limiting toxicities have occurred, and most AEs were Grade ≤ 2. The most common Grade 1/2 AEs (≥ 15%) were headache (39%), diarrhea (33%) and URI (16%). Grade 3/4 AEs that occurred in ≥ 3 patients were anemia (7%), pneumonia (7%) and hypertension (5%). No major hemorrhage (including subdural hematomas), atrial fibrillation, tumor lysis syndrome or pneumonitis have occurred suggesting an improved safety profile compared with other BCR and BCL-2-targeted therapies. Clinical activity has been observed in patients with R/R CLL/SLL at all doses evaluated. All patients experienced rapid reductions in lymphadenopathy. Treatment-related lymphocytosis (defined as ≥ 50% increase from baseline and above absolute lymphocyte count [ALC] of 5 K/µL) occurred in 61% (37/61) of patients and resolved in 81% (31/37) of these patients. In general, lymphocytosis peaked at a median of 3 weeks and resolved by a median of 19 weeks (range 1 to 58 weeks). The rapid decrease in lymphadenopathy and treatment-related lymphocytosis along with concurrent improvement in baseline cytopenias has led to a high proportion of partial responses (PRs) early in treatment (Figure 1). Best overall response rate including PR and PR with lymphocytosis (PR+L) was 93% (PR=70%, PR+L=23%, SD=7%, PD=0%). For patients with del(17)(p13.1), the response rate was 100% (PR=72%, PR+L=28%). In the 4 patients with prior idelalisib therapy, the response rate also was 100% (PR=75%, PR+L=25%). To date, no disease progression or Richter's transformation has occurred (Figure 2). Pharmacokinetic results showed exposure of ACP-196 was dose proportional with no drug accumulation. At dosages as low as 100 mg QD, pharmacodynamic results showed low intra-patient variability, high Btk occupancy (> 90% over 24 hr) and high phospho-Btk inhibition (> 90% over 24 hr). Conclusion ACP-196 is a highly potent and selective oral Btk inhibitor with a favorable safety profile. Responses occur early in treatment with no disease progression to date either in heavily pretreated patients or those with high-risk prognosis factors. ACP-196 is currently in Phase 3 trials for TN (ClinicalTrials.gov NCT0247568) and R/R high-risk CLL (ClinicalTrials.gov NCT02477696). Disclosures Byrd: Acerta Pharma BV: Research Funding. Jones:Acerta Pharma BV: Research Funding. O'Brien:Acerta Pharma BV: Research Funding. Schuh:Acerta Pharma BV: Research Funding. Hillmen:Abbvie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Acerta Pharma BV: Research Funding; Gilead: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Stephens:Immunomedics: Research Funding; Acerta Pharma BV: Research Funding. Ghia:Pharmacyclics: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Acerta Pharma BV: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding; Roche: Consultancy, Research Funding; AbbVie: Consultancy. Devereux:Acerta Pharma BV: Research Funding. Chaves:Acerta Pharma BV: Research Funding. Barrientos:Acerta Pharma BV: Research Funding. Wang:Acerta Pharma BV: Employment, Equity Ownership. Huang:Acerta Pharma BV: Employment, Equity Ownership. Covey:Acerta Pharma BV: Employment, Equity Ownership, Patents & Royalties. Navarro:Acerta Pharma BV: Employment, Equity Ownership. Rothbaum:Acerta Pharma BV: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Izumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties. Hamdy:Acerta Pharma BV: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Furman:Gilead: Consultancy; Acerta Pharma BV: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau.
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- 2015
162. Efficacy and safety in genetic and clinical subgroups: Phase III RESONATETM trial of ibrutinib vs ofatumumab in CLL/SLL
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Ulrich Jaeger, Danelle F. James, Peter Hillmen, Steven Coutre, Stephen P. Mulligan, Nishitha Reddy, Susan O'Brien, John C. Byrd, Jennifer R. Brown, and Jacqueline C. Barrientos
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Oncology ,medicine.medical_specialty ,chemistry.chemical_compound ,chemistry ,business.industry ,Internal medicine ,Ibrutinib ,medicine ,Hematology ,Ofatumumab ,business - Published
- 2015
163. PP-054 EFFICACY OF IDELALISIB IN CLL SUBPOPULATIONS HARBORING DEL(17P) AND OTHER ADVERSE PROGNOSTIC FACTORS: RESULTS FROM A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL
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S. Stilgenbauer, Peter Hillmen, Bertrand Coiffier, Jeffrey P. Sharman, Richard R. Furman, Jacqueline C. Barrientos, Ian W. Flinn, John M. Pagel, B. Cheson, Thomas J. Kipps, Paolo Ghia, Michael Hallek, Susan O'Brien, Steven Coutre, and A. Zelenetz
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Double blind ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,Placebo-controlled study ,medicine ,Hematology ,Idelalisib ,business - Published
- 2014
164. Response to second-line therapy defines the potential for cure in patients with recurrent diffuse large B-cell lymphoma: implications for the development of novel therapeutic strategies
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Katya Ostrow, Morton Coleman, Richard R. Furman, Tsiporah B. Shore, Michael W. Schuster, Jacqueline C. Barrientos, Peter Martin, Rebecca Elstrom, John P. Leonard, Ari Melnick, Leandro Cerchietti, Jia Ruan, and Amy Chadburn
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Disease-Free Survival ,Young Adult ,Autologous stem-cell transplantation ,Refractory ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,In patient ,Young adult ,Aged ,Salvage Therapy ,Chemotherapy ,business.industry ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Lymphoma ,Surgery ,Recurrent Diffuse Large B-Cell Lymphoma ,Transplantation ,Treatment Outcome ,Female ,Lymphoma, Large B-Cell, Diffuse ,Neoplasm Recurrence, Local ,business ,Stem Cell Transplantation - Abstract
Background Patients with diffuse large B-cell lymphoma (DLBCL) who are not cured by initial therapy sometimes experience disease-free survival after autologous stem cell transplantation. Chemotherapy responsiveness before transplantation is a major predictor of outcome. Patients not responding to second-line regimens may receive third-line therapy in the hopes of achieving response, but outcome data are limited. Patients and Methods We identified patients with relapsed or refractory DLBCL at Weill Cornell Medical Center for whom data on responses to second-line chemotherapy were available. Results A total of 74 patients with relapsed or refractory DLBCL who underwent second-line chemotherapy between 1996 and 2007 were identified. Of these patients, 27 (36%) did not respond. The median overall survival of nonresponding patients was 4 months, and only 1 patient (4%) survived for 1 year. The choice of third-line aggressive chemotherapy instead of less intensive approaches did not confer a survival benefit. Conclusion Our data demonstrate that patients with recurrent DLBCL not responding to second-line chemotherapy demonstrate dismal outcomes. Trials of novel regimens should be prioritized as management strategies for these patients. Our data provide an important benchmark in the evaluation of the potential clinical value of such approaches.
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- 2010
165. Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib
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Y L Wang, Amy Chadburn, C Yang, Francis Y. Lee, John P. Leonard, Dongyun Zhang, Pin Lu, Daniel M. Knowles, F Ye, and Jacqueline C. Barrientos
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Cancer Research ,medicine.drug_class ,Dasatinib ,Syk ,Receptors, Antigen, B-Cell ,Antineoplastic Agents ,Biology ,Tyrosine-kinase inhibitor ,immune system diseases ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Humans ,Syk Kinase ,Interphase ,Protein Kinase Inhibitors ,Cell Proliferation ,Cell growth ,Phospholipase C gamma ,Intracellular Signaling Peptides and Proteins ,Hematology ,BCR Signaling Pathway ,Protein-Tyrosine Kinases ,medicine.disease ,Thiazoles ,Pyrimidines ,src-Family Kinases ,Oncology ,Drug Resistance, Neoplasm ,Cancer research ,Lymphoma, Large B-Cell, Diffuse ,Tyrosine kinase ,Diffuse large B-cell lymphoma ,Proto-oncogene tyrosine-protein kinase Src ,medicine.drug - Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although some patients can be cured by current therapies, novel agents are needed to further improve outcomes. We hypothesized that Src tyrosine kinase inhibition by dasatinib may have antilymphoma effects. Here, we demonstrate that dasatinib inhibits cell growth through G(1)-S blockage in five of seven DLBCL cell lines at clinically achievable concentrations. Compared to resting B cells, DLBCL has increased tyrosine phosphorylation activities. As expected, dasatinib inhibits phosphorylation of several Src family kinase members. However, this inhibition occurs in all cell lines regardless of their proliferative response to the drug. In contrast, the activity of two downstream signaling molecules, Syk and phospholipase Cgamma2 (PLCgamma2), are well correlated with cell line sensitivity to dasatinib, suggesting that these molecules are crucial in mediating the proliferation of activated lymphoma cells. Furthermore, dasatinib inhibits B-cell receptor signaling in primary lymphoma cells. Together, our findings not only show dasatinib as a potentially useful therapy for DLBCL but also provide insights into the pathogenesis of the lymphoma. The results further suggest the possibility of using Syk and PLCgamma2 as biomarkers to predict dasatinib therapeutic response in prospective clinical trials.
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- 2008
166. New monoclonal antibodies for non-Hodgkin's lymphoma
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Peter Martin, Jia Ruan, Morton Coleman, Rebecca Elstrom, Richard R. Furman, John P. Leonard, and Jacqueline C. Barrientos
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Oncology ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Monoclonal antibody ,Clinical Trials, Phase II as Topic ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,CD20 ,Chemotherapy ,biology ,Clinical Trials, Phase I as Topic ,business.industry ,Lymphoma, Non-Hodgkin ,Cancer ,Antibodies, Monoclonal ,Hematology ,medicine.disease ,Non-Hodgkin's lymphoma ,Lymphoma ,Treatment Outcome ,biology.protein ,Rituximab ,Antibody ,business ,medicine.drug - Abstract
The anti-CD20 rituximab represents the first widely available antibody for the treatment of cancer based on significant singleagent activity in indolent lymphoma [1]. In diffuse large B-cell lymphoma (DLBCL), the incorporation of rituximab with standard chemotherapy improves survival [2]. However, while it is clear that the use of rituximab has had a significant impact in improving outcomes in B-cell lymphoma, primary and secondary resistance remains an issue. Given the proof of principle for antibody-based lymphoma therapy with rituximab, a number of groups have pursued the development of monoclonals which either target CD20 in a potentially enhanced fashion or are directed against novel targets. Many of these efforts have demonstrated early promise; however, the challenges of developing new treatments in this era remain substantial.
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- 2008
167. Novel and engineered anti-B-cell monoclonal antibodies for non-Hodgkin's lymphoma
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Jacqueline C. Barrientos, Rebecca Elstrom, Richard R. Furman, Ruben Niesvizky, Morton Coleman, Peter Martin, John P. Leonard, and Jia Ruan
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medicine.drug_class ,Antibodies, Neoplasm ,Sialic Acid Binding Ig-like Lectin 2 ,Monoclonal antibody ,Antibodies, Monoclonal, Murine-Derived ,Mice ,Antigen ,immune system diseases ,Antigens, Neoplasm ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,CD40 Antigens ,B cell ,CD20 ,B-Lymphocytes ,Clinical Trials as Topic ,biology ,business.industry ,Lymphoma, Non-Hodgkin ,Antibody-Dependent Cell Cytotoxicity ,Antibodies, Monoclonal ,Hematology ,Drugs, Investigational ,medicine.disease ,Antigens, CD20 ,Non-Hodgkin's lymphoma ,Lymphoma ,Antigens, Differentiation, B-Lymphocyte ,medicine.anatomical_structure ,Immunology ,Monoclonal ,biology.protein ,B7-1 Antigen ,Rituximab ,business ,medicine.drug - Abstract
Over the past decade, the safety and efficacy of the anti-CD20 antibody rituximab has resulted in its use in virtually all patients with B-cell non-Hodgkin's lymphoma (NHL). Unfortunately, many patients who initially benefit from rituximab develop resistance while others may never respond. Both the successes and limitations of rituximab have heralded an explosion in research and development of novel monoclonal antibodies. Strategies employed to improve upon rituximab have included developing antibodies to target new epitopes of CD20 and new antigens, humanizing or creating fully human antibodies, and engineering antibodies with a potentially greater capacity for interaction with the host immune system. Each of these strategies has shown varying degrees of preclinical and clinical success. In this review we discuss the rationale for various strategies and report results from clinical trials employing these agents.
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- 2008
168. Adherence To The Ibrutinib 420 mg Dose Administered To Patients With Previously Treated CLL
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Steven Coutre, Paul M. Barr, Juthamas Sukbuntherng, Carol Moreno, Samuel Suzuki, John M. Pagel, Richard R. Furman, Jacqueline C. Barrientos, Tadeusz Robak, George Cole, Nishitha Reddy, Danelle F. James, Claire Dearden, Peter Hillmen, Ulrich Jaeger, Florence Cymbalista, Jennifer R. Brown, Jan A. Burger, Susan O'Brien, John C. Byrd, Stephen P. Mulligan, and Marco Montillo
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Oncology ,Cancer Research ,medicine.medical_specialty ,Mutation ,business.industry ,Cell ,Clone (cell biology) ,Hematology ,medicine.disease_cause ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,hemic and lymphatic diseases ,Internal medicine ,Ibrutinib ,medicine ,Previously treated ,business - Abstract
S24 analysis. Results: Trisomy12 (38-80% of cells) and NOTCH1 mutation (53-100% of cells) was detected in all patients. All patients had two or more cell populations defined by NOTCH1 mutation, Trisomy12 or both (major clone in 2/5 cases). Two patients demonstrated further intra-clonal diversity through either convergent or parallel evolution of two different or identical NOTCH1 mutations in Trisomy12 sub-clones, respectively. Conclusions: Trisomy12-NOTCH1 evolution is more complex than previously thought and may provide insight into progression and transformation. Grant Acknowledgements: Wessex Medical Research Innovation award, Kay Kendal Leukaemia Fund.
