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3109 A Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Azacitidine for the Treatment of Relapsed/Refractory Myelodysplastic Syndrome

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Poster III
Hematology Disease Topics & Pathways:
Clinically relevant
Monday, December 7, 2020, 7:00 AM-3:30 PM

Amer M. Zeidan, MBBS, MHS1, Daniel A. Pollyea, MD2, Jacqueline S. Garcia3, Andrew M. Brunner4*, Fernando Roncolato5*, Uma Borate6, Olatoyosi Odenike, MD7, Ashish Bajel, FRACP8, Anne-Marie Watson9*, Katharina S. Götze10, Florian Nolte, MD11*, Peter Tan, MBBS12*, Haifa K Al-Ali13*, Wan-Jen Hong, MD14, Ying Zhou, PhD15*, Martin Dunbar16*, Lori Gressick16*, William Ainsworth17, Jason Harb, PhD17*, Relja Popovic16, Ahmed H Salem16, John Hayslip16*, Ronan Swords16 and Guillermo Garcia-Manero, MD18

1Section of Hematology, Department of Internal Medicine, Yale University School of Medicine and Yale Cancer Center, New Haven, CT
2UCHealth University of Colorado Hospital, Denver, CO
3Department of Medicine, Dana Farber Cancer Institute, Boston, MA
4Center for Leukemia, Massachusetts General Hospital, Boston, MA
5Department of Hematology, University of New South Wales, Sydney, NSW, Australia
6Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR
7University of Chicago Medicine and Comprehensive Cancer Center, Chicago, IL
8Haematology Department, Royal Melbourne Hospital, Parkville, Australia
9Department of Haematology, Liverpool Hospital, Liverpool, AUS
10Department of Medicine III, Technical University of Munich, Munich, Germany
11Department of Hematology and Oncology, Medical Faculty Mannheim of the Heidelberg University, Mannheim, Germany
12Department of Haematology Cell and Tissue Therapies, Royal Perth Hospital, Perth, Australia
13Department of Hematology and Medical Oncology, University Hospital of Halle, Halle, Germany
14Genentech, Inc., South San Francisco, CA
15AbbVie Inc., North Chicago, IL
16AbbVie Inc, North Chicago, IL
17AbbVie, Inc., North Chicago, IL
18Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

Background Patients (pts) with relapsed/refractory (RR) higher-risk myelodysplastic syndrome (MDS) have a median overall survival (OS) of less than 6 months. No standard of care exists for these pts. Over-expression of the anti-apoptotic protein BCL-2 in MDS has been implicated in disease progression and drug resistance. Venetoclax (Ven) is a selective, potent, orally bioavailable BCL-2 inhibitor that in combination with azacitidine has been shown to improve overall survival in older or co-morbid pts with newly-diagnosed acute myeloid leukemia.

Aims Here we present an updated analysis of the safety and efficacy of Ven in combination with the HMA azacitidine (Ven+Aza) for the treatment of pts with RR-MDS.

Methods This ongoing phase 1b, open-label, multicenter study (NCT02966782) is evaluating the safety and efficacy of either Ven monotherapy or Ven+Aza combination therapy. Pts enrolled and treated with Ven+Aza were ≥18 years with RR-MDS and had Eastern Cooperative Oncology Group scores ≤2. Pts were excluded if they had myelodysplastic/myeloproliferative neoplasms, had received prior therapy with a BH3 mimetic, or had undergone allogeneic hematopoietic stem cell transplantation or solid organ transplantation. Pts were treated with escalating oral doses of Ven:100, 200, or 400 mg daily for 14 days every 28-day cycle. Aza was administered at 75 mg/m2/day for the first 7 days every cycle. Responses were recorded using the modified International Working Group 2006 criteria. Mutation status was determined in the peripheral blood of 32 (84%) pts by targeted next-generation sequencing.

