327 results on '"Gary J. Schiller"'
Search Results
2. Efficacy and safety of once weekly selinexor 40 mg versus 60 mg with pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
- Author
-
Darrell White, Gary J. Schiller, Sumit Madan, Suzanne Lentzsch, Evgeni Chubar, Noa Lavi, Dane R. Van Domelen, Ohad S. Bentur, and Muhamed Baljevic
- Subjects
selinexor ,once weekly dose ,optimal triplet combination ,relapsed/refractory multiple myeloma ,pomalidomide ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
ObjectiveTo identify the optimal dose of selinexor in combination with pomalidomide and dexamethasone (SPd).MethodsAn analysis of efficacy and safety of 2 once-weekly selinexor regimens (60 mg and 40 mg) with pomalidomide and dexamethasone (SPd-60 and SPd-40, respectively) given to patients with relapsed/refractory multiple myeloma (RRMM) in the STOMP (NCT02343042) and XPORT-MM-028 (NCT04414475) trials.ResultsTwenty-eight patients (60.7% males, median age 67.5 years) and 20 patients (35.0% males, median age 65.5 years) were analyzed in the SPd-40 and SPd-60 cohorts, respectively. Overall response rate was 50% (95% confidence interval [CI] 30.6-69.4%) and 65% (95% CI 40.8-84.6%), respectively. Very good partial response or better was reported in 28.6% (95% CI 13.2-48.7%) and 30.0% (95% CI 11.9-54.3%) of patients, respectively. Among 27 responders in both cohorts, the 12-month sustained response rate was 83.3% (95% CI 64.7-100.0%) for SPd-40 and 28.1% (95% CI 8.9-88.8%) for SPd-60. Median progression-free survival was 18.4 months (95% CI 6.5 months, not evaluable [NE]) and 9.5 months (95% CI 7.6 months-NE) for SPd-40 and SPd-60, respectively. Twenty-four-month survival rates were 64.2% (95% CI 47.7-86.3%) for SPd-40 and 51.1% (95% CI 29.9-87.5%) for SPd-60. Treatment-emergent adverse events (TEAEs) included neutropenia (all grades: SPd-40 64.3% versus SPd-60 75.0%), anemia (46.4% versus 65.0%), thrombocytopenia (42.9% versus 45.0%), fatigue (46.4% versus 75.0%), nausea (32.1% versus 70.0%) and diarrhea (28.6% versus 35.0%).ConclusionThe all-oral combination of SPd exhibited preliminary signs of efficacy and was generally tolerable in patients with RRMM. The overall risk-benefit profile favored the SPd-40 regimen.
- Published
- 2024
- Full Text
- View/download PDF
3. P367: LONG-TERM OUTCOMES OF ADULTS WITH RELAPSED OR REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH BREXUCABTAGENE AUTOLEUCEL IN ZUMA-3 BY AGE, PRIOR THERAPIES, AND SUBSEQUENT TRANSPLANT
- Author
-
Bijal Shah, Ryan D. Cassaday, Jae H. Park, Roche Houot, Olalekan O. Oluwole, Aaron C. Logan, Nicolas Boissel, Thibaut Leguay, Michael R. Bishop, Max S. Topp, Kristen M. O’dwyer, Maria R. Baer, Gary J. Schiller, Mehrdad Abedi, Monique C. Minnema, Patrick Stiff, Lang Zhou, Tsveta Hadjivassileva, Rita Damico Khalid, and Armin Ghobadi
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
- Full Text
- View/download PDF
4. Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study
- Author
-
Bijal D. Shah, Armin Ghobadi, Olalekan O. Oluwole, Aaron C. Logan, Nicolas Boissel, Ryan D. Cassaday, Thibaut Leguay, Michael R. Bishop, Max S. Topp, Dimitrios Tzachanis, Kristen M. O’Dwyer, Martha L. Arellano, Yi Lin, Maria R. Baer, Gary J. Schiller, Jae H. Park, Marion Subklewe, Mehrdad Abedi, Monique C. Minnema, William G. Wierda, Daniel J. DeAngelo, Patrick Stiff, Deepa Jeyakumar, Jinghui Dong, Sabina Adhikary, Lang Zhou, Petra C. Schuberth, Imi Faghmous, Behzad Kharabi Masouleh, and Roch Houot
- Subjects
B-precursor acute lymphoblastic leukemia ,Brexucabtagene autoleucel ,CAR T-cell therapy ,KTE-X19 ,SCHOLAR-3 ,ZUMA-3 ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care. Methods Adults with R/R B-ALL received a single infusion of KTE-X19 (1 × 106 CAR T cells/kg). Long-term post hoc subgroup assessments of ZUMA-3 were conducted. Outcomes from matched patients between historical clinical trials and ZUMA-3 patients were assessed in the retrospective historical control study SCHOLAR-3. Results After 26.8-months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients (N = 55) in phase 2 was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients (N = 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 (N = 49) and matched historical controls (N = 40) was 25.4 and 5.5 months, respectively. Conclusions These data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult R/R B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population. Trial Registration: NCT02614066.
- Published
- 2022
- Full Text
- View/download PDF
5. Selinexor‐based regimens in patients with multiple myeloma after prior anti‐B‐cell maturation antigen treatment
- Author
-
Muhamed Baljevic, Cristina Gasparetto, Gary J. Schiller, Sascha A. Tuchman, Natalie S. Callander, Suzanne Lentzsch, Jorge Monge, Rami Kotb, Nizar J. Bahlis, Darrell White, Christine I. Chen, Heather J. Sutherland, Sumit Madan, Richard LeBlanc, Michael Sebag, Christopher P. Venner, William I. Bensinger, Noa Biran, Andrew DeCastro, Dane R. Van Domelen, Chris Zhang, Jatin J. Shah, Sharon Shacham, Michael G. Kauffman, Ohad S. Bentur, and Brea Lipe
- Subjects
anti‐BCMA ,multiple myeloma ,selinexor ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract There is a lack of consensus on therapy sequencing in previously treated multiple myeloma, particularly after anti‐B‐cell maturation antigen (BCMA) therapy. Earlier reports on selinexor (X) regimens demonstrated considerable efficacy in early treatment, and after anti‐BCMA‐targeted chimeric antigen receptor‐T cell therapy. Here, we present data from 11 heavily pretreated patients who predominantly received BCMA‐antibody‐drug conjugate therapy. We observe that X‐containing regimens are potent and achieve durable responses with numerically higher overall response and clinical benefit rates, as well as median progression free survival compared to patients’ prior anti‐BCMA therapies, despite being used later in the treatment course. In an area of evolving unmet need, these data reaffirm the efficacy of X‐based regimens following broader anti‐BCMA therapy.
- Published
- 2022
- Full Text
- View/download PDF
6. Recurrent heart failure with preserved ejection fraction associated with carfilzomib administration for multiple myeloma
- Author
-
Eric H. Yang, Cynthia Courtney, Vinisha Garg, Michael G. Fradley, and Gary J. Schiller
- Subjects
Carfilzomib ,Proteasome inhibitors ,Multiple myeloma ,Heart failure ,Cardiac biomarkers ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Carfilzomib, an epoxyketone proteasome inhibitor, has demonstrated improved progression-free survival in patients when used with standard treatment (lenalidomide and dexamethasone) in patients with relapsed multiple myeloma (MM). However, there are reports of adverse cardiac events with carfilzomib manifested by dyspnea and heart failure. A patient is presented who had recurrent, clinically mild cardiotoxicity, as manifested by recurrent heart failure with preserved ejection fraction, with ongoing maintenance carfilzomib in a patient with resistant MM is presented.
- Published
- 2018
- Full Text
- View/download PDF
7. A Phase 1 study of intravenous infusions of tigecycline in patients with acute myeloid leukemia
- Author
-
Gregory A. Reed, Gary J. Schiller, Suman Kambhampati, Martin S. Tallman, Dan Douer, Mark D. Minden, Karen W. Yee, Vikas Gupta, Joseph Brandwein, Yulia Jitkova, Marcela Gronda, Rose Hurren, Aisha Shamas‐Din, Andre C. Schuh, and Aaron D. Schimmer
- Subjects
Cox‐1 ,Cox‐4 ,mitochondrial protein synthesis ,pharmacodynamics ,pharmacokinetics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Acute myeloid leukemia (AML) cells meet the higher energy, metabolic, and signaling demands of the cell by increasing mitochondrial biogenesis and mitochondrial protein translation. Blocking mitochondrial protein synthesis through genetic and chemical approaches kills human AML cells at all stages of development in vitro and in vivo. Tigecycline is an antimicrobial that we found inhibits mitochondrial protein synthesis in AML cells. Therefore, we conducted a phase 1 dose‐escalation study of tigecycline administered intravenously daily 5 of 7 days for 2 weeks to patients with AML. A total of 27 adult patients with relapsed and refractory AML were enrolled in this study with 42 cycles being administered over seven dose levels (50–350 mg/day). Two patients experienced DLTs related to tigecycline at the 350 mg/day level resulting in a maximal tolerated dose of tigecycline of 300 mg as a once daily infusion. Pharmacokinetic experiments showed that tigecycline had a markedly shorter half‐life in these patients than reported for noncancer patients. No significant pharmacodynamic changes or clinical responses were observed. Thus, we have defined the safety of once daily tigecycline in patients with refractory AML. Future studies should focus on schedules of the drug that permit more sustained target inhibition.
