Venetoclax and Azacitidine in the Treatment of Patients with Relapsed/Refractory Myelodysplastic Syndrome

Abstract

Abstract Introduction Patients (pts) with relapsed/refractory (R/R) higher-risk myelodysplastic syndromes (MDS) have a dismal median overall survival (OS) of 4.3 - 5.6 months (mos) and a 1-year survival probability of 28% after failure of the 2 approved hypomethylating agents (HMAs) azacitidine (Aza), and decitabine (Dec). There is no existing standard of care for pts after failure of HMA therapy; hence, there is a critical need for effective therapeutic strategies. Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor that in combination with Aza improved clinical outcomes as frontline therapy in pts with higher-risk MDS in an early phase clinical trial. We present an updated analysis of the safety and efficacy of Ven+Aza for the treatment of pts with R/R MDS. Methods This ongoing, phase 1b, open-label, multicenter study (NCT02966782) evaluated the safety and efficacy of either Ven monotherapy or Ven+Aza combination. Pts enrolled and treated with Ven+Aza were ≥18 yrs with R/R MDS and Eastern Cooperative Oncology Group performance status ≤2. Pts were considered R/R if they received a prior therapy with no response or had a response but subsequently relapsed after receiving at least 4 cycles of Aza or Dec within the last 5 yrs. Pts were excluded if they had myelodysplastic/myeloproliferative overlap neoplasms, had prior therapy with a BH3 mimetic, or underwent allogeneic hematopoietic stem cell or solid organ transplantation. For the Ven+Aza combination, pts were treated with escalating oral doses of Ven: 100, 200, or 400 mg daily for 14 days (d) every 28-d cycle. Aza was administered at 75 mg/m 2/d on 1─7 d every cycle. Responses were assessed per modified International Working Group 2006 criteria. Results Due to limited efficacy with Ven monotherapy, this analysis focuses on outcomes in pts treated with Ven+Aza combination only. As of April 30, 2021, 44 pts were treated with Ven+Aza (male 86%, median age 74 yrs [range 44-91]). Prior to enrollment, pts received a median of 1 HMA regimen and 65% of pts received >6 cycles of HMAs. The median follow-up was 21.2 mos, range 0.4 ─ 37.5. Pts received a median of 4 cycles (range 1 ─ 32) of Ven treatment. Forty-two pts (96%) reported ≥3 grade treatment-emergent adverse events (AEs). The most common ≥3 grade hematological AEs were febrile neutropenia (34%), thrombocytopenia (32%), neutropenia (27%), and anemia (18%). Pneumonia (23%) was the most common ≥3 grade infection. Serious AEs were reported in 61%. There were 29 (66%) deaths, of which 1 (2%) occurred ≤30 d after the first Ven dose, and 3 (7%) occurred within ≤60 d of first dose. Nine (21%) deaths occurred due to disease progression, and 4 (9%) were due to AEs (gastrointestinal hemorrhage [n=1], and infections [n=3]). Twenty-one (48%) pts required Ven dose interruptions due to an AE, most frequently due to febrile neutropenia (n=7; 15%) and neutropenia (n=4; 9%). Five (11%) pts required dose duration reductions, and 9 (21%) pts required Ven discontinuation. Fifteen (34%) pts were alive at the time of data cutoff. The objective response rate (mORR, defined as complete remission [CR] + marrow CR [mCR] + partial remission [PR]) rate was 38.6%, observed in 17 pts (CR 3, mCR 14, PR 0). Median time to first response of CR or mCR was 1.2 mos (range 0.7 ─ 6.3), and the duration of response for mORR was 8.6 mos (95% CI 6.0 ─ 13.3) (Fig A). Overall median progression-free survival was 8.6 mos (95% CI 5.4 ─ 14.3) and median OS was 12.6 mos (95% CI 9.1 ─ 17.2); mOS for pts with mORR was 14.8 mos (95% CI 11.3 ─ not estimable) (Fig B). Six pts with mCR also achieved hematological improvement. Post-baseline RBC and platelet transfusion independence (TI) was achieved by 16 (36%) pts overall with a median first duration of 4.0 mos (range 1.9 ─ 8.3). Nine pts (20.5%) moved to post-study transplant. Nine pts (20.5%) progressed to acute myeloid leukemia (AML). The median time to AML progression was 4.97 mos (range 0.03 ─ 19.84), and the median time to subsequent therapy was 5.7 mos (95% CI 4.8 ─ 8.8). Conclusion With longer follow-up, the tolerability and efficacy of the Ven+Aza combination in pts with R/R MDS were consistent with what was previously reported. In a very difficult-to-treat pt population, an ORR of 39%, RBC and platelet TI rate of 36%, and a median OS of 12.6 mos all suggest that Ven+Aza treatment leads to meaningful clinical benefits. Additional analyses, including associations of genetic mutations with clinical outcomes and patient-reported outcomes, will be presented. Figure 1 Figure 1. Disclosures Zeidan: Daiichi Sankyo: Consultancy; BeyondSpring: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; ADC Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Aprea: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Geron: Other: Clinical Trial Committees; Agios: Consultancy; BioCryst: Other: Clinical Trial Committees; Genentech: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Astellas: Consultancy; Astex: Research Funding; Pfizer: Other: Travel support, Research Funding; Jazz: Consultancy; Jasper: Consultancy; Ionis: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Acceleron: Consultancy, Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding. Borate: Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Jazz Pharma: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Pollyea: Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kiadis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Syndax: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syros: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Teva: Research Funding; Curis, Servier: Other; Pfizer: Research Funding; Agios: Other, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: advisory board; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Other: advisory board; Aprea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Brunner: Celgene, Forty Seven Inc, Jazz: Other: Advisory Board; Novartis, Celgene, Takeda, AstraZeneca: Research Funding. Roncolato: AbbVie: Other: Investigator in AbbVie funded Clinical Trials. Garcia: AstraZeneca: Research Funding; Pfizer: Research Funding; Prelude: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding; AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Watson: Astellas Pharma, Inc.: Consultancy; Roche, Amgen: Other: Travel support. Krishnadasan: AbbVie: Other: Investigator in AbbVie funded Clinical Trials. Bajel: Amgen: Speakers Bureau; Abbvie, Amgen, Novartis, Pfizer: Honoraria. Naqvi: Genentech/Roche: Current Employment, Current holder of stock options in a privately-held company. Zha: AbbVie: Current Employment, Current holder of stock o

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