Mini-Hyper-CVD Plus Venetoclax Yields Safety and Activity Among Patients With Heavily Pretreated R/R ALL

Findings from a Phase 1/2 Trial

According to a phase 1/2 trial published in Blood Advances, combining mini-hyper-CVD low-intensity chemotherapy, which consisted of dose-attenuated hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate and cytarabine, plus venetoclax yielded safety and activity among patients with heavily pretreated relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). 

Nicholas J. Short, MD, The University of Texas MD Anderson Cancer Center, Houston, Texas, and coauthors explained that “Preclinical studies suggest that [BCL2] inhibition with venetoclax has antileukemic activity in acute lymphoblastic leukemia (ALL) and may synergize with conventional chemotherapy.” Based on this data, the study authors aimed to further evaluate the combination regimen of mini-hyper-CVD and venetoclax among patients with R/R ALL. 

In part 1, primary end points included a definition of the maximum tolerated dose of venetoclax, as well as the dose-limiting toxicities of the combination. The primary end point of part 2 was the combined rate of complete remission (CR) and CR with incomplete hematologic recovery (CRi). Secondary end points consisted of the rate of measurable residual disease (MRD) negativity by multiparameter flow cytometry, duration of response, relapse-free survival, overall survival, and safety. 

This trial included a total of 22 patients with R/R ALL, who were treated with mini-hyper CVD, plus venetoclax at 200 mg or 400 mg daily on days 1 to 4 in cycle 1 and on days 1 to 7 in the consolidation cycle. These patients had received a median of 2 prior therapies, and 59% (n = 13) had undergone prior allogeneic stem cell transplant. Additionally, 39%, or 7 of the 18 patients with B-cell ALL, had previously been treated with both inotuzumab ozogamicin and blinatumomab. 

According to study results, the recommended phase 2 dose of venetoclax in this combination regimen was 400 mg daily. The composite CR/CRi rate was 57%. Among patients who responded to treatment, 45% achieved MRD negativity. A total of 4 patients proceeded to receive allogeneic stem cell transplants. The median duration of response was 6.3 months. The median overall survival was 7.1 months, with a 1-year overall survival rate of 29%. 

In terms of safety, infection, which occurred in 77% (n = 17) of patients, and febrile neutropenia, which occurred in 18% (n = 4) of patients, were the most common grade ≥3 nonhematologic adverse events to occur. 

Short et al concluded, “Overall, the combination of mini-hyper-CVD plus venetoclax was active in heavily pretreated relapsed/refractory ALL.” 

Source: 

Short NJ, Jabbour E, Jain N, et al. A phase 1/2 study of mini-hyper-CVD plus venetoclax in patients with relapsed/refractory acute lymphoblastic leukemia. Blood Adv. Published online: February 15, 2024. doi: 10.1182/bloodadvances.2023012231