- Published
- 2016
- Full Text
- View/download PDF
8. Phase 3 results for vosaroxin/cytarabine in the subset of patients ≥60 years old with refractory/early relapsed acute myeloid leukemia
- Author
-
Farhad Ravandi, Ellen K. Ritchie, Hamid Sayar, Jeffrey E. Lancet, Michael D. Craig, Norbert Vey, Stephen A. Strickland, Gary J. Schiller, Elias Jabbour, Arnaud Pigneux, Heinz-August Horst, Christian Récher, Virginia M. Klimek, Jorge E. Cortes, Angelo-Michele Carella, Miklos Egyed, Utz Krug, Judith A. Fox, Adam R. Craig, Renee Ward, Jennifer A. Smith, Gary Acton, Hagop M. Kantarjian, and Robert K. Stuart
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2018
- Full Text
- View/download PDF
9. An exploratory phase 2 study of investigational Aurora A kinase inhibitor alisertib (MLN8237) in acute myelogenous leukemia and myelodysplastic syndromes
- Author
-
Stuart L. Goldberg, Pierre Fenaux, Michael D. Craig, Emmanuel Gyan, John Lister, Jeannine Kassis, Arnaud Pigneux, Gary J. Schiller, JungAh Jung, E. Jane Leonard, Howard Fingert, and Peter Westervelt
- Subjects
Aurora A kinase inhibitor ,Alisertib ,Safety ,Acute myeloid leukemia (AML) ,Myelodysplastic syndrome (MDS) ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Alisertib (MLN8237) is an investigational, oral, selective, Aurora A kinase (AAK) inhibitor. In this phase 2 trial, 57 patients with acute myeloid leukemia (AML) or high-grade myelodysplastic syndrome received alisertib 50 mg BID for 7 days in 21-day cycles. Responses in 6/35 AML patients (17% response rate with an additional 49% stable disease, 34% transfusion independence) included 1 complete response lasting >1 year. No responses were observed in MDS patients. Adverse events >30% included diarrhea, fatigue, nausea, febrile neutropenia, and stomatitis. Results suggest modest activity in AML, supporting further research to better understand how AAK inhibition may induce leukemic cell senescence.
- Published
- 2014
- Full Text
- View/download PDF
10. Minimal Residual Disease as a Predictive Factor for Relapse after Allogeneic Hematopoietic Stem Cell Transplant in Adult Patients with Acute Myeloid Leukemia in First and Second Complete Remission
- Author
-
Rada M. Grubovikj, Asif Alavi, Ahrin Koppel, Mary Territo, and Gary J. Schiller
- Subjects
minimal residual disease ,allogeneic hematopoietic stem cell transplantation ,acute myeloid leukemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with acute myeloid leukemia (AML) in morphologic first and second complete remission undergoing allo-SCT. Fifty nine patients were eligible for the study of 160 patients transplanted over ten years. For the MRD assessment we used multiparametric flow cytometry, cytogenetics and fluorescent in situ hybridization; 19 patients (32.2%) were identified as MRD positive. Patients with MRD had a consistently worse outcome over those without MRD, with 3-years leukemia-free survival (LFS) of 15.8% vs. 62.4% and overall survival (OS) of 17.5% vs. 62.3%. Relapse rate was significantly higher in MRD-positive patients; 3 years relapse rate in MRD-positive patients was 57.9% vs. 15.1% in MRD-negative patients. Detection of MRD in complete remission was associated with increased overall mortality (HR = 3.3; 95% CI: 1.45–7.57; p = 0.0044) and relapse (HR = 5.26; 95% CI: 2.0–14.0; p = 0.001), even after controlling for other risk factors. Our study showed that for patients in morphologic complete remission the presence of MRD predicts for significantly increased risk of relapse and reduced LFS and OS.
- Published
- 2012
- Full Text
- View/download PDF
11. Autologous blood cell transplantation versus HLA-identical sibling transplantation for acute myeloid leukemia in first complete remission: a registry study from the Center for International Blood and Marrow Transplantation Research
- Author
-
Armand Keating, Gisela DaSilva, Waleska S. Pérez, Vikas Gupta, Corey S. Cutler, Karen K. Ballen, Mitchell S. Cairo, Bruce M. Camitta, Richard E. Champlin, James L. Gajewski, Hillard M. Lazarus, Michael Lill, David I. Marks, Chadi Nabhan, Gary J. Schiller, Gerald Socie, Jeffrey Szer, Martin S. Tallman, and Daniel J. Weisdorf
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The optimal post-remission treatment for acute myeloid leukemia in first complete remission remains uncertain. Previous comparisons of autologous versus allogeneic hematopoietic cell transplantation noted higher relapse, but lower treatment-related mortality though using bone marrow grafts, with treatment-related mortality of 12-20%. Recognizing lower treatment-related mortality using autologous peripheral blood grafts, in an analysis of registry data from the Center for International Blood and Transplant Research, we compared treatment-related mortality, relapse, leukemia-free survival, and overall survival for patients with acute myeloid leukemia in first complete remission (median ages 36-44, range 19-60) receiving myeloablative HLA-matched sibling donor grafts (bone marrow, n=475 or peripheral blood, n=428) versus autologous peripheral blood (n=230). The 5-year cumulative incidence of treatment-related mortality was 19% (95% confidence interval, 16-23%), 20% (17-24%) and 8% (5-12%) for allogeneic bone marrow, allogeneic peripheral blood and autologous peripheral blood stem cell transplant recipients, respectively. The corresponding figures for 5-year cumulative incidence of relapse were 20% (17-24%), 26% (21-30%) and 45% (38-52%), respectively. At 5 years, leukemia-free survival and overall survival rates were similar: allogeneic bone marrow 61% (56-65%) and 64% (59-68%); allogeneic peripheral blood 54% (49-59%) and 59% (54-64%); autologous peripheral blood 47% (40-54%) and 54% (47-60%); P=0.13 and P=0.19, respectively. In multivariate analysis the incidence of treatment-related mortality was lower after autologous peripheral blood transplantation than after allogeneic bone marrow/peripheral blood transplants [relative risk 0.37 (0.20-0.69); P=0.001], but treatment failure (death or relapse) after autologous peripheral blood was significantly more likely [relative risk 1.32 (1.06-1.64); P=0.011]. The 5-year overall survival, however, was similar in patients who received autologous peripheral blood (n=230) [relative risk 1.23 (0.98-1.55); P=0.071] or allogeneic bone marrow/peripheral blood (n=903). In the absence of an HLA-matched sibling donor, autologous peripheral blood may provide acceptable alternative post-remission therapy for patients with acute myeloid leukemia in first complete remission.
- Published
- 2013
- Full Text
- View/download PDF
12. A Critical Reappraisal of Gastrointestinal Complications of Allogeneic Bone Marrow Transplantation
- Author
-
Gary J. Schiller and Robert Peter Gale
- Subjects
Medicine - Abstract
Gastrointestinal toxicity is a common early complication of allogeneic bone marrow transplants. Etiologies include mucosal damage from pretransplant conditioning, opportunistic infection, and graft-versus-host disease. Because the clinical, laboratory, radiographic, and histological findings of acute graft-versus-host disease are nonspecific, accurate diagnosis is difficult or impossible. We review the differential diagnosis of gastrointestinal complications of bone marrow transplants and implications for therapy.
- Published
- 1992
- Full Text
- View/download PDF
13. Pevonedistat with azacitidine in older patients with TP53-mutated AML: a phase 2 study with laboratory correlates
- Author
-
Antoine N. Saliba, Scott H. Kaufmann, Eytan M. Stein, Prapti A. Patel, Maria R. Baer, Wendy Stock, Michael Deininger, William Blum, Gary J. Schiller, Rebecca L. Olin, Mark R. Litzow, Tara L. Lin, Brian J. Ball, Michael M. Boyiadzis, Elie Traer, Olatoyosi Odenike, Martha L. Arellano, Alison Walker, Vu H. Duong, Tibor Kovacsovics, Robert H. Collins, Abigail B. Shoben, Nyla A. Heerema, Matthew C. Foster, Kevin L. Peterson, Paula A. Schneider, Molly Martycz, Theophilus J. Gana, Leonard Rosenberg, Sonja Marcus, Ashley O. Yocum, Timothy Chen, Mona Stefanos, Alice S. Mims, Uma Borate, Amy Burd, Brian J. Druker, Ross L. Levine, John C. Byrd, and James M. Foran
- Subjects
Hematology - Published
- 2023
14. A Risk-Adapted Study to Assess the Efficacy of Enasidenib and Subsequent Response-Driven Addition of Azacitidine for Newly Diagnosed IDH2-Mutant AML Patients: 3-Year Follow-up
- Author
-
Eytan Stein, Sheng F Cai, Ying Huang, Andrew Dunbar, Maria R. Baer, Wendy Stock, Tibor Kovacsovics, William G. Blum, Gary J. Schiller, Rebecca L. Olin, James M. Foran, Mark R. Litzow, Tara L. Lin, Prapti A. Patel, Matthew C. Foster, Michael M. Boyiadzis, Robert H. Collins, Jordan Chervin, Abigail B. Shoben, Jo-Anne Vergilio, Nyla A. Heerema, Leonard Rosenberg, Timothy Chen, Ashley O. Yocum, Franchesca Druggan, Sonja Marcus, Mona Stefanos, Molly Martycz, Brian J. Druker, Alice S. Mims, Uma Borate, Amy Burd, John C. Byrd, and Ross L. Levine
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
15. A Phase 1b Dose Escalation and Expansion Study of SNDX-5613, Azacitidine (AZA) and Venetoclax (VEN) in Newly Diagnosed, Patients ≥ 60 Years with Untreated NPM1-Mutated/ FLT3-Wild Type AML or KMT2A-Rearranged Acute Myeloid Leukemia (AML)
- Author
-
Joshua F. Zeidner, Matthew C. Foster, Mary Johnson, Ying Huang, Ronan T. Swords, Eytan Stein, James M. Foran, Maria R. Baer, Wendy Stock, Yazan F. Madanat, Tibor Kovacsovics, Rebecca L. Olin, William G. Blum, Gary J. Schiller, Tara L. Lin, Robert L. Redner, Zeina Al-Mansour, Emily K Curran, Nyla A. Heerema, Molly Martycz, Leonard Rosenberg, Sonja Marcus, Ashley O. Yocum, Timothy Chen, Mona Stefanos, Franchesca Druggan, Amy Burd, Ross L. Levine, Brian J. Druker, Uma Borate, John C. Byrd, and Alice S. Mims
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
16. Once Weekly Selinexor, Carfilzomib and Dexamethasone (XKd) in Triple Class Refractory Multiple Myeloma
- Author
-
Gary J. Schiller, Sascha A. Tuchman, Natalie Callander, Muhamed Baljevic, Adrianna C Rossi, Rami Kotb, Darrell J White, Nizar J. Bahlis, Heather J. Sutherland, Sumit Madan, Richard Leblanc, Christopher P. Venner, William I. Bensinger, Dane R. Van Domelen, Chris Zhang, Ohad S. Bentur, and Brea Lipe
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
17. Efficacy and Safety of Add-on Parsaclisib to Ruxolitinib Therapy in Myelofibrosis Patients With Suboptimal Response to Ruxolitinib: Final Results From a Phase 2 Study
- Author
-
