Venetoclax and hypomethylating agents followed by allogeneic stem cell transplantation in patients with acute myeloid leukemia

Background So far, it was a treatment paradigm to induce remission in patients with either newly diagnosed (ND) or relapsed/refractory (R/R) acute myeloid leukemia (AML) prior to allogeneic stem cell transplantation (allo-SCT) using intensive therapies with anthracyclins in combination with low- or intermediate to high-dose cytarabine. For AML patients ineligible for intensive therapy, the combination of hypomethylating agents (HMA) and the BCL2 inhibitor Venetoclax (VEN) has become the new treatment standard due to high and rapidly achieved remission rates and a favorable toxicity profile. These properties make this combination also attractive for frontline induction of ND-AML or as salvage therapy in R/R-AML patients with borderline fitness to tolerate and/or limited chance to achieve remission by intensive therapy. Considering the limited evidence from the literature so far, we here report our single-center experience of allo-SCT after HMA/VEN-based therapy. Design/Methods: We retrospectively analyzed all consecutive ND and R/R AML patients, who had received HMA/VEN therapy followed by allo-SCT at our center from 2021 to 2022, regarding outcome after transplant. The study was approved by the ethics committee of the University Duisburg/Essen (approval number: 22-10708-BO) and all patients gave written informed consent for scientific use of their data. Results: Overall, 26 patients (median age 64 years, range 26 to 75) with ND (n=14, 54%) or R/R (n=12, 46%) AML were treated with a median of 2 cycles HMA/VEN (range, 1 to 5; Azacitidine n=10, Decitabine n=16). Overall response rate (CR/CRi, MLFS) in the entire cohort was 58% with no difference between patients with ND and R/R AML (57% vs. 58%, p>0.99). Minimal residual disease (MRD) determined by molecular genetics as part of the clinical routine was not detectable prior transplant in 43% of the responding patients. Allo-SCT using PBSC (n=25, 96%) or BM (n=1, 4%) from a matched sibling (n=4, 15%), unrelated (n=19, 73%) or haploidentical donor (n=3, 12%) was performed in median 98 days (range, 31 to 220) after start of HMA/VEN treatment. Neither the rate of MRD negativity nor time to allo-SCT differed between ND and R/R patients. A reduced-intensity conditioning (RIC) was used in all patients including 11 patients (42%) receiving melphalan- or FLAMSA-based sequential conditioning. Median follow-up from start of HMA/VEN therapy was 10 months (range, 4 to 19 months) and from allo-SCT 6 months (range, 1 to 15 months), respectively. Median overall survival (OS) calculated from start of HMA/VEN therapy and from allo-SCT is both not reached, while the estimated 1-year OS rates were 81% and 80% respectively. OS after transplant was numerically higher in patients with CR at transplant (90% vs. 69%), but did not differ between patients with ND and those with R/R AML (75% vs. 80%) nor between MRD negative and positive CR patients (75% vs. 100%). All patients achieved CR following allo-SCT, but 1 patient had a persistence of his cytogenetic marker and two patients had mixed chimerism. Incidence of acute GvHD was 31% (including 8% with acute GvHD grade III/IV) and of chronic GvHD 4%. A total of 6 patients relapsed after allo-SCT and a total of 4 patients have died due to relapse (n=3) or treatment-related toxicity (n=1). Median relapse-free survival (RFS) after allo-SCT was not reached and the estimated 1-year RFS rate was 67%. Again, RFS numerically differed between in patients in remission and with active disease at transplant (84% vs. 48%), but did not differ between patients with ND and those with R/R AML (70% vs. 64%) nor between MRD negative and positive CR patients (83% vs. 86%). Conclusion: Treatment with HMA/VEN either as induction or salvage therapy in ND or R/R AML leads to reasonable remission rates facilitating subsequent allo-SCT with promising survival rates. This warrants confirmatory analyses in larger patient cohorts with longer follow-up, ideally in a prospective clinical trial.