Prophylactic maintenance with venetoclax/azacitidine after reduced-intensity conditioning allogeneic transplant for high-risk MDS and AML.

"Conflict-of-interest disclosure: J.S.G. reports grants from and serves on advisory boards for 10.13039/100006483AbbVie, Astellas, 10.13039/100002491Bristol Myers Squibb, 10.13039/100004328Genentech, and 10.13039/501100011725Servier, and receives grants/research funding from 10.13039/100006483AbbVie, 10.13039/100004328Genentech, New Wave, and 10.13039/100004319Pfizer. C.S.C. serves on the advisory board/consults for Sanofi, InhibRx, Cellarity, Astellas, Rigel, Novartis, Incyte, Cimeio, and Oxford Immune Algorithmics, and serves on the data and safety monitoring board for AlloVir and Angiocrine. J.K. serves on board and consults for Mallinckrodt, EMD Serono, Merck, Cugene, Cue Biotherapeutics, Biolojic Design, Gentibio, Nekonal, Equillium, and Amgen, and receives grants/research support from Bristol Myers Squibb, Miltenyi, 10.13039/100009857Regeneron, Equillium, 10.13039/100002429Amgen and Clinigen. R.R. receives grant support from CRISPR Therapeutics and serves on the advisory board for Glycostem. D.J.D. consults for AbbVie, Amgen, Agios, Autolus, Blueprint, Forty-Seven, Glycomimetics, Incyte, Jazz, Kite, Novartis, Pfizer, Servier, and Takeda. R.M.S. reports grants and personal fees from 10.13039/100006483AbbVie, 10.13039/100016471Agios, and 10.13039/100004336Novartis; personal fees from Actinium, Argenx, Astellas, AstraZeneca, BioLineRx, Celgene, Daiichi Sankyo, Elevate, GEMoaB, Janssen, Jazz, MacroGenics, Otsuka, Pfizer, Hoffmann–La Roche, Stemline, Syndax, Syntrix, Syros, Takeda, and Trovagene; and grants from Arog. J.H.A. serves on the data and safety monitoring board for CSL Behring and Janssen, and serves on the scientific advisory board for Pharmacosmos. J.R. receives research support from Equillium, Kite/10.13039/100005564Gilead, 10.13039/100004336Novartis, and Oncternal Therapeutics, and serves on advisory boards for Akron Biotech, Clade Therapeutics, Garuda Therapeutics, LifeVault Bio, Novartis, Smart Immune, and TScan Therapeutics. A.L. serves on the scientific advisory board of Flash Therapeutics, Trueline Therapeutics, and Zentalis Pharmaceuticals. The remaining authors declare no competing financial interests."

"Research reported in this publication was supported by the Ted and Eileen Pasquarello Tissue Bank in Hematologic Malignancies, the 10.13039/100000054National Cancer Institute (NCI) of the 10.13039/100000002National Institutes of Health (NIH) under award numbers CA066996 and K08CA245209, the American Society of Hematology MRHAP award (H.M.M.), and a scholar award from the Leukemia & Lymphoma Society (R.C.L.). This work was also supported by grants from the 10.13039/100017683Frederick A. DeLuca Foundation and the Jock and Bunny Adams Research and Education Endowment. Genentech provided trial and drug (venetoclax) support."

"We conducted a phase 1 trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) for patients with high-risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) undergoing reduced intensity allogeneic stem cell transplantation (allo-SCT) after Ven and fludarabine/busulfan conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT (55.6% with prior Ven exposure, and 96% with positive molecular measurable residual disease), 22 received maintenance therapy with Aza 36 mg/m2 intravenously on days 1 to 5, and Ven 400 mg by mouth on days 1 to 14 per assigned dose schedule/level (42-day cycles × 8, or 28-day cycles × 12). During maintenance, the most common grade 3-4 adverse events were leukopenia, neutropenia, and thrombocytopenia, which were transient and manageable. Infections were uncommon (n = 4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% confidence interval [CI], 0.3%-18%) and 22% (95% CI, 9%-40%), respectively. After a median follow-up of 25 months among survivors, the median overall survival (OS) was not reached. Among the 22 patients who received Ven/Aza maintenance, the 2-year OS, progression-free survival, nonrelapse mortality, and cumulative incidence of relapse rates were 67% (95% CI, 43%-83%), 59% (95% CI, 36%-76%), 0%, and 41% (95% CI, 20%-61%), respectively. Immune monitoring demonstrated no significant impact on T-cell expansion but identified reduced B-cell expansion compared with controls. This study demonstrates prophylactic Ven/Aza maintenance can be safely administered for patients with high-risk MDS/AML, but a randomized study is required to properly assess any potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT03613532."