Abdulraheem Yacoub, Uma Borate, Raajit K Rampal, Haris Ali, Eunice Wang, Aaron T. Gerds, Gabriela S. Hobbs, Marina Kremyanskaya, Elliott Winton, Casey O'Connell, Swati Goel, Stephen T Oh, Gary J. Schiller, Albert Assad, Sue Erickson-Viitanen, Feng Zhou, and Naval Daver
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
18. Entospletinib (ENTO) in Combination with Cytarabine (Ara-C) and Daunorubicin (DNR) in Newly Diagnosed (ND) Adult Patients with NPM1-Mutated and FLT3-ITD Wild-Type Acute Myeloid Leukemia (AML) Is Associated with Good Response and Survival: A Phase 2 Sub-Study of the Beat AML Master Trial
- Author
-
Uma Borate, Rui Li, Ying Huang, Ronan T. Swords, Elie Traer, Eytan Stein, James M. Foran, Maria R. Baer, Vu H. Duong, Wendy Stock, Olatoyosi Odenike, Prapti Patel, Robert H. Collins, Yazan F. Madanat, Tibor Kovacsovics, Michael W. Deininger, Catherine Smith, Rebecca L. Olin, Martha L. Arellano, William G. Blum, Gary J. Schiller, Tara L. Lin, Matthew C. Foster, Michael M. Boyiadzis, Robert L. Redner, Zeina Al-Mansour, Emily K Curran, Nyla A. Heerema, Theophilus J Gana, Molly Martycz, Leonard Rosenberg, Sonja Marcus, Ashley O. Yocum, Timothy Chen, Mona Stefanos, Franchesca Druggan, Amy Burd, Ross L. Levine, Brian J. Druker, John C. Byrd, and Alice S. Mims
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
19. Selinexor‐based regimens in patients with multiple myeloma after prior anti‐B‐cell maturation antigen treatment
- Author
-
Brea Lipe, Sascha A. Tuchman, Noa Biran, Michael Sebag, Jatin J. Shah, Sumit Madan, Michael Kauffman, Heather J. Sutherland, William I. Bensinger, Nizar J. Bahlis, Jorge Monge, Ohad S. Bentur, Rami Kotb, Cristina Gasparetto, Richard Leblanc, Muhamed Baljevic, Christopher P. Venner, Darrell White, Gary J. Schiller, Andrew DeCastro, Dane Van Domelen, Chris Zhiyi Zhang, Natalie S. Callander, Suzanne Lentzsch, Sharon Shacham, and Christine Chen
- Subjects
business.industry ,B-Cell Maturation Antigen ,Immunology ,medicine ,Cancer research ,In patient ,Cell Biology ,Hematology ,medicine.disease ,business ,Biochemistry ,Multiple myeloma - Abstract
Background Multiple myeloma (MM) is considered an incurable hematologic malignancy despite a plethora of standard and novel agents. There is no consensus on the optimal sequencing of available therapies in relapsed/refractory MM (RRMM), even in the second line setting. Novel agents such as selinexor (XPOVIO [X]), an oral, first-in-class selective inhibitor of nuclear export (SINE) compound that blocks XPO1, or those that target B-cell maturation antigen (BCMA), have shown significant activity in RRMM. X is approved with bortezomib (V) and dexamethasone (XVd) in patients (pts) with at least 1 prior therapy and is not associated with known long-term clinically significant toxicities such as visual loss, cardiac dysfunction, renal failure, neuropathy, irreversible bone marrow suppression, second malignancies, venous thromboembolism, or rash. Currently, BCMA-targeting agents include 1 form each of chimeric antigen receptor T cell (CAR-T cell) and antibody drug conjugate (ADC) therapy approved in RRMM: idecabtagene vicleucel and belantamab mafodotin, respectively. BCMA-refractory MM represents an area of unmet need in MM without known standards for best treatment. Various novel combinations with X have demonstrated strong benefit in RRMM after 1 or more lines of therapy and activity even in CAR-T cell BCMA-refractory MM (N=7): 1 pt stringent complete (sCR), 3 very good partial (VGPR), 2 partial (PR), and 1 minimal (MR) response (Chari BJH 2020). Here we report on the outcomes of heavily pretreated RRMM pts, a majority of whom had received ADC-BCMA, and who were treated with X-containing regimens on the STOMP trial. Methods STOMP (NCT02343042) is a phase 1b/2, multi-arm, open-label trial of various combinations of X with backbone agents for pts with RRMM or newly diagnosed MM. Here we report on all pts in STOMP with prior anti-BCMA treatment who were treated on STOMP with X+pomalidomide +dexamethasone (XPd); XVd; X+carfilzomib+d (XKd); XPVd; and XPd+elotuzumab (E) (XPEd). Results In total, 11 pts with prior anti-BCMA therapy (6 pts with belantamab mafodotin; 1 each with MEDI2228, SEA-BCMA, BCMA BITE; 2 with idecabtagene vicleucel) were treated with 5 X-containing regimens (Table 1): 9 pts were treated with triplets XPd (4), XVd (3), or XKd (2) and 2 pts with quadruplets XPVd (1) or XPEd (1). Median age was 71 years (range 46-85), 7 pts (63.6%) were women, 11 pts were white. Median duration from MM diagnosis to treatment with a STOMP regimen was 6.9 years (range 2.3-12.8). Five pts (45.5%) had high-risk cytogenetics; pts received median of 6 prior therapies (range 4-10). Eight pts (72.7%) received anti-BCMA in their immediate prior line of therapy. Ten pts (90.9%) were previously treated with all backbone drugs of the STOMP treatments (i.e., X was the only new drug). The overall response rate (ORR) and clinical benefit rate (CBR) for the prior anti-BCMA-containing regimens were 40.0% (2 pts VGPR, 2 PR, 5 stable disease [SD], 1 progressive disease, 1 unknown). Median progression free survival (PFS) was 1.8 months (95% CI: 1.5, NE), and the 6-month PFS probability was 12.5% (95% CI: 2.1, 76.2). ORR for the X-based treatments was 54.5% and CBR was 81.8%: 1 pt VGPR, 5 PR, 3 MR, 2 SD. Median PFS was not reached (95% CI: 5.9, NE) and the 6-month PFS probability was 68.6% (95% CI: 40.3, 100.0). Median overall survival was 10.5 months (95% CI: 9.6, NE) and median time to discontinuation was 8.1 months (95% CI: 6.1, NE). The most common treatment-emergent adverse events were nausea and thrombocytopenia. Nausea was Grade (G) 1/2 (n=8, 72.7%); thrombocytopenia G1-4 in 8 pts (72.7%), 4 with ≥G3; there were no concurrent bleeding events. One pt on XPEd died of pulmonary nocardiosis considered to be associated with the 4-drug regimen. No new safety signals or long-term toxicities due to X were reported. Conclusions In this follow-up cohort of heavily pretreated pts, a majority of whom with MM refractory to ADC-BCMA, we demonstrate impressive potency and durability of the X-based treatments, particularly as compared to that of their prior anti-BCMA therapies. These data support the rationale for the development of novel regimens containing X plus immunomodulatory drugs or proteasome inhibitors in earlier lines of therapy, including first relapse, and further suggest their strong value in the emerging BCMA RRMM space. Figure 1 Figure 1. Disclosures Baljevic: Exelixis: Research Funding; Amgen: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen Research: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gasparetto: Karyopharm: Consultancy, Honoraria, Speakers Bureau; Gsk: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; Oncopeptide: Consultancy, Honoraria, Speakers Bureau. Schiller: Sangamo: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Celator: Research Funding; Geron: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; PrECOG: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Genentech-Roche: Research Funding; Karyopharm: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Abbvie: Research Funding; Forma: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; FujiFilm: Research Funding; Gamida Cell Ltd.: Research Funding; Constellation Pharmaceuticals: Research Funding; Mateon: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Arog: Research Funding; Delta-Fly: Research Funding; Tolero: Research Funding; Samus: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Trovagene: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Bio: Research Funding; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Tuchman: Caelum: Consultancy, Research Funding; Sanofi / Genzyme: Consultancy, Research Funding; Shattuck Labs: Consultancy; Karyopharm: Research Funding; Oncopeptides: Consultancy. Lentzsch: Sanofi: Consultancy, Research Funding; Celularity: Consultancy; AbbVie: Consultancy; GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy; Caelum Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Ossium Health: Consultancy; Magenta Therapeutics: Current equity holder in publicly-traded company; Kadmon: Current equity holder in publicly-traded company. Monge: Karyopharm: Research Funding; BMS: Consultancy. Kotb: Celgene: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Pfizer: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BMS: Honoraria; Sanofi: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Akcea: Honoraria. Bahlis: GlaxoSmithKline: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Genentech: Consultancy. White: Forus: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Chen: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Sutherland: GSK: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Research Funding; Amgen: Consultancy. Madan: Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Sanofi: Consultancy, Research Funding; GSK: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; Takeda: Speakers Bureau. Leblanc: Celgene/BMS: Research Funding; BMS/Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Canada: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag: Janssen: Research Funding; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Research Funding; Amgen: Research Funding. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhang: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding.
- Published
- 2022
20. Figure S1 from CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
- Author
-
Yvonne Y. Chen, Antoni Ribas, John M. Timmerman, Gary J. Schiller, Caspian Oliai, Patricia A. Young, Sven de Vos, Monica Mead, Karla Nawaly, Jonathan Said, Martin S. Allen-Auerbach, Melanie Ayala Ceja, Amr Almaktari, Stanley B. Gosliner, Beata Berent-Maoz, Thomas Schweppe, Mobina Khericha, Caitlin Harris, Mobina Roshandell, Jia Ming Chen, Jacqueline Trent, Jacob Naparstek, Sanaz N. Ghafouri, Brenda Ji, Christopher M. Walthers, and Sarah M. Larson
- Abstract
CART19/20 cell product characteristics. (A) % CD4+ among total T cells and CAR-expressing T cells. (B) Comparison of T-cell subtype frequency among CD4+ vs. CD8+ T cells in cryopreserved CART19/20 cell products. Te/exh: effector/exhausted T cells, CD45RA+/CD45RO–/CD62L–; Tem: effector-memory T cells, CD45RA–/CD45RO+/CD62L–; Tcm: central-memory T cells: CD45RA–/CD45RO+/CD62L+; naïve: CD45RA+/CD45RO–/CD62L+. (C) Phenotype of leukopak content prior to cell isolation. (D) Phenotype of cells obtained after isolation. (E) CD14 and CD25 expression patterns among CD62L+ cells in patient leukopak content prior to cell isolation.
- Published
- 2023
21. Data from CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
- Author
-
Yvonne Y. Chen, Antoni Ribas, John M. Timmerman, Gary J. Schiller, Caspian Oliai, Patricia A. Young, Sven de Vos, Monica Mead, Karla Nawaly, Jonathan Said, Martin S. Allen-Auerbach, Melanie Ayala Ceja, Amr Almaktari, Stanley B. Gosliner, Beata Berent-Maoz, Thomas Schweppe, Mobina Khericha, Caitlin Harris, Mobina Roshandell, Jia Ming Chen, Jacqueline Trent, Jacob Naparstek, Sanaz N. Ghafouri, Brenda Ji, Christopher M. Walthers, and Sarah M. Larson
- Abstract
To address antigen escape and loss of T-cell functionality, we report a phase I clinical trial (NCT04007029) evaluating autologous naive and memory T (TN/MEM) cells engineered to express a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR; CART19/20) for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), with safety as the primary endpoint. Ten patients were treated with 36 × 106 to 165 × 106 CART19/20 cells. No patient experienced neurotoxicity of any grade or over grade 1 cytokine release syndrome. One case of dose-limiting toxicity (persistent cytopenia) was observed. Nine of 10 patients achieved objective response [90% overall response rate (ORR)], with seven achieving complete remission [70% complete responses (CR) rate]. One patient relapsed after 18 months in CR but returned to CR after receiving a second dose of CART19/20 cells. Median progression-free survival was 18 months and median overall survival was not reached with a 17-month median follow-up. In conclusion, CART19/20 TN/MEM cells are safe and effective in patients with relapsed/refractory NHL, with durable responses achieved at low dosage levels.Significance:Autologous CD19/CD20 bispecific CAR-T cell therapy generated from TN/MEM cells for patients with NHL is safe (no neurotoxicity, maximum grade 1 cytokine release syndrome) and demonstrates strong efficacy (90% ORR, 70% CR rate) in a first-in-human, phase I dose-escalation trial.This article is highlighted in the In This Issue feature, p. 517
- Published
- 2023
22. Table S2 from CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
- Author
-
Yvonne Y. Chen, Antoni Ribas, John M. Timmerman, Gary J. Schiller, Caspian Oliai, Patricia A. Young, Sven de Vos, Monica Mead, Karla Nawaly, Jonathan Said, Martin S. Allen-Auerbach, Melanie Ayala Ceja, Amr Almaktari, Stanley B. Gosliner, Beata Berent-Maoz, Thomas Schweppe, Mobina Khericha, Caitlin Harris, Mobina Roshandell, Jia Ming Chen, Jacqueline Trent, Jacob Naparstek, Sanaz N. Ghafouri, Brenda Ji, Christopher M. Walthers, and Sarah M. Larson
- Abstract
Representativeness of study participants
- Published
- 2023
23. Real-World Safety and Health Care Resource Utilization Analysis of Venetoclax and Hypomethylating-Agent Treatment for AML in an Academic-Affiliated Urban Community Oncology Network
- Author
-
Sophie G Carlson, Jonathan Boiarsky, Claire E. Daniel, Daria Gaut, Catherine Cascavita, Christine Lam, Michael Doyel, Gary J. Schiller, and Wanxing Chai-Ho
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
24. Initial Results from SELECT-AML-1, a Phase 2 Study of Tamibarotene in Combination with Venetoclax and Azacitidine in RARA-Positive Newly Diagnosed AML Patients Ineligible for Standard Induction Chemotherapy
- Author
-
Suman Kambhampati, Christine M. McMahon, Alireza Eghtedar, Daniel A. Pollyea, Stephane de Botton, Arnaud Pigneux, Mohamad Cherry, Brian J Ball, Gautam Borthakur, Thomas Cluzeau, Gary J. Schiller, Beibei Hu, Angela Volkert, Joanie Aasen Gausman, Graeme Hodgson, David A. Roth, Erica D. Warlick, Michael J. Kelly, and Eytan Stein
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
25. Trial in Progress: Tagraxofusp-Based Therapy to Eradicate Measurable Residual Disease of Acute Myelogenous Leukemia Prior to Allogeneic Hematopoietic Cell Transplantation
- Author
-
Daria Gaut, Caspian Oliai, Steven Tsai, Chi-Hong Tseng, Aaron C. Logan, and Gary J. Schiller
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
26. Measurable Residual Disease Conversion Rate with Consolidation Chemotherapy in Acute Myeloid Leukemia
- Author
-
Daria Gaut, Caspian Oliai, Jonathan Boiarsky, Shiliang Zhang, Tali Azenkot, Vanessa E. Kennedy, Vishesh Khanna, Karla Olmedo Gutierrez, Navika D. Shukla, Benjamin Moskoff, Anand Ashwin Patel, Deepa Jeyakumar, Gabriel N. Mannis, Aaron C. Logan, Brian A. Jonas, and Gary J. Schiller
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
27. Neihulizumab (ALTB-168) in Patients with Steroid-Refractory Acute Graft-Versus-Host-Disease (SR-aGVHD) or Treatment-Refractory Acute Graft-Versus-Host-Disease (TR-aGVHD)
- Author
-
Sameem Abedin, Mehdi Hamadani, Shernan G Holtan, Gary J. Schiller, Molly Gallogly, Edmund K. Waller, Satyajit Kosuri, Sunil H Abhyankar, Sarah M. Anand, Mahasweta Gooptu, Iming Cho, Simona Reed, Shih-Yao Lin, Jesse W Hall, and Paul J Martin
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
28. Comparative risk of pulmonary adverse events with transfusion of pathogen reduced and conventional platelet components
- Author
-
Edward L. Snyder, Allison P. Wheeler, Majed Refaai, Claudia S. Cohn, Jessica Poisson, Magali Fontaine, Mary Sehl, Ajay K. Nooka, Lynne Uhl, Philip Spinella, Maly Fenelus, Darla Liles, Thomas Coyle, Joanne Becker, Michael Jeng, Eric A. Gehrie, Bryan R. Spencer, Pampee Young, Andrew Johnson, Jennifer J. O'Brien, Gary J. Schiller, John D. Roback, Elizabeth Malynn, Ronald Jackups, Scott T. Avecilla, Jin‐Sying Lin, Kathy Liu, Stanley Bentow, Ho‐Lan Peng, Jeanne Varrone, Richard J. Benjamin, and Laurence M. Corash
- Subjects
Blood Platelets ,Respiratory Distress Syndrome ,Photosensitizing Agents ,pathogen reduction ,Clinical Sciences ,Immunology ,Transfusion Reaction ,Platelet Transfusion ,Hematology ,Cardiorespiratory Medicine and Haematology ,pulmonary adverse events ,Cohort Studies ,Rare Diseases ,Cardiovascular System & Hematology ,Clinical Research ,Respiratory ,Humans ,Immunology and Allergy ,Blood Transfusion ,Patient Safety ,assisted mechanical ventilation ,Lung ,Acute Respiratory Distress Syndrome - Abstract
BackgroundPlatelet transfusion carries risk of transfusion-transmitted infection (TTI). Pathogen reduction of platelet components (PRPC) is designed to reduce TTI. Pulmonary adverse events (AEs), including transfusion-related acute lung injury and acute respiratory distress syndrome (ARDS) occur with platelet transfusion.Study designAn open label, sequential cohort study of transfusion-dependent hematology-oncology patients was conducted to compare pulmonary safety of PRPC with conventional PC (CPC). The primary outcome was the incidence of treatment-emergent assisted mechanical ventilation (TEAMV) by non-inferiority. Secondary outcomes included: time to TEAMV, ARDS, pulmonary AEs, peri-transfusion AE, hemorrhagic AE, transfusion reactions (TRs), PC and red blood cell (RBC) use, and mortality.ResultsBy modified intent-to-treat (mITT), 1068 patients received 5277 PRPC and 1223 patients received 5487 CPC. The cohorts had similar demographics, primary disease, and primary therapy. PRPC were non-inferior to CPC for TEAMV (treatment difference -1.7%, 95% CI: (-3.3% to -0.1%); odds ratio=0.53, 95% CI: (0.30, 0.94). The cumulative incidence of TEAMV for PRPC (2.9%) was significantly less than CPC (4.6%, p= .039). The incidence of ARDS was less, but not significantly different, for PRPC (1.0% vs. 1.8%, p= .151; odds ratio=0.57, 95% CI: (0.27, 1.18). AE, pulmonary AE, and mortality were not different between cohorts. TRs were similar for PRPC and CPC (8.3% vs. 9.7%, p= .256); and allergic TR were significantly less with PRPC (p= .006). PC and RBC use were not increased with PRPC.DiscussionPRPC demonstrated reduced TEAMV with no excess treatment-related pulmonary morbidity.
- Published
- 2022
29. Supplementary Data from A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia
- Author
-
Eunice S. Wang, Mark Erlander, Sandra L. Silberman, Errin Samuëlsz, Michaela L. Tsai, Alexander I. Spira, Prapti A. Patel, Gary J. Schiller, Pamela S. Becker, Tara L. Lin, Maya Ridinger, and Amer M. Zeidan
- Abstract
Supplementary Tables and Figure
- Published
- 2023
30. Data from A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia
- Author
-
Eunice S. Wang, Mark Erlander, Sandra L. Silberman, Errin Samuëlsz, Michaela L. Tsai, Alexander I. Spira, Prapti A. Patel, Gary J. Schiller, Pamela S. Becker, Tara L. Lin, Maya Ridinger, and Amer M. Zeidan
- Abstract
Purpose:The Polo-like kinase 1 (PLK1) is a master regulator of mitosis and overexpressed in acute myeloid leukemia (AML). We conducted a phase Ib study of the PLK1 inhibitor, onvansertib, in combination with either low-dose cytarabine (LDAC) or decitabine in patients with relapsed or refractory (R/R) AML.Patients and Methods:Onvansertib was administered orally, in escalating doses, on days 1–5 in combination with either LDAC (20 mg/m2; days 1–10) or decitabine (20 mg/m2; days 1–5) in a 28-day cycle. The primary endpoint was to evaluate first-cycle dose-limiting toxicities and the MTD. Secondary and exploratory endpoints included safety, pharmacokinetics, antileukemic activity, and response biomarkers.Results:Forty patients were treated with onvansertib (12–90 mg/m2) in combination with LDAC (n = 17) or decitabine (n = 23). Onvansertib was well tolerated with most grades 3 and 4 adverse events related to myelosuppression. In the decitabine arm, the MTD was established at 60 mg/m2, and 5 (24%) of the 21 evaluable patients achieved complete remission with or without hematologic count recovery. Decrease in mutant circulating tumor DNA (ctDNA) during the first cycle of therapy was associated with clinical response. Engagement of the PLK1 target, TCTP, was measured in circulating blasts and was associated with greater decrease in bone marrow blasts.Conclusions:The onvansertib and decitabine combination was well tolerated and had antileukemic activity particularly in patients with target engagement and decreased mutant ctDNA following treatment. This combination will be further investigated in the ongoing phase II trial.
