Venetoclax Plus Chemotherapy Improves MRD Response, Survival in Ph-Negative ALL

Optimizing First-Line Therapy for Philadelphia Chromosome-Negative ALL

Outcomes for adolescents and adults with acute lymphoblastic leukemia (ALL) have historically lagged behind those seen in pediatric populations, with complete remission rates in the relapsed or refractory setting sometimes as low as 18% in adults [1]. While the adoption of pediatric-inspired chemotherapy regimens has improved survival for younger adults, relapse remains a significant challenge, highlighting an unmet need for more effective frontline strategies [2]. The BCL-2 inhibitor venetoclax has shown potent anti-leukemic activity in various hematologic malignancies by promoting apoptosis in cancer cells [3, 4]. Its use has been explored in combination with other agents for relapsed or refractory ALL and as post-transplant maintenance [5, 6, 7, 8]. However, its specific role and efficacy when integrated into the initial treatment for newly diagnosed Philadelphia chromosome-negative ALL remained undefined, creating a critical knowledge gap for clinicians managing these patients [9].

Study Design and Patient Cohort

To define the role of venetoclax in the upfront setting, investigators designed a prospective phase 2 study for patients with newly diagnosed (ND) Philadelphia chromosome-negative (Ph⁻) ALL. The trial enrolled 167 adolescents and adults, aged 14 to 60 years, who received venetoclax combined with a pediatric-inspired chemotherapy regimen. The study's primary endpoint was the rate of measurable residual disease (MRD) negativity after the induction phase, a highly sensitive measure of treatment response that serves as a key prognostic factor for long-term survival in ALL. Assessment was performed using multiparameter flow cytometry (MFC). The trial was registered with ClinicalTrials.gov under the identifier NCT05660473.

Achieving Deep Remissions: MRD Negativity and Complete Remission Rates

The addition of venetoclax to standard chemotherapy resulted in high rates of both clinical and molecular remission. Overall, the combination regimen produced a complete remission rate of 91.0% among the study participants. Beyond achieving complete remission, the treatment was highly effective at clearing leukemia cells to undetectable levels. The study successfully met its primary endpoint, as 73.0% of responders achieved multiparameter flow cytometry (MFC)-MRD negativity after induction. Achieving MRD negativity is clinically vital, as it is strongly associated with a lower risk of relapse and improved disease-free survival, indicating a deeper and more durable response to therapy.

Survival Outcomes: Two-Year Estimates and Comparative Efficacy

The encouraging remission rates translated into durable survival benefits. After a median follow-up of 19.3 months, both median overall survival and median disease-free survival were not reached, indicating that more than half of the patients remained alive and free of disease at the time of analysis. The estimated survival rates provide a clearer picture of the regimen's impact, with a 2-year overall survival rate of 78.5% and a 2-year disease-free survival rate of 76.7%. To validate these findings against a standard-of-care benchmark, the researchers conducted a propensity score-matched analysis. This statistical method creates a balanced comparison by accounting for differences in baseline characteristics between the study group