Background: Relapse is the main cause of transplant failure. We previously reported safety and durable remissions with venetoclax (Ven) added to fludarabine/busulfan (FluBu2) reduced intensity conditioning allogeneic hematopoietic cell transplantation (HCT) without planned maintenance therapy in patients (pts) with high risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) (Garcia, Blood Advances, 2021). Detectable measurable residual disease (MRD) at day +100 frequently resulted in relapse after transplant. To address relapse risk after VenFluBu2 transplant in this high risk population, we assessed the safety and activity of Ven/Azacitidine (VenAza) maintenance therapy.

Methods: In a Phase 1 trial (NCT03613532), pts with an 8/8 HLA-matched donor and diagnosis of AML with <5% blasts (ELN adverse, secondary, or flow MRD positive) or MDS/MPN or MDS with ≥10% blasts (secondary, IPSS higher risk, or TP53mut or RAS pathway mutations) received VenFluBu2 (Ven 400 mg on D-8 to D-2; fludarabine 30 mg/m2/d on D-5 to D-2; IV busulfan 0.8 mg/kg bid on D-5 to D-2), followed by PBSC infusion (D0) and tacrolimus/methotrexate GVHD prophylaxis. Between D42-D90, VenAza maintenance therapy (Ven 400 mg on D1-D14 and Aza 36 mg/m2 IV on D1-D5) was initiated in pts who engrafted and had no evidence of morphologic relapse or uncontrolled GVHD in 42-day (dose level 1) or 28-day (dose level 2) cycles for up to 1 year. DLT was defined as Gr 4 neutropenia/thrombocytopenia >2 wks. Clinical NGS (sensitivity 1-3%) was performed before and after HCT (+28, +100). BH3 profiling analysis was performed on 11 paired blood samples before/after cycle 1 of VenAza.

Results: As of 6/2022, 27 pts were enrolled and had the following disease status at time of HCT: 10 AML pts (8 CR, 2 CRi); 16 MDS pts (1 CR, 5 marrow CR (mCR) with hematologic improvement (HI), 5 mCR without HI, 1 HI-erythroid alone, and 4 active disease (5-10% blasts)); and 1 MDS/MPN pt in CR. Pts had a median age of 67y (range 47,78), co-morbidities (52% HCT-CI≥4), 44% were flow MRD negative, and 56% had Ven exposure prior to HCT. Baseline TP53mut was present in 59% (16/27).

After VenFluBu2 RIC HCT, 22 of 27 pts received VenAza maintenance therapy (n=11 per dose level); remaining 5 of 27 pts did not (3 relapsed early, 2 withdrew). No DLTs were observed. The most common grade 3-4 treatment emergent adverse events (AE) during maintenance were anemia (45%), neutropenia (95%) and thrombocytopenia (91%), which were mainly transient. Cycle 1 nadir occurred on D29 for ANC (median 1.2 K/µL, range 0,3.7) and on D15 for platelet (median 119 K/µL, range 70,169). Infection during maintenance was reported in only 1 pt (n=1 BK viruria). Serious AEs were reported in 2 (1 rash; 1 BK case). Median of 4 VenAza cycles were received in DL1 (range 1,8); DL2 on-going. Cumulative incidence of grade ≥2 acute GVHD at 6 mo was 22% (95% CI: 9,39) and chronic GVHD at 1y was 23% (95% CI: 8,42).

With a median 12 mo follow up (range 4-21), regardless of maintenance status, 1y OS, PFS, NRM and relapse were 70% (95% CI: 46,85), 57% (95% CI: 36,74), 0% and 43% (95% CI: 28,57), respectively. To date, 12 of 27 pts have relapsed (4 before, 7 during, and 1 after maintenance on D523). Ven use prior to HCT did not impact outcome. Pre-transplant flow MRD negativity was associated with improved 1y OS (88% vs 50%, p=0.03) and 1y PFS (81% vs 39%, p=0.08). Flow MRD was positive in 17% (4/24) at D28 and in 44% (11/25) at D100. At time of HCT, NGS was positive in 89% (24/27), but this reduced to 42% (10/24) at D28 and 58% (14/24) at D100 (Figure 1). PFS was similar for those with or without TP53mut at HCT (p=0.14).