- Published
- 2023
31. Supplementary Table S7 from A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia
- Author
-
Eunice S. Wang, Mark Erlander, Sandra L. Silberman, Errin Samuëlsz, Michaela L. Tsai, Alexander I. Spira, Prapti A. Patel, Gary J. Schiller, Pamela S. Becker, Tara L. Lin, Maya Ridinger, and Amer M. Zeidan
- Abstract
Detailed list of variants identified by targeted-NGS
- Published
- 2023
32. Pomalidomide, dexamethasone, and daratumumab immediately after lenalidomide-based treatment in patients with multiple myeloma: updated efficacy, safety, and health-related quality of life results from the phase 2 MM-014 trial
- Author
-
Nizar J. Bahlis, David S. Siegel, Gary J. Schiller, Christy Samaras, Michael Sebag, Jesus Berdeja, Siddhartha Ganguly, Jeffrey Matous, Kevin Song, Christopher S. Seet, Mirelis Acosta-Rivera, Michael Bar, Donald Quick, Bertrand Anz, Gustavo Fonseca, Weiyuan Chung, Kim Lee, Jorge Mouro, Amit Agarwal, and Donna Reece
- Subjects
Cancer Research ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Quality of Life ,Antibodies, Monoclonal ,Humans ,Hematology ,Neoplasm Recurrence, Local ,Multiple Myeloma ,Lenalidomide ,Neoplasms, Plasma Cell ,Dexamethasone ,Thalidomide - Abstract
Patients with relapsed/refractory multiple myeloma (RRMM) need proven subsequent therapies after early-line lenalidomide treatment failure. The phase 2 MM-014 trial (NCT01946477) investigated pomalidomide, dexamethasone, and daratumumab after 1 to 2 prior treatment lines (62.5%, 1 prior line) in patients with RRMM and prior lenalidomide (75.0%, lenalidomide refractory). With a median follow-up of 28.4 months, overall response rate was 77.7% (52.7% achieved very good partial response or better) and median progression-free survival was 30.8 months. For patients with lenalidomide-refractory disease, these outcomes were 76.2%, 47.6%, and 23.7 months, respectively. No new safety signals were observed; 64.3% experienced grade 3/4 neutropenia. Health-related quality of life was preserved or trended toward improvement through 12 treatment cycles. Pomalidomide, dexamethasone, and daratumumab given immediately after early-line lenalidomide-based treatment continues to demonstrate safety and efficacy, supporting pomalidomide-dexamethasone as a foundation of combination therapy in RRMM and providing evidence that the immunomodulatory agent class delivers benefit after lenalidomide treatment failure.
- Published
- 2022
33. Open-Label Phase II Prospective, Randomized, Controlled Study of Romyelocel-L Myeloid Progenitor Cells to Reduce Infection During Induction Chemotherapy for Acute Myeloid Leukemia
- Author
-
Suman Kambhampati, Iskra Pusic, James M. Foran, John G. Edwards, John Lister, Farhad Ravandi, John M. Pagel, Charalambos Andreadis, Camille N. Abboud, Swapna Panuganti, Lois Kellerman, Martin S. Tallman, Richard David Mamelok, Delong Liu, Lawrence E. Morris, Saar Gill, Alicia Wong, Jack W. Hsu, Gary J. Schiller, Pinkal Desai, Hagop M. Kantarjian, Melham M. Solh, Irum Khan, Olga Frankfurt, Rodney Van Syoc, Patrick J. Stiff, Ramkumar Mandalam, Janice M. Brown, Wendy Stock, Luke P. Akard, Celalettin Ustun, and Matthew J Wieduwilt
- Subjects
Male ,Myeloid ,Cancer Research ,Antifungal Agents ,Neutrophils ,030204 cardiovascular system & hematology ,law.invention ,0302 clinical medicine ,Randomized controlled trial ,law ,Granulocyte Colony-Stimulating Factor ,Cytotoxic T cell ,Prospective Studies ,Cancer ,Leukemia ,Myeloid leukemia ,Induction Chemotherapy ,Hematology ,Middle Aged ,Leukemia, Myeloid, Acute ,Infectious Diseases ,medicine.anatomical_structure ,Oncology ,6.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Female ,Open label ,Infection ,Adult ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Oncology and Carcinogenesis ,Acute ,Neutropenia ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,medicine ,Humans ,Oncology & Carcinogenesis ,Myeloid Progenitor Cells ,Aged ,Progenitor ,business.industry ,Evaluation of treatments and therapeutic interventions ,Induction chemotherapy ,medicine.disease ,Cancer research ,business - Abstract
PURPOSE Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy. PATIENTS AND METHODS One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital. RESULTS Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed. CONCLUSION Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.
- Published
- 2021
34. Subgroup Analyses of Kte-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy, in Adult Patients (Pts) with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (R/R B-ALL) in Zuma-3
- Author
-
Bijal D. Shah, Ryan D. Cassaday, Jae H. Park, Roch Houot, Olalekan O. Oluwole, Aaron C. Logan, Nicolas Boissel, Thibaut Leguay, Michael R. Bishop, Max S. Topp, Dimitrios Tzachanis, Kristen M. O’Dwyer, Martha L. Arellano, Yi Lin, Maria R. Baer, Gary J. Schiller, Marion Subklewe, Mehrdad Abedi, Monique C. Minnema, William G. Wierda, Daniel J. DeAngelo, Patrick Stiff, Deepa Jeyakumar, Jinghui Dong, Sabina Adhikary, Lang Zhou, Petra C. Schuberth, Behzad Kharabi Masouleh, and Armin Ghobadi
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
35. Efficacy of the Addition of RGI-2001 to Tacrolimus and Methotrexate for Acute Gvhd Prevention in Myeloablative HSCT Using HLA-Matched Donors
- Author
-
Dr. Yi-Bin Chen, Shatha Farhan, Lazaros J. Lekakis, Gary J. Schiller, Jean Adel Yared, Amer Assal, Dana D Lee, Hayley Lane, Ted A. Gooley, Zachariah DeFilipp, and Dr. Ayman Saad
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
36. Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials
- Author
-
Chenyu Lin, Aurelie Schwarzbach, Jaime Sanz, Pau Montesinos, Patrick Stiff, Suhag Parikh, Claudio Brunstein, Corey Cutler, Caroline A. Lindemans, Rabi Hanna, Liang Piu Koh, Madan H. Jagasia, David Valcarcel, Richard T. Maziarz, Amy K. Keating, William Y.K. Hwang, Andrew R. Rezvani, Nicole A. Karras, Juliana F. Fernandes, Vanderson Rocha, Isabel Badell, Ron Ram, Gary J. Schiller, Leonid Volodin, Mark C. Walters, Nelson Hamerschlak, Daniela Cilloni, Olga Frankfurt, Joseph P. McGuirk, Joanne Kurtzberg, Guillermo Sanz, Ronit Simantov, and Mitchell E. Horwitz
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
37. Outcomes in Patients with FLT3-Mutated Relapsed/ Refractory Acute Myelogenous Leukemia Who Underwent Transplantation in the Phase 3 ADMIRAL Trial of Gilteritinib versus Salvage Chemotherapy
- Author
-
Alexander E. Perl, Richard A. Larson, Nikolai A. Podoltsev, Stephen Strickland, Eunice S. Wang, Ehab Atallah, Gary J. Schiller, Giovanni Martinelli, Andreas Neubauer, Jorge Sierra, Pau Montesinos, Christian Recher, Sung-Soo Yoon, Yoshinobu Maeda, Naoko Hosono, Masahiro Onozawa, Takayasu Kato, Hee-Je Kim, Nahla Hasabou, Rishita Nuthethi, Ramon Tiu, and Mark J. Levis
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Abstract
The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib improved the survival of patients with relapsed or refractory (R/R) FLT3-mutated acute myelogenous leukemia (AML) in the phase 3 ADMIRAL trial. In this study, we assessed survival and relapse rates of patients in the ADMIRAL trial who underwent hematopoietic stem cell transplantation (HSCT), as well as safety outcomes in patients who received post-transplantation gilteritinib maintenance therapy. ADMIRAL was a global phase 3 randomized controlled trial that enrolled adult patients with FLT3-mutated R/R AML. Patients with R/R AML who harbored FLT3 internal tandem duplication mutations in the juxtamembrane domain or D835/I836 point mutations in the tyrosine kinase domain were randomized (2:1) to gilteritinib (120 mg/day) or to preselected high- or low-intensity salvage chemotherapy (1 or 2 cycles). Patients in the gilteritinib arm who proceeded to HSCT could receive post-transplantation gilteritinib maintenance therapy if they were within 30 to 90 days post-transplantation and had achieved composite complete remission (CRc) with successful engraftment and no post-transplantation complications. Adverse events (AEs) during HSCT were recorded in the gilteritinib arm only. Survival outcomes and the cumulative incidence of relapse were assessed in patients who underwent HSCT during the trial. Treatment-emergent AEs were evaluated in patients who restarted gilteritinib as post-transplantation maintenance therapy. Patients in the gilteritinib arm underwent HSCT more frequently than those in the chemotherapy arm (26% [n = 64] versus 15% [n = 19]). For all transplantation recipients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplantation CRc, post-transplantation survival was comparable in the 2 arms. Patients who resumed gilteritinib after HSCT had a low relapse rate after pretransplantation CRc (20%) or CR (0%). The most common AEs observed with post-transplantation gilteritinib therapy were increased alanine aminotransferase level (40%), pyrexia (43%), and diarrhea (40%); grade ≥3 AEs were related primarily to myelosuppression. The incidences of grade ≥III acute graft-versus-host disease and related mortality were low. Post-transplantation survival was similar across the 2 study arms in the ADMIRAL trial, but higher remission rates with gilteritinib facilitated receipt of HSCT. Gilteritinib as post-transplantation maintenance therapy had a stable safety and tolerability profile and was associated with low relapse rates. Taken together, these data support a preference for bridging therapy with gilteritinib over chemotherapy in transplantation-eligible patients.