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- 2015
169. Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Results From the Randomized Phase III RESONATE™ (PCYC-1112) Trial
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Nishitha Reddy, Neil E. Kay, Paul M. Barr, Jacqueline C. Barrientos, Richard R. Furman, Thomas J. Kipps, Florence Cymbalista, Susan O'Brien, Ulrich Jaeger, Jennifer R. Brown, Stephen Devereux, Constantine S. Tam, Fong Clow, John C. Byrd, Danelle F. James, Maria Fardis, Peter Hillmen, Stephen P. Mulligan, Steven Coutre, and Jesse McGreivy
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Cancer Research ,medicine.medical_specialty ,business.industry ,Nausea ,Chronic lymphocytic leukemia ,Cancer ,Context (language use) ,Hematology ,Ofatumumab ,medicine.disease ,chemistry.chemical_compound ,Oncology ,chemistry ,Internal medicine ,Ibrutinib ,Medicine ,medicine.symptom ,business ,Adverse effect ,Progressive disease - Abstract
304 Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Results From the Randomized Phase III RESONATETM (PCYC-1112) Trial J Jennifer R. Brown, MD, PhD1, John C. Byrd, MD2, Susan O’Brien, MD3, Jacqueline C. Barrientos, MD4, Neil E. Kay, MD5, Nishitha M. Reddy, MBBS, MD6, Steven Coutre, MD7, Constantine S. Tam, MBBS, MD8, Stephen Mulligan, MBBS, PhD, FRACP, FRCPA9, Ulrich Jaeger, MD10, Stephen Devereux, PhD, FRCP, FRCPath11, Paul M. Barr, MD12, Richard Furman, MD13, Thomas Kipps, MD, PhD14, Florence Cymbalista, MD, PhD15, Maria Fardis, PhD, MBA16, Jesse McGreivy, MD16, Fong Clow, DSc16, Danelle F. James, MD, MAS16, Peter Hillmen, MD, PhD, FRCP, FRCPath17 1Dana-Farber Cancer Institute, Boston, MA, USA; 2The Ohio State University Medical Center, Columbus, OH, USA; 3University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4North Shore Long Island Jewish Health System, Manhasset, NY, USA; 5Mayo Clinic, Rochester, MN, USA; 6Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 7Stanford University School of Medicine, Stanford, CA, USA; 8Peter MacCallum Cancer Centre and St. Vincent’s Hospital, Melbourne, Australia; 9Royal North Shore Hospital, Sydney, Australia; 10Medical University of Vienna, Vienna, Austria; 11Kings College Hospital, NHS Foundation Trust Denmark Hill, London, UK; 12University of Rochester Cancer Center, Rochester, NY, USA; 13Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY, USA; 14Moores UCSD Cancer Center, San Diego, CA, USA; 15Hopital Avicenne, Paris, France; 16Pharmacyclics, Inc., Sunnyvale, CA, USA; 17The Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds, UK Context: Ibrutinib, a first-in-class, once-daily oral, covalent inhibitor of Bruton’s tyrosine kinase, demonstrated single-agent activity and an acceptable safety profile in a phase II relapsed/refractory (R/R) CLL/SLL study (Byrd et al. NEJM 2013). Ibrutinib is FDA approved for CLL patients who have received ≥1 prior therapy, and for patients with del(17p) CLL. Objective: Interim safety and efficacy results from an international, multicenter, open-label, randomized phase III study of single-agent ibrutinib vs ofatumumab in R/R CLL/SLL Patients: Patients with R/R CLL/SLL who received ≥1 previous therapy considered inappropriate for purine analogs Main Outcome Measures: Independent Review Committee-assessed PFS (primary); overall survival (OS), ORR, safety (secondary) Intervention: 420 mg oral ibrutinib daily or IV ofatumumab 300/2000 mg (12 doses) Results: 391 patients (median age 67 years, 40% ≥70 years, 30% del17p); 195 randomized to ibrutinib, 196 to ofatumumab. Ibrutinib patients had median 3 prior therapies vs 2 for ofatumumab. Ibrutinib significantly improved PFS (median not reached vs 8.1 months; HR 0.215, 95% CI 0.146-0.317, P
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- 2015
170. Long-term follow-up of a phase Ib trial of idelalisib (IDELA) in combination with chemoimmunotherapy (CIT) in patients (pts) with relapsed/refractory (R/R) CLL including pts with del17p/TP53 mutation
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Jeff Porter Sharman, Ian W. Flinn, Thomas E. Boyd, Nina D. Wagner-Johnston, Kanti R. Rai, Sven de Vos, Marshall T. Schreeder, Thomas Jahn, Richard R. Furman, Steven Coutre, Bess Sorensen, John P. Leonard, Jacqueline C. Barrientos, and Anthony Viggiano
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Long term follow up ,business.industry ,Relapsed CLL ,Tp53 mutation ,Surgery ,Chemoimmunotherapy ,Internal medicine ,Relapsed refractory ,medicine ,Rituximab ,In patient ,Idelalisib ,business ,medicine.drug - Abstract
7011 Background: IDELA is a first-in-class PI3Kδ inhibitor approved in combination with rituximab for pts with relapsed CLL. Methods: Pts with R/R CLL were treated continuously with 150 mg BID oral...
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- 2015
171. Dose adherence and baseline exposure analysis of the ibrutinib 420 mg dose administered to patients with previously treated chronic lymphocytic leukemia (CLL)
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Samuel Suzuki, Richard R. Furman, Tadeusz Robak, Paul M. Barr, Jan A. Burger, John C. Byrd, Jennifer R. Brown, Susan O'Brien, Marco Montillo, John M. Pagel, Nishitha Reddy, Danelle F. James, Jacqueline C. Barrientos, Peter Hillmen, Claire Dearden, Stephen P. Mulligan, Ulrich Jäger, Steven Coutre, Carol Moreno, and Florence Cymbalista
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Cancer Research ,biology ,business.industry ,Chronic lymphocytic leukemia ,Pharmacology ,medicine.disease ,stomatognathic diseases ,chemistry.chemical_compound ,Oncology ,chemistry ,Oral administration ,hemic and lymphatic diseases ,Ibrutinib ,biology.protein ,medicine ,Bruton's tyrosine kinase ,Previously treated ,business ,Tyrosine kinase - Abstract
7012 Background: Ibrutinib (ibr), a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK), is rapidly eliminated from plasma after oral administration (Advani, JCO ...
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- 2015
172. A phase 1b trial of duvelisib, a PI3K-δ,γ inhibitor, in combination with obinutuzumab in patients with CLL/SLL previously treated with a Bruton’s tyrosine kinase inhibitor (BTKi)
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Jill Rodstrom, Jennifer R. Brown, John C. Byrd, Nitin Jain, James S. Blachly, Jacqueline C. Barrientos, Virginia Kelly, Shijie Tang, Jennifer Sweeney, and Stephanie Garnick
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Cancer Research ,biology ,business.industry ,Pharmacology ,Duvelisib ,chemistry.chemical_compound ,Oncology ,chemistry ,immune system diseases ,Obinutuzumab ,hemic and lymphatic diseases ,biology.protein ,Medicine ,Bruton's tyrosine kinase ,In patient ,Previously treated ,Receptor ,business ,PI3K/AKT/mTOR pathway ,Bruton's tyrosine kinase inhibitor - Abstract
TPS7100 Background: Abrogating B-cell receptor pathway signaling through BTK inhibition is an effective treatment strategy for CLL. However, some patients (pts) do not respond, or progress despite ...
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- 2015
173. CLL Sera Drive Maturation of Normal Monocytes to M2-like Macrophages By Direct and Indirect Mechanisms
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Sonia Marsilio, Jacqueline C. Barrientos, Nicholas Chiorazzi, Steven L. Allen, Jonathan E. Kolitz, Xiao J. Yan, Barbara Sherry, and Kanti R. Rai
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Interferon type II ,medicine.medical_treatment ,CD14 ,Immunology ,Antigen presentation ,CD23 ,Cell Biology ,Hematology ,CD38 ,Biology ,CD16 ,Biochemistry ,Molecular biology ,Cytokine ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Interleukin 4 ,medicine.drug - Abstract
Background. Chronic lymphocytic leukemia (CLL) is a prototypic microenvironment-dependent B-cell malignancy, in which neoplastic B cells co-evolve with a supportive tissue microenvironment to promote leukemia cell survival, growth, and drug-resistance. Within the microenvironment, hematopoietic and non-hematopoietic stromal and tumor cells produce factors that recruit circulating monocytes to tumor sites and induce differentiation into macrophages. Mirroring the Th1/Th2 paradigm, cells of monocyte-macrophage lineage reprogram their functions in response to environmental signals, undergoing M1 (classical) or M2 (alternative) activation, which represent extremes of a broad continuum of functional states. Classical M1 cells (activated by IFNs and TLR) are involved as inducer and effectors cells in polarized Th1 responses and as effectors of resistance against intracellular parasites and tumors. In contrast, M2 cells (activated by IL4 and IL13) are poor at antigen presentation, suppress Th1 adaptive immunity, actively scavenge debris, contribute to the dampening of inflammation, promote angiogenesis and tissue remodeling, and support tumor progression. One way to distinguish the two types of macrophages is based on surface antigen expression: M1-like cells up-regulate Fcg receptors I, II, III such as CD16, CD32 and CD64, whereas M2-like macrophages display abundant levels of CD23, CD163, and scavenger receptors (e.g. MCR1). Understanding the microenvironment and the crosstalk between B-CLL cells and their tissue neighbors can give insight into disease biology and for therapy. Aim. To investigate if the CLL milieu, contained within serum, influences monocyte-to-macrophage differentiation, promoting an anti (M2)- or pro (M1)- inflammatory microenvironment. Methods. Monocytes from healthy donors were isolated using Monocytes Isolation Kit II (Miltenyi) and cultured in Ultra-Low Attachment plates with 10% normal human AB serum or 10% CLL-derived serum -/+ IL4 or IFNg for 3 days. Macrophages were stained for CD23, CD64, CD32, MRC1, CD14, CD16, and data were acquired with a BD LSRII flow cytometer and analyzed by FlowJo V7.2.4 software. Results. Normal monocytes were differentiated to macrophages in vitro in the presence of sera from 24 untreated CLL patients with different prognostic factors (genomic aberrations, % CD38 and IGHVmutational status). About 45% of the CLL sera (N=10; 6 M-CLL, 4 U-CLL) drove macrophage maturation toward an M2-like phenotype, as assessed by surface expression of CD23, CD64, CD32, CD36, MRC1, etc. These 10 sera induced higher CD23 expression after 3 days in culture compared to AB human serum, whereas the levels of M1-specific markers (CD64 and CD32) did not change relative to the control. Interestingly all of these 10 CLL sera came from patients bearing 13q14 Δ (N=5), 17p13 Δ (N=3) or a combination of these (13q14 Δ + 17p13 Δ; N=1) and 17p13 Δ + trisomy12; N=1)). On the contrary, no increase in CD23 expression was detected in presence of sera from patients with 11q22 Δ (N=1) alone or in combination with 13q14 Δ (13q14 + 11q22 Δ; N=5). Of note, treatment with a neutralizing mAb specific for IL-4 did not block the CLL serum induced up-regulation of CD23 (N=2). In a parallel set of studies, normal monocytes were incubated with each of the 24 CLL sera in combination with the M1 promoting cytokine, IFNg or the M2 promoting cytokine, IL4. In all cases IL4 induced CD23 up-regulation and an M2 phenotype. Paradoxically, IFNg, which normally induces an M1 phenotype, also induced an M2 phenotype (i.e., enhanced CD23 expression) when co-cultured with sera from a subset patients (N=8; 6 M-CLL and 2 U-CLL). Of note, the IFNg stimulatory effect on CD23 expression was observed with a different set of sera from those that directly stimulated CD23 expression. Furthermore, CD64 expression did change after incubation with IFNg + CLL serum in 6 of 8 cases, yielding another unusual (CD23+CD64+) macrophage phenotype. The 2 sera that did not yield such hybrids were from M-CLL patients. Conclusions. Sera from CLL patients contain two apparently novel activities that mature normal monocytes to M2-like macrophages. The first acts directly by an action that is apparently independent of IL-4 and associates with 13q14 Δ or 17p13 Δ abnormalities. The second acts indirectly through IFNg and leads to macrophages with a hybrid M2/M1 phenotype (CD23+CD64+), suggestive of a new type of macrophage. Disclosures No relevant conflicts of interest to declare.
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- 2014
174. IGHV-D-J Ultra-Deep Sequencing Reveals APOBEC and AID Targeted Mutations during Clonal Evolution of CLL in a Xenograft Mouse Model
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Piers E.M. Patten, Jonathan E. Kolitz, Charles C. Chu, Xiao-Jie Yan, Steven L. Allen, Kanti R. Rai, Jacqueline C. Barrientos, Nicholas Chiorazzi, Thomas MacCarthy, and Chaohui Yuan
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APOBEC ,Genetics ,Chronic lymphocytic leukemia ,Immunology ,Somatic hypermutation ,Cell Biology ,Hematology ,Cytidine deaminase ,Biology ,medicine.disease ,Biochemistry ,Somatic evolution in cancer ,Germline mutation ,hemic and lymphatic diseases ,medicine ,Mutation frequency ,IGHV@ - Abstract
Targeted ultra-deep sequencing of chronic lymphocytic leukemia (CLL) cells has enabled the assessment of subclone development based on mutations in the IGHV-D-J signature sequence in the dominant CLL clone. We have utilized the Roche 454 FLX pyrosequencing system, which can generate long sequencing reads containing both the immunoglobulin variable region (IGHV-D-J) and part of the immunoglobulin μ constant region (IGHM) in a single sequence, to analyze the mutational characteristics of newly evolved subclones to determine if they derive from AID/APOBEC activity. APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide) is a family of cytidine deaminases that includes AID (activation-induced cytidine deaminase). AID is required for somatic hypermutation in germinal center B lymphocytes. CLL cells, like most non-germinal center B lymphocytes, generally do not express AID. However, AID expression in a small fraction of the CLL clone correlates with worse patient outcome. This observation has led to the hypothesis that abnormal AID expression promotes new off-target non-immunoglobulin mutations and DNA deletions and rearrangements leading to the development of more aggressive disease. CLL is not alone in this hypothesis, as AID is involved in the evolution of other leukemias/lymphomas and reportedly in other types of tumors such as breast and gastrointestinal cancers. Large scale cataloguing of somatic mutations by ultra-deep sequencing of a wide array of cancers has revealed an AID/APOBEC mutational signature in many cancers, including CLL (Alexandrov et al. 2013 Nature). Thus, AID/APOBEC family members may be involved in somatic mutations leading to the evolution of aggressive cancers. To test if AID/APOBEC proteins could be mutationally active in CLL, we analyzed the characteristics of new mutations found in IGHV-D-J-M in CLL cells that were activated in vivo after adoptive transfer into alymphoid NOD/Shi-scid,γcnull (NSG) mice. This CLL xenograft model activates a large fraction of CLL cells, which become AID+ and facilitates the detection of new subclones expressing mutated IGHV-D-Js by ultra-deep sequencing. Four unmutated IGHV CLL (U-CLL) and 3 mutated IGHV (>2% compared to germline) CLL (M-CLL) samples were each adoptively transferred into individual NSG mice. After expansion of CLL, the mice were sacrificed and the specific CLL clone IGHV-D-J-M was amplified from xenograft mouse spleen cDNA. Pre-transfer CLL cell cDNA was also amplified to establish a baseline comparison. Ultra-deep sequencing of these samples resulted in 2,318,800 sequence reads, which were subsequently trimmed according to the Roche 454 algorithm and further processed by custom R scripts. The sequence reads were aligned to the dominant CLL clone IGHV-D-J-M sequence to remove insertions, deletions, and poor quality ( AID mutational characteristics in new subclones were assessed using the SHMTool (http://scb.aecom.yu.edu/shmtool) algorithms to calculate mutation frequencies in IGHV-D-J relative to IGHM and at AID mutation hotspots and coldspots. Other APOBEC family members have a different mutation hotspot site, which we analyzed by custom R scripts. All CLL samples showed evidence of AID mutational activity: higher IGHV-D-J versus IGHM mutations in all cases, increased AID hotspot mutation frequency in five cases, and decreased AID coldspot mutation frequency in five cases. Increased APOBEC hotspot mutational activity was seen in four cases. This APOBEC mutational activity is consistent with increased APOBEC3 gene expression and the genomic somatic mutation pattern observed recently in CLL (Rebhandl et al. 2014 Leukemia). Thus, both U-CLL and M-CLL are capable of producing mutations characteristic of AID or APOBEC activity. These data are consistent with the hypothesis that AID/APOBEC may promote new mutations leading to the evolution of aggressive CLL. Disclosures No relevant conflicts of interest to declare.
