A phase 1/2 study of mini-hyper-CVD plus venetoclax in patients with relapsed/refractory acute lymphoblastic leukemia.

"Conflict-of-interest disclosure: E.J. has received research funding and honoraria from 10.13039/100006483AbbVie. M.K. has received research funding from 10.13039/100006483AbbVie. The remaining authors declare no competing financial interests."

"This research is supported in part by The University of Texas MD Anderson Cancer Center Leukemia SPORE CA100632 and the 10.13039/100000002National Institutes of Health/National Cancer Institute Cancer Center support grant P30 CA016672."

"Patient characteristics were summarized using the median (range) for continuous variables and frequencies (percentages) for categorical variables. Remission duration, RFS, and OS were calculated with Kaplan-Meier estimates, and survival estimates were compared with the log-rank test. The data cutoff for this analysis was 1 March 2023. The data analyses were done using GraphPad Prism 9. This study was registered at www.clinicaltrials.gov as #NCT03808610. Preclinical studies suggest that Bcl-2 inhibition with venetoclax has antileukemic activity in acute lymphoblastic leukemia (ALL) and may synergize with conventional chemotherapy. We designed a phase 1/2 clinical trial to evaluate the safety and efficacy of low-intensity chemotherapy in combination with venetoclax in adults with relapsed or refractory ALL. Patients received the mini-hyper-CVD regimen (dose-attenuated hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate and cytarabine) in combination with venetoclax (200 mg or 400 mg daily) on days 1 to 14 in cycle 1 and on days 1 to 7 in consolidation cycles. Twenty-two patients were treated. The median number of prior therapies was 2 (range, 1-6). Thirteen patients (59%) had undergone prior allogeneic stem cell transplant (allo-SCT), and 7 of 18 patients (39%) with B-cell ALL had previously received both inotuzumab ozogamicin and blinatumomab. The recommended phase 2 dose of venetoclax in the combination regimen was 400 mg daily. The composite complete remission (CR) and CR with incomplete hematologic recovery (CRi) rate was 57% (CR, 43%; CRi, 14%), and 45% of responders achieved measurable residual disease negativity by multiparameter flow cytometry. Four patients proceeded to allo-SCT. The median duration of response was 6.3 months. The median overall survival was 7.1 months, and the 1-year overall survival rate was 29%. The most common grade ≥3 nonhematologic adverse events were infection in 17 patients (77%) and febrile neutropenia in 4 patients (18%). Overall, the combination of mini-hyper-CVD plus venetoclax was active in heavily pretreated relapsed/refractory ALL. Further development of venetoclax-based combinations in ALL is warranted. This trial is registered at www.clinicaltrials.gov as #NCT03808610."