- Published
- 2023
38. Spliceosome mutations are common in persons with myeloproliferative neoplasm-associated myelofibrosis with RBC-transfusion-dependence and correlate with response to pomalidomide
- Author
-
Sonja Zweegman, Shanti Natarajan-Amé, Francesco Passamonti, Raajit K. Rampal, Moshe Talpaz, Daobin Zhou, Kelly McCaul, Mary Frances McMullin, Candido E. Rivera, Hiroshi Kawabata, Günther Gastl, H. Joachim Deeg, Heinz Gisslinger, Angela Hamblin, Vincent Ribrag, Reinier Raymakers, John Catalano, P. Mineur, Fabrizio Pane, Giuseppe Saglio, Jean Loup Demory, Josef T. Prchal, Qian Jiang, Kudrat Abdulkadyrov, Emmanuel C. Besa, Richard F. Schlenk, Gary J. Schiller, John T. Reilly, Adam J. Mead, Robert Peter Gale, William Stevenson, Gemma Buck, Kazuma Ohyashiki, Dominique Bordessoule, Mark Drummond, Jianyong Li, Ayalew Tefferi, Ting Liu, Tomoko Hata, Jianhua Zhong, Juan Carlos Hernandez Boluda, Damiano Rondelli, Norio Komatsu, John Mascarenhas, Zhixiang Shen, Timothy Devos, Alessandro M. Vannucchi, Katsuto Takenaka, Randall Brown, Haifa K. Al-Ali, Thomas J. Nevill, Jen Chin Wang, Daniel Tesfa, Jennifer O'Sullivan, Andrew Turner, Guanlin Wang, Galina Salogub, Claire N. Harrison, Dragana Milojkovic, Giovanni Barosi, James W. Vardiman, Peter A. W. te Boekhorst, Ruben A. Mesa, Jan Van Droogenbroeck, Manana Sokolova, Vikas Gupta, Lennart Nilsson, Andrey Zaritskiy, Nikolaos Barkas, Werner Linkesch, Mario Cazzola, Jean-Jacques Kiladjian, Ramon V. Tiu, Kiyoshi Ando, Onima Chowdhury, Emilio Ojeda, Martin Griesshammer, Christian Recher, Alessandro Rambaldi, Francisco Cervantes, Giorgina Specchia, Hematology, and CCA - Cancer biology and immunology
- Subjects
Cancer Research ,Spliceosome ,Treatment outcome ,medicine.disease_cause ,Article ,Disease susceptibility ,SDG 3 - Good Health and Well-being ,Humans ,Medicine ,Myelofibrosis ,Myeloproliferative neoplasm ,Rbc transfusion ,Mutation ,Myeloproliferative Disorders ,business.industry ,Disease Management ,Hematology ,medicine.disease ,Pomalidomide ,Thalidomide ,Treatment Outcome ,Oncology ,Primary Myelofibrosis ,Spliceosomes ,Cancer research ,Disease Susceptibility ,Erythrocyte Transfusion ,business ,medicine.drug - Published
- 2021
39. Trial in Progress: Acalabrutinib Maintenance Following Cellular Therapy for Large B-Cell Lymphoma Patients at High Risk for Relapse
- Author
-
Daria Gaut, Caspian Oliai, Steven Tsai, Chiung-Yu Huang, Joseph Tuscano, Herbert Eradat, and Gary J. Schiller
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
40. A Phase 1 Dose-Escalation Study of the Oral Epichaperome Inhibitor, Zelavespib (ZEL) in Combination with Ruxolitinib (RUX), in Patients with Relapsed Myelofibrosis: Results of the Dose Escalation Stage
- Author
-
Naveen Pemmaraju, Krishna Gundabolu, Jack Snyder, Michael H Silverman, Geraldine Bardelli, Srdan Verstovsek, and Gary J. Schiller
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
41. Early Clinical Evaluation of Potential Synergy of Targeted Radiotherapy with Lintuzumab-Ac225 and Venetoclax in Relapsed/Refractory AML
- Author
-
Tiffany F. Lin, Gary J. Schiller, Johnnie J. Orozco, Gail J. Roboz, Mohamed M. Hegazi, Laura Finn, and Mary M Chen
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Venetoclax ,Targeted Radiotherapy ,Immunology ,Cell Biology ,Hematology ,Lintuzumab ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Relapsed refractory ,Medicine ,business ,Clinical evaluation ,medicine.drug - Abstract
Background: Resistance to venetoclax, a BCL2 inhibitor, has been shown to be mediated by co-expression of other BCL2 proteins including BCLXL and MCL1 in relapsed/refractory AML (R/R AML). Therapeutic agents reducing resistance to BCL2 inhibitors and exhibiting anti-tumor activity could synergize with venetoclax to increase response rates further. One approach to enhance the potency of venetoclax is through combination with targeted radiotherapy. Studies in tumor cells have shown that DNA damage reduces the level of MCL1, a known mediator of venetoclax resistance. The monoclonal antibody radioconjugate, lintuzumab-Ac225, is a highly cytotoxic alpha-radiation emitter that selectively targets CD33, a cell surface antigen expressed on majority of AML cells. The high-energy alpha-particle emissions from lintuzumab-Ac225 as a single agent elicits single and double-strand DNA breaks in targeted tumor cells as demonstrated from prior clinical studies. (ASH 2017, 2018). In venetoclax-resistant cell lines in vitro, lintuzumab-Ac225 promotes MCL1 degradation through DNA damage resulting in increased cell sensitivity to venetoclax. Similarly, mouse xenograft models with venetoclax-resistant AML tumor lines demonstrated tumor regression and increased survival in mice receiving both venetoclax and lintuzumab-Ac225. The aims of this phase I/II study are to assess the safety, tolerability and efficacy of lintuzumab-Ac225 in combination with venetoclax in R/R AML. Study Design: The Phase I portion of the study uses a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 when given in combination with venetoclax. The dose levels for lintuzumab-Ac225 are 0.5, 0.75, and 1.0 µCi/kg. The Phase II portion of the study will enroll up to an additional 20 patients and treat with the recommended phase II dose (RP2D) with venetoclax to determine the best overall response (CR+CRh+CRi) up to 6 months after starting treatment. Eligible patients include R/R-AML patients aged 18 years and older with adequate organ function, ECOG Performance Status 0-2, and more than 25% CD33 positive of leukemic blasts by flow cytometry. Patients with antecedent MDS, MPNs, or therapy-related AML are eligible. During Cycle 1, venetoclax dosing will be ramped up during the first 4 days in order to minimize the risk of tumor lysis syndrome (TLS). After Cycle 1, all patients will receive venetoclax at 400 mg/day PO on Days 1 to 21 of each cycle. Lintuzumab-Ac225 is administered as a single dose on Day 5 of each cycle. Results: Ten R/R AML patients were treated with lintuzumab-Ac225 at 0.5 µCi/kg (n=3), 0.75 µCi/kg (n=6) and 1.0 µCi/kg (n=1) in combination with venetoclax in the phase I dose escalation portion as of 1-August-2021. The median age was 67 years (range 49-83) with 5/10 (50%) refractory; 8/10 (80%) had unfavorable risk (ELN). Three patients were enrolled on the first cohort at dose level 0.5 µCi/kg of lintuzumab-Ac225 and showed clinically acceptable safety profile with no DLTs. In addition, one patient achieved CRi at the end of cycle 1. Results from the first cohort were encouraging and acceptable for dose escalation. An intermediate Cohort 2B at dose level 0.75 µCi/kg, was implemented. To date, 6 patients were enrolled on cohort 2B, and based on the Safety Committee recommendation, dose level at 1.0 µCi/kg may be resumed. In preliminary data on all patients, lintuzumab-Ac225 treatment-related grades 3/4 adverse events (AEs) include hematologic AEs and only one count of non-hematologic event (hyponatremia) (Table 1). There were no early deaths (≤30d) in any cohort. Overall, lintuzumab-Ac225 can be combined with venetoclax with a manageable toxicity profile. While sample size is limited, ORR (CR/CRi) for all R/R AML patients and TP53-mutant R/R patients were 20% (2/10) and 67% (2/3), respectively. Updated safety and response data will be presented at ASH2021. Conclusion: Combining lintuzumab-Ac225 with venetoclax in patients with R/R AML has an acceptable clinical safety profile with 0% 30-day mortality rate. 67% ORR is particularly encouraging in TP53-mutant R/R AML. These data support the further evaluation of lintuzumab-Ac225 in combination with venetoclax in patients with R/R AML, especially in TP53-mutant R/R patients. Figure 1 Figure 1. Disclosures Schiller: FujiFilm: Research Funding; Forma: Research Funding; Arog: Research Funding; Gamida Cell Ltd.: Research Funding; Karyopharm: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Geron: Research Funding; Mateon: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; PrECOG: Research Funding; Regimmune: Research Funding; Delta-Fly: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Actuate: Research Funding; Samus: Research Funding; Constellation Pharmaceuticals: Research Funding; Deciphera: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Research Funding; Takeda: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Sangamo: Research Funding; Genentech-Roche: Research Funding; Celator: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; Trovagene: Research Funding; Tolero: Research Funding; Daiichi-Sankyo: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Bio: Research Funding; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Finn: Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Speakers Bureau. Roboz: Mesoblast: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Janssen: Consultancy; Actinium: Consultancy; Blueprint Medicines: Consultancy; Jasper Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy; Astex: Consultancy; Helsinn: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Agios: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Otsuka: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy. Orozco: Actinium Pharmaceuticals, Inc.: Other: site PI for clinical trial(s) sponsored by Actinium, Research Funding. Lin: Actinium Pharmaceuticals, Inc.: Current Employment. Chen: Actinium Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: Venetoclax use in relapsed-refractory AML
