Venetoclax-augmented RIC allogeneic HCT with PTCy-based GVHD prophylaxis and venetoclax/azacitidine maintenance for poor risk MDS and AML.

Authors

H Moses Murdock, Kyle Hebert, Mahasweta Gooptu, Roman Shapiro, Gregory Abel, Corey Cutler, Amar Kelkar, Vincent T Ho, John Koreth, Thomas P O'Connor, Jennifer Brock, Elise Auriemma, Denbaa Bat-Erdene, Kevin Panaro, Jerome Ritz, R Coleman Lindsley, Joseph H Antin, Robert J Soiffer, Jacqueline S Garcia

Published in

Transplantation and cellular therapy. Aug 19, 2026. Epub Aug 19, 2026.

Abstract

Relapse remains the main cause of death following allogeneic hematopoietic cell transplantation (HCT) for patients with high-risk myeloid malignancies. Post-transplant maintenance therapy may reduce relapse risk and improve outcomes. We previously showed that post-transplant azacitidine + venetoclax (ven/aza) maintenance after reduced intensity conditioning (RIC) HCT with tacrolimus/methotrexate (Tac/MTX) graft-vs-host disease (GVHD) prophylaxis is feasible, safe, and associated with encouraging outcomes. The ability to deliver prophylactic maintenance after modified RIC conditioning including post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) GVHD prophylaxis has not yet been shown.
We sought to determine the extent to which PTCy/Tac/MMF GVHD prophylaxis affected the safety, tolerability, and preliminary efficacy of venetoclax/FluBu2 RIC HCT followed by ven/aza maintenance in patients with high-risk MDS and AML.
Venetoclax was administered at 400 mg daily dose on days -8 to -2, overlapping with FluBu2. Eligible patients included those with adverse risk AML (by ELN 2017/2022 or therapy-related AML) or adverse risk MDS (IPSS Intermediate-2/High or MDS with high-risk mutations). We compared clinical outcomes with our previously published venetoclax/FluBu2 RIC HCT Tac/MTX cohort. This phase 1 trial was registered at clinicaltrials.gov/NCT03613532.
Twenty-three patients enrolled in the PTCy cohort including 13/23 (57%) whose disease harbored TP53 mutations (12/13 multi-hit). At pre-transplant screening (within 28 days of day -8), multi-parameter flow cytometry-measurable residual disease was detected in 11/20 (55%) patients in CR. With this study regimen, neutrophils engrafted at a median of 15 days and platelets engrafted at a median of 22 days from transplant. 100-day non-relapse mortality (NRM) was 0%, 6-month grade II-IV acute GVHD rate was 4.4% (95% confidence interval [CI] 0.3 - 18.8) and 1-year chronic GVHD was 9.1% (95% CI: 1.4 - 26.1). 100-day event-free survival (EFS) was 59.1% (95% CI: 41.7 - 83.7). With median 14.9 months follow-up (range: 7.34 - 21.6), 1 year overall survival (OS) was 59.1% (95% CI: 41.6 - 84.0), progression-free survival (PFS) was 47% (95% CI: 30.2 - 73.1), relapse was 48.7% (95% CI: 26.4 - 67.8), and GVHD-free relapse free survival (GRFS) was 37.7% (95% CI: 21.9 - 64.7). We further compared safety and efficacy with another prospective cohort enrolled with identical inclusion criteria who underwent ven/FluBu2 HCT with Tac/MTX GVHD prophylaxis (n=27). No differences were observed in 100-day cumulative incidence of grade ≥2 infections, though the PTCy cohort had numerically increased bacterial (26% vs 15%) and viral (17% vs 7%) infections. We did not identify differences in OS (P = 0.33), PFS (P = 0.55), relapse (P = 0.76), NRM (P = 0.28), GRFS (P = 0.97), EFS (P = 0.6), acute GVHD (P = 0.12), or chronic GVHD (P = 0.41). Furthermore, no significant differences were detected in FACT-BMT quality of life scores when comparing longitudinal changes between pre-transplant and post-transplant/pre-maintenance timepoints by GVHD prophylaxis cohort.
We demonstrate acceptable safety and encouraging efficacy of ven/FluBu2 with PTCy in an exceedingly high risk cohort and equivalent outcomes in comparison with Tac/MTX GVHD prophylaxis. Subtle differences in tolerability however highlight the need for additional studies to confirm the optimal backbone for poor-risk MDS/AML cases.

PMID:
42617873
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.

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