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- 2014
175. Vemurafenib Has Potent Antitumor Activity in Patients with Relapsed/Refractory BRAF Mutant Hairy Cell Leukemia
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Jae H. Park, Kanti R. Rai, Michael F. Berger, Helen Won, Eunhee Kim, Stephen S. Chung, Martin S. Tallman, Alan Saven, Ross L. Levine, Michael R. Grever, Martha Wadleigh, Young Rock Chung, Omar Abdel-Wahab, Jessica K. Altman, Mario E. Lacouture, Richard Stone, Jacqueline C. Barrientos, and Neal Rosen
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business.industry ,medicine.medical_treatment ,Immunology ,Purine analogue ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Minimal residual disease ,medicine.anatomical_structure ,Cytokine ,Refractory ,Median follow-up ,medicine ,Cancer research ,Hairy cell leukemia ,Bone marrow ,Vemurafenib ,business ,medicine.drug - Abstract
Background: Although treatment with purine analogs is associated with a high response rate, hairy cell leukemia (HCL) remains incurable with a 30-40% relapse rate. For these patients (pts) and those intolerant to purine analogs, novel therapies are needed. The major finding that BRAFV600E mutations occur in 98% of HCL suggests BRAF as a promising therapeutic target. We therefore designed a phase II trial to (1) determine the clinical efficacy of the BRAF inhibitor vemurafenib in pts with relapsed/ refractory HCL and (2) identify biologic determinants of response and resistance to vemurafenib in HCL. Patients and Methods: Pts with BRAF mutant HCL who were refractory or resistant to purine analogs, or who had ≥2 relapses with an indication for treatment (ANC ≤1.0, HGB ≤10, or PLT ≤100K) were enrolled. Eligible pts received vemurafenib 960mg twice daily for 3 months. Bone marrow (BM) evaluations were performed after 3 months to assess response. Pts with partial (PR) or complete response (CR) with detectable minimal residual disease (MRD) were allowed to receive vemurafenib for up to 3 additional months. The primary endpoint of the study was overall response rate (ORR: CR + PR). Using a Simon’s mini-max two-stage design, if at least 4 of the 19 pts (≥20%) achieve ORR in the first stage, an additional 17 patients will be accrued to the second stage. If 11 or more pts achieve ORR out of the 36 pts, the study would be considered worthy of further investigation. Serial peripheral blood and/or BM samples were collected during the study for quantitative BRAF mutant allele burden, serum cytokine, multiparameter flow cytometry, and targeted next-generation sequencing analysis of a 350-gene panel to detect potential predictors of resistance and identify genes collaborating with BRAF mutations in HCL. Results: 22 pts have been enrolled and 20 pts received treatment. The median age was 61 years (range 44-77), and the median number of prior treatments was 3.5 (range 1-7). 20 pts are evaluable for toxicity and 17 patients for disease response with a median follow up of 10 months (range 2-19). The most common adverse events were rash (40%, Gr1-2), arthralgia (30%, Gr1-2), photosensitivity (20%, Gr1), and pruritis (15%, Gr1). Three pts developed squamous cell carcinoma (SCC), all of whom had previous history of SCC. All patients were able to complete the intended treatment (3 cycles: 11 pts, >3 cycles: 6 pts). All 17 evaluable pts achieved complete hematologic recovery with an overall response rate (ORR) of 100%. 6 pts achieved CR (4 MRD- and 2 MRD+) and 11 pts achieved PR with very minimal disease (Figure 1). Responses were rapid with reduction of circulating hairy cells within 24 hours and normalization of sCD25 within 2-3 weeks (Figure 2). This correlated with dephosphorylation of ERK at 1 month. Several additional inflammatory cytokines correlated with the leukemic cell burden identifying novel tumor markers in HCL including sTNF-R2, sIL-1R2, and sIL4R. Genetic analysis identified a median of 3 (range 0-5) somatic mutations co-existing with the BRAFV600E mutation in HCL including recurrent mutations in MLL2 and CREBBP (Figure 2). Several of these alterations were present as minor clones identifying a clonal architecture in HCL which was not previously appreciated. One pt was found to have de novo resistance to vemurafenib. Genetic analysis identified that this pt’s pretreatment HCL cells harbored a previously undescribed missense mutation in IRS1 (IRS1P1201S) in addition to BRAFV600E mutation. Given prior knowledge that IRS1 (Insulin Receptor Substrate 1) activates both MAP kinase and PI3K-AKT signaling, we compared the effects of expression of wildtype and mutant IRS1 cDNAs on signaling. This revealed robust activation of PI3K-AKT signaling induced by IRS1P1201S-mutant cells relative to wildtype. Conclusions: While longer follow-up is needed to assess the durability of the response, our results indicate that vemurafenib has potent antitumor activity in pts with relapsed/refractory BRAF mutant HCL. These data confirm the MAP kinase pathway as a rational promising therapeutic target in HCL and identify activation of signaling pathways parallel to the MAP kinase pathway as a first mechanism of RAF inhibitor resistance in a hematological malignancy. Subsequent studies will be required to prove that inhibition of B-raf may be the best initial therapy in HCL pts who require treatment. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Park: Genentech: Research Funding. Off Label Use: Vemurafenib in hairy cell leukemia. Rosen:Novartis: Consultancy.
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- 2014
176. Reciprocal Densities of CXCR4 and CD5 Define Subfractions of Chronic Lymphocytic Leukemia Clones Differing in Phenotype and Response to Environmental Stimuli: Towards a Better Definition of Targetable Components of Leukemic Clones
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Jacqueline C. Barrientos, Jonathan E. Kolitz, Cristina Sison, Kanti R. Rai, Rajendra N Damle, Sonal Temburni, Nicholas Chiorazzi, and Jaison Jain
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education.field_of_study ,Chronic lymphocytic leukemia ,Immunology ,Population ,breakpoint cluster region ,Syk ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Phenotype ,Immunoglobulin D ,CD19 ,immune system diseases ,hemic and lymphatic diseases ,Cancer research ,medicine ,biology.protein ,CD5 ,education - Abstract
Although chronic lymphocytic leukemia (CLL) is an accumulative disorder of CD5+ B cells, a proliferative fraction exists and the extent of this proliferation correlates with clinical course. We previously demonstrated heterogeneous in vivo labeling kinetics of cells in 3 clonal fractions sorted based on reciprocal densities of chemokine (C-X-C motif) receptor 4 (CXCR4) and CD5 from CLL cases recruited on an in vivo labeling study. In that study, the CXCR4dimCD5br fraction contained more 2H-labeled DNA and hence recently divided cells (proliferative fraction) than the CXCR4brCD5dim(resting) fraction. Here, we have analyzed multiple CXCR4/CD5 based subclonal fractions and characterized their phenotypic differences and ability to respond to signals via the BCR and CXCR4 or a combination of the two. PBMCs from a cohort of 50 untreated IgM+ CLL cases were used for this study. Subclonal fractions marked based on differences in relative densities of CXCR4 and CD5 by CLL cells are referred to as CXCR4br, CXCR4int or CXCR4dim and CD5br, CD5int or CD5dim. Sub-populations adjacent to each other on flow cytometric plots differed at least 5 fold in the densities of both CXCR4 and CD5. When subcategorizing CLL clones based on these markers, 9 subfractions were identified. To permit comparisons between these fractions, each was defined as containing only 2-5% of the total clonal CD19+CD5+population while ensuring no overlap in CXCR4 or CD5 densities among each fraction. Interestingly, certain phenotypic and signaling features consistently clustered with distinct subfractions of the CLL clone. Subfraction analyses confirmed an enrichment of Ki-67+ cells in the CXCR4dimCD5br proliferative fraction of every CLL case. In addition, this subfraction showed the highest percentage of cells expressing smIgM and smIgD (p When analyzing phosphorylation of Akt, Erk, p38MAPK and Syk by phosphoflow among all cases, the CXCR4brCD5br fraction exhibited the highest constitutive levels. Constitutive levels of phospho-Btk and - Syk were significantly higher in the CXCR4int CD5br subfraction in M-CLL than in U-CLL cases (p Together, these findings highlight the impact of the molecules expressed by the different subfractions on their ability to relay/inhibit signals elicited via the BCR or CXCR4. They also provide a general frame of reference to further understand functional post-replicative intraclonal heterogeneity of CLL clones and help define aggressive subfractions of the CLL clone as target populations for future therapies. Disclosures No relevant conflicts of interest to declare.
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- 2014
177. Ibrutinib Inhibits Concomitant TLR and BCR- Driven Proliferation of Chronic Lymphocytic Leukemia Cells and Overrides the Supportive Survival-Promoting Effects of Microenvironmental Signals
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Jacqueline C. Barrientos, Kanti R. Rai, Jonathan E. Kolitz, Nicholas Chiorazzi, Steven L. Allen, Betty Chang, Rajendra N Damle, and Sonal Temburni
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Stromal cell ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,Immunology ,B-cell receptor ,breakpoint cluster region ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,Chemokine receptor ,Cytokine ,chemistry ,immune system diseases ,hemic and lymphatic diseases ,Ibrutinib ,medicine ,Cancer research ,biology.protein ,Stromal cell-derived factor 1 - Abstract
Chronic lymphocytic leukemia (CLL) cells interact with external stimuli via several receptors, including the B cell receptor (BCR) and cytokine/chemokine receptors. CLL cells also express varying levels of functional Toll-like receptors (TLR), including TLR7 and TLR9. In vivo, the interaction of CLL cells via BCR or TLR occurs within a supportive microenvironment that provides them with survival and proliferative signals. CLL clonal turnover, occurring as an outcome of these and other interactions might lead to the release of naked nuclear material into the microenvironment and permit an interaction with these remnants of dying/dead cells. This could lead to repeated low level T cell-independent activation, possibly resulting in disease progression. To this effect, concomitant engagement of BCR and TLR leads to differential Erk phosphorylation and apoptosis rescue in CLL cases segregated by IgV gene mutational status. Here, we have studied the impact of stromal cells on TLR-mediated activation of negatively selected CLL cells from 24 untreated cases. Marked increases in percentages of CD69+ CLL cells and density of HLA-DR expression were observed within 18 hrs after exposure to TLR7 or TLR9 agonists (Imiquimod or ODN2006, respectively). However, although CLL cells activated via their TLRs in the presence of irradiated stromal cells (HS-5) did not show further changes in CD69 and HLA-DR expression, they exhibited significantly elevated levels (p Ibrutinib covalently binds and inhibits Bruton tyrosine kinase, BTK, a molecule critical for BCR signaling. In addition, ibrutinib inhibits cell signaling occurring when CXCR4 binds its ligand, stromal derived factor-1/CXCL12. However, the effects of ibrutinib on concomitant TLR+ BCR-mediated signaling in CLL have not yet been reported. We evaluated the impact of ibrutinib over a dose range of 0.1 - 25mg/ml on TLR-mediated CLL cell apoptosis and proliferation in presence/absence of stromal help, as mentioned above. Pre-incubation of CLL cells with ibrutinib for 2 hrs significantly lowered TLR-mediated induction of Survivin and Mcl-1 within 36 hrs of culture. Exposure to ibrutinib also inhibited 3H-thymidine incorporation in non-stimulated (average: 22%; range: 7-43%) and TLR7- (average: 21%; range: 7-49%) or TLR9- (average: 43%; range: 11-98%) activated CLL cells in 14/14 cases. Ibrutinib treatment resulted in an increase in TLR7-induced apoptosis in 3 of 4 CLL cases and in TLR9-induced apoptosis in 2 of 4 CLL cases. Even when CLL cells from 6 patients were cocultured with stromal cells, ibrutinib reduced cell proliferation to 45-65% of that observed in untreated cells induced via TLR7 or TLR9 alone or when combined with an anti-BCR signal. These findings reiterate the pivotal role of the microenvironment in nurturing CLL cells activated via several types of receptors. Ibrutinib, known to be efficacious in inhibiting BCR signaling, can also abrogate events downstream of TLR7 and TLR9 signaling in CLL. Importantly, inhibition of TLR 7 and 9 signaling by ibrutinib can override the protective effects from stroma-derived signals. These anti-proliferative effects of ibrutinib may be especially relevant and important for curbing concomitant activation via the BCR, TLR, and chemokine receptor pathways that likely synergize and thereby contribute to the aggressiveness of the disease. Disclosures Barrientos: Pharmacyclics, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rai:Pharmacyclics, Inc: Membership on an entity's Board of Directors or advisory committees. Chang:Pharmacyclics, Inc: Employment, Equity Ownership. Chiorazzi:Pharmacyclics, Inc: Research Funding.
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- 2014
178. Long-Term Follow-up of a Phase 1 Study of Idelalisib (ZYDELIG®) in Combination with Anti-CD20 Antibodies (Rituximab [R] or Ofatumumab [O]) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
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Ian W. Flinn, Yeonhee Kim, Jacqueline C. Barrientos, Richard R. Furman, Thomas E. Boyd, Nathan Fowler, Sven de Vos, Marshall T. Schreeder, Kanti R. Rai, Jeff P. Sharman, Steven Coutre, John P. Leonard, Anthony Viggiano, and Thomas Jahn
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Bendamustine ,medicine.medical_specialty ,Performance status ,business.industry ,Immunology ,Cell Biology ,Hematology ,Ofatumumab ,Biochemistry ,Rash ,Gastroenterology ,Fludarabine ,Discontinuation ,Surgery ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Medicine ,Rituximab ,medicine.symptom ,business ,Idelalisib ,medicine.drug - Abstract
Introduction: PI3Kδ signaling is critical for the proliferation, survival and homing/tissue retention of malignant B cells. Idelalisib is a first-in-class, highly selective, oral inhibitor of PI3Kδ recently approved for the treatment of relapsed CLL in combination with R. This report summarizes the long-term follow-up of the Phase 1 combination experience of idelalisib with anti-CD20 antibodies. Methods: This Phase 1 study evaluated idelalisib for relapsed/refractory CLL continuously given at 100 mg BID (4 of the pts receiving R) or 150 mg BID (all other pts) in combination with a total of 8 infusions of rituximab (R, 375 mg/m2 weekly x 8), or a total of 12 infusions of ofatumumab (O, 300mg initial dose either on Day 1 or Day 2 relative to the first dose of idelalisib, then 1,000 mg weekly x 7, then 1,000 mg every 4 wks x 4). Pts on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical response was evaluated according to published criteria (Hallek 2008; Cheson 2012). Results: 40 pts (12F/28M) with a median (range) age of 66 (43-87) years and a WHO performance status of 0 (24, 60%) or 1 (16, 40%) were enrolled. 19 pts received idelalisib in combination with R and 21 with O. Adverse disease characteristics (n, %) included Rai Stage III/IV (20, 50%), bulky lymphadenopathy (23, 58%), refractory disease (15, 38%), multiple prior therapies (median 2, range: 1-9). Almost all pts (39, 98%) had at least 1 prior therapy containing R, and 3 of the 21 pts (14%) receiving idelalisib + O had received prior O. 63% of the pts receiving idelalisib + R, and 48% of the pts receiving idelalisib + O were refractory to R. Prior therapies also included alkylating agents (31, 78%, [bendamustine: 20, 50%]) and purine analogs (31, 78%, [fludarabine: 28, 70%]). Data available from 39 pts showed that 11 (28%) pts had evidence of del(17p) and/or TP53 mutations and 30 (75%) had unmutated IGHV. As of 7/15/2014, the median (range) treatment duration was 18 (0-44) months. 23 (58%) pts have completed the primary study and enrolled into the extension study. Primary reasons for study discontinuation (as reported by investigators) included disease progression (14, 35%), adverse events (AEs) (12, 30%), investigator request (3, 8%), withdrawal of consent (n=1), BMT (n=1). There were a total of 8 deaths on study: 2 deaths occurred after disease progression, and 6 pts died because of AEs (all assessed as unrelated/unlikely related to idelalisib by investigators). A total of 4 pts (10%) were continuing idelalisib treatment on the extension study at time of analysis. Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea/colitis (55%/23%), cough (40%/3%), pyrexia (40%/3%), dyspnea (30%/3%), fatigue (25%/0%) nausea (25%/0%), rash (20%/0%), pneumonia (20%/18%), and pneumonitis (8%/5%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 30%/10%. Re-exposure to idelalisib after resolution of TA elevation generally was successful; only 1 patient discontinued the study because of (recurrent) TA elevation. Other AEs leading to study discontinuation and reported as possibly/probably related to idelalisib included diarrhea/colitis (4, 10%), pyrexia (n=1), interstitial lung disease (n=1), pneumonia (n=1), rash (n=1), psoriasis (n=1). Secondary malignancies leading to discontinuation (all reported as unrelated) were breast cancer (n=1), recurrent colon cancer (n=1), AML (n=1). There was no obvious overall difference in the toxicity reported for pts receiving idelalisib with rituximab compared to those with ofatumumab. The ORR (N=40) was 83% (33/40), with 2 CRs (5%) reported. Median PFS (N=40) and duration of response (DOR) (n=33) were 24 months. Median (range) time to response was 1.9 (range 1.7-16.9) months. Median overall survival (OS) has not been reached with a KM estimate for OS of 80% at 24 months. For the 11 pts with del(17p) and/or TP53 mutations, the response rate was 73%, and the median PFS and DOR were 20 and 24 months, respectively. Conclusions: Combinations of idelalisib with anti-CD20 antibodies such as R or O represent non-cytotoxic regimens with acceptable safety profiles and considerable activity resulting in durable tumor control in pts with relapsed/refractory CLL, including those with high risk factors such as del(17p) or TP53 mutations. A Phase 3 trial evaluating the efficacy of idelalisib in combination with ofatumumab is ongoing (NCT01659021). Disclosures Furman: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. de Vos:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Fowler:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment, Equity Ownership. Viggiano:Gilead Sciences: Employment, Equity Ownership. Jahn:Gilead Sciences: Employment, Equity Ownership. Coutre:Gilead Sciences: Research Funding.
