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Clinical Trial
. 2024 Feb 27;8(4):909-915.
doi: 10.1182/bloodadvances.2023012231.

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

Nicholas J Short  1 , Elias Jabbour  1 , Nitin Jain  1 , Jayastu Senapati  1 , Lewis Nasr  1 , Fadi G Haddad  1 , Zhenhua Li  2 , Yu-Chih Hsiao  2 , Jun J Yang  2 , Naveen Pemmaraju  1 , Maro Ohanian  1 , William G Wierda  1 , Guillermo Montalban-Bravo  1 , Gautam Borthakur  1 , Lina Han  1 , Lianchun Xiao  3 , Xuelin Huang  3 , Regina Abramova  1 , Min Zhao  1 , Rebecca Garris  1 , Marina Konopleva  1   4 , Farhad Ravandi  1 , Hagop Kantarjian  1
Affiliations
Clinical Trial

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

Nicholas J Short et al. Blood Adv. .

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.

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Conflict of interest statement

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

Figures

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Graphical abstract
Figure 1.
Figure 1.
Responses and disposition of study patients.
Figure 2.
Figure 2.
Outcomes of the study cohort. (A) RFS, (B) OS.
See this image and copyright information in PMC

References

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