A Phase II Study of Azacitidine Plus Venetoclax As Maintenance Therapy in Acute Myeloid Leukemia: Durable Responses with Longer Term Follow-up

Background: Relapse is the major cause of treatment failure in acute myeloid leukemia (AML). Patients with AML who are ineligible for allogeneic stem cell transplantation (SCT) have limited options to delay or prevent relapse once they have completed their initial therapy. Oral azacitidine (CC-486) has been shown to improve relapse-free survival (RFS) and overall survival (OS) in patients with AML who have achieved first complete remission (CR) after intensive chemotherapy, and is currently the only agent approved as maintenance therapy in AML. The combination of azacitidine (AZA) and venetoclax (VEN) is synergistic and highly effective in AML. To further improve outcomes in the post-remission setting, we studied the combination of low-dose IV/SQ AZA plus VEN as maintenance therapy in AML. Methods: This phase II study enrolled patients with AML ≥ 18 years, not immediately eligible for SCT, and who had achieved a first CR/CRi (regardless of measurable residual disease [MRD] status) following at least 2 cycles of intensive chemotherapy (defined as intermediate or higher dose cytarabine; cohort 1) or low-intensity therapy (defined as hypomethylating agent or low-dose cytarabine-based; cohort 2). Patients in CR2 or beyond were also eligible if positive for MRD. Patients were treated with AZA 50 mg/m2 IV/SQ on days 1-5 plus VEN 400 mg PO on days 1-14, every 28 days for up to 24 cycles. VEN duration could be reduced to 7 days in patients at high risk for cytopenias. VEN dosing was adjusted for concomitant azole antifungal use. The primary outcome was RFS (defined as enrollment to relapse or death, whichever occurred first). Secondary outcomes included OS, MRD clearance rates, and safety/toxicity. Patients becoming eligible for SCT could be taken off protocol to undergo the procedure and were censored at the time of SCT. This study was registered on ClinicalTrials.gov (NCT04062266). Results: As of July 14th, 2022, 34 patients have been enrolled (25 in cohort 1, 9 in cohort 2). The median follow-up time is 13.3 months (IQR 8.6-21.6). The baseline patient characteristics are shown in table 1. Nineteen (76%) patients had been previously exposed to VEN as part of their induction regimen. During cycle 1, 21 (62%) patients received 7 days of VEN and 13 (38%) received 14 days of VEN. The median number of cycles given is 9.5 (range 1-24). The median RFS is not reached (NR) in cohort 1 (70% at 12 months) and NR in cohort 2 (58% at 12 months). The median OS is NR in cohort 1 (95% at 12 months) and NR in cohort 2 (63% at 12 months). When stratified by ELN 2017, median RFS is NR (85% at 12 months), NR (70% at 12 months), and 4 months (23% at 12 months) for ELN favorable, intermediate, and adverse, respectively (figure 1). Eight patients have gone off protocol to receive SCT. There was no significant effect of prior venetoclax exposure on RFS or OS. Of the 7 MRD-positive patients at enrollment, 2 (29%) converted to MRD-negative while on maintenance therapy. The MRD-positive patients in our study had a high incidence of adverse prognostic factors (5/7 ELN adverse, 3/7 complex karyotypes). Of these MRD-positive patients, 3 went off study to receive SCT and remain in remission. The 4 remaining MRD-positive patients have relapsed after 1.9, 2.5, 4.0, and 6.0 months. The most common grade 3/4 adverse events were thrombocytopenia (21%), infections (21%), neutropenia (18%), and neutropenic fever (6%). Four patients (12%) required VEN dose reductions at cycle 2 for cytopenias. Seven (21%) patients died, all following relapse of AML or from SCT complications. Conclusions: With over 13 months of follow up, this is the first experience demonstrating the tolerability and feasibility of low-dose AZA plus VEN as maintenance therapy in AML. RFS and OS are encouraging, especially in the non-adverse risk ELN categories (favorable or intermediate). Further studies are needed to improve maintenance strategies in patients with ELN adverse or MRD-positive disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal