This phase 2 study evaluated the safety and efficacy of venetoclax added to cladribine (CLAD)/low-dose AraC (LDAC) alternating with 5-azacitidine (AZA) in older patients with newly diagnosed acute myeloid leukemia (AML).
The study enrolled older (age ≥60 years) or unfit patients with newly diagnosed AML (excluding acute promyelocytic leukemia and core-binding factor disease). Induction therapy consisted of CLAD (5 mg/m2 IV [intravenously] over 30 minutes, days 1-5) and AraC (20 mg SQ BID [subcutaneously twice daily], days 1-10). Consolidation/maintenance therapy consisted of 2 cycles of CLAD (5 mg/m2 IV, days 1-3) and AraC (20 mg SQ BID, days 1-10) alternating with 2 cycles of AZA (75 mg/m2, days 1-7) for up to 18 cycles, plus venetoclax (400 mg, days 1-21 of each cycle); 1 cycle was 4 weeks. The primary end point was composite complete response rate (CRc; complete response [CR]/CR with incomplete hematologic recovery [CRi]); secondary end points were overall survival (OS), disease-free survival (DFS), overall response rate, and toxicity.
The study enrolled 60 patients. The median age of the patient cohort was 68 years; 37% of patients were aged ≥70 years, 23% of patients had secondary AML, 60% had diploid cytogenetics, and 20% had adverse cytogenetics. By European LeukemiaNet (ELN) risk, 23% of patients had favorable risk, 33% had intermediate risk, and 43% had adverse risk. The most commonly mutated genes were NPM1 (33%), DNMT3A (32%), TET2 (30%), SRSF2 (25%), NRAS (20%), IDH2 (18%), RUNX1 (18%), ASXL1 (15%), and TP53 (7%).
In the intent-to-treat population (n = 60), a CRc rate of 93% was achieved, with CRs achieved in 48 (80%) patients and CRis achieved in 8 (13%) patients. In responding patients evaluable for measurable residual disease (MRD) assessment (n = 51), 84% achieved MRD negativity. A CR/CRi rate of 93% was achieved in patients with secondary AML, 89% in patients with adverse/complex cytogenetics, 96% in patients with ELN adverse risk, and 100% of patients harboring disease with TP53 mutations. Overall, 19 (34%) responders underwent allogeneic stem-cell transplantation. Early mortality was low; 1 patient died within 4 weeks and 3 patients died within 8 weeks.
The regimen was associated with low rates of grade 3/4 adverse events. The most common grade 3/4 nonhematologic adverse events were febrile neutropenia (n = 33), pneumonia (n = 14), atrial fibrillation (n = 2), and allergic reaction (n = 2); 1 event each of grade 4 tumor lysis syndrome and grade 4 hypophosphatemia were reported.
At a median follow-up of 22.1 months, median DFS was not yet reached; estimated 12- and 24-month DFS rates were 71% and 60%, respectively. Median OS was not yet reached; estimated 12- and 24-month OS were 73% and 64%, respectively. The DFS and OS benefit was preserved across all ELN risk subgroups.
These findings indicate that the addition of venetoclax to CLAD/LDAC alternating with AZA in a phase 2 setting was an effective, lower-intensity regimen that was well-tolerated and produced high response rates with durable MRD-negative remissions among older and unfit patients with newly diagnosed AML.
Source: Daver N, et al. ASH 2021; abstr 367.