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Clinical Trial
. 2023 Feb;98(2):272-281.
doi: 10.1002/ajh.26771. Epub 2022 Nov 10.

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes

Amer M Zeidan  1 , Uma Borate  2 , Daniel A Pollyea  3 , Andrew M Brunner  4 , Fernando Roncolato  5 , Jacqueline S Garcia  6 , Robin Filshie  7 , Olatoyosi Odenike  8 , Anne Marie Watson  9 , Ravitharan Krishnadasan  10 , Ashish Bajel  11 , Kiran Naqvi  12 , Jiuhong Zha  13 , Wei-Han Cheng  13 , Ying Zhou  13 , David Hoffman  13 , Jason G Harb  13 , Jalaja Potluri  13 , Guillermo Garcia-Manero  14
Affiliations
Clinical Trial

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes

Amer M Zeidan et al. Am J Hematol. 2023 Feb.

Abstract

Patients with relapsed/refractory (R/R) higher-risk myelodysplastic syndromes (MDS) have a dismal median overall survival (OS) after failing hypomethylating agent (HMA) treatment. There is no standard of care for patients after HMA therapy failure; hence, there is a critical need for effective therapeutic strategies. Herein, we present the safety and efficacy of venetoclax + azacitidine in patients with R/R MDS. This phase 1b, open-label, multicenter study enrolled patients ≥18 years. Patients were treated with escalating doses of oral venetoclax: 100, 200, or 400 mg daily for 14 days every 28-day cycle. Azacitidine was administered on Days 1-7 every cycle at 75 mg/m2 /day intravenously/subcutaneously. Responses were assessed per modified 2006 International Working Group (IWG) criteria. Forty-four patients (male 86%, median age 74 years) received venetoclax + azacitidine treatment. Median follow-up was 21.2 months. Hematological adverse events of Grade ≥ 3 included febrile neutropenia (34%), thrombocytopenia (32%), neutropenia (27%), and anemia (18%). Pneumonia (23%) was the most common Grade ≥ 3 infection. Marrow responses were seen including complete remission (CR, n = 3, 7%) and marrow CR (mCR, n = 14, 32%); 36% (16/44) achieved transfusion independence (TI) for RBCs and/or platelets, and 43% (6/14) with mCR achieved hematological improvement (HI). The median time to CR/mCR was 1.2 months, and the median duration of response for CR + mCR was 8.6 months. Median OS was 12.6 months. Venetoclax + azacitidine shows activity in patients with R/R MDS following prior HMA therapy failure and provides clinically meaningful benefits, including HI and TI, and encouraging OS.

Trial registration: ClinicalTrials.gov NCT02966782.

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Conflict of interest statement

AM Zeidan: Leukemia and Lymphoma Society Scholar in Clinical Research. Research funding (institutional) from Celgene/BMS, AbbVie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer‐Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. Participated in advisory boards and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer‐Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. Served on clinical trial committees for Novartis, AbbVie, Gilead, BioCryst, AbbVie, ALX Oncology, Geron, and Celgene/BMS. U Borate: Advisory board for Genentech, Daiichi Sankyo, Takeda, Pfizer, Novartis, Research funding from Novartis, Pfizer, Jazz, Kura Oncology, and Servier. Investigator in AbbVie‐funded Clinical Trials. DA Pollyea: Advisory board member for AbbVie, Jazz, Bristol Myers Squibb, Novartis, BeiGene, BerGenBio, Arcellx, Syros, Immunogen, Astra Zeneca, Notable Labs, Kura, Ryvu; Consultant for Syros, Genentech; Research Funding from Teva, Bristol Myers Squibb, Karyopharm and AbbVie. AM Brunner: Research funding to my institution from Novartis, Celgene, Takeda, AstraZeneca, and consulting for BMS/Celgene, Forty‐Seven, Inc, Gilead, Novartis, Takeda, Keros Therapeutics, Taiho, Agios, AbbVie, and Jazz Pharmaceuticals. F Roncolato: Investigator in AbbVie‐funded Clinical Trials. Jacqueline S Garcia: Institutional research funding (for trials) from AbbVie, Genentech, Pfizer, Prelude, Astra Zeneca; advisory board for AbbVie, Astellas, Takeda. R Filshie: Investigator in AbbVie‐funded Clinical Trials. T Odenike: Consulting or Advisory Role: AbbVie, Celgene; Research Funding: Celgene (Inst), Incyte (Inst), Astra Zeneca, Astex Pharmaceuticals (Inst), NS Pharma (Inst), AbbVie (Inst), Gilead Sciences (Inst), Janssen Oncology (Inst), Oncotherapy (Inst), Agios (Inst), CTI/Baxalta (inst). A‐M Watson: Received Travel Support from Roche, Amgen. R Krishnadasan: Investigator in AbbVie‐funded Clinical Trials. A Bajel: Honoraria—AbbVie, Amgen, Astellas Novartis, Pfizer, Takeda Speaker Fees—Amgen. K Naqvi: Employee of Genentech and may own Roche stock or options. J Zha, WH Cheng, Y Zhou, D Hoffman, JG Harb, J Potluri: Employees of AbbVie and may own stock. G Garcia‐Manero: Research support from Genentech and AbbVie.

Figures

FIGURE 1
FIGURE 1
(A) Duration of response (DoR). (B) Overall survival (OS) in patients treated with venetoclax (Ven) and azacitidine (Aza). [Color figure can be viewed at wileyonlinelibrary.com]
See this image and copyright information in PMC

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