Results As of August 30, 2019, 38 pts were treated with Ven+Aza [male 84%, median age 74 years (range 44–91)]. Pts received a median of 8 cycles (range 2 – 72)] or prior treatment with an HMA and 63% (24/38) received either RBC or platelet transfusion within 8-weeks prior to first dose of Ven. Fourteen genes were found mutated in ≥ 5%, including TP53, RUNX1, ASXL1, STAG2, and U2AF1. Median follow-up time was 6.8 months (range 0 – 16.6). Common grade 3 or 4 adverse events (AEs) occurring in ≥15% pts were neutropenia (50%), thrombocytopenia (42%), leukopenia (39%), febrile neutropenia (29%), anemia (16%), and pneumonia (16%). Other AEs included low grade constipation (39%) and diarrhea (34%). Serious AEs in >2 pts were febrile neutropenia (n=9) and pneumonia (n=6). Fourteen (37%) pts discontinued the study. Two pts died ≤30 days of first Ven dose and 1 pt died >30 days and ≤60 days of first Ven dose. Thirty-seven pts were response evaluable. Complete remission (CR) + marrow CR (mCR) was 40%, observed in 15 pts (CR 3, mCR12) (Figure). Hematological improvement (HI) was achieved by 25% (9/36) and mCR+HI was achieved by 42% (5/12). Transfusion independence was achieved by 34% (13/38) in either RBC or platelet with median duration of 4.1 months (range 2 – 7). Of 13 pts who completed 4 cycles of Ven+Aza, 9 achieved CR/mCR. Median time to response for CR+mCR was 1.2 months (range 0.7 – 6.3). Overall, median progression free survival (PFS) was 9.1 months (95% CI 5.9 –not estimable) and 12-month OS estimate was 65% (95% CI 37 – 83). Among pts who obtained mCR, median PFS was 10.1 months (95% CI 5.4 – not estimable) and the 12-month estimate of OS was 78% (95% CI 37–94).

Conclusion Ven+Aza combination therapy was well tolerated in pts with RR-MDS and the AEs were manageable. The CR+mCR of 40% and estimated 12-month OS of 65% with Ven+Aza is encouraging. Updated analyses on safety, efficacy, biomarker analyses including associations of genetic mutations and BCL-2 family members expression with clinical outcomes will be presented.

Abstract was previously published at EHA25

Disclosures: Zeidan: Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Trovagene: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; Seattle Genetics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; CCITLA: Other; Abbvie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; BeyondSpring: Consultancy, Honoraria; Cardiff Oncology: Consultancy, Honoraria, Other; Ionis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria. Pollyea: Takeda: Consultancy; Daiichi Sankyo: Consultancy; Abbvie: Consultancy, Research Funding; Syros: Consultancy; Syndax: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Genentech: Consultancy; 47: Consultancy, Research Funding; Janssen: Consultancy; Glycomimetics: Other; Agios: Consultancy; Celgene/BMS: Consultancy; Pfizer: Consultancy. Garcia: Pfizer: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding. Brunner: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Roncolato: AbbVie: Other: Investigator on an AbbVie funded clinical trial. Borate: Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Odenike: Incyte: Other: Institutional research funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding. Bajel: Novartis: Honoraria; Astellas: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau. Watson: Roche: Other: Travel support; Amgen: Other: Travel support. Götze: Celgene: Research Funding. Nolte: AbbVie: Other: Investigator on an AbbVie funded clinical trial. Tan: Novartis: Other, Research Funding; AbbVie: Other: Investigator on an AbbVie funded clinical trial; Agios: Research Funding; Janssen: Research Funding; NOHLA Therapeutics: Research Funding. Al-Ali: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Pfizer: Consultancy, Honoraria; Incyte: Research Funding; AOP Orphan: Other: travel, accommodations, expenses. Hong: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Zhou: AbbVie: Current Employment, Other: may hold stock or other options. Dunbar: AbbVie: Current Employment, Current equity holder in publicly-traded company. Gressick: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ainsworth: AbbVie: Current Employment, Current equity holder in publicly-traded company. Harb: AbbVie: Current Employment, Other: may hold stock or stock options. Popovic: AbbVie: Current Employment, Current equity holder in publicly-traded company. Salem: AbbVie: Current Employment, Current equity holder in publicly-traded company. Hayslip: AbbVie: Current Employment, Current equity holder in publicly-traded company. Swords: AbbVie: Current Employment, Current equity holder in publicly-traded company. Garcia-Manero: Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Amphivena Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

*signifies non-member of ASH