437 results on '"Gary J. Schiller"'
Search Results
2. 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
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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
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. 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)
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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
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
4. Once Weekly Selinexor, Carfilzomib and Dexamethasone (XKd) in Triple Class Refractory Multiple Myeloma
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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
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
5. 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
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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
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
6. 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
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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
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
7. Selinexor‐based regimens in patients with multiple myeloma after prior anti‐B‐cell maturation antigen treatment
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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
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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.
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- 2022
8. Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial
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Vu H. Duong, Amy S. Ruppert, Alice S. Mims, Uma Borate, Eytan M. Stein, Maria R. Baer, Wendy Stock, Tibor Kovacsovics, William Blum, Martha L. Arellano, Gary J. Schiller, Rebecca L. Olin, James M. Foran, Mark R. Litzow, Tara L. Lin, Prapti A. Patel, Matthew C. Foster, Robert L. Redner, Zeina Al‐Mansour, Christopher R. Cogle, Ronan T. Swords, Robert H. Collins, Jo‐Anne Vergilio, Nyla A. Heerema, Leonard Rosenberg, Ashley O. Yocum, Sonja Marcus, Timothy Chen, Franchesca Druggan, Mona Stefanos, Theophilus J. Gana, Abigail B. Shoben, Brian J. Druker, Amy Burd, John C. Byrd, Ross L. Levine, and Michael M. Boyiadzis
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Cancer Research ,Oncology - Published
- 2023
9. 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
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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
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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.
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- 2023
10. Figure S6 from CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
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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
T cell populations become CD8-dominant post CART19/20 cell infusion. % CD8+ among (A) CAR-expressing T cells and (B) all CD3+ T cells was quantified by flow cytometry. Data are shown for CAR-T cells only up to day 90 post infusion as values post day 90 become unreliable due to low CAR+ cell count detected by flow. FP: final product (i.e., cryopreserved CART19/20 cells).
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- 2023
11. Figure S4 from CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
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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
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PET scans taken for all patients treated with CART19/20 cell therapy.
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- 2023
12. Figure S2 from CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
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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
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CD14/CD20 depletion did not significantly alter regulatory T (Treg) cell content in CART19/20 cell product and in patient peripheral blood post infusion. Intracellular staining of starting (unactivated) TN/MEM population, CART19/20 final product, and patient PBMC collected 14 days post CART19/20 infusion. FOXP3+ frequency is shown as a percentage of CD3+CD4+ T cells.
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- 2023
13. Data from CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
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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
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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
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- 2023
14. 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
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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
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Representativeness of study participants
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- 2023
15. Figure S5 from CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
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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
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Flow-cytometry analysis of post-infusion peripheral blood samples. (A) Gating strategy for T-cell analysis in CART19/20 cell products and post-infusion patient peripheral mononuclear blood cells (PBMCs). Two viable gates were set based on side scatter (SSC-A) vs. forward scatter (FSC-A). The more restrictive “Viable” gate includes only viable lymphocytes, to enable more precise identification of T cells. The “Viable (inclusive)” gate includes all viable PBMCs, to enable calculation of CAR-T cells as a fraction of PBMCs. Truncated epidermal growth factor receptor (EGFRt) is co-expressed with the CAR, and EGFRt staining is used for CAR expression detection. Percent CAR+ T cells among viable singlets as shown in main-text Fig. 4b is the EGFRt+ population as a % of grandparent in the viable PBMC branch.Percent CAR expression among T cells as shown in main-text Fig. 4c is the EGFRt+ population as a % of parent in the viable lymphocyte branch. (B) Examples of post-infusion patient sample analysis.
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- 2023
16. Table S1 from CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
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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
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Comparison of CART19/20 cell therapy results with reported data from trials evaluating other CD19/CD20 bispecific CAR-T cell therapies and commercially available CD19 CAR-T cell therapies.
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- 2023
17. Figure S3 from CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
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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
Patient 009 exhibited elevated cytokine, C-reactive protein, and ferritin levels prior to and after CART19/20 cell infusion. (A) Serum levels of various cytokines measured by Luminex multiplex assay. (B) C-reactive protein (CRP) levels for Patient 009 (left-most) and all patients (second from left). Peak and median CRP levels are shown in box-and-whisker plots. (C) Ferritin levels for Patient 009 (left-most) and all patients (second from left). Peak and median ferritin levels are shown in box-and-whisker plots.
