In acute lymphoblastic leukemia (ALL), the B-cell lymphoma 2 inhibitor venetoclax may enhance the efficacy of chemotherapy, allowing dose reductions. This phase 1b study of venetoclax plus attenuated chemotherapy enrolled 19 patients with ALL either newly diagnosed (aged ≥60 years, n=11 [B-cell, n=8; T-cell, n=3]) or relapsed/refractory (R/R; aged ≥18 years, n=8 [B-cell, n=3; T-cell, n=5]). Venetoclax was given for 21days with each cycle of mini-hyper-CVD (mini-HCVD; cyclophosphamide, vincristine, dexamethasone alternating with methotrexate and cytarabine). There were no dose-limiting toxicities at dose level 1 (DL1; n=3, 400mg/d) or DL2 (n=6, 600mg/d); DL2 was the recommended phase 2 dose and explored further (n=10). The most common nonhematologic adverse events were grade ≥3 infections. There were no deaths within 60days. There was no tumor lysis syndrome, hepatotoxicity, prolonged cytopenias, or early discontinuation for toxicity. Among patients with newly diagnosed ALL, 10 of 11 (90.9%) achieved a measurable residual disease-negative (<0.01% sensitivity) complete remission (CR) including 6 patients with hypodiploid TP53-mutated ALL. All patients in CR bridged to hematopoietic stem cell transplant (n=9) or completed protocol (n=1). With a median follow-up of 60months, median disease-free survival (DFS) for patients with newly diagnosed ALL was 54.6months (95% confidence interval [CI], 35.5 to not available), with a 2-year DFS rate of 90% (95%CI, 71-100). Among patients with R/R ALL, 3 of 8 (37.5%) achieved CR. In summary, for patients with newly diagnosed ALL, venetoclax plus mini-HCVD is well tolerated with promising efficacy. This trial was registered at www.clinicaltrials.gov as #NCT03319901.
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