- Published
- 2022
42. Suppression of Multiple Myeloma Via Inhibition of EFNB2 Reverse Signaling
- Author
-
Joshua P. Sasine, Jennifer Dukov, Dana Tran, Heather A Himburg, Natalia Kozlova, Michelle Li, Jenny Kan, Mary Sehl, Gary J. Schiller, Ritchie Ho, Brijesh Singh, Bryanna Reinhardt, Peibin Yue, Christina Termini, Elena Pasquale, and John P. Chute
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
43. The Trend of Respiratory Virus Infection in Allogeneic Bone Marrow Transplant Recipients during the COVID Pandemic
- Author
-
Guneet Kaleka, John Sharp, Kailyn Kim, Pryce Gaynor, Gary J. Schiller, and Wanxing Chai-Ho
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
44. RGI-2001 Infusion for Prevention of Acute Gvhd after Allogeneic Hematopoietic Cell Transplantation
- Author
-
Yi-Bin Chen, Ayman Saad, Shatha Y. Farhan, Lazaros J. Lekakis, Gary J. Schiller, Jean A. Yared, Amer Assal, Dana D Lee, Hayley Lane, Ted A. Gooley, and Zachariah Defilipp
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
45. Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses
- Author
-
Donna E. Hogge, Jonathan E. Kolitz, Stefan Faderl, Daniel H. Ryan, Tara L. Lin, Jeffrey E. Lancet, Matthew J. Wieduwilt, Robert J. Ryan, Scott R. Solomon, Jorge E. Cortes, Geoffrey L. Uy, David A. Rizzieri, and Gary J. Schiller
- Subjects
medicine.medical_specialty ,Clinical Trials and Observations ,business.industry ,Myelodysplastic syndromes ,Daunorubicin ,Hazard ratio ,Cytarabine ,Hematology ,Middle Aged ,medicine.disease ,Gastroenterology ,Chemotherapy regimen ,Confidence interval ,Transplantation ,Leukemia, Myeloid, Acute ,Hypomethylating agent ,Myelodysplastic Syndromes ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,business ,Aged ,medicine.drug - Abstract
CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). In a pivotal phase 3 study, patients aged 60 to 75 years with newly diagnosed, high-risk/secondary AML were randomized to receive CPX-351 or conventional 7+3 chemotherapy. In the primary endpoint analysis, CPX-351 demonstrated significantly prolonged median overall survival (OS) vs 7+3. These exploratory post hoc subgroup analyses evaluated the impact of achieving complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 (73/153 [48%]) vs conventional 7+3 (52/56 [33%]) on outcomes. CPX-351 improved median OS vs 7+3 in patients who achieved CR or CRi (25.43 vs 10.41 months; hazard ratio = 0.49; 95% confidence interval, 0.31, 0.77). Improved median OS was seen across AML subtypes (t-AML, AML-MRC), age subgroups (60 to 69 vs 70 to 75 years), patients with prior hypomethylating agent exposure, and patients who did not undergo transplantation. Patients who achieved CR or CRi with CPX-351 also had a higher rate of transplantation, a longer median OS landmarked from the date of transplantation (not reached vs 11.65 months; hazard ratio = 0.43; 95% confidence interval, 0.21, 0.89), and a safety profile that was consistent with the known safety profile of 7+3. These results suggest deeper remissions may be achieved with CPX-351, leading to improved OS. This study was registered at www.clinicaltrials.gov as #NCT01696084.
- Published
- 2021
46. A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia
- Author
-
Prapti A. Patel, Michaela L. Tsai, Sandra Silberman, Eunice S. Wang, Pamela S. Becker, Maya Ridinger, Amer M. Zeidan, Mark Erlander, Errin Samuelsz, Alexander I. Spira, Tara L. Lin, and Gary J. Schiller
- Subjects
Adult ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Maximum Tolerated Dose ,Combination therapy ,Decitabine ,Piperazines ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,Humans ,Medicine ,Adverse effect ,Aged ,Aged, 80 and over ,Salvage Therapy ,business.industry ,Cytarabine ,Myeloid leukemia ,Middle Aged ,Prognosis ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Quinazolines ,Pyrazoles ,Female ,Bone marrow ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies ,medicine.drug - Abstract
Purpose: The Polo-like kinase 1 (PLK1) is a master regulator of mitosis and overexpressed in acute myeloid leukemia (AML). We conducted a phase Ib study of the PLK1 inhibitor, onvansertib, in combination with either low-dose cytarabine (LDAC) or decitabine in patients with relapsed or refractory (R/R) AML. Patients and Methods: Onvansertib was administered orally, in escalating doses, on days 1–5 in combination with either LDAC (20 mg/m2; days 1–10) or decitabine (20 mg/m2; days 1–5) in a 28-day cycle. The primary endpoint was to evaluate first-cycle dose-limiting toxicities and the MTD. Secondary and exploratory endpoints included safety, pharmacokinetics, antileukemic activity, and response biomarkers. Results: Forty patients were treated with onvansertib (12–90 mg/m2) in combination with LDAC (n = 17) or decitabine (n = 23). Onvansertib was well tolerated with most grades 3 and 4 adverse events related to myelosuppression. In the decitabine arm, the MTD was established at 60 mg/m2, and 5 (24%) of the 21 evaluable patients achieved complete remission with or without hematologic count recovery. Decrease in mutant circulating tumor DNA (ctDNA) during the first cycle of therapy was associated with clinical response. Engagement of the PLK1 target, TCTP, was measured in circulating blasts and was associated with greater decrease in bone marrow blasts. Conclusions: The onvansertib and decitabine combination was well tolerated and had antileukemic activity particularly in patients with target engagement and decreased mutant ctDNA following treatment. This combination will be further investigated in the ongoing phase II trial.
- Published
- 2020
47. Selinexor, daratumumab, and dexamethasone in patients with relapsed or refractory multiple myeloma
- Author
-
Brea Lipe, Kazuharu Kai, Muhamed Baljevic, Rami Kotb, Suzanne Lentzsch, Cristina Gasparetto, Chris Venner, Nizar J. Bahlis, Natalie S. Callander, Jatin P. Shah, Heather J. Sutherland, Noa Biran, Dane Van Domelen, Darrell White, Jean-Richard Saint-Martin, Gary J. Schiller, Michael Sebag, Sharon Shacham, Richard Leblanc, Adriana C Rossi, William I. Bensinger, Sascha A. Tuchman, Michael Kauffman, Heidi Sheehan, and Christine Chen
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Daratumumab ,In patient ,Refractory Multiple Myeloma ,business ,medicine.disease ,Dexamethasone ,Multiple myeloma ,medicine.drug - Abstract
We assessed the safety, efficacy, maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of selinexor, a first in class oral selective inhibitor of nuclear export (100 mg once weekly [QW] or 60 mg twice weekly), in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) (SDd) in patients with relapsed refractory multiple myeloma (RRMM). Thirty-four patients (median prior therapies, 3 [range, 2-10]) were enrolled; MM was refractory to proteasome inhibitor (PI) in 85%, immunomodulatory agent (IMiD) in 76%, both in 74%, and daratumumab in 6% of patients. Two dose-limiting toxicities (DLTs) were reported in the selinexor 60 mg twice-weekly cohort with no DLTs in the 100 mg QW cohort, making 100 mg QW the MTD and RP2D. Common treatment-related adverse events included thrombocytopenia (70.6%), nausea (70.6%), fatigue (61.8%), anemia (61.8%), and neutropenia (50.0%). Overall response rate was 73% and median progression-free survival 12.5 months in daratumumab-naïve patients. SDd was well tolerated and its promising efficacy suggests that further study of this PI- and IMiD-free regimen in RRMM patients who had at least one prior line of therapy including a PI and an IMiD but whose disease is naïve to daratumumab is warranted.