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- 2023
18. 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
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Sophie G Carlson, Jonathan Boiarsky, Claire E. Daniel, Daria Gaut, Catherine Cascavita, Christine Lam, Michael Doyel, Gary J. Schiller, and Wanxing Chai-Ho
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
19. 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
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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
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
20. Trial in Progress: Tagraxofusp-Based Therapy to Eradicate Measurable Residual Disease of Acute Myelogenous Leukemia Prior to Allogeneic Hematopoietic Cell Transplantation
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Daria Gaut, Caspian Oliai, Steven Tsai, Chi-Hong Tseng, Aaron C. Logan, and Gary J. Schiller
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
21. Measurable Residual Disease Conversion Rate with Consolidation Chemotherapy in Acute Myeloid Leukemia
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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
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
22. 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)
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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
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
23. Comparative risk of pulmonary adverse events with transfusion of pathogen reduced and conventional platelet components
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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
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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.
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- 2022
24. 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
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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
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Supplementary Tables and Figure
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- 2023
25. 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
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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.
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- 2023
26. 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
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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
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- 2023
27. 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
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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
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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.
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- 2022
28. Open-Label Phase II Prospective, Randomized, Controlled Study of Romyelocel-L Myeloid Progenitor Cells to Reduce Infection During Induction Chemotherapy for Acute Myeloid Leukemia
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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
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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.
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- 2021
29. CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naïve/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
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Sarah M. Larson, Christopher M. Walthers, Brenda Ji, Sanaz N. Ghafouri, Jacob Naparstek, Jacqueline Trent, Jia Ming Chen, Mobina Roshandell, Caitlin Harris, Mobina Khericha, Thomas Schweppe, Beata Berent-Maoz, Stanley B. Gosliner, Amr Almaktari, Melanie Ayala Ceja, Martin S. Allen-Auerbach, Jonathan Said, Karla Nawaly, Monica Mead, Sven de Vos, Patricia A. Young, Caspian Oliai, Gary J. Schiller, John M. Timmerman, Antoni Ribas, and Yvonne Y. Chen
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Oncology - 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
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- 2022
30. 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
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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
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
31. Efficacy of the Addition of RGI-2001 to Tacrolimus and Methotrexate for Acute Gvhd Prevention in Myeloablative HSCT Using HLA-Matched Donors
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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
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
32. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study
