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

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.