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- 2014
179. IGHV4-34 B-Cell Receptor Immunoglobulins from CLL Stereotyped Subset 4 React with Influenza A Virus: Requirement for IGHV-D-J/Iglv-J Rearrangement and Isotype Switching to IgG
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Nicholas Chiorazzi, Ten Feizi, Florian Krammer, Rosa Catera, Jacqueline C. Barrientos, Xiao-Jie Yan, Steven L. Allen, Chao Gao, Kanti R. Rai, Adolfo García-Sastre, Yun Liu, and Jonathan E. Kolitz
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biology ,Immunology ,B-cell receptor ,Hemagglutinin (influenza) ,Cell Biology ,Hematology ,medicine.disease_cause ,Biochemistry ,Isotype ,Virology ,Epitope ,Immunoglobulin class switching ,Antigen ,biology.protein ,Influenza A virus ,medicine ,Antibody - Abstract
B-cell chronic lymphocytic leukemia (CLL) clones from different patients can express stereotyped BCR immunoglobulins (IGs) that share very similar IGHV-D-J rearrangements and HCDR3s, often with similar IGLV gene usage, suggesting that they were selected by common antigenic epitope(s). Patients bearing IGHV4-34/D5-18/JH6/VK2-30/JK2 rearrangements belong to one of such stereotyped subsets, subset 4. In addition, subset 4 BCRs are always IgG switched and exhibit IGHVsomatic mutations. The germline IGHV4-34 gene is inherently autoreactive and is often found in antibodies that bind to the surfaces of erythrocytes and B lymphocytes through the linear i blood group antigen, poly-N-acetyllactosamine (NAL). To test the reactivity of subset 4 monoclonal antibodies (mAbs) to auto and foreign antigens, we expressed a panel of CLL BCR IGs carrying IGHV4-34, 1-69, 3-21, and 4-39 as recombinant human IgGs and tested the binding of these CLL mAbs to HEp-2 cells by intracellular immunostaining. Three subset 4 mAbs (183, 240 and 342) showed only weak binding to permeabilized HEp-2 cells compared to other CLL mAbs which often showed strong binding to cytoplasmic structures. Furthermore, because apoptotic cells are a source of autoantigens in autoimmune conditions, the reactivity of CLL mAbs to non-permeabilized, irradiated Ramos B and Jurkat T cell line cells was also tested by flow cytometry. Surprisingly, the average binding percentage to apoptotic Ramos B cells of subset 4 mAbs 183, 240, and 342 was only 6, 5, and 4%, respectively. Moreover, all three subset 4 mAbs exhibited minimum binding to live or apoptotic Jurkat T cells (1-10% and 4-6% to each population, respectively). We next tested the reactivity of subset 4 mAbs to i/I carbohydrate epitopes, the known targets of many non-stereotyped IGHV4-34 mAbs, using an i/I focused microarray containing 60 i/I related oligosaccharides. Notably, the subset 4 mAbs showed no binding at a concentration of 10 μg/mL. Together, the above results suggest that CLL subset 4 mAbs have weak or no interaction to the known autoantigens recognized by other non-stereotyped IGVH4-34 IGs. Hence we hypothesized that the restricted IGHV-D-Jrearrangement, somatic mutations, and IgG switch of subset 4 were acquired by selection for other auto or foreign antigens. To test this possibility, we screened CLL mAbs against a library of over 8,000 full length human proteins, including an influenza A virus and some human viral gene encoded proteins. Each subset 4 mAb showed selective and strong binding to influenza A virus H3N2 Texas 1/77 at concentration of 50 μg/mL; this binding was 6-15 times higher than that of other non-subset 4 mAbs, which included two IGHV4-34, non-stereotyped CLL mAbs. Because the binding to virus is usually mediated via its glycoprotein hemagglutinin (HA), we tested reactivity of subset 4 mAbs to the HA of influenza A H3N2 Texas 1/77. Subset 4 mAbs had on average 2 fold (1.8-2.2) higher binding signals than the two non-stereotyped IGHV4-34mAbs. To explore if subset 4 mAbs recognize other influenza A virus strains, we tested the binding of a representative subset 4 mAb 183 to HAs from 11 strains that belong to 3 subtypes: H1 (4 strains), H2 (1 strain) and H3 (6 strains). Clear preferential binding to all 6 H3s and to some of H1s was found. mAb 183 did not bind to H2 (A/Japan/305/1957 H2N2). The average binding signal ratio to H3s, H1s and H2 was 2.4:1.6:1. Testing to another hemagglutinin subtype H7 (A/Anhui/1/13 H7N9) showed that mAb 183 did not interact with H7. Intrigued by the observation that CLL subset 4 BCR IGs are always the IgG isotype, we tested if isotype switching contributed to antigen recognition by expressing CLL 183 IGHV-D-Jas divalent human IgM (mAb183M) and checked its reactivity to virus A H3N2 Texas 1/77. Switching isotype from IgG to IgM led to a 48% loss in reactivity to intact virus and 74% loss to hemagglutinin H3 (A/Philippines/2/1982 H3N2). Taken together, our results indicate that unlike other IGHV4-34 bearing IGs, CLL subset 4 mAbs have only limited reactivity to autoantigens, including linear NAL epitopes. Instead, this subset has acquired specific recognition of subtypes of an infectious agent, influenza A (H3 and H1), apparently via its envelope protein hemagglutinin. The shift in antigen recognition appears to be dependent upon both the stereotyped IGVH-D-Jrearrangement and isotype switching to IgG. Disclosures No relevant conflicts of interest to declare.
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- 2014
180. Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG®) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors
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Bruce D. Cheson, Michael Hallek, Susan O'Brien, Stephan Stilgenbauer, Ian W. Flinn, Richard R. Furman, Bertrand Coiffier, Steven Coutre, Peter Hillmen, Karl-Anton Kreuzer, John M. Pagel, Eugen Tausch, Daniel Li, Wendy Jiang, Thomas J. Kipps, Jeff P. Sharman, Thomas Jahn, Mirella Lazarov, Andrew D. Zelenetz, Paolo Ghia, and Jacqueline C. Barrientos
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,Placebo ,Interim analysis ,Biochemistry ,Internal medicine ,Clinical endpoint ,medicine ,Rituximab ,Chills ,medicine.symptom ,IGHV@ ,business ,Idelalisib ,medicine.drug - Abstract
BACKGROUND: There is high unmet need in frail pts with relapsed CLL, particularly in those characterized by adverse prognostic factors such as presence of del(17p) and/or TP53 mutations. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kd recently approved for the treatment of relapsed CLL in combination with R. This report describes results from the 2nd interim analysis (IA) of a Phase 3 study evaluating IDELA in combination with R in relapsed CLL with focus on various risk subgroups of pts. METHODS: A Phase 3 study evaluated IDELA+R vs placebo (PBO)+R in pts with CLL requiring therapy after progression RESULTS: 220 pts (110/group) with median age of 71 yrs (78% ≥65 yrs), median time since diagnosis of 8.5 yrs, and median number of 3 prior therapies (range: 1-12) were randomized. 43% had del(17p)/TP53 mutation and 84% had unmutated IGHV. At the time of data cut-off, the median (range) exposure was 5 (0-17) mos on IDELA+R and 4 (0-15) mos on PBO+R. 76% of pts on IDELA+R and 46% of pts on PBO+R were continuing on study. Median PFS was not reached for pts on IDELA+R and was 5.5 mos for pts on the comparator arm. At 12 months, the PFS rates for pts on IDELA treatment was 66% compared to 13% for pts on PBO+R. PFS strongly favored IDELA+R in all risk-subgroups, including those with genetic risk factors such as del(17p)/TP53 mutations, del(11q) (FIGURE 1) or unmutated IGHV as well as with disease-related risk factors like advance Rai stage or high levels of β2-microglobulin. Adverse events (any Gr/Gr ≥3) occurring in ≥20% of pts on IDELA treatment were: pyrexia (IDELA+R 35%/3%; PBO+R 17%/1%), fatigue (IDELA+R 28%/3%; PBO+R 27%/2%), nausea (IDELA+R 26%/0%; PBO+R 21/0%), chills (IDELA+R 21%/2%; PBO+R 16%/0%), diarrhea/colitis (IDELA+R 21%/5%; PBO+R 15%/0%). ALT/AST elevation (any Gr/Gr ≥3) occurred in 40%/8% of pts on IDELA+R and in 20%/1% of pts on PBO+R. At the time of this analysis, 19 total deaths had occurred on the primary study: 6 on IDELA+R and 13 on PBO+R. TABLE 1: Summary of efficacy in various risk subgroups, and safety. TABLE 1:. Summary of efficacy in various risk subgroups, and safety. a) Number of patients on both arms evaluable at the time of analysis b) Number of patients on both arms with respective test result. Note: Distribution of risk features on both arms was balanced. c) Includes 16 preferred terms FIGURE 1: KM estimates of PFS in pts with del(17p) or TP53mutation or del(11q) vs pts without any of these factors. IDELA+R without these risk factors: median PFS 12.1 mos (74% at 12 mos); IDELA+R with these risk factors: median PFS not reached (62% at 12 mos); PBO+R without these risk factors: median PFS 8.2 mos (19% at 12 mos); and PBO+R with these risk factors: median PFS 4 mos (8% at 12 mos). Curve comparison: Pts with these risk factors: HR = 0.16 (95% CI: 0.08, 0.32); Pts without these risk factors: HR = 0.24 (95% CI: 0.09, 0.66). FIGURE 1:. KM estimates of PFS in pts with del(17p) or TP53mutation or del(11q) vs pts without any of these factors. IDELA+R without these risk factors: median PFS 12.1 mos (74% at 12 mos); IDELA+R with these risk factors: median PFS not reached (62% at 12 mos); PBO+R without these risk factors: median PFS 8.2 mos (19% at 12 mos); and PBO+R with these risk factors: median PFS 4 mos (8% at 12 mos). Curve comparison: Pts with these risk factors: HR = 0.16 (95% CI: 0.08, 0.32); Pts without these risk factors: HR = 0.24 (95% CI: 0.09, 0.66). CONCLUSIONS: IDELA+R demonstrated statistically significant improvement over PBO+R in PFS, ORR, and OS with an acceptable safety profile in these frail pts with relapsed CLL. These results confirm the 1st interim analysis of comparable efficacy of IDELA+R across all risk groups, including those with high-risk genomic markers like del(17p), TP53 mutations, and del(11q). Disclosures Sharman: Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. Furman:Gilead Sciences: Research Funding. Cheson:Gilead Sciences: Research Funding. Pagel:Gilead Sciences: Research Funding. Hillmen:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Ghia:Gilead Sciences: Research Funding. Hallek:Gilead Sciences: Research Funding. Coiffier:Gilead Sciences: Research Funding. O'Brien:Gilead Sciences: Research Funding. Tausch:Gilead Sciences: Research Funding. Kreuzer:Gilead Sciences: Research Funding. Jiang:Gilead Sciences: Employment, Equity Ownership. Lazarov:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Science: Employment, Equity Ownership. Jahn:Gilead Sciences: Employment, Equity Ownership. Stilgenbauer:Gilead Sciences: Research Funding.
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- 2014
181. TLR-9 and IL-15-Driven Clonal Expansion of B-CLL Cells
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Charles C. Chu, Kanti R. Rai, Steven L. Allen, Jonathan E. Kolitz, Patricia K. A. Mongini, Jacqueline C. Barrientos, Tatjana Stankovic, Joanna Stein, Rashmi Gupta, and Nicholas Chiorazzi
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Stromal cell ,Lymphoblast ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,Immunology ,Clone (cell biology) ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Cytokine ,Interleukin 15 ,hemic and lymphatic diseases ,medicine ,Cancer research ,Bone marrow ,IGHV@ - Abstract
Clinical progression of B cell chronic lymphocytic leukemia (B-CLL) is linked to clonal growth within pseudo-follicles, typically within lymph nodes, bone marrow and spleen, and occasionally lungs and skin. Both the clone’s antigen receptor and stromal milieu appear to influence its growth rate. An involvement of TLR signals seems probable based on atypically elevated TLR-9 expression within B-CLL cells and the likelihood that the specificity of B-CLL antigen receptors (BCR) facilitates the internalization of molecules from apoptotic cells and/or microbes that are physically linked to CpG DNA. Nevertheless, recent findings that a large subset of B-CLL undergoes in vitro apoptosis upon stimulation with CpG-rich oligodeoxynucleotides (ODN) raised questions about a central role for TLR-9 signaling. Using a CFSE-based model for examining in vitro B-CLL clonal expansion/viability and a cohort consisting of 19 IGHV mutated (M) and 19 unmutated (U) B-CLL, we report that TLR-9 signaling is uniformly stimulatory when accompanied by signals from IL-15. Importantly, this cytokine is known to be constitutively produced by stromal cells in normal bone marrow, lymph nodes, and spleen and in a constitutive/inducible manner within skin and lungs. We show that B-CLL display reproducible inter-clonal differences in the number of division cycles attained and/or lymphoblast survival that were not linked to IGHV mutation status, but were statistically linked to whether the patient leukemic population contained subclones with trisomy-12 (p=0.0003) or contained subclones with both an ATM anomaly (11q22 del and/or ATM mutation) and 13q14 del (p=0.009). When all B-CLL clones were assessed, in vitro high-division or high-viability status in response to ODN + IL-15 was not statistically linked to clinical progression as determined by time to first treatment (TFT). Nonetheless, in vitro high-division status showed a statistically-significant direct linkage to patient survival (OS) (p=0.019 for OS within B-CLL manifesting > 50% cells with > 2 divisions versus B-CLL with < 50% cells with > 2 divisions). Subdivision of the total cohort into U-CLL and M-CLL subsets revealed that the link of high division status with overall survival is most characteristic of U-CLL. Immunohistological evidence of IL-15-producing cells within or proximal to Ki-67-positive pseudo-follicles in B-CLL-infiltrated spleen is consistent with a role for ODN + IL-15 signaling in promoting in vivo leukemic cell growth. Taken together, the findings from this study support the concept that in vivo B-CLL clonal expansion is dependent upon leukemic B-CLL homing to tissue sites where IL-15 is typically sequestered along with intrinsic properties of the B-CLL clone, e.g. cytogenetic anomalies within members of a B-CLL clone that heighten leukemic cell growth and/or survival and an expression of U-BCRs specific for apoptotic cell debris that increase the opportunity for TLR-9 signaling. Disclosures No relevant conflicts of interest to declare.
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- 2014
182. Long-Term Follow-up of a Phase 1 Trial of Idelalisib (ZYDELIG®) in Combination with Bendamustine (B), Bendamustine/Rituximab (BR), Fludarabine (F), Chlorambucil (Chl), or Chlorambucil/Rituximab (ChlR) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
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Ian W. Flinn, Kanti R. Rai, Steven Coutre, Sven de Vos, Marshall T. Schreeder, Yeonhee Kim, Thomas Jahn, John P. Leonard, Jeff P. Sharman, Nina D. Wagner-Johnston, Anthony Viggiano, Thomas E. Boyd, Richard R. Furman, and Jacqueline C. Barrientos
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Bendamustine ,medicine.medical_specialty ,Chlorambucil ,business.industry ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Fludarabine ,Internal medicine ,medicine ,Rituximab ,Refractory Chronic Lymphocytic Leukemia ,Idelalisib ,business ,Progressive disease ,medicine.drug - Abstract
BACKGROUND: PI3Kδ signaling is critical for the proliferation and survival as well as for homing and tissue retention of malignant B cells. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ with considerable activity as monotherapy and in combination with R in patients with relapsed/refractory CLL, and was recently approved for the treatment of relapsed CLL in combination with R. This report summarizes the long-term follow-up of the Phase 1 combination experience of idelalisib with chemo- and immuno-chemotherapies. METHODS: 74 subjects were sequentially enrolled into one of 5 regimens of idelalisib combined with either B (70 or 90 mg/m2 IV on D1,2 of cycles 1-6, N=18, enrolled Apr 2011-Nov 2011), BR (B: 70 mg/m2 IV on D1,2 of cycles 1-6; R: 375 mg/m2 IV on D1 of cycles 1-6, N=15, enrolled Apr 2011-Aug 2011), F (40 mg/m2 po D1-5 of cycles 1-6, N=12, enrolled Apr 2011-Aug 2011), Chl (10 mg/m2 po D1-7 x 3(min)-12(max) cycles, N=15, enrolled Mar 2012-Aug 2012), or ChlR (N=14, enrolled Mar 2012-Jul 2012). Idelalisib was administered at 100 (4 of the pts receiving B) or 150 mg po BID (all other patients) continuously. Patients on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical responses were evaluated according to published criteria (Hallek 2008; Cheson 2012). RESULTS: Of 74 subjects enrolled, 66% were male. Median age was 65 years, and median time since diagnosis was 8 years with a median of 3 (range 1-9) prior regimens. Overall, prior therapies included R (97%), F (78%), B (45%), and Chl (14%), and 55% of patients were refractory to last therapy. 65% of patients had Rai stage III/IV disease at enrollment. Adverse prognostic factors included del(17p) and/or TP53 mutation (30%), IGHV unmutated status (82%), NOTCH1 mutation (28%). As of 7/15/2014, the median idelalisib exposure for patients of all cohorts was 12.8 (range 1-48) months. 41 (55%) of patients completed the 48 weeks of the primary study, and 20 subjects (27%) were still on treatment on the extension study at the time of analysis. The most common reasons for discontinuation reported by investigators were adverse events (AEs) (15, 20%) or progressive disease (PD) (12, 16%). There were 13 deaths reported on study; 4 patients experienced PD before death. Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea/colitis (51%/18%), pyrexia (47%/5%), fatigue (35%/7%), cough (35%/0%), nausea (31%/1%), pneumonia (23%/14%), rash (22%/7%), dyspnea (19%/3%), and pneumonitis (3%/3%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 37%/14%. Of those, only 1 patient discontinued the study because of (recurrent) TA elevation. Richter’s transformation as category of progressive disease was reported in 1 patient (3%). The ORR was 82% for all 74 patients with a CR rate of 10%. 4 of 74 patients (5%) were not evaluable because of missing follow-up assessments. Among 69 subjects with genetic data available, the ORR in the 22 subjects with either del(17p) and/or TP53 mutation was 68% vs. 87% among 47 subjects with neither aberration. The overall median PFS was not reached at the time of analysis (Figure 1); KM estimate of PFS was 57% [43-72%, 95% CI] at 24 months. Overall median time to response was 1.9 months, and overall median DOR was not yet reached. CONCLUSIONS: These preliminary results in patients with relapsed or refractory disease and multiple prior therapies suggest that idelalisib can be combined with B, BR, F, Chl, and ChlR with acceptable safety and that these combinations have substantial clinical activity. A Phase 3 study evaluating the combination of idelalisib with BR in relapsed CLL is ongoing (NCT01732926). Figure 1: Overall PFS Figure 1:. Overall PFS Disclosures Barrientos: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Coutre:Gilead Sciences: Research Funding. de Vos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment, Equity Ownership. Viggiano:Gilead Sciences: Employment, Equity Ownership. Jahn:Gilead Sciences: Employment, Equity Ownership. Furman:Gilead Sciences: Research Funding.