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Deepa Jeyakumar, Ryan D. Cassaday, Roch Houot, Chaoling Feng, Dimitrios Tzachanis, Maria R. Baer, John M. Rossi, Patrick J. Stiff, Marion Subklewe, Max S. Topp, Behzad Kharabi Masouleh, Bijal D. Shah, Remus Vezan, Martha Arellano, Olalekan O. Oluwole, Aaron C Logan, William G. Wierda, Kristen M. O'Dwyer, Tong Shen, Monique C. Minnema, Jinghui Dong, Daniel J. DeAngelo, Nicolas Boissel, Mehrdad Abedi, Francesca Milletti, Gary J. Schiller, Thibaut Leguay, Armin Ghobadi, Michael R. Bishop, Yi Lin, Jae H. Park, H. Lee Moffitt Cancer Center and Research Institute, Washington University in Saint Louis (WUSTL), Vanderbilt University [Nashville], Helen Diller Family Comprehensive Cancer Center [San Francisco], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Washington [Seattle], CHU Bordeaux [Bordeaux], The University of Chicago Medicine [Chicago], University Hospital of Würzburg, University of California [San Diego] (UC San Diego), University of California, Mayo Clinic [Rochester], University of Rochester [USA], Emory University [Atlanta, GA], University of Maryland [Baltimore], David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, State University of New York at New Paltz (SUNY New Paltz), State University of New York (SUNY), Memorial Sloan Kettering Cancer Center (MSKCC), Ludwig-Maximilians-Universität München (LMU), California State University [Sacramento], University Medical Center [Utrecht], The University of Texas M.D. Anderson Cancer Center [Houston], Dana-Farber Cancer Institute [Boston], Loyola University [Chicago], University of California [Irvine] (UCI), Kite (Gilead), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], University of California (UC), University of California (UC)-University of California (UC), University of California [Irvine] (UC Irvine), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
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Adult ,Male ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Population ,030204 cardiovascular system & hematology ,Immunotherapy, Adoptive ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Recurrence ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,030212 general & internal medicine ,education ,Survival analysis ,Aged ,Chemotherapy ,education.field_of_study ,Receptors, Chimeric Antigen ,business.industry ,General Medicine ,Leukapheresis ,Middle Aged ,Survival Analysis ,Minimal residual disease ,3. Good health ,Clinical trial ,Treatment Outcome ,Female ,business - Abstract
International audience; BACKGROUND: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies. METHODS: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 10(6) CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066. FINDINGS: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p
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- 2021
33. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial
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Dale L. Bixby, Jeffrey E. Lancet, Robert K. Stuart, Scott R. Solomon, Laura F. Newell, Ellen K. Ritchie, Donna E. Hogge, Geoffrey L. Uy, Daniel H. Ryan, Stephen A. Strickland, Gary J. Schiller, Stefan Faderl, Tara L. Lin, Jorge E. Cortes, Jonathan E. Kolitz, and Matthew J Wieduwilt
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Male ,medicine.medical_specialty ,Myeloid ,Daunorubicin ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Hematopoietic stem cell transplantation ,Drug Administration Schedule ,law.invention ,Randomized controlled trial ,law ,Internal medicine ,Humans ,Medicine ,Infusions, Intravenous ,Adverse effect ,Aged ,Proportional Hazards Models ,Chemotherapy ,business.industry ,Cytarabine ,Hematopoietic Stem Cell Transplantation ,Induction chemotherapy ,Neoplasms, Second Primary ,Hematology ,Middle Aged ,Leukemia, Myeloid, Acute ,Treatment Outcome ,medicine.anatomical_structure ,Female ,business ,Follow-Up Studies ,medicine.drug - Abstract
Summary Background Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60–75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results. Methods This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60–75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m2 administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m2 per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m2 on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m2 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov , NCT01696084 , and is complete. Findings Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06–62·98) in the CPX-351 group and 59·93 months (59·73–60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37–11·86) with CPX-351 and 5·95 months (4·99–7·75) with 7+3 (HR 0·70, 95% CI 0·55–0·91). 5-year overall survival was 18% (95% CI 12–25%) in the CPX-351 group and 8% (4–13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment. Interpretation After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60–75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. Funding Jazz Pharmaceuticals.
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- 2021
34. CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naïve/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
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Sarah M. Larson, Christopher M. Walthers, Brenda Ji, Sanaz N. Ghafouri, Jacob Naparstek, Jacqueline Trent, Jia Ming Chen, Mobina Roshandell, Caitlin Harris, Mobina Khericha Gandhi, Thomas Schweppe, Beata Berent-Maoz, Stanley B. Gosliner, Amr Almaktari, Martin Allen-Auerbach, Jonathan Said, Karla Nawaly, Monica Mead, Sven De Vos, Patricia Young, Caspian Oliai, Gary J. Schiller, John M. Timmerman, Antoni Ribas, and Yvonne Y. Chen
- Abstract
To address antigen escape and loss of T-cell functionality, we report a phase-1 clinical trial (NCT04007029) evaluating autologous naïve and memory T (TN/MEM) cells engineered to express a bispecific anti-CD19/CD20 CAR (CART19/20) for patients with relapsed/refractory NHL, with safety as the primary end point. Ten patients were treated with 36–165 × 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 ten patients achieved objective response (90% ORR), with seven achieving complete remission (70% 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 and overall survival were 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.
