A Phase 1/2 Study of Mini-Hyper-CVD plus Venetoclax in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.

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 in combination with venetoclax (200 mg or 400mg daily) on days 1-14 in cycle 1 and on days 1-7 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 (alloSCT), 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 400mg 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 alloSCT. The median duration of response was 6.3 months. The median OS was 7.1 months, and the 1-year OS rate was 29%. The most common grade 3 or higher non-hematologic 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.