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- 2014
183. Determination of Recommended Phase 2 Dose of ABT-199 (GDC-0199) Combined with Rituximab (R) in Patients with Relapsed / Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)
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Constantine S. Tam, Jianning Yang, Rod A. Humerickhouse, Nikita Rudersdorf, Ming Zhu, Mary Ann Anderson, Jacqueline C. Barrientos, Shuo Ma, Elisa Cerri, Lori A. Gressick, Sari H. Enschede, Matthew S. Davids, Wijith Munasinghe, Andrew W. Roberts, Thomas J. Kipps, John F. Seymour, Tanita Mason-Bright, and Danielle M. Brander
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Bendamustine ,medicine.medical_specialty ,Combination therapy ,business.industry ,Anemia ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Fludarabine ,Surgery ,Internal medicine ,medicine ,Rituximab ,business ,Febrile neutropenia ,Progressive disease ,medicine.drug - Abstract
Introduction: ABT-199 is a selective, orally bioavailable BCL-2 inhibitor that rapidly induces responses in ~80% of patients (pts) with relapsed/refractory (R/R) CLL or small lymphocytic lymphoma (SLL) as a single agent (Seymour, EHA 2014). Rituximab (R) has only modest and short-lived activity as a single-agent in CLL; it can enhance the activity of other agents with minimal additional toxicity. ABT-199 and R demonstrate synergy in preclinical models of CD20-positive lymphoid malignancies, and the combination has the potential to improve efficacy. Methods: Primary objectives of this phase 1b, open-label, dose-escalation, multicenter study were to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RPTD) of ABT-199 + R in pts with R/R CLL/SLL and evaluate the safety profile; secondary objectives examine the pharmacokinetics (PK) and efficacy of the combination. Eligible pts began treatment with 20 or 50 mg ABT-199 (modified to 20 mg during the study) daily, with weekly increases in a ramp-up phase to a final cohort dose of 200 - 600 mg. After completion of the ramp-up phase, R was added starting at 375 mg/m2 and then 500 mg/m2 monthly for a total of 6 doses. ABT-199 was continued daily until progressive disease (PD) or unacceptable toxicity. Adverse events (AEs) were graded according to NCI-CTCAE v4.0. The MTD was determined using the Continual Reassessment Method. Responses were assessed using established criteria for CLL/SLL, including CT scan at month 3 and CT scan and bone marrow (BM) biopsy at the end of combination therapy. MRD was assessed using four color flow cytometry in peripheral blood (PB) and/or BM aspirate ≥2 months after response criteria were first met, and in PB every 12 weeks until MRD negativity was achieved. Results: As of July 6, 2014, 49 pts enrolled in 5 dose escalation cohorts (n = 41) and a safety expansion cohort (n = 8), with a median time on study of 201 days (1 – 624). Median age was 68 years (range 50–88) and 30 (61%) were male. The median number of prior therapies was 3 (1–10). Thirteen (27%) had fludarabine-refractory disease and 9 (18%) R-refractory. Nine (18%) had del (17p) and 19/27 (70%) with available data had unmutated IGVH. Thirteen pts have discontinued therapy: 6 due to PD; 3 after attaining complete remission; 2 due to AEs and 2 withdrew consent. Preliminary PK data suggest a negligible effect of R on ABT-199 exposure. The most common overall treatment-emergent AEs (>25% pts) were neutropenia (47%), nausea (41%), diarrhea (37%), pyrexia (31%), headache (31%), fatigue, upper respiratory tract infection, and cough (each 29%). The most common overall grade 3/4 AEs were neutropenia (47%), thrombocytopenia (16%), and anemia (14%). Treatment-emergent SAEs occurred in 20 (41%) pts; the most common were pyrexia (6%), and febrile neutropenia, infusion-related reaction, TLS, and Richter's Transformation (each 4%). Six pts experienced a DLT: 1 febrile neutropenia (200mg), 1 each thrombocytopenia, hematophagocytic syndrome, neutropenia (300mg), 1 neutropenia (600mg), and 1 pt experienced a fatal event of hyperkalemia in the setting of TLS after the first dose (50mg). That event led to a modified dosing scheme; no TLS was observed in the 32 subsequent pts using the revised ramp up dosing scheme. No MTD was identified. Of 34 pts who were evaluable for response in dose escalation cohorts, the overall response rate (ORR) was 88%, with 11 (32%) achieving a CR/CRi and 20 (56%) achieving a partial response (PR). MRD was quantified by local laboratory in 19 pts. Thirteen pts (7 in CR (6 at 10-4 and 1 at 10-3 sensitivity) and 6 in PR (10-4 sensitivity)) were MRD negative in bone marrow while one was MRD negative in peripheral blood (10-4 sensitivity). The RPTD of ABT-199 is 400 mg daily based on safety data; key safety and efficacy data for the dose selection are summarized in the table. Conclusions: The combination of ABT-199 and R is well-tolerated and achieves an overall response rate of 86% with 31% CRs in pts with CLL/SLL. Efficacy was observed across all dose cohorts. The RPTD of ABT-199 is 400mg daily, supported by a trend of lower rates of neutropenia and GI toxicity events in the absence of a clear difference in efficacy, compared to the higher doses. A phase 3 trial comparing ABT-199 and R versus bendamustine and R in pts with previously treated CLL is underway. Figure 1 Figure 1. Disclosures Roberts: Walter and Eliza Hall Institute of Medical Research : Employment, Research Funding; AbbVie: Research Funding; Genentech: Research Funding. Ma:Genentech: Consultancy; AbbVie: Research Funding. Kipps:AbbVie: Consultancy, Research Funding. Barrientos:Gilead: institutional funding Other; Pharmacyclics: Consultancy, institutional funding, institutional funding Other; AbbVie: institutional funding, institutional funding Other; Celgene: Consultancy. Davids:Genentech: Consultancy; Infinity Pharmaceuticals: Consultancy. Anderson:Walter and Eliza Hall Institute of Medical Research: Employment, milestone payments related to ABT-199 Other; AbbVie: Research Funding; Genentech: Research Funding. Tam:Roche: Honoraria. Mason-Bright:AbbVie : Employment. Rudersdorf:AbbVie: Employment. Gressick:AbbVie: Employment. Yang:AbbVie, Inc: Employment. Munasinghe:AbbVie: Employment. Zhu:AbbVie, Inc: Employment. Cerri:AbbVie: Employment. Enschede:AbbVie, Inc: Employment. Humerickhouse:AbbVie, Inc: Employment. Seymour:AbbVie: Research Funding; Genentech: Consultancy, Research Funding; Roche: Consultancy.
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- 2014
184. Kinetic Measurement of Leukemia-Cell Proliferation Rate By Deuterium Labeling Predicts Time to Initial Treatment of Patients with Chronic Lymphocytic Leukemia
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Jennifer R. Brown, Neil E. Kay, Elizabeth Murphy, Nicholas Chiorazzi, Andrew W. Greaves, Thomas J. Kipps, Coline McConnel, Gregory M. Hayes, Scott Turner, John C. Byrd, Robert A. Redd, Kanti R. Rai, Laura Z. Rassenti, Jacqueline C. Barrientos, Marc K. Hellerstein, William G. Wierda, Claire L. Emson, Robert Busch, Kelvin W. Li, and Donna Neuberg
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medicine.medical_specialty ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Birth rate ,Log-rank test ,Leukemia ,Median follow-up ,Internal medicine ,Medicine ,business ,IGHV@ ,Prospective cohort study ,Survival analysis - Abstract
Background: Chronic lymphocytic leukemia (CLL) patients exhibit variable times from diagnosis to the need to initiate therapy. Previous studies have demonstrated that the rates of CLL cell proliferation (birth) and elimination (death plus recirculation to solid tissues) could be estimated using the incorporation of deuterium (2H), taken in the form of heavy water (2H2O), into the DNA of dividing cells. In a cross-sectional study of patients with early and late stage CLL, birth rates above 0.35% per day were associated with more aggressive disease. The NIH-sponsored CLL Research Consortium (CRC) conducted a prospective study on patients with early stage disease to assess the relationship between CLL-cell birth rate and the length of time to initiation of initial therapy. Methods: Eligible patients had untreated early stage (Rai 0, 1 or 2) disease, and were no more than 3 years from diagnosis. Additional clinical parameters included age at diagnosis, gender, mutational status of the immunoglobulin heavy chain variable region (IGHV), 70-kD zeta-associated protein (ZAP-70) (binary split at 20%) and CD38 (binary split at 30%) expression, and FISH cytogenetics by the Dohner hierarchy. Heavy water was administered daily for 6 weeks, and peripheral blood was obtained for kinetic measurements at the end of weeks 3, 6, 9, 12, and 16. CLL birth rates for blood samples were measured at the same facility (KineMed, Inc, Emeryville, CA) by quantifying deuterium incorporation into the deoxyribose moiety of DNA of tumor cells, using isotope ratio mass spectrometry (IRMS). Subjects were followed for time to administration of therapy; subjects still without treatment at time of analysis were censored, as were subjects who exited the study to receive treatment outside of the established criteria. To assess the impact of birth rate and other factors on time to first therapy, Kaplan-Meier curves were compared using the logrank test for univariable analyses; stepwise Cox proportional hazards regression models were used to build multivariable models. Results: Between July 2005 and February 2009, 119 subjects were enrolled through the CRC. 107 subjects were eligible. For 10 eligible patients, exit from the study prior to completion of protocol-mandated heavy water consumption (n=5) or technical issues (n=5) made it impossible to obtain estimates of birth rate. The 97 eligible subjects for whom birth rates were available form the basis of this report. 60% of subjects were male; median age 57 years (range 40-85). Median birth rate was 0.32%/day (range 0.07-1.31%/day). 43 subjects (44%) had birth rates higher than the previously reported threshold of 0.35%/day. With a median follow up of 4 years, 33 eligible subjects (34%) required treatment. IGHV status (31 subjects unmutated), elevated ZAP-70 (31 subjects), elevated CD38 (21 subjects), and hierarchical categorization of FISH anomalies (4 del(17p), 5 del(11q), 8 tri(12), 50 del(13q)) were examined for association with differential time to first therapy in univariable analyses. All were associated with earlier need for therapy (p 0.35%/day was also significantly associated with shorter time to first therapy (p < 0.001). In multivariable modeling, only birth rate and IGHV status met the criteria for inclusion (Wald p-value < 0.05). Hazard ratios were 3.51 (p = 0.002) for birth rate above 0.35%/day and 5.0 for unmutated IGHV status (p < 0.001). The association between elevated birth rate and shorter time to first treatment was observed within subjects with both unmutated and mutated IGHV (see Figure 1). Conclusion: An increased birth rate of CLL cells early in the disease course is a strong predictor of an earlier need for treatment in univariable analysis, as are unmutated IGHV, elevated ZAP-70 expression and elevated CD38 expression. However, only unmutated IGHV and an increased birth rate contribute significantly to the multivariable model. This adds a direct measure of B-cell kinetics to the array of biomarkers available to subjects with CLL. Figure 1 Time to treatment by birth rate and IGHV status Figure 1. Time to treatment by birth rate and IGHV status Disclosures Murphy: KineMed, Inc: Equity Ownership. Emson:KineMed, Inc.: Employment, Equity Ownership. Li:KineMed, Inc.: Employment, Equity Ownership. McConnel:KineMed, Inc.: Equity Ownership. Turner:KineMed, Inc.: Employment, Equity Ownership. Busch:KineMed, Inc.: Equity Ownership. Hellerstein:KineMed Inc: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Chiorazzi:KineMed, Inc.: Stock options Other.
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- 2014
185. Hematologic and Immunologic Function and Patient Well-Being for the Phase III RESONATETM Study of Ibrutinib Vs Ofatumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
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S. Devereux, Jennifer R. Brown, Tanja Kierschniak, Stephen P. Mulligan, Susan O'Brien, Gavin Cull, John C. Byrd, Samuel Suzuki, Jacqueline C. Barrientos, Carol Moreno, Ulrich Jaeger, Tadeusz Robak, Karl Eckert, Devinder Gill, Christopher Pocock, Jeffrey A. Jones, Neil E. Kay, Nishitha Reddy, Anna Schuh, Steven Coutre, Adrian Bloor, Constantine S. Tam, Danelle F. James, Peter Hillmen, Emily Hsu, Stephen J. Schuster, Michael R. Hamblin, and Claire Dearden
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Cytopenia ,medicine.medical_specialty ,education.field_of_study ,Anemia ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Population ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Interim analysis ,Ofatumumab ,Biochemistry ,Gastroenterology ,Surgery ,chemistry.chemical_compound ,chemistry ,Ibrutinib ,Internal medicine ,medicine ,business ,education - Abstract
Introduction : Ibrutinib (Imbruvica®), an oral, first-in-class covalent BTK inhibitor, is a new treatment option approved by FDA for chronic lymphocytic leukemia (CLL) patients (pts) with ≥1 prior therapy. We previously reported results from the phase III trial, in which ibrutinib (ibr) significantly improved progression-free and overall survival vs ofatumumab (ofa) in pts with relapsed/refractory CLL or small lymphocytic lymphoma (SLL) (Byrd et al. NEJM, 2014). Here, we report measures of patient well-being, including hematologic, immunologic, and quality of-life parameters, at interim analysis (IA). Methods : Pts with CLL/SLL after ≥1 prior therapy were randomized 1:1 to ibr 420 mg/day until progression or unacceptable toxicity, or to ofa for up to 24 weeks. At IA, secondary efficacy endpoints of hematologic improvement (sustained improvement ≥56 days without transfusions or growth factors) and FACiT-Fatigue (FACiT-F) outcomes were analyzed, along with exploratory endpoints assessing disease-related symptoms (DRS), serum immunoglobulin, patient-reported outcomes (PROs) by EORTC QLQ-C30, and medical resource utilization (MRU). Results : Of 391 enrolled pts (ibr n=195; ofa n=196), 63% had cytopenia(s) at baseline: 45% had anemia (hemoglobin ≤11 g/dL), 35% thrombocytopenia (platelets ≤100×109/L), and 20% neutropenia (absolute neutrophil counts [ANC] ≤1.5×109/L). On the ibr arm, 69% of pts with baseline cytopenias experienced sustained improvement in blood counts compared to 43% on ofa ( P
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- 2014
186. 2.12 Provision of Human Multimeric sCD40L and Interleukin-4 to Immune-Deficient NOD/SCID/γcnull Mice Permits Efficient and Effective Adoptive Transfer and T-Cell–Independent Proliferation of CLL Cells In Vivo
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Davide Bagnara, Philip Chum, Rita Simone, Nicholas Chiorazzi, Jacqueline C. Barrientos, and Kanti R. Rai
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Cancer Research ,Adoptive cell transfer ,business.industry ,T cell ,Hematology ,Nod ,Immune system ,medicine.anatomical_structure ,Oncology ,In vivo ,Immunology ,Medicine ,business ,Interleukin 4 - Published
- 2011
187. Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL
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Jeff Porter Sharman, Ian W. Flinn, Andrew D. Zelenetz, Andrew R. Pettitt, Paolo Ghia, Yeonhee Kim, Richard R. Furman, Herbert Eradat, Nicole Lamanna, John M. Pagel, Michael Hallek, Susan O'Brien, Peter Hillmen, Jacqueline C. Barrientos, Bertrand Coiffier, Steven Coutre, Thomas Jahn, Thomas J. Kipps, Thomas J. Ervin, and Bruce D. Cheson
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,Relapsed CLL ,Interim analysis ,Surgery ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Single agent ,Rituximab ,Idelalisib ,business ,medicine.drug - Abstract
7012 Background: Idelalisib (IDELA), an oral inhibitor of PI3Kδ, is highly active in heavily pretreated patients with CLL as single agent or combined with rituximab (R) as demonstrated in Phase 1 t...
