Feasibility, Safety and Efficacy of Oral Maintenance Therapy with Venetoclax Plus Decitabine/Cedazuridine after Venetoclax Plus FluBu2 for High Risk MDS/AML Undergoing RIC Allo-HCT

Background: We previously demonstrated that adding venetoclax to reduced intensity conditioning (RIC) chemotherapy for patients undergoing alloHCT followed by maintenance therapy with intravenous azacitidine and venetoclax (Ven) was safe and associated with encouraging outcomes in older patients with high risk MDS/AML (Garcia 2024). Yet repeated parenteral administration of chemotherapy is burdensome after transplant. We asked to what extent an all-oral maintenance regimen promotes adherence and efficacy to prevent relapse. We report the safety and efficacy of venetoclax and decitabine/cedazuridine (Ven+Dec/Ced) maintenance therapy following venetoclax and fludarabine/busulfan (VenFluBu2) RIC HCT.

Methods: In this single-center Phase 1 trial (NCT03613532), subjects with an 8/8 HLA-matched related or unrelated donor and diagnosis of AML (adverse ELN risk or secondary) requiring <5% blasts at entry, or MDS (IPSS ≥1.5, secondary, or mutation in TP53 or RAS pathway) requiring ≤10% blasts at entry, received VenFluBu2, PBSC HCT, and tacrolimus/methotrexate GVHD prophylaxis, as previously described (Garcia 2021). Following neutrophil and platelet engraftment (days+42-90), in the absence of morphologic relapse or uncontrolled GVHD, maintenance therapy was initiated with venetoclax 400 mg (days 1-14) and a fixed-dose combination tablet containing 35 mg decitabine/100 mg cedazuridine on days 1, 3, and 5 (Dose Level 1 [DL1]) or days 1-3 (DL2). A total of eight 42-day-cycles were planned. DLT was defined as grade 4 neutropenia or thrombocytopenia lasting >2 weeks beyond 42-days, or new grade 4 non-hematologic toxicity. Anti-bacterial agents were required during cycle 1 and later for ANC<0.5K/µL. Flow MRD (0.02%) and clinical NGS (sensitivity 1-3%) were performed pre- and post-HCT.

Results: Thirty subjects (20 males and 10 females; 27 white, 1 black, and 2 other) underwent VenFluBu2 HCT (15 AML, 14 MDS and 1 MDS/MPN). Median age at transplant was 69 years (range, 39-78). Most had high/very high DRI (67%) and high HCT-CI ≥4 (57%). Nineteen (63%) received prior VEN for initial MDS/AML therapy; one was VEN-refractory. TP53 was mutated at diagnosis in 19 (63%). Pre-transplant disease was detected by flow MRD in 12/30 (40%) or by clinical NGS in 21/30 (70%).

Ultimately, 26/30 (87%) subjects started maintenance Ven+Dec/Ced (13 on DL1 and 13 on DL2). Among four subjects who did not start maintenance, three relapsed and one withdrew consent. Maintenance therapy was initiated at a median of day +55 (range, 41-106; one delayed start due to UTI).

On maintenance, the most common grade 3-4 TEAEs were hematologic and transient, including grade 4 neutropenia (50%), grade 4 leukopenia (31%), and grade 4 thrombocytopenia (15%). In Cycle 1, ANC nadir was day 29 (median 0.5K/µL [IQR 0.3-1.3] for DL1; median 0.6K/µL [IQR 0.3-1.2] for DL2), and PLT nadir was day 15 (median 77K/µL [IQR 45-94] for DL1; median 100K/µL [IQR 69-113] for DL2). Infections were uncommon (grade 3 febrile neutropenia [1] and grade 3 sepsis [1]). Grade II (2) or III (1) acute GVHD occurred in 3/26 (12%). At 1-year, moderate cGVHD was reported in 4 (15%). No DLTs were observed. Maintenance was interrupted/restarted in 2 (8%) for non-heme TEAE. Ven was dose reduced by 50% in 6 (23%) for tolerability. Maintenance is ongoing in 3 (12%), completed in 14 (54%), and discontinued in 9 (35%) (due to GVHD in 2 and relapse in 7).

After a median follow-up of 18mo (range, 7.4-25.7), in the ITT population, the 1-year OS, PFS, NRM and relapse rates were 76% (95% CI, 55-88), 63% (95% CI, 43-77), 0% and 37% (95% CI, 20-55), respectively. Among subjects who initiated maintenance, the 1-year OS, PFS, NRM and relapse rates were 84% (95% CI, 62-94), 72% (95% CI, 50-86), 0% and 28% (95% CI, 12-46), respectively. Subjects that completed all 8 maintenance cycles remain in remission. Flow MRD converted from positive to negative by day +100 in 7/9 (78%) on maintenance. All relapses except one occurred <1 year after HCT and most (82%) had diagnostic TP53mut. Notably, 11/16 (69%) subjects with diagnostic TP53mut who started maintenance are still in remission.

Conclusions: Oral maintenance therapy with Ven+Dec/Ced after HCT is feasible with protocol guided dose reductions. Although a RCT is required to confirm the true benefit of this regimen, relapse rates appear lower than historical data for a high risk population. This trial is currently enrolling a separate cohort using a PTCy backbone.