Among 22 pts that received VenAza maintenance therapy, 1y PFS and 1y OS were 65% (95% CI: 40,82) and 79% (95% CI: 52,92), respectively. BH3 profiling did not reveal any significant changes in baseline apoptotic priming in CD3+, CD3+CD4+, CD3+CD8+ T cells, and CD3+CD4+CD127-CD25+ Treg cells, suggesting VenAza was not cytotoxic to T cells. Flow cytometry to assess for immune recovery is in process.

Conclusions: VenAza maintenance therapy after VenFluBu2 RIC alloHCT appears to be safe with low infection rate and no excessive GVHD. This Ven-based peri-transplant strategy for high risk MDS/AML pts has encouraging activity though relapses still occurred. A cohort assessing all oral maintenance (Ven plus decitabine/cedazuridine) is enrolling. A randomized trial will be required to evaluate the benefit of Ven with conditioning chemotherapy or with maintenance therapy.

Figure 1
Figure 1
View largeDownload PPT

Garcia:AbbVie, Astellas, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board ; AbbVie, Genentech, AstraZeneca, Prelude and Pfizer: Other: Clinical trial support (institutional) , Research Funding; AbbVie: Research Funding. DeAngelo:AbbVie, Blueprint Medicines Corporation, GlycoMimetics, and Novartis: Research Funding; AbbVie, Amgen, Autolus, Blueprint Medicines Corporation, Forty-Seven, GlycoMimetics, Incyte, Jazz, Kite, Novartis, Pfizer, Servier, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Luskin:Pfizer: Honoraria; Abbvie: Research Funding; Novartis: Research Funding. Nikiforow:GlaxoSmithKline: Consultancy; Iovance: Consultancy; Kite/Gilead: Consultancy. Romee:Glycostem Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Skyline Therapeutics: Research Funding; Crispr Therapeutics: Research Funding; xNK therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; InnDura Therapeutics: Current equity holder in publicly-traded company. Shapiro:Miltenyi: Honoraria. Stone:Innate: Consultancy; Syntrix: Consultancy; Syndax: Consultancy; OncoNova: Consultancy; Novartis: Consultancy; Kura Oncology: Consultancy; Jazz: Consultancy; Janssen: Consultancy; GSK: Consultancy; Gemoab: Consultancy; Foghorn Therapeutics: Consultancy; Epizyme: Consultancy; Elevate Bio: Consultancy; BMS: Consultancy; Boston Pharmaceuticals: Consultancy; BerGenBio: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Apteva: Consultancy; Aprea: Consultancy; Actinium: Consultancy; Abbvie: Consultancy, Research Funding; Syros: Consultancy; Takeda: Consultancy. Winer:Novartis, Jazz Pharmaceuticals, Pfizer, Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy; Abbvie: Consultancy; Curis: Consultancy. Ryan:Zentalis Pharmaceuticals: Consultancy. Letai:Dialectic Therapeutics: Membership on an entity's Board of Directors or advisory committees; Flash Therapeutics: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Zentalis Therapeutics: Membership on an entity's Board of Directors or advisory committees. Lindsley:bluebird bio: Consultancy; Qiagen: Consultancy; Thermo Fisher: Consultancy; Nuprobe: Consultancy; Takeda Pharmaceuticals: Consultancy. Soiffer:Jazz: Consultancy; Juno: Membership on an entity's Board of Directors or advisory committees; VOR Biopharma: Consultancy; Alexion: Consultancy; Rheos Therapeutics: Consultancy; Gilead: Consultancy; Be The Match/National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees. Ritz:Equillium: Research Funding; Gadeta: Research Funding; Kite/Gilead: Research Funding; Oncternal: Research Funding; Novartis: Research Funding; Akron Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AvroBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Clade Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Draper: Consultancy, Membership on an entity's Board of Directors or advisory committees; Garuda Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; LifeVault Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Smart Immune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Talaris Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; TScan Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

venetoclax plus conditioning; venetoclax/azacitidine for post-transplant maintenance

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
Sign in via your Institution