A Prospective Clinical Study of Venetoclax Plus Azacitidine for the Maintenance Treatment of Post-Remission Acute Myeloid Leukemia

Background: Although acute myeloid leukemia (AML) patients eligible for intensive treatment often achieve remission, most patients eventually relapse, highlighting a significant clinical need to reduce the risk of relapse. Oral azacitidine (CC-486) maintenance has shown improved overall and relapse-free survival (QUAZAR AML-001 study). Additionally, a phase 2 study (NCT04062266) demonstrated the tolerability and feasibility of low-dose azacitidine combined with venetoclax as maintenance therapy in AML. We plan a larger prospective study to further evaluate the efficacy and safety of azacitidine with venetoclax as maintenance therapy in AML by optimizing the treatment interval. Methods: Patients ≥ 18 years of age with non-APL AML in first complete remission (CR) or CR with incomplete count recovery (CRi), who were not immediately eligible for allogeneic stem cell transplantation (SCT), were eligible for this study. Cohort 1 included patients who had received intensive chemotherapy for induction. Cohort 2 included patients who had received low-intensity therapy for induction. All patients received at least 2 cycles of consolidation therapy. Patients with negative measurable residual disease (MRD) by flow cytometry within 3 months before enrollment were eligible for the study. Other inclusion requirements were ECOG ≤ 3 and adequate hepatic/renal function. The treatment consisted of azacitidine 50 mg/m2 SQ/IV on D1-5 and venetoclax 400 mg PO on D1-14 in 28-day cycles. Treatment was repeated for 6 cycles in the absence of disease progression or unacceptable toxicity, and every other cycle thereafter until 2 years in total. Venetoclax duration could be reduced to D1-10 or azacitidine could be reduced to D1-3 to mitigate myelosuppression. The primary objective was relapse-free survival (RFS), defined as time from enrollment to progression or death. Secondary objectives included overall survival (OS) and safety/toxicity. Patients subsequently becoming eligible for SCT were taken off the study and censored for analyses at the time of SCT. Results: The median follow-up was 4 months. A total of 29 patients have been enrolled, with 20 in cohort 1 and 9 in cohort 2. The median age was 53 years in cohort 1 and 65 years in cohort 2. When stratified by ELN 2022, patients were favorable (n=7), intermediate(n=17), and adverse (n=5). Overall, 10(35%) patients had been previously exposed to venetoclax as part of their induction regimens. In cohort 1, 2(10%) patients had been previously exposed to venetoclax. In cohort 2, 8 patients were treated with venetoclax combined with azacitidine for induction therapy, and another ultra-elderly patient was treated with azacitidine with cytarabine. During consolidation therapy, 7 (35%) patients in cohort 1 received venetoclax-containing regimens and 13 (65%) received cytarabine. In cohort 2, 6 (56%) patients continued consolidation treatment with venetoclax and azacitidine, 3 patients converted to cytarabine and azacitidine. All patients were in their first complete remission at the time of enrollment. Median time from complete remission or complete remission with incomplete blood count recovery to enrolment into maintenance was 7.9 months (IQR 5.5-10.8) for the full cohort, 8 months (IQR 6.6-11.1) in cohort 1, and 7 months (IQR 3.7-9.4) in cohort 2. The median number of maintenance cycles given was 3 (range 1-6). No patients reduced treatment days due to myelosuppression or serious infection. All patients were in sustained remission, except for 1 relapse. The patient unfortunately relapsed after 1 cycle of maintenance therapy, and then was given a salvage therapy with venetoclax combined with mitoxantrone, etoposide and cytarabine. Median relapse-free survival in the full cohort was not reached. Conclusions: Preliminary, venetoclax combined with lower dose azacitidine is a feasible and safe maintenance strategy regardless of whether venetoclax has been exposed to previous treatment. We will update the results of this study with a longer follow-up. Conflict of interest: The authors declare that they have no conflict of interest. Acknowledgments: The authors would like to express their sincere thanks to Ms. Li He from AbbVie Medical Affairs.