- Published
- 2020
48. Enasidenib (ENA) Monotherapy with Addition of Azacitidine in Non-Responders Is Effective in Older Patients with Newly Diagnosed IDH2 Mutated Acute Myeloid Leukemia (AML): A Completed Phase 2/1b Sub-Study of the Beat AML Master Trial
- Author
-
Jordan Chervin, Ross L. Levine, Tara L. Lin, Ying Huang, William Blum, Sonja Marcus, Tibor Kovacsovics, Ashley O. Yocum, Franchesca Druggan, Gary J. Schiller, Brian J. Druker, Mona Stefanos, Uma Borate, Matthew C. Foster, Mark R. Litzow, John C. Byrd, Nyla A. Heerema, Robert H. Collins, Abigail B. Shoben, Wendy Stock, Leonard Rosenberg, Amy Burd, Michael Boyiadzis, James M. Foran, Rebecca L. Olin, Jo-Anne Vergilio, Prapti A. Patel, Maria R. Baer, Timothy L. Chen, Eytan M. Stein, and Alice S. Mims
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Azacitidine ,Beat (acoustics) ,Myeloid leukemia ,Cell Biology ,Hematology ,Newly diagnosed ,Enasidenib ,Biochemistry ,IDH2 ,Non responders ,Older patients ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Background: ENA is an oral, selective inhibitor of IDH2 approved for the treatment (Tx) of patients (pts) with relapsed/refractory IDH2 mutated (IDH2m) AML. Here we report the results of a Phase 2 expansion and Phase 1b of the Beat AML Master Trial Phase 2/1b sub-study to assess the efficacy of Tx of newly diagnosed (ND) IDH2m AML pts ≥ 60 years of age with ENA monotherapy (ENAm) and subsequent response-driven addition of AZA Tx. (ClinicalTrials.gov NCT03013998). Methods: The study initiated with a 3-outcome, 2-stage Phase 2 design, which enrolled patients on ENAm for up to 5 cycles. Pts without CR/CRi after 5 cycles of ENAm, or progression/intolerance prior to this time, were transferred to Phase 1b to receive ENA + AZA (Figure 1). Key eligibility included ND IDH2m AML pts with age ≥ 60 years and ECOG performance status 0-2. Pts received ENAm 100 mg/day in continuous 28-day cycles and ENA + AZA (75 mg/m2 days 1-7 every 28 days) for Phase 1b. Response was assessed using 2017 ELN AML criteria. The primary endpoint was CR/CRi rate. The 2-stage design required 24 pts and tested the null hypothesis (H0) that CR/CRi rate equaled 20% vs 50% and then expanded to test a revised H0 of 30% vs 50% in 60 pts (conditional alpha=0.025, power=77%). Expansion also allowed further assessment of safety of this treatment regimen. Results: At data cut off (06/18/2020), 60 pts enrolled, received ENAm, and were evaluable for the primary endpoint. Median age was 75 years and 52% were female (Table 1). Median time on ENAm was 4.7 months (mos). At data cut off, 12 pts were still on ENAm Tx. Most common reasons for discontinuing ENAm were Tx failure (defined as no response to treatment) (23 or 38%), disease progression (loss of response to treatment) (7 or 12%) and adverse events (AEs; 6 or 10%). Five pts (8%) went to transplant. CR/CRi was achieved in 28 pts (47%; adjusted 95% CI 28-59, unadjusted exact 95% CI 34-60) (Table 2). Responses were higher (p=0.04) among the 44 pts with IDH2 R140 (55%) as compared to the 16 with IDH2 R172 mutation (25%) further supporting distinct biology between these subsets. After a median follow up of 14.6 mos, the median overall survival (mOS) was 24.4 mos (95% CI 10.6-not reached). The median duration of response was not reached with 12 mos estimation of 57% (95% CI 34-75). Overall, 20 ENA-related serious adverse events (SAEs) occurred in 15 pts, the most common was differentiation syndrome (12 or 20%) and 1 had ENA-related SAE of tumor lysis syndrome (1.7%). One pt had ENA-related Grade 5 AE (renal failure/death). Most common AEs of any grade (in ≥20%) were nausea, anemia, and low potassium (Table 3). The 7-day/30-day/60-day deaths observed with ENAm were 2%/5%/11%, respectively. Phase 1b: Seventeen pts had inadequate response to ENAm and transferred to Phase 1b to receive ENA + AZA. Median time on Tx (including ENAm) was 6.2 mos and median time on Tx after pts started ENA + AZA was 2.1 mos (Table 2). Most common reasons for discontinuing ENA + AZA included Tx failure (5 or 29%), disease progression (2 or 12%), transplant, death and AEs (each 2 or 12%). CR/CRi was 41% (exact 95% CI 18-67). After a median follow up of 12.7 mos, the mOS from start of ENA + AZA combination Tx was 8.9 mos. Four ENA-related SAEs occurred in 3 pts on ENA + AZA Tx and the most common was differentiation syndrome (2 or 12.5%). One dose-limiting toxicity (Grade 3 nausea) related to both Txs was observed. Most common AEs (≥20%) of any grade were anemia, low albumin and vomiting (Table 3). One death occurred at day 13 of ENA + AZA. Conclusions: In newly diagnosed pts ≥60 years old with IDH2m AML, ENA had a low early death rate, high CR/CRi rate (47%, adjusted 95% CI 28-59), and yielded durable remissions. The most common unique toxicity with ENA was differentiation syndrome that occurred in 20% of patients. In pts who did not achieve CR/CRi with ENAm, a subset of patients achieved CR/CRi with addition of AZA. This combined approach of serial therapy with ENA monotherapy followed by AZA addition in pts with sub-optimal response resulted in a mOS exceeding 2 years for pts enrolled on study. Further focus on improving response among patients with IDH2 R172 mutations, identifying subsets of pts not responding to ENA monotherapy, and integrating new targeted agents into this treatment regimen are warranted. Figure 1 Disclosures Stein: Syndax: Consultancy, Research Funding; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Biotheryx: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Borate:Genentech: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Baer:Takeda: Other: Institutional research funding; AbbVie: Other: Institutional research funding; Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Incyte: Other: Institutional research funding. Kovacsovics:Agios: Honoraria; Astella: Honoraria; Pfizer: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Jazz: Honoraria. Schiller:Astellas Pharma: Honoraria, Research Funding; Celator: Research Funding; Constellation: Research Funding; Abbvie: Research Funding; Actinium: Research Funding; Ariad: Research Funding; Stemline: Speakers Bureau; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; DeltaFly: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; FujiFilm: Research Funding; Gamida: Research Funding; Genentech-Roche: Research Funding; Geron: Research Funding; Jazz Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Gilead: Speakers Bureau. Olin:Astellas: Other: Site PI; Genentech: Other: Site PI; Pfizer: Other: Site PI; Daiichi Sankyo: Other: Site PI; Genentech: Consultancy; Amgen: Consultancy. Foran:Trillium: Research Funding; Xencor: Research Funding; H3Biosciences: Research Funding; Agios: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Boehringer Ingelheim: Research Funding; Actinium: Research Funding; Aprea: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Takeda: Research Funding; Revolution Medicine: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Lin:Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Prescient Therapeutics: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Astellas Pharma: Research Funding; Aptevo: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Mateon Therapeutics: Research Funding; Ono Pharmaceutical: Research Funding; Jazz: Research Funding; Gilead Sciences: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Celgene: Research Funding. Patel:DAVA Pharmaceuticals: Honoraria; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy; France Foundation: Honoraria. Foster:Daiichi Sankyo: Consultancy; Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding. Druker:Leukemia & Lymphoma Society: Research Funding; Henry Stewart Talks: Patents & Royalties; Iterion Therapeutics (formerly Beta Cat Pharmaceuticals): Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Patient True Talks: Consultancy; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millipore (formerly Upstate Biotechnology): Patents & Royalties; MolecularMD (acquired by ICON): Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; McGraw Hill: Patents & Royalties; Merck & Co: Patents & Royalties; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dana-Farber Cancer Institute: Patents & Royalties; EnLiven: Consultancy, Research Funding; Aptose Therapeutics Inc. (formerly Lorus): Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; Blueprint Medicines: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Aileron Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Oregon Health & Science University: Patents & Royalties. Byrd:Acerta Pharma: Research Funding; Syndax: Research Funding; Vincera: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Trillium: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding. Levine:Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Amgen: Honoraria; Astellas: Consultancy; Morphosys: Consultancy; Novartis: Consultancy; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Lilly: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Gilead: Honoraria. Mims:Abbvie: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Novartis: Speakers Bureau. OffLabel Disclosure: Enasidenib is not approved for the treatment of newly diagnosed AML.
- Published
- 2020
49. Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment
- Author
-
Donald P. Quick, David S. Siegel, Kevin W. Song, Siddhartha Ganguly, Jeffrey Matous, Weiyuan Chung, Gustavo Fonseca, Nizar J. Bahlis, Giampaolo Talamo, William E. Pierceall, Jesus G. Berdeja, Michael Bar, Christy J. Samaras, Christopher S. Seet, Michael Sebag, Gary J. Schiller, Mirelis Acosta-Rivera, Donna E. Reece, Amit Agarwal, Bertrand Anz, and Faiza Zafar
- Subjects
Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Population ,Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Myeloma ,Neutropenia ,Antibodies ,Article ,Phase II trials ,Dexamethasone ,Rare Diseases ,Clinical Research ,Internal medicine ,Monoclonal ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,education ,Lenalidomide ,Multiple myeloma ,Cancer ,Aged ,education.field_of_study ,business.industry ,Daratumumab ,Evaluation of treatments and therapeutic interventions ,Antibodies, Monoclonal ,Hematology ,medicine.disease ,Pomalidomide ,Progression-Free Survival ,Thalidomide ,Regimen ,Neoplasm Recurrence ,Local ,6.1 Pharmaceuticals ,Female ,Neoplasm Recurrence, Local ,business ,Multiple Myeloma ,medicine.drug - Abstract
Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1–21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.
- Published
- 2020
50. A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease
- Author
-
Madan Jagasia, Karl Staser, Michael Pratta, Gary J. Schiller, Jaebok Choi, Yi-Bin Chen, Peter Langmuir, Gabrielle Meyers, Miguel-Angel Perales, Haris Ali, Leah Gehrs, Ying Yan, H. Jean Khoury, Nithya Srinivas, John F. DiPersio, Mark A. Schroeder, and Michael C. Arbushites
- Subjects
Adult ,medicine.medical_specialty ,Adolescent ,Anemia ,medicine.medical_treatment ,Clinical Trials and Supportive Activities ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Gastroenterology ,law.invention ,Rare Diseases ,Randomized controlled trial ,Adrenal Cortex Hormones ,Stem Cell Research - Nonembryonic - Human ,Clinical Research ,law ,hemic and lymphatic diseases ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,Adverse effect ,Protein Kinase Inhibitors ,6.2 Cellular and gene therapies ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Evaluation of treatments and therapeutic interventions ,Janus Kinase 1 ,Hematology ,Stem Cell Research ,medicine.disease ,Clinical trial ,Orphan Drug ,surgical procedures, operative ,Tolerability ,6.1 Pharmaceuticals ,Steroids ,business - Abstract
Acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic cell transplantation (HCT) is a primary cause of nonrelapse mortality and a major barrier to successful transplant outcomes. Itacitinib is a Janus kinase (JAK)1–selective inhibitor that has demonstrated efficacy in preclinical models of aGVHD. We report results from the first registered study of a JAK inhibitor in patients with aGVHD. This was an open-label phase 1 study enrolling patients aged ≥18 years with first HCT from any source who developed grade IIB to IVD aGVHD. Patients with steroid-naive or steroid-refractory aGVHD were randomized 1:1 to itacitinib 200 mg or 300 mg once daily plus corticosteroids. The primary endpoint was safety and tolerability; day 28 overall response rate (ORR) was the main secondary endpoint. Twenty-nine patients (200 mg, n = 14; 300 mg, n = 15) received ≥1 dose of itacitinib and were included in safety and efficacy assessments. One dose-limiting toxicity was reported (grade 3 thrombocytopenia attributed to GVHD progression in a patient receiving 300 mg itacitinib with preexisting thrombocytopenia). The most common nonhematologic treatment-emergent adverse event was diarrhea (48.3%, n = 14); anemia occurred in 11 patients (38%). ORR on day 28 for all patients in the 200-mg and 300-mg groups was 78.6% and 66.7%, respectively. Day 28 ORR was 75.0% for patients with treatment-naive aGVHD and 70.6% in those with steroid-refractory aGVHD. All patients receiving itacitinib decreased corticosteroid use over time. In summary, itacitinib was well tolerated and demonstrated encouraging efficacy in patients with steroid-naive or steroid-refractory aGVHD, warranting continued clinical investigations. This trial was registered at www.clinicaltrials.gov as #NCT02614612.
- Published
- 2020
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.