Phase II trial of venetoclax in combination with azacitidine as maintenance therapy for acute lymphoblastic leukemia following allogeneic stem cell transplantation

Abstract Background: Allogeneic stem cell transplantation (alloSCT) remains the only potentially curative therapy for patients with acute lymphoblastic leukemia (ALL), although outcomes are suboptimal in those with high-risk features. While maintenance strategies are well-established in other hematological malignancies, such as acute myeloid leukemia and multiple myeloma, their role in non-Ph+ ALL remains less well defined. We report our results from cohort 2 (ALL, B-or T cell lineage) of a single center, open label, Phase II trial (NCT04128501) evaluating the safety and efficacy of venetoclax (VEN) in combination with azacitidine (AZA) as maintenance therapy following alloSCT. Methods: This trial includes four high-risk cohorts. This abstract focuses on cohort 2 with ALL patients. Inclusion criteria: 1) In complete remission (CR) without detectable measurable residual disease (MRD) after alloSCT 2) Absolute neutrophil count ≥ 1.0 × 10⁹/L and platelet count ≥ 30 × 10⁹/L without transfusion support. 3) No active graft versus host disease or infection 4) Enrollment between day +42 and +100 post-SCT. All donor and stem cell sources were included. Treatment: Up to 12 cycles of VEN 200 mg on Days 1–7 and AZA 32 mg/m² SC on Days 1–5 every 28 days. VEN was reduced for patients on CYP3A inhibitors (e.g., 40 mg with posaconazole). Further dose adjustments were made for hematological toxicity. Treatment delays of up to 70 days were permitted. Primary endpoints were relapse-free survival (RFS) and safety/tolerability. Results: Twelve patients were enrolled in the trial between December 2012 through March 2015 and 10 were evaluable for response. One patient did not complete the first cycle of maintenance, and another patient had just initiated therapy at the time of data cutoff. The median age was 38.5 years (range, 21-63). Per protocol design, the cohort included 3 patients with B cell lineage ALL (30 %) and 7 with T cell lineage ALL (70%). All were in CR at transplant, with 5 in first CR. Of the 10 evaluable patients, 5 had detectable MRD by multi-parameter flow cytometry at SCT. All patients received myeloablative conditioning. Median time to maintenance initiation was 89 days post-SCT (range, 48-100). At the time of analysis, 4 patients remained on treatment: 6 discontinued (2 with relapse, 2 toxicity, 1 physician discretion, and 1 patient request). One patient successfully completed all 12 planned cycles. With a median follow-up 16.6 months among 9 surviving patients, 2 relapsed (91 and 92 days after initiation of maintenance). RFS was 77.8% at 1 year and 2 years (95% CI, 54.9–100 %) as shown in the figure. Overall survival (OS) time was 85.7% (95% CI, 63.3%–100 %) at 1 year and 2 years after initiation of maintenance. Grade ≥3 adverse events occurred in 5 of 10 patients. Common grade 3–4 toxicities included anemia (n=17, 29.3%), neutropenia (n=2, 20%), thrombocytopenia (n=3, 30%). We did not observe any treatment-related infections and no deaths unrelated to relapse occurred before day 90 after initiation of maintenance. Non-relapse mortality did not occur in any patient and we did not observe any graft failure in this cohort Conclusion: VEN/AZA maintenance post-SCT in high-risk ALL is feasible and well-tolerated, with promising RFS and OS outcomes. Our findings support further investigation of VEN+AZA maintenance in larger, multi-center studies.