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- 2022
35. 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
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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, Roch Houot, H. Lee Moffitt Cancer Center and Research Institute, Washington University School of Medicine [Saint Louis, MO], Vanderbilt University [Nashville], Medical Center [San Francisco] (UCSF Medical Center), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], University of Chicago, University Hospital Wuerzburg / Universitätsklinikum Würzburg, University of California [San Diego] (UC San Diego), University of California (UC), University of Rochester [USA], Emory University [Atlanta, GA], Mayo Clinic [Rochester], University of Maryland [Baltimore], David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Memorial Sloane Kettering Cancer Center [New York], Ludwig-Maximilians-Universität München (LMU), University of California [Davis] (UC Davis), University Medical Center [Utrecht], The University of Texas M.D. Anderson Cancer Center [Houston], Dana-Farber Cancer Institute [Boston], Loyola University [Chicago], University of California [Irvine] (UC Irvine), Kite (Gilead), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], and This study was funded by Kite.
- Subjects
Adult ,Cancer Research ,Pediatric Research Initiative ,ZUMA-3 ,Childhood Leukemia ,Pediatric Cancer ,CAR T-cell therapy ,Adoptive ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Cardiorespiratory Medicine and Haematology ,MESH: Historically Controlled Study ,Rare Diseases ,Recurrence ,Clinical Research ,Brexucabtagene autoleucel ,Receptors ,Humans ,MESH: Receptors, Chimeric Antigen ,Antigens ,Molecular Biology ,Retrospective Studies ,Cancer ,MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Pediatric ,MESH: Humans ,MESH: Antigens, CD19 ,CD19 ,Historically Controlled Study ,Chimeric Antigen ,MESH: Adult ,MESH: Retrospective Studies ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,SCHOLAR-3 ,Stem Cell Research ,MESH: Recurrence ,B-precursor acute lymphoblastic leukemia ,Oncology ,MESH: Immunotherapy, Adoptive ,KTE-X19 ,Immunotherapy - 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.
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- 2022
36. Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials
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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
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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
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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
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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.
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- 2023
38. Spliceosome mutations are common in persons with myeloproliferative neoplasm-associated myelofibrosis with RBC-transfusion-dependence and correlate with response to pomalidomide
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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
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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
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Daria Gaut, Caspian Oliai, Steven Tsai, Chiung-Yu Huang, Joseph Tuscano, Herbert Eradat, and Gary J. Schiller
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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
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Naveen Pemmaraju, Krishna Gundabolu, Jack Snyder, Michael H Silverman, Geraldine Bardelli, Srdan Verstovsek, and Gary J. Schiller
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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
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Tiffany F. Lin, Gary J. Schiller, Johnnie J. Orozco, Gail J. Roboz, Mohamed M. Hegazi, Laura Finn, and Mary M Chen
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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
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- 2022
42. Suppression of Multiple Myeloma Via Inhibition of EFNB2 Reverse Signaling
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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
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
43. The Trend of Respiratory Virus Infection in Allogeneic Bone Marrow Transplant Recipients during the COVID Pandemic
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Guneet Kaleka, John Sharp, Kailyn Kim, Pryce Gaynor, Gary J. Schiller, and Wanxing Chai-Ho
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
44. RGI-2001 Infusion for Prevention of Acute Gvhd after Allogeneic Hematopoietic Cell Transplantation
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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
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
45. AML-397 Integrated Safety Analysis of Tagraxofusp, a CD123-Directed Targeted Therapy, in Patients With Hematologic Malignancies
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Naveen Pammaraju, Hagop Kantarjian, Kendra Sweet, Eunice S. Wang, Andrew A. Lane, Haris Ali, Anthony S. Stein, Abdulraheem Yacoub, David Rizzieri, Sumithira Vasu, Vikas Gupta, Sangmin Lee, Gary J. Schiller, James M. Foran, Minakshi S. Taparia, Todd L. Rosenblat, Roland B. Walter, Deborah Sieminski, Madhu Anant, Mrinal M. Patnaik, Tariq I. Mughal, and Marina Konopleva
