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TOPLINE:

A venetoclax-based pediatric-inspired regimen achieved high rates of postinduction measurable residual disease negativity and was associated with improved survival compared with a propensity score-matched historical chemotherapy cohort among adolescents and adults with newly diagnosed Philadelphia chromosome-negative (Ph^-) acute lymphoblastic leukemia (ALL), according to a phase 2 study. The overall incidence of grade ≥ 3 adverse events was similar to that observed in the historical cohort, but the venetoclax-based regimen was associated with a markedly higher rate of grade ≥ 3 intestinal obstruction (18.1% vs 5.6%) as well as treatment-related deaths during induction.

METHODOLOGY:

• Adolescents and adults with Ph^- ALL generally have worse survival outcomes than children. Venetoclax, a B-cell lymphoma 2 inhibitor, has shown promising preclinical and early clinical activity in patients with ALL, but its safety and efficacy in the first-line setting for newly diagnosed Ph^- ALL cases remain unclear.
• To evaluate venetoclax in combination with a pediatric-inspired chemotherapy regimen, researchers conducted a single-center, single-arm phase 2 trial involving 167 adolescents and adults aged 14-60 years (median age, 31 years) with newly diagnosed Ph^- ALL.
• The induction regimen combined venetoclax with a pediatric-inspired chemotherapy backbone that included vincristine, daunorubicin, cyclophosphamide, pegylated asparaginase, and prednisone. On day 14 of the induction phase, all patients underwent bone marrow aspiration. Patients exhibiting ≥ 10% residual leukemic blasts in bone marrow on day 14 of induction therapy received an additional 7-day course of venetoclax.
• The primary endpoint was the rate of measurable residual disease negativity after induction chemotherapy, and secondary endpoints included overall survival, disease-free survival, cumulative incidence of relapse, and safety. The median follow-up duration was 19.3 months. Outcomes were compared with a propensity score-matched historical cohort treated using chemotherapy only.

TAKEAWAY:

• Among 160 patients assessed for efficacy, 152 (91%) achieved complete remission following induction chemotherapy, and 73% of responders (111 of 152) achieved measurable residual disease negativity, meeting the primary endpoint.
• The median overall survival and disease-free survival were not reached at a median follow-up of 19.3 months; the estimated 2-year overall survival was 78.5%, and disease-free survival was 76.7%. However, in the propensity score-matched analysis, the venetoclax combination cohort was associated with higher 2-year overall survival (78.2% vs 58.1%; P = .001) and 2-year disease-free survival (76.4% vs 58.2%; P = .002) than the historical chemotherapy-only control cohort.
• The measurable residual disease status assessed after the first consolidation cycle demonstrated significant prognostic value for the risk for relapse, with measurable residual disease-positive patients exhibiting inferior disease-free survival (59.8% vs 80.8%; P = .029) and elevated cumulative incidence of relapse (34.6% vs 11.8%; P = .007) compared with measurable residual disease-negative patients.
• Regarding adverse events, 4.2% of patients died early during the induction period, primarily from pulmonary infection. Adverse events of grade ≥ 3 were primarily hematologic toxicities and pneumonia, with the overall incidence similar to that in the historical cohort. However, the incidence of grade ≥ 3 intestinal obstruction was markedly higher with the venetoclax regimen (18.1% vs 5.6%; P < .001).

IN PRACTICE:

The study demonstrated that the “incorporation of venetoclax into a pediatric-inspired chemotherapy framework significantly enhances the frontline treatment of Ph^- ALL, as evidenced by improved [measurable residual disease] negativity rates and survival outcomes,” the authors of the study wrote. However, they added that the regimen “remains an intensive chemotherapy strategy, characterized by notable treatment-related toxicity and the potential for fatal complications.”

SOURCE:

The study, led by Xiaoyuan Gong, National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China, was published online in Blood.

LIMITATIONS:

The single-arm, nonrandomized design may have introduced potential biases despite the use of propensity score matching with a historical control cohort. A short follow-up period and a small number of events may have limited the ability to assess long-term survival and late toxicity. Comparisons of survival outcomes relied on a historical control cohort rather than randomized contemporaneous control cohort.

DISCLOSURES:

The study was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the CAMS Innovation Fund for Medical Sciences, the Tianjin Natural Science Foundation project, and the Tianjin Municipal Science and Technology Commission Grant. The authors reported having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.