A Phase I/II Study of Venetoclax in Combination with 5-Azacytidine in Treatment-Naïve and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)
Authors: Bazinet Alexandre , Jabbour Elias J. , Kantarjian Hagop , Chien Kelly S. , DiNardo Courtney D. , Ohanian Maro , Daver Naval , Kanagal-Shamanna Rashmi , Kadia Tapan M. , Takahashi Koichi , Masarova Lucia , Short Nicholas J. , Alvarado Yesid , Thompson Philip A. , Montalban-Bravo Guillermo , Yilmaz Musa , Ravandi Farhad , Kornblau Steven M. , Pemmaraju Naveen , Schneider Heather , Mirabella Bailey , Naqvi Kiran , Garcia-Manero Guillermo 
Published: November 2021

Abstract
Background: MDS is a clonal hematological disorder characterized by bone marrow dysplasia, ineffective hematopoiesis, and an increased risk of transformation to acute myeloid leukemia (AML). For the majority of high-risk MDS patients who are not eligible for curative allogeneic hematopoietic stem cell transplantation (aHSCT), hypomethylating agents (HMAs) such as 5-azacytidine (AZA) represent the standard of care. However, overall response rates (ORRs) with AZA monotherapy remain relatively low (28-48%) and the length of response is limited (median 8-10m). In patients who fail or relapse after HMA therapy, prognosis is dismal and therapeutic options are limited. Pre-clinical data suggest BCL-2 inhibitors such as Venetoclax (VEN) are synergistic with HMAs in MDS. We designed this phase I/II study (NCT04160052) to evaluate the safety, tolerability, and response rate of the AZA-VEN combination for the treatment of high-risk MDS and chronic myelomonocytic leukemia (CMML).
Methods: Patients ≥ 18 years of age were eligible for enrollment if they were diagnosed with HMA-naïve high-risk MDS (IPSS Int-2/High), relapsed/refractory MDS after at least 4 cycles of HMA therapy, or CMML. Bone marrow (BM) blast count &gt; 5% was required. Patients with prior BCL-2 inhibitor exposure and low risk MDS (IPSS Low/Int-1) were excluded. AZA 75 mg/m 2 IV/SC on days 1-5 and escalating doses (3+3 algorithm) of VEN PO on days 1-7 or 1-14 were administered every 28 days. VEN dosage was adjusted for concomitant CYP3A inhibitor use. The primary objective is safety and tolerability (phase I) and ORR (phase II). The incidence and severity of adverse events (AEs) were evaluated using CTCAE v 5.0. ORR was defined as the proportion of patients who achieved complete remission (CR), partial remission (PR), marrow CR (mCR), or hematological improvement (HI) lasting at least 4 weeks (Modified IWG Response Criteria for MDS, Cheson 2006). Overall survival (OS) and progression-free survival (PFS) were assessed as secondary objectives.
Results: As of July 31 st 2021, 17 patients (median age 68, range 58-84) have been enrolled in the phase I portion of the study (8 HMA-naïve MDS, 4 MDS after HMA failure, and 5 CMML). The median BM blast count was 11% (6-19%). 13 patients (76%) were Int-2 and 4 patients (24%) were High risk by IPSS. Good, intermediate, and poor risk cytogenetics were observed in 6 (35%), 4 (24%), and 7 (41%) patients, respectively. 6 patients (35%) had complex karyotypes and 5 (29%) had TP53 mutations. Of the 7 previously treated patients, the median number of prior therapies was 1 (1-5). The median number of cycles of AZA-VEN completed on study at the time of data cutoff was 3 (0-10) and the median follow-up was 11.6m. VEN dose ranged from 20 to 400 mg daily. 5 (29%) patients went off study for aHSCT but continued to be followed for the survival analysis. The most common grade 3/4 AEs were thrombocytopenia (35%), lung infections (29%), and neutropenia (24%). 2 grade 5 AEs (sepsis) occurred on study, one in a patient whose best response was SD after 5 cycles and one in a patient who had completed only 2 days of cycle 1. 30-day mortality was 6%. 15 patients were evaluable for response because they had completed at least 1 cycle of the study drugs. The ORR was 93% (1 CR, 9 mCR, 4 mCR with HI). In responders, the median number of cycles to response was 1 (range 1-2) and median duration of response 6.3m. No patient responded beyond cycle 2. Median PFS and OS for the evaluable cohort were 8.4m and 13m, respectively. Transformation to AML occurred in 3 patients (20%). Of the 4 survivors beyond 10m, 3 (75%) have undergone consolidative aHSCT.
Conclusions: AZA-VEN was a tolerable and effective treatment strategy in this high-risk group of patients. Notably, a very high ORR was observed in this phase I study. Responses were rapid compared to historical data with AZA alone. AZA-VEN was an effective bridge to aHSCT. Recruitment is ongoing to determine the MTD/RP2D.
Figure 1 Figure 1.

Disclosures
Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kantarjian: Novartis: Honoraria, Research Funding; Astra Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; Aptitude Health: Honoraria; Ascentage: Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Astellas Health: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DiNardo: Agios/Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: Astellas: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; Trillium: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Sevier: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Glycomimetics: Research Funding; Novimmune: Research Funding; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Kadia: Sanofi-Aventis: Consultancy; Cellonkos: Other; Ascentage: Other; Novartis: Consultancy; Liberum: Consultancy; Genfleet: Other; Astellas: Other; AstraZeneca: Other; Jazz: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Aglos: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; AbbVie: Consultancy, Other: Grant/research support. Takahashi: Celgene/BMS: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GSK: Consultancy. Short: Takeda Oncology: Consultancy, Research Funding; Astellas: Research Funding; Novartis: Honoraria; NGMBio: Consultancy; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Honoraria. Alvarado: Sun Pharma: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding. Thompson: Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Ravandi: Astex: Honoraria, Research Funding; Prelude: Research Funding; Taiho: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Pemmaraju: Plexxicon: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Aptitude Health: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; DAVA Oncology: Consultancy; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy.

OffLabel Disclosure:
Venetoclax is not currently approved for MDS but has promising pre-clinical activity data.