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- 2014
188. ABT-199 (GDC-0199) combined with rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Interim results of a phase 1b study
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Matthew S. Davids, Andrew W. Roberts, Elisa Cerri, Wijith Munasinghe, John F. Seymour, Sari H. Enschede, Tanita Mason-Bright, Ming Zhu, Jacqueline C. Barrientos, Mark C. Lanasa, Rod A. Humerickhouse, Shuo Ma, Jianning Yang, Thomas J. Kipps, and Nikita Rudersdorf
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Cancer Research ,business.industry ,Chronic lymphocytic leukemia ,Antagonist ,Pharmacology ,medicine.disease ,stomatognathic diseases ,Oncology ,immune system diseases ,Apoptosis ,hemic and lymphatic diseases ,Relapsed refractory ,Cancer research ,Medicine ,In patient ,Rituximab ,business ,neoplasms ,medicine.drug - Abstract
7013 Background: ABT-199 is a selective, orally bioavailable Bcl-2 antagonist that induces rapid apoptosis of CLL cells and > 80% response rate as monotherapy in pts with R/R CLL. R synergizes with...
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- 2014
189. Efficacy of idelalisib in CLL subpopulations harboring del(17p) and other adverse prognostic factors: Results from a phase 3, randomized, double-blind, placebo-controlled trial
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Bruce D. Cheson, Karl Anton Kreuzer, Eugen Tausch, Mirella Lazarov, Peter Hillmen, Stephan Stilgenbauer, Paolo Ghia, Bertrand Coiffier, Ian W. Flinn, Michael Hallek, Susan O'Brien, John M. Pagel, Jeff Porter Sharman, Wendy Jiang, Richard R. Furman, Andrew D. Zelenetz, Thomas Jahn, Jacqueline C. Barrientos, Steven Coutre, and Thomas J. Kipps
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Oncology ,Double blind ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,medicine ,Placebo-controlled study ,business ,Idelalisib ,Homing (hematopoietic) - Abstract
7011^ Background: Idelalisib (IDELA) is a potent and selective inhibitor of PI3Kδ, which is critical for activation, proliferation and survival of B cells and their homing and retention in lymphoid...
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- 2014
190. Health-related quality of life (HRQL) impact of idelalisib (IDELA) in patients (pts) with relapsed chronic lymphocytic leukemia (CLL): Phase 3 results
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Thomas J. Kipps, Jeff Porter Sharman, Peter Hillmen, Ian W. Flinn, Nicole Lamanna, Michael Hallek, Susan O'Brien, Andrew R. Pettitt, Herbert Eradat, Richard R. Furman, Steven Coutre, Jacqueline C. Barrientos, John M. Pagel, Lynne I. Wagner, Thomas Jahn, Bertrand Coiffier, Andrew D. Zelenetz, Wei Ye, Bruce D. Cheson, and Paolo Ghia
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Oncology ,Health related quality of life ,Cancer Research ,medicine.medical_specialty ,Pediatrics ,business.industry ,Placebo ,Relapsed chronic lymphocytic leukemia ,humanities ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Rituximab ,In patient ,business ,Idelalisib ,medicine.drug - Abstract
7099 Background: Pt-reported outcomes (PROs) evaluated HRQL among CLL pts randomized to IDELA + rituximab (R) (n=110) vs double-blind placebo + R (n=110). Methods: The 44-item Functional Assessment...
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- 2014
191. Evaluation of IGHV Ultra-Deep Sequences for Activation-Induced Deaminase Characteristics in CLL Cells after T Cell Stimulation
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Jonathan E. Kolitz, Thomas MacCarthy, Charles C. Chu, Kanti R. Rai, Steven L. Allen, Jacqueline C. Barrientos, Piers E.M. Patten, Nicholas Chiorazzi, and Xiao-Jie Yan
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Genetics ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,Biology ,Gene mutation ,medicine.disease ,Biochemistry ,Germline ,Immunoglobulin class switching ,hemic and lymphatic diseases ,Activation-induced (cytidine) deaminase ,biology.protein ,medicine ,Primer (molecular biology) ,Mutation frequency ,IGHV@ - Abstract
Ultra-deep sequencing has revolutionized our ability to acquire large amounts of genetic data. We have applied this technology towards understanding the mutational process in B-cell chronic lymphocytic leukemia (CLL), which may be a key to understanding CLL pathogenesis. Acquisition of new cytogenetic aberrations and gene mutations in the CLL clone is associated with worse patient outcome. CLL is not unique in this aspect, as new somatic mutations and DNA rearrangements are also found during the evolution of other solid and liquid tumors. In many of these, activation-induced deaminase (AID), an enzyme normally expressed in germinal center B lymphocytes to induce IGHV-D-J mutations and isotype class switch recombination, is abnormally expressed. Its mutational activity, acting outside of the Ig loci, is implicated in the evolution to more aggressive disease. In CLL, the detection of leukemic cells expressing AID ex vivo correlates with significantly shorter patient survival. To test if AID mutational activity is functional in CLL cells and therefore could contribute to CLL evolution, we analyzed mutations in IGHV-D-J, the preferred substrate for AID. Because the rate of AID-induced mutation is low and only a small percentage of CLL cells express AID ex vivo, we used ultra-deep sequencing to analyze CLL cells that were activated under conditions that simulate the CLL microenvironment. Specifically, CLL cells were activated (1) in vitro by simulating the provision of T-cell help or (2) in vivo after adoptive transfer into alymphoid recipient mice, which requires the presence of T-cells for CLL cell growth. Each of these conditions induce AID in a large fraction of CLL cells. To analyze IGHV-D-J mutations, the specific CLL clone IGHV was amplified from cDNA obtained on day 0 or from the activated CLL samples using IGHV family-specific and IGHM primers to enable subsequent comparison of IGHV-D-J with IGHM mutation frequencies. Three unmutated IGHV CLL (U-CLL) and 3 mutated IGHV (>2% compared to germline) CLL (M-CLL) samples were sequenced with the Roche 454 FLX system, resulting in a total of 1,367,522 sequence reads. After using the Roche 454 algorithm to trim sequence reads, they were prepared using custom R scripts that separated 5’ IGHV and 5’ IGHM primer sequences, aligned sequences to the CLL clone IGHV-D-J rearrangement, and removed poor quality ( To evaluate AID mutational characteristics in new subclones, SHMTool (http://scb.aecom.yu.edu/shmtool) was employed to calculate mutation frequencies in IGHV-D-J relative to the IGHM constant region, at AID mutation hotspot sites (GYW or WRC), at AID mutation coldspot sites (SYC or GRS), at C/G base pairs, and at error-prone DNA polymerase eta repair hotspot sites (WA or TW). To calculate statistical significance, we utilized a custom R script that used a bootstrap method to account for the large sample sizes provided by ultra-deep sequencing as well as to correct for differences in sequencing sample size. All samples showed an increase in IGHV-D-J versus IGHM mutations after T cell activation. Five of 6 cases showed an increase in AID hostpot mutation frequency. AID coldspot mutation frequency decreased in 3/6 CLL cases. Percent transition mutation at C/G sites was higher than random in 2/6 CLL cases, which correlated with low frequencies of DNA polymerase eta hotspot mutation. In the other 4/6 CLL cases, the lower percent transitions at C/G sites may reflect the contribution of error-prone DNA repair. In summary, we developed a method to analyze ultra-deep IGHV-D-J sequences that revealed AID mutational characteristics in both U-CLL and M-CLL cells after activation with T-cell help in vitro or in vivo. These data are consistent with the hypothesis that AID, perhaps along with error-prone DNA repair, creates new mutations leading to the evolution of aggressive CLL. Disclosures: Rai: Sanofi: Membership on an entity’s Board of Directors or advisory committees; GSK: Membership on an entity’s Board of Directors or advisory committees; Teva: Membership on an entity’s Board of Directors or advisory committees; Genentech: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees.
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- 2013
192. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib and Rituximab for Previously Treated Patients with Chronic Lymphocytic Leukemia (CLL)
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Stephan Stilgenbauer, Herbert Eradat, Bertrand Coiffier, Bruce D. Cheson, Paula Cramer, Shuo Ma, Michael Hallek, Susan O'Brien, Roger Dansey, Thomas Jahn, Dave Johnson, Ian W. Flinn, Andrew D. Zelenetz, Jacqueline C. Barrientos, Andrew R. Pettitt, Thomas J. Kipps, Steven Coutre, Richard R. Furman, Jeff P. Sharman, Peter Hillmen, Nicole Lamanna, John M. Pagel, Langdon L. Miller, Daniel Li, Maria Aiello, Paolo Ghia, and Thomas J. Ervin
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medicine.medical_specialty ,business.industry ,Immunology ,Placebo-controlled study ,Phases of clinical research ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Placebo ,Interim analysis ,Biochemistry ,Gastroenterology ,Internal medicine ,medicine ,Chills ,medicine.symptom ,business ,Idelalisib ,Febrile neutropenia - Abstract
Background Idelalisib (IDELA) is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues. Phase 1 trials demonstrated that IDELA is highly active as a single agent or in combination with rituximab (R) in heavily pretreated patients (pts) with CLL. Pts in these trials experienced reductions in disease-associated chemokines, improvement of organomegaly and cytopenias, profound reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (Brown 2013; Barrientos 2013). Patients with early progression and significant co-morbidities have limited treatment options; single-agent rituximab is an option in these pts (NCCN 2013; Zelenetz 2013). Methods This Phase 3 study evaluated the efficacy and safety of IDELA + R vs placebo + R in pts with previously treated CLL. Eligibility criteria included the need for treatment per IWCLL guidelines, measurable lymphadenopathy, and CLL progression 6), renal dysfunction, or cytopenias due to poor marrow reserve. All pts received R at 375 mg/m2 [1st dose] and then 500 mg/m2q2 wks x 4, followed by q4 wks x 3 [8 doses total]) and were randomized to Arm A (n=110; IDELA 150 mg BID continuously) or Arm B (n=110; placebo BID continuously). Primary endpoint was progression-free survival (PFS). Response and progression in both arms were assessed by an independent review committee using standard criteria (Hallek 2008; Cheson 2012). Results were reviewed by an external Data Monitoring Committee (DMC). Results Results are from a pre-specified interim analysis after ∼50% of the total number of 119 planned events of CLL progression or death from any cause. Data cutoff was 30 Aug 2013. Pt characteristics (n=220) included a median age of 71 yrs (78% ≥ 65 yrs); CIRS > 6 in 85%; median creatinine clearance of 63.6 mL/min; and presence of anemia (73%), thrombocytopenia (61%), neutropenia (34%). Median time since diagnosis was 8.5 yrs, median number of prior therapies was 3 (range: 1-12), 44% had del(17p)/TP53 mutation, and 84% had unmutated IGHV. PFS in the IDELA + R arm was superior to placebo +R (HR [95% CI] = 0.15 [0.08, 0.28]; p = 3.0 x 1011). Median PFS of pts treated with IDELA + R was not reached and for placebo + R was 5.5 mos. At 24 wks, the PFS rate for IDELA +R was 93% compared to 46% for placebo + R. PFS strongly favored IDELA + R in all subgroups, including those with del(17p)/TP53 or unmutated IGHV. Pts treated with IDELA + R and with ≥1 post-baseline assessment also had a superior overall response rate (ORR) relative to those in the control arm (81% vs. 13%; odds ratio 29.9; p = 3.0 x 1019) and a higher lymph node response (LNR) rate (93% vs. 4%; odds ratio 264.5; p = 1.3 x 10-30). Relative to the control group, pts treated with IDELA +R also had a significant improvement in overall survival (OS): HR (95% CI) = 0.28 (0.09, 0.86), p = 0.018. Adverse events (AEs) occurring in ≥20% of pts (any Gr/Gr ≥3) by arm were: pyrexia (IDELA + R 29%/3%; placebo + R 16%/1%), fatigue (IDELA + R 24%/3%; placebo + R 27%/2%), nausea (IDELA + R 24%/0%; placebo + R 22%/0%), chills (IDELA + R 22%/2%; placebo + R 16%/0%), infusion-related reactions (IDELA + R 16%/0%; placebo + R 28%/4%), and cough (IDELA + R 15%/0%; placebo + R 25%/2%). Other selected AEs (any Gr/Gr ≥3) included diarrhea (IDELA + R 19%/4%; placebo + R 14%/0%) and rash (IDELA + R 10%/2%; placebo + R 6%/0%). Select lab abnormalities (any Gr/Gr ≥3) included ALT elevation (IDELA + R 31%/6%; placebo + R 9%/1%), anemia (IDELA + R 26%/6%; placebo + R 30%/14%), neutropenia (IDELA + R 55%/34%; placebo + R 49%/22%), and thrombocytopenia (IDELA + R 17%/10%; placebo + R 26%/16%). The most common SAEs were pneumonia (6.4%), pyrexia (6.4%), and febrile neutropenia (4.5%) in IDELA + R, and pneumonia (8.4%), febrile neutropenia (5.6%), and dyspnea (3.7%) in placebo + R. AEs led to study drug discontinuation in 9 pts (8.2%) in IDELA + R and 11 pts (10.3%) in placebo + R. Based on a review of efficacy and safety, the DMC recommended stopping the study early. Conclusions IDELA + R demonstrated statistically significant improvement with acceptable safety over placebo + R in PFS, ORR, LNR and OS in heavily pretreated pts with relapsed CLL, including those with adverse genetic features. Disclosures: Furman: Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Consultancy, Research Funding. Coutre:Gilead Sciences: Research Funding. Cheson:Gilead Sciences: Research Funding. Pagel:Gilead Sciences: Research Funding. Hillmen:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Ghia:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Eradat:Gilead Sciences: Research Funding. Ervin:Gilead Sciences: Research Funding. Lamanna:Gilead Sciences: Research Funding. Hallek:Gilead Sciences: Research Funding. Coiffier:Gilead Sciences: Research Funding. Pettitt:Gilead Sciences: Research Funding. Ma:Gilead Sciences: Research Funding. Stilgenbauer:Gilead Sciences: Honoraria, Research Funding. Aiello:Gilead Sciences: Employment. Johnson:Gilead Sciences: Employment, Equity Ownership. Miller:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment, Equity Ownership. O'Brien:Gilead Sciences: Research Funding.