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Cancer Research ,Oncology ,Hematology - Published
- 2022
46. Differential use of the hematopoietic cell transplantation-comorbidity index among adult and pediatric transplant physicians
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Larisa Broglie, Brian D. Friend, Saurabh Chhabra, Caitrin Bupp, Gary J. Schiller, Brent Logan, Marcelo C. Pasquini, Bipin Savani, Edward A. Stadtmauer, Monica S. Thakar, and Mohamed Sorror
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Adult ,Cancer Research ,Transplantation Conditioning ,Oncology ,Physicians ,Hematopoietic Stem Cell Transplantation ,Humans ,Transplantation, Homologous ,Hematology ,Comorbidity ,Child ,Retrospective Studies - Published
- 2022
47. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial
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Justin M, Watts, Maria R, Baer, Jay, Yang, Thomas, Prebet, Sangmin, Lee, Gary J, Schiller, Shira N, Dinner, Arnaud, Pigneux, Pau, Montesinos, Eunice S, Wang, Karen P, Seiter, Andrew H, Wei, Stephane, De Botton, Montserrat, Arnan, Will, Donnellan, Anthony P, Schwarer, Christian, Récher, Brian A, Jonas, P Brent, Ferrell, Christophe, Marzac, Patrick, Kelly, Jennifer, Sweeney, Sanjeev, Forsyth, Sylvie M, Guichard, Julie, Brevard, Patrick, Henrick, Hesham, Mohamed, and Jorge E, Cortes
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Hematology - Abstract
Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aims for phase 1 of this phase 1/2 study were to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of olutasidenib, as monotherapy or in combination with azacitidine, in patients with acute myeloid leukaemia or myelodysplastic syndrome, harbouring mutant IDH1.In this phase 1/2, multicentre, open-label clinical trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia or intermediate, high, or very high risk myelodysplastic syndrome harbouring mutant IDH1 at 18 study sites in the USA, Australia, France, and Spain. Other key eligibility criteria included Eastern Cooperative Oncology Group performance status 0-2 with adequate liver and renal function. The primary outcomes were dose-limiting toxicities and the maximum tolerated dose, maximum evaluated dose, and the recommended phase 2 dose of olutasidenib. Olutasidenib was administered orally in doses of 150 mg once daily, 150 mg twice per day, and 300 mg once daily. Azacitidine (75 mg/mPatients were enrolled between Aug 8, 2016, and Nov 14, 2018. 78 patients received olutasidenib as monotherapy (n=32) or in combination with azacitidine (n=46). The median follow-up was 8·3 months (IQR 3·1-13·3) for monotherapy and 10·1 months (4·2-15·3) for combination therapy. 16 (50%) of 32 patients in the monotherapy group and 24 (52%) of 46 patients in the combination therapy group were women. Most patients were White (26 [81%] for monotherapy and 31 [67%] for combination therapy). No dose-limiting toxicities were reported in the dose-escalation cohorts and 150 mg twice per day was declared the recommended phase 2 dose on the basis of safety, pharmacokinetics and pharmacodynamics, and clinical activity. The most common (≥20%) grade 3-4 treatment-emergent adverse events with monotherapy were thrombocytopenia (nine [28%] of 32 patients), febrile neutropenia (seven [22%] of 32), and anaemia (seven [22%] of 32); and with combination therapy were thrombocytopenia (19 [41%] of 46), febrile neutropenia (13 [28%] of 46), neutropenia (13 [28%] of 46), and anaemia (nine [20%] of 46). 11 (34%) of 32 patients in the monotherapy group and nine (20%) of 46 patients in the combination therapy group died (most commonly from disease progression [three (9%) of 32 and four (9%) of 46]). No deaths were considered study-drug related. For patients with relapsed or refractory acute myeloid leukaemia, 41% (95% CI 21-64; nine of 22) receiving monotherapy and 46% (27-67; 12 of 26) receiving combination therapy had an overall response. For treatment-naive patients with acute myeloid leukaemia, 25% (1-81; one of four) receiving monotherapy and 77% (46-95; ten of 13) receiving combination therapy had an overall response.Olutasidenib, with or without azacitidine, was well tolerated and showed meaningful clinical activity in patients with IDH1-mutated acute myeloid leukaemia. The results of this phase 1 study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies.Forma Therapeutics.
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- 2022
48. Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses
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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
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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
49. A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia
- Author
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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
50. Selinexor, daratumumab, and dexamethasone in patients with relapsed or refractory multiple myeloma
- Author
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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
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