Ven+FluBu2 with ptcy/tac/MMF RIC transplant followed by venetoclax/azacitidine maintenance for high-risk MDS/AML

Abstract Background: We previously demonstrated that incorporating venetoclax (Ven) into reduced intensity conditioning (RIC) chemotherapy for patients undergoing allogeneic hematopoietic cell transplantation (HCT) with tacrolimus (Tac)/methotrexate (MTX) graft-vs-host disease (GVHD) prophylaxis followed by maintenance with azacitidine (Aza) and Ven was safe and associated with promising outcomes in older patients with high risk MDS/AML (Garcia Blood Adv 2021). BMT CTN 1703 findings indicate that post-transplant cyclophosphamide (PTCy) should be considered standard prophylaxis for older adults. Here, we report the safety of Ven plus fludarabine/busulfan (Ven+FluBu2) with PTCy/Tac/mycophenolate mofetil (MMF) followed by Ven/Aza maintenance in patients with high risk MDS/AML. Methods: In this Phase 1 trial (NCT03613532), patients with an 8/8 HLA-matched donor and diagnosis of AML with <5% blasts (adverse ELN 2022) or MDS with ≤10% blasts (IPSS Intermediate-2/High, or TP53 mutation) received Ven+FluBu2 HCT, as previously described (Garcia Blood Adv 2021), with PTCy/Tac/MMF GVHD prophylaxis. Following neutrophil and platelet engraftment and in the absence of relapse or uncontrolled GVHD, maintenance therapy was initiated (days +42-90) with Ven 400 mg (days 1-14) and Aza 36 mg/m2 (days 1-5 by IV/SC). In exploratory analyses, we compare early outcomes in the current cohort (PTCy) with a previously reported cohort of Ven+FluBu2+Tac/MTX (MTX-cohort, n=27). Results: At 6/1/25 data-cut, 23 patients underwent Ven+FluBu2 HCT + PTCy/Tac/MMF (11 AML and 12 MDS) with a matched unrelated donor. Median age at HCT was 70 years (range, 55-76) with median HCT-CI of 4 (range, 1-10). 16 (70%) received prior Ven for initial MDS/AML therapy. 20 (87%) had <5% blasts at screening; 9 (39%) in CR. Diagnostic TP53 mutations were present in 14 (61%), with 13/14 (93%) multihit TP53 allelic status. Neutrophil engraftment for those who nadired (18/23, 78%) occurred at median 17 days (range, 5-26); platelet engraftment for those who nadired (20/23, 87%) occurred at median 20.5 days (range, 10-42). Median granulocyte and T-cell donor chimerism at day +28 was 100% (range, 99-100) and 80% (range, 37-100%), and at day +100 was 100% (range, 88-100) and 92.5% (range, 65-100), respectively. 17/23 (74%) started maintenance, 4 relapsed at a median of 58.5 days from HCT (all TP53-mutated), and 2 withdrew. Maintenance was initiated at a median 69 days (range, 47-90) after HCT (vs 57 days after HCT in the MTX-cohort). Patients have received a median of 3 of 8 cycles, with 6 patients still-ongoing. Maintenance was prematurely discontinued in 11 patients due to relapse (n=6), GVHD (n=3), and other (n=2). Ven was dose reduced in 9% for adverse events (AE) or tolerability. From day -8 until day +100, all patients experienced at least 1 grade 3-4 treatment-emergent AE (TEAE), including 100% with a grade 3-4 hematologic TEAE and 5/23 (22%) with ≥1 non-hematologic grade 3-4 TEAE. Non-hematologic grade 3-4 TEAEs were mucositis (n=2) and ALT increase, hyperbilirubinemia, anorexia, diarrhea, esophagitis, nausea, and renal colic, each in 1 patient. There were no graft failures. Grade 1 CRS occurred in 2 patients. There was 1 DLT: a grade 4 subdural hematoma on day +14 surgically managed. Infection of any grade during this period occurred in 9 (39%) patients, including 6 patients (26%) with grade 3-4 infection (all bacteremia). This compares to 9/27 (33%) infection (any grade) and 3/27 (11%) grade 3-4 infection in the MTX-cohort. Median follow-up in the PTCy cohort is 349 days (range, 111-562). There have been 11 relapses (7/11 were TP53 mutated), with median time from HCT to relapse of 97 days (range, 55-373). Among the 7 deaths to date, 6 were due to primary disease. Comparing early outcomes (PTCy-cohort vs MTX-cohort): 100-day non-relapse mortality was 0% vs 0% and 6-month cumulative incidence of acute GVHD grade 2-4 was 4.6% vs 18.5%, respectively. To date, the PTCy-cohort has had 1 mild and 1 moderate chronic GVHD events. Clinical outcomes with mature follow-up and NGS-MRD will be presented at the meeting. Conclusions: Ven+FluBu2 HCT with PTCy/Tac/MMF followed by Ven/Aza maintenance was safe but associated with delayed maintenance start and a higher proportion of severe infections as compared to our prior MTX-based GVHD prophylaxis cohort. Incidence of acute GVHD was low.