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- 2013
193. Apparent Involvement Of The Interferon, RNA Processing, and Wnt Signaling Pathways In Monoclonal B Lymphocytosis
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Kanti R. Rai, Scarfo Lydia, Claudia Fazi, Paolo Ghia, Jacqueline C. Barrientos, Xiao-Jie Yan, Nicholas Chiorazzi, Steven L. Allen, Wentian Li, and Jonathan E. Kolitz
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biology ,Chronic lymphocytic leukemia ,Immunology ,Wnt signaling pathway ,chemical and pharmacologic phenomena ,Cell Biology ,Hematology ,bacterial infections and mycoses ,medicine.disease ,Biochemistry ,CD19 ,Gene expression profiling ,Leukemia ,Interferon ,hemic and lymphatic diseases ,TCF3 ,biology.protein ,medicine ,Cancer research ,CD5 ,medicine.drug - Abstract
Introduction Chronic lymphocytic leukemia (CLL) develops in a stepwise fashion, starting in a restricted set of normal B lymphocytes that clonally expand, presumably due to antigen stimulation, reaching levels exceeding normal homeostasis but less than required for a diagnosis of CLL. Immunologic, genetic, and epidemiologic studies suggest these clonal expansions, termed monoclonal B lymphocytosis (MBL), are requisite precursors of CLL. Although ∼5% of normal subjects over age of 60 years old exhibit MBL, only ∼1% evolve to overt CLL each year. Hence, it is likely the genetic factors leading to the development of MBL from normal B cells are not sufficient to automatically lead to CLL and additional genetic lesions are needed for the final conversion to leukemia. To understand the development of MBL and its evolution to CLL, we investigated gene expression profiles of normal blood (N) B cells, MBL cells, and CLL cells using microarray technology. Methods RNA was purified from 31 N CD19+ B cells, 21 CD19+CD5+CD20dimIgL-restricted MBL cells, and 65 CD5+CD19+ CLL cells. Microarray assays were performed using Illumina Human HT12 BeadChips. Genes differentially expressed between the 3 populations were identified (MBL vs N and MBL vs CLL) and sets of significant genes (≥1.5 fold change and P Results Focusing on comparisons between MBL and N B cells, 1040 genes were higher and 868 lower in MBL than N B cells. Genes higher in MBL fall into different IPA categories including “PI3K/AKT Signaling” and “Inflammatory Disease”, thereby further underscoring a potential role of antigenic/inflammatory stimuli at the origin of MBL. In the “Inflammatory Disease” category, genes belonging to IFNα pathway were over-expressed in MBL. Eighteen of these IFN-associated genes overlapped with 74 genes in a type I IFN signature characteristic of systemic lupus erythematosus (SLE). Interestingly, 4 genes belonging to the “Post-Translational Modification” category that were more expressed in MBL - SPOP, SPK1, SRRM1, and ADAR (all P In contrast, the 683 genes more expressed in CLL than MBL B cells fall into the “Cell Death and Survival” and “Cancer” categories. Of note, several of the genes in the Wnt pathway over-expressed between MBL and N were lower in CLL B cells; however, since these comparisons were not paired (i.e., MBL clones that evolved to CLL were not studied), some of these differences may be spurious since we expect that not all MBL cases would evolve into CLL. Discussion Our studies implicate several pathways in the development and evolution of MBL. First, an interferon pathway, similar to that activated in SLE, may be operational in MBL, hinting such signaling is involved in the amplification of MBL clones and associating CLL precursors with autoimmunity, a well documented fact for overt CLL cells. Second, over-representation of genes involved in RNA processing suggests this function is also important in MBL. This again associates MBL with CLL and autoimmunity as splicing factor mutations have been identified in CLL and the small nuclear ribonucleoproteins involved in splicing are often autoantibody targets in SLE. Of note, mutations that affect SF3B1 and its splicing function have been recently described in a subset of CLL patients and implicated in its pathogenesis. Finally, our data strongly incriminate the Wnt/b-catenin pathway in MBL. Since both Wnt ligand and receptor genes are upregulated, autocrine as well as paracrine loops may be operative. It is interesting that the WNT effector, LEF1, which has been reported as upregulated in MBL previously, is an interferon-responsive gene, possibly linking those two pathways. Finally, if not an artifact of sample availability, it is curious that most of the Wnt pathway genes diminish in expression at the level of manifest CLL. Additional studies are needed to determine the functional relevance of our observations to MBL and CLL B-cell biology. Disclosures: No relevant conflicts of interest to declare.
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- 2013
194. Chemo-Immunotherapy Combination Of Idelalisib With Bendamustine/Rituximab Or Chlorambucil/Rituximab In Patients With Relapsed/Refractory CLL Demonstrates Efficacy and Tolerability
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Ian W. Flinn, Henry Adewoye, Leanne Holes, Steven Coutre, Yeonhee Kim, Richard R. Furman, John P. Leonard, Jacqueline C. Barrientos, Jeff P. Sharman, Kanti R. Rai, Sven de Vos, Marshall T. Schreeder, Roger Dansey, and Nina D. Wagner-Johnston
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Bendamustine ,medicine.medical_specialty ,Chlorambucil ,Anemia ,business.industry ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Regimen ,Tolerability ,Internal medicine ,medicine ,Rituximab ,Idelalisib ,business ,medicine.drug - Abstract
Background PI3K-delta signaling is critical for proliferation, survival, homing and tissue retention of malignant B cells. Idelalisib is a selective, oral inhibitor of PI3Kδ that has been previously shown to be safe and tolerable and has demonstrated considerable activity as monotherapy or in combination with other agents in patients with relapsed/refractory (R/R) CLL. We provide an update on the safety and efficacy of a phase 1 study of idelalisib (IDELA) 150mg po BID administered continuously on a 28-day cycle in combination with two chemo-immunotherapy regimens: bendamustine/rituximab (IDELA+BR) and chlorambucil/rituximab (IDELA+ChR). Methods Twenty-nine adult subjects (15/14 IDELA+BR; IDELA+ChR) with R/R CLL requiring treatment were enrolled between April and Aug 2011 for the IDELA+BR cohort and Mar and Jul 2012 for the IDELA+ChR cohort. Median age 64 yrs (Min, Max: 41, 82), gender M/F (%) 65/35, WHO PS (%) 0/1/2 59/38/3, current Binet stage (%) A/B/C 21/28/41, and 62% of subjects had bulky adenopathy (presence of ≥1 node with diameter ≥5 cm). Median number of prior therapies was 3 (Min, Max: 1, 9). Thirty-five percent of subjects had refractory disease (not responding to a standard regimen or progressing within 6 month of the last course of a standard regimen) and 55% of subjects were refractory to rituximab. The treatment schedule was as follows: IDELA+BR (IDELA 150 mg BID po d1-28 until progression or withdrawal, rituximab 375 mg/m2 IV on d1 of cycles 1-6, bendamustine 70 or 90 mg/m2 intravenously on d1 and d2 of cycles 1-6). For the IDELA+RCh cohort (IDELA 150 mg BID po on d1-28 until progression or withdrawal, chlorambucil 10 mg/m2 po once a d1-7 of cycles 1-12, rituximab 375 mg/m2 IV d1 of cycles 1-6). Response was assessed by the investigators based on scheduled CT evaluations and clinical criteria following IWCLL 2008. Results The data cut-off date for this analysis was May 2013. Objective response rates for the 2 cohorts were 89.7% (95% CI (%): 72.6-97.8). Median time to response in both cohorts was 1.9 months. For IDELA+BR, the ORR was 86.7% (95% CI (%): 59.5-98.3) (CR 6.7%, PR 80%), neither median DOR nor median PFS have been reached and median exposure was 18.4 months (Min, Max: 1.2, 24.7). For IDELA+ChR, the ORR was 92.9% (95% CI (%): 66.1-99.8) (CR 14.3%, PR 78.6%), neither median DOR nor median PFS has been reached, and median exposure was 7.7 months (Min, Max: 1.9, 11.1). Commonly reported treatment-emergent AEs (≥20% of all subjects) and lab abnormalities of interest for IDELA+BR were (total(%)/≥grade 3 (%)): pyrexia (46.7/0) diarrhea (26.7/13.3), fatigue (20/0), neutropenia (86.7/60), thrombocytopenia (26.7/6.7), transaminase elevations (26.7/0), anemia (33.3/13.3). For IDELA+ChR, common TEAEs were: pyrexia (57.1/7.1), diarrhea (64.3/7.1), fatigue (42.9/21.4), neutropenia (64.3/42.9), thrombocytopenia (42.9/21.4), transaminase elevations (50.0/21.4), and anemia (42.9/14.3). Conclusion The combination of IDELA+BR or IDELA+ChR is tolerable and demonstrates strong activity with an ORR of 89.7%. Median PFS and DOR have not been reached in the IDELA+BR or the IDELA+ ChR cohorts. The ability to induce responses in this particularly difficult-to-treat patient population with refractory disease, the non-overlapping toxicity with these agents, and the ease of administration makes this an option in this patient population. These results support further studies with these chemo-immunotherapy regimens in patients with CLL. Disclosures: Barrientos: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. Wagner-Johnston:Gilead Sciences: Research Funding. De Vos:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Dansey:Gilead Sciences: Employment. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Adewoye:Gilead Sciences: Employment. Furman:Gilead Sciences: Research Funding.
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- 2013
195. Idelalisib, a Selective Inhibitor Of PI3Kδ, In Combination With Bendamustine, Fludarabine Or Chlorambucil In Patients With Relapsed Or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)
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Leanne Holes, Thomas E. Boyd, Ian W. Flinn, Roger Dansey, Yeonhee Kim, Sven de Vos, Jacqueline C. Barrientos, Ronald L. Dubowy, Jeff P. Sharman, Nina D. Wagner-Johnston, Richard R. Furman, Steven Coutre, and John P. Leonard
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Bendamustine ,medicine.medical_specialty ,Chlorambucil ,business.industry ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Gastroenterology ,Fludarabine ,Regimen ,Internal medicine ,medicine ,Rituximab ,business ,Idelalisib ,Febrile neutropenia ,medicine.drug - Abstract
Background PI3K-delta (δ) is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib (IDELA) is a potent and selective orally administered inhibitor of PI3Kδ with demonstrated activity in patients with R/R CLL as a single agent (Brown, ASCO 2013), in combinations with cytotoxic chemotherapy or with anti-CD20 mAbs, and in triplet combinations with chemotherapy and anti-CD20 mAbs (Barrientos ASCO 2013; Coutre EHA 2013; Barrientos EHA 2013). This report summarizes the Phase 1 combination experience of IDELA with cytotoxic chemotherapies. Methods Subjects were sequentially enrolled into one of 3 regimens of IDELA in combination with either (1) Bendamustine (B), 90 mg/m2 IV days 1,2 every 28 days x 6 cycles (N=15, enrolled Apr 2010-Nov 2011); (2) Fludarabine (F), 40 mg/m2 orally days 1-5, every 28 days x 6 cycles (N=12, enrolled Apr 2011-Aug 2011), or (3) Chlorambucil (Ch), 10 mg/m2 orally days 1-7, every 28 days x minimum of 3 and maximum of 12 cycles (N=18, enrolled Mar 2012-Aug 2012). IDELA was dosed at 150 mg po BID continuously. Response assessment was investigator determined, using scheduled CT scans and clinical criteria and applying IWCLL 2008 guidelines. Results 45 subjects were enrolled. The median age was 65 years; 73% Rai III/IV; median 3 prior regimens, (range 1-9); 58% refractory to last therapy. Prior therapy included rituximab (93%), F (82%), an alkylating agent (80%), and B (38%). 44% of B cohort subjects had prior B, and 75% of F cohort had prior F. Adverse prognostic factors: 42% del(17p)/TP53 mutated; 84% IGHV unmutated; 26% NOTCH1 mutated. As of May 1, 2013, the median idelalisib exposure for the B, F and Ch cohorts was 10.6 mo (range 1-32.5), 13.1 mo (2-22.4), and 11.1 mo (0.9-12.9), respectively. 18 (40%) subjects remain on treatment. Of the 27 discontinuations (D/C), 8 were for AEs, including diarrhea in 4 (9%); febrile neutropenia led to D/C in only 1. The most common (≥10% overall) Grade ≥3 AEs were febrile neutropenia (22%) and diarrhea (16%). Treatment-emergent Grade≥3 lab abnormalities in B/F/Ch/total (%) were neutropenia in 67/58/73/67, thrombocytopenia in 22/17/33/24, anemia in 28/17/20/22 and ALT/AST increased in 22/25/0/16. 42 subjects were evaluable for response. The ORR was 78% for the entire group of 45. Best responses (PR%/CR%) were 78/0 with B, 92/0 with F, and 60/7 with Ch; all non-responding subjects had stable disease. Among 42 subjects with genetic data, the ORR in the 19 with either del(17p) and/or TP53 mutation was 70% vs. 83% among 23 subjects with neither. The median time to response was 1.9 mos for each regimen. Median duration of response (mos) / median PFS (mos) was 26.6/19.9 for B, NR/NR for F, NR/NR for Ch, and 26.6/28.5 for the entire group (NR: not reached). Conclusions IDELA can be combined with the cytotoxic single agents B, F and Ch with acceptable safety. In this heavily pretreated group of patients, many with refractory disease and adverse genetic markers, the ORR of 78% and estimated DOR and PFS of 28.5 months are indicative of significant clinical activity. Disclosures: De Vos: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. Furman:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Dansey:Gilead Sciences: Employment. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Dubowy:Gilead Sciences: Employment. Coutre:Gilead Sciences: Research Funding.
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- 2013
196. A Phase 1 Study Of The Selective PI3Kδ Inhibitor Idelalisib (GS-1101) In Combination With Therapeutic Anti-CD20 Antibodies (Rituximab or Ofatumumab) In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia
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Richard R. Furman, Sven De Vos, John P. Leonard, Jacqueline C. Barrientos, Marshall T. Schreeder, Ian W. Flinn, Jeff P. Sharman, Thomas Boyd, Nathan Fowler, Kanti R. Rai, Yeonhee Kim, Leanne M. Holes, Roger Dansey, Thomas M. Jahn, and Steven E. Coutre
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Bendamustine ,medicine.medical_specialty ,Performance status ,business.industry ,Immunology ,Cell Biology ,Hematology ,Ofatumumab ,Biochemistry ,Gastroenterology ,Rash ,Fludarabine ,Surgery ,Discontinuation ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,Rituximab ,medicine.symptom ,business ,Idelalisib ,medicine.drug - Abstract
Introduction PI3Kδ signaling is critical for the proliferation and survival as well as for homing and tissue retention of malignant B cells. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in patients with heavily pretreated CLL. Methods This Phase 1 study evaluated idelalisib for relapsed/refractory CLL continuously given at 150 mg BID in combination with a total of 8 infusions of rituximab (R, 375 mg/m2 weekly x 8), or a total of 12 infusions of ofatumumab (O, 300mg initial dose either on Day 1 or Day 2 relative to the first dose of idelalisib, then 1,000 mg weekly x 7, then 1,000 mg every 4 wks x 4). Pts on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical response was evaluated according to published criteria (Hallek 2008; Cheson 2012). Results 40 pts (12F/28M) with a median (range) age of 66 (43-87) years and a WHO performance status of 0 (24, 60%) or 1 (16 40%) were enrolled. 19 pts received idelalisib in combination with R, 21 with O. Adverse disease characteristics (n, %) included Rai Stage III/IV (20, 50%), bulky lymphadenopathy (24, 60%), refractory disease (14, 35%), multiple prior therapies (median 2, range: 1-;9). Almost all patients (39, 98%) had at least 1 prior therapy containing R, and 3 of the 21 pts (14%) receiving idelalisib + O had received prior O. 63% of the pts receiving idelalisib + R, and 43% of the pts receiving idelalisib + O were refractory to R. Prior therapies also included alkylating agents (31, 78%, [bendamustine: 20, 50%]) and purine analogs (31, 78%, [fludarabine: 28, 70%]). Data available from 39 pts showed that 11 (28%) pts had evidence of del(17p) and/or TP53 mutations and 30 (75%) had unmutated IGHV. As of May 2013, the median (range) treatment duration was 18 (0-33) months. 23 (58%) pts have completed the primary study and enrolled into the extension study. A total of 14 pts (35%) were continuing idelalisib treatment on the extension study. The most common reasons for discontinuation either from the primary or extension study were disease progression (10, 25%) and adverse events (AEs) (9, 23%). There were 6 deaths reported on study; 3 pts experienced PD before death. Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea (53%/10%), cough (40%/3%), pyrexia (40%/3%), dyspnea (30%/3%), fatigue (25%/0%) nausea (25%/0%), rash (20%/0%), pneumonia (18%/15%), colitis (10%/10%) and pneumonitis (10%/7.5%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 30%/10%. Of those, only 1 pt discontinued the study because of (recurrent) TA elevation. The ORR (N=40) was 83% (33/40), with 3 CRs (8%), and a median (range) time to response of 1.9 (1.7-21.8) months. Median progression-free survival (PFS) for all patients (N=40) and duration of response (n=33) were 20 and 19 months, respectively. Median overall survival (OS) has not been reached. For the 11 pts with del(17p) and/or TP53 mutations, the response rate was 73% (8/11) and the median PFS and DOR were 19 months. Conclusions Combinations of idelalisib with therapeutic anti-CD20 antibodies such as rituximab or ofatumumab represent non-cytotoxic regimens with acceptable safety profiles and high activity resulting in durable tumor control in pts with heavily pretreated relapsed/refractory CLL. Phase 3 trials evaluating the efficacy of idelalisib in combination with R or O are ongoing (NCT01539512, NCT01659021). Disclosures: Furman: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. De Vos:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Fowler:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Coutre:Gilead Sciences: Research Funding.
