A Phase 1/2 Study of Mini-Hyper-Cvd Plus Venetoclax in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

Authors

Nicholas J Short
Elias Jabbour
Nitin Jain
Jayastu Senapati
Lewis Nasr
Fadi G Haddad
Zhenhua Li
Yu-Chih Hsiao
Jun J Yang
Naveen Pemmaraju
Maro Ohanian
William G Wierda
Guillermo Montalban-Bravo
Gautam Borthakur
Lina Han
Lianchun Xiao
Xuelin Huang
Regina Abramova
Min Zhao
Rebecca Garris
Marina Konopleva
Farhad Ravandi
Hagop Kantarjian

Publication Date

2-27-2024

Journal

Blood Advances

Abstract

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.

Keywords

Adult, Humans, Inotuzumab Ozogamicin, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Bridged Bicyclo Compounds, Heterocyclic, Cardiovascular Diseases, Sulfonamides

Comments

Supplementary Materials

PMID: 38207208