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- 2013
197. Lenalidomide Promotes The Expansion Of CD8 T Cells With An Effector Memory Phenotype In a Murine Xenograft Model Of Chronic Lymphocytic Leukemia
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Sonia Marsilio, Steven L. Allen, Andrea Nicola Mazzarello, Nicholas Chiorazzi, Gerardo Ferrer, Kanti R. Rai, Shih-Shih Chen, Jacqueline C. Barrientos, Xiao J. Yan, Stefano Vergani, Piers E.M. Patten, Rita Simone, and Jonathan E. Kolitz
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business.industry ,Chronic lymphocytic leukemia ,Immunology ,CD28 ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Aldesleukin ,medicine ,Cytotoxic T cell ,Bone marrow ,CD5 ,business ,CD8 ,Lenalidomide ,medicine.drug - Abstract
Lenalidomide (Revlimid®), a thalidomide analogue, is an orally administered second generation immunomodulator with anti-angiogenic and anti-neoplastic properties. Initial studies treating patients with chronic lymphocytic leukemia (CLL) suggest that lenalidomide can have considerable efficacy and that its mode of action is mainly indirect, affecting non-malignant cells in the microenvironment, in particular T lymphocytes. Because a recently described xenograft model for CLL has highlighted the importance of CLL-derived, autologous T cells in promoting leukemic B-cell engraftment and growth in vivo, we have studied the influence of lenalidomide on the expansion of CLL B- and T-lymphocytes in this model. After an initial 12 day culture of FACS-isolated CLL-derived T cells with or without anti-CD3/CD28 beads plus IL-2 (30 IU/ml), T lymphocytes were transferred into alymphoid NSG mice via the retro-orbital plexus (day 0). On day 7, CLL cells were delivered retro-orbitally. These recipient animals are referred to as “T + PBMC mice”. Mice that did not receive T cells on day 0 but were given CLL PBMCs at day 7, with or without lenalidomide, served as controls (“PBMC only mice”). Recipient mice received lenalidomide (10mg/kg/day) or vehicle control daily by gavage starting at day 0. All mice were sacrificed at day 28 (28 days after T-cell and 21 days after B-cell transfer), and blood, spleen, and bone marrow were collected. On this material, four analyses were performed: [1] level of human CD45+ cell engraftment; [2] numbers and types of CLL-derived T cells; [3] numbers of CLL B cells; and [4] levels of cytokines reflective of Th1 and Th2 immune responses. There was a clear enhancement in human hematopoietic (CD45+) cell engraftment in those mice exposed to lenalidomide. This was most marked for the PBMC only mice (vehicle: 10.64%; lenalidomide: 38.53%), although it was also evident for T + PBMC mice (vehicle: 55.96%; lenalidomide: 69.65%). T-cell phenotyping was carried out, before and after cell culture and also at sacrifice. Prior to culture, CLL samples contained on average ∼96% CD5+CD19+ cells and ∼3% CD5+CD19- cells; for the latter, ∼67% were CD4+ and ∼33% CD8+. After 12-day culture, these percentages remained largely unchanged. However, the numbers and types of T cells recovered from the spleens at sacrifice were quite different after in vivo exposure to lenalidomide. For the PBMC only, the percentages of CD4+ and CD8+ cells in the spleens differed somewhat based on lenalidomide exposure (CD4: Vehicle 86% vs. Lenalidomide 61%; CD8: Vehicle 10% vs. Lenalidomide 28%). However, this change was dramatic for the T + PBMC mice (CD4: Vehicle 64.1% vs. Lenalidomide 28.9%; CD8: Vehicle 34% vs. Lenalidomide 62%). Furthermore, when the CD8+ cells from these animals were subsetted based on antigen-experience and function, it appeared that lenalidomide exposure had led to the outgrowth of a greater number of effector memory (CD45RO+ CD62L-) than central memory (CD45RO+ CD62L+) T-cells. For CLL-derived B cells, the numbers differed, based not only on lenalidomide exposure but also on prior in vitro activation. Specifically, in PBMC only mice, the addition of lenalidomide led to increased numbers of CLL B cells in the spleen (Vehicle: 7.81% vs. Lenalidomide: 14%). Conversely, in the T + PBMC mice, the numbers of B cells decreased (Vehicle: 2.36% vs. Lenalidomide: 0.34%). An analysis of Th1 and Th2-related cytokines in the plasmas of the mice at sacrifice revealed a fall in IL-4, IL-5, and IL-10 and a marked increase in IFNg, consistent with a Th2 to Th1 transition. The above data suggest that administration of lenalidomide permits greater engraftment of human hematopoietic cells in alymphoid mice. Although this enhancement involves all members of the hematopoietic lineage, T cells, in particular CD8+ effector memory T cells, emerge in excess over time. This CD8 expansion is associated with diminished levels of CLL B cells suggesting that the decrease is due to T-cell mediated cytolysis. In contrast, in the absence of prior T-cell activation, CLL T cells appear to support better CLL B-cell growth. These findings suggest that lenalidomide alters B-cell expansion in vivo depending on the activation and differentiation state of the autologous T-cell compartment. They also implicate the generation of cytolytic T cells as one mechanism whereby lenalidomide leads to clinical improvement in CLL. Disclosures: Allen: Celgene Corporation: Honoraria.
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198. Concomitant, T-Independent TLR9-Mediated and BCR-Mediated Activation Provides Signals For Optimal Telomerase Induction In Chronic Lymphocytic Leukemia Cells Regardless Of IGHV Mutation Status
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Rajendra N. Damle, Nicholas Chiorazzi, Kanti R. Rai, Steven L. Allen, Jacqueline C. Barrientos, Ryon M. Andersen, Sonal Temburni, and Jonathan E. Kolitz
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Telomerase ,Stromal cell ,CD40 ,medicine.diagnostic_test ,Chronic lymphocytic leukemia ,Immunology ,breakpoint cluster region ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Molecular biology ,Flow cytometry ,immune system diseases ,hemic and lymphatic diseases ,Monoclonal ,medicine ,biology.protein ,Cell activation - Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the clonal amplification of CD5-expressing B cells that appear to develop and evolve based on signals from the microenvironment. In vitro and in vivo evidence suggests that the B-cell antigen receptor (BCR) and Toll-like receptors (TLRs) may be keys to this stimulation. Because clonal turnover can lead to the release of naked nuclear material into the cellular microenvironment, these remnants of dying/dead cells may contribute to disease progression by repeated low level T-independent activation of CLL cells through the combination of the BCR and TLRs. To test this hypothesis, we assessed TLR9-driven or BCR + TLR9-driven CLL B-cell activation, focusing on its impact on telomerase activation in CLL cells, which is known to be important in the disease and which we have shown to be selectively activated by BCR stimulation in Ig V-unmutated (U-CLL) clones but not in Ig V-mutated (M-CLL) clones. B cells, isolated by negative selection from peripheral blood of IgM+ CLL patients and cryopreserved until use, were cultured for 16 hr without/ with TLR9 agonist, ODN 2006, alone and were assayed for apoptosis using Annexin V and flow cytometry. To study the relative contribution of simultaneous TLR9 activation and BCR activation, B cells were exposed to ODN2006 alone or HB57dex (monoclonal anti IgM Ab conjugated onto dextran) alone or a combination of the two reagents. Extracts from cells cultured for a period of 3 days were assayed for functional telomerase activity using TRAP. Parallel cultures of B cells exposed to the same stimuli were harvested at day 3 and assayed for cell activation and proliferation, which was assessed by 3H thymidine incorporation. CLL cells cultured with ODN2006 exhibited significant apoptosis within 16 hours in 6/12 cases. However at day 3, the same stimulus elicited significant increases in percentages of CD69-expressing cells and densities of HLA-DR in all CLL cases studied. As compared to BCR activation, which upregulates telomerase activity in U-CLL only, TLR9-mediated activation of CLL induced telomerase activation in all CLL cases. Furthermore, ODN2006 elicited significantly higher induction of telomerase activity in M-CLL cases compared to U-CLL cases (p=0.01). In addition, in M-CLL cases, simultaneous activation via TLR9 and BCR significantly upregulated the telomerase activity (p=0.05) that was induced by TLR9 activation alone. IRAK-1/4 inhibitor down modulated both TLR9 mediated and TLR9 +BCR mediated telomerase activity to a greater extent in M-CLL cases than in U-CLL cases. TLR9 activation of CLL cells induced a 3.75 + 0.8 fold (range 1.1 to 19.6; n=32) increase in cell proliferation. When segregated by Ig V mutation, U-CLL cells (n=16) responded significantly better (6.0 + 1.6 fold) compared to M-CLL cells (2.1 + 0.3 fold, n=16; p=0.03). However, co-stimulation of cells via their BCR significantly increased TLR-mediated responses only in M-CLL cases (from 2.3 + 0.4 fold to 5.4 + 1.7 fold; p=0.05). IRAK-1/4 inhibitor did not exert a significant effect on TLR9 mediated cell proliferation in either the U-CLL or M-CLL cases. Co-culture of CLL cells with human stromal cells, HS5, further upregulated the concerted TLR9 + BCR induced proliferative responses in 70% of the cases studied. Together, these results indicate that simultaneous stimulation of CLL cells via both their TLR9 and BCR molecules positively impacts on telomerase activity in all patients studied. Since telomerase is crucial in maintaining longevity of repeatedly stimulated cells, this could represent a mechanism for worse clinical outcome in CLL. These studies stress the need for devising therapeutic agents or combinations thereof to effectively target multiple pathways downstream of these signaling receptors and to ultimately eradicate newly evolving CLL cells. Disclosures: No relevant conflicts of interest to declare.
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199. Preliminary results of PI3Kδ inhibitor idelalisib (GS-1101) treatment in combination with everolimus, bortezomib, or bendamustine/rituximab in patients with previously treated mantle cell lymphoma (MCL)
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Wayne R. Godfrey, Nathan Fowler, Roger Dansey, Jeff Porter Sharman, Sven de Vos, Marshall T. Schreeder, Ian W. Flinn, Yeonhee Kim, Leanne Holes, Ralph V. Boccia, Nina D. Wagner-Johnston, Steven Coutre, Jacqueline C. Barrientos, John P. Leonard, Thomas E. Boyd, and David Michael Johnson
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Bendamustine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Everolimus ,business.industry ,Bortezomib ,Pharmacology ,medicine.disease ,Regimen ,Internal medicine ,Medicine ,Rituximab ,In patient ,Mantle cell lymphoma ,business ,Idelalisib ,medicine.drug - Abstract
8501 Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown monotherapy activity in recurrent MCL (Kahl, ICML 2011). Methods: This phase 1 study is evaluating the activity of continuous idelalisib (Id), 150 mg BID, in combination with everolimus (E) (10 mg PO qD) (Id+E regimen), with bortezomib (V) (1.3 mg/m2 SC day 1, 8, 15 per 28 day cycle) (Id+V regimen), or with rituximab (R) (375 mg/m2, on Day 1) and bendamustine (B) (90 mg/m2x 2), for 6 cycles (Id+BR regimen). Investigators assessed response according to standard criteria (Cheson 2007). Results: Study enrolled 22 patients with relapsed/refractory MCL. Results are from 14 Jan 2013 data cutoff. The 3 cohorts included Id+E (N=12), Id+V (N=6), and Id+BR (N=4). Patients were 73% male, median age [range] of 68 [47E79] years, 32% with refractory disease and 73% stage III/IV. The median [range] number of prior therapies was 3 [1E7]. The median [range] duration of treatment was 2.5 [0.5-8.3+] months. Overall response rate (ORR) was 10/22 (46%), with 2 CR (9%). The ORR/CR for Id+E, was 25%/0%, Id+V was 50%/0%, and Id+BR was 100%/50%. The median duration of response (mDOR) and median PFS (mPFS) were not reached. Most common adverse events included (total%/≥G3%) diarrhea (41/9), fatigue (41/0), rash (27/14), cough (27/0), decreased appetite (23/0), and epistaxis (23/0). Lab abnormalities included (total%/≥G3%) thrombocytopenia (82/27), neutropenia (32/14), and ALT/AST elevations (50/5). Conclusions: Preliminary data indicates idelalisib-based combination therapy is active in patients with relapsed/refractory MCL. All combinations were tolerable. These data support further clinical development in larger trials to further characterize safety and response duration. Clinical trial information: NCT01088048.
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200. Tolerability and activity of combinations of the PI3Kδ inhibitor idelalisib (GS-1101) with rituximab and/or bendamustine in patients with previously treated, indolent non-Hodgkin lymphoma (iNHL): Updated results from a phase I study
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Jeff Porter Sharman, John P. Leonard, Jacqueline C. Barrientos, Ralph V. Boccia, Nathan Fowler, Roger Dansey, Yeonhee Kim, Richard R. Furman, Steven Coutre, Ian W. Flinn, Kanti R. Rai, Wayne R. Godfrey, Thomas E. Boyd, Nina D. Wagner-Johnston, Leanne Holes, Sven de Vos, Marshall T. Schreeder, and David Michael Johnson
- Subjects
Bendamustine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Pharmacology ,Phase i study ,Tolerability ,Internal medicine ,Indolent Non-Hodgkin Lymphoma ,Medicine ,In patient ,Rituximab ,business ,Idelalisib ,Previously treated ,medicine.drug - Abstract
8500 Background: PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in recurrent iNHL (Kahl, ICML 2011), as well as combination therapy (Fowler, ASCO 2012). Methods: This phase I study evaluated the activity of continuous (48 weeks) idelalisib (Id), 100/150 mg BID, in combination with rituximab (R) (375 mg/m2 weekly x 8 doses) (Id+R), with bendamustine (B) (90 mg/m2 x 2, for 6 cycles) (Id+B), or in combination with R (375 mg/m2 monthly x 6) and B (90 mg/m2 x 2), for 6 cycles (Id+BR). Investigators assessed response according to standard criteria (Cheson 2007). Patients who continued to benefit were able to enroll on an extension study. Results: Study enrolled 78 pts with relapsed/refractory iNHL, with 34 (44%) pts continuing on treatment in the ongoing extension protocol. The 3 cohorts included Id+R (N=30), Id+B (N=34), and Id+BR (N=14). Pts were 67% male, median age [range] of 62 [37E84] years, 41% with refractory disease, 88% stage III/IV, and 36% of FL with high FLIPI scores. The median [range] number of prior therapies was 3 [1E10]. The median [range] duration of treatment was 10.6 [0.5-29.2] months. Overall response rate (ORR) was 63/78 (81%), with 22/78 (28%) CR. The ORR/CR for Id+R was 77%/20%, Id+B was 85%/29%, and Id+BR was 79%/43%. At 20 months, the PFS was 66%. For responders, 73% were progression-free at 20 months. Most common adverse events included (total%/≥G3%) pyrexia (56/4), fatigue (45/4), nausea (41/0), rash (40/8), cough (37/0), diarrhea (36/8), chills (18/0), URI (18/1), and pneumonia (17/15). Lab abnormalities included (total%/≥G3%) ALT/AST elevations (56/17). Conclusions: Idelalisib-based combination therapy is highly active and well tolerated in patients with relapsed/refractory iNHL. These data support further clinical development. Phase III trials evaluating the efficacy of idelalisib in combination with R, or BR in iNHL are ongoing (NCT01732913, NCT01732926). Clinical trial information: NCT01732913, NCT01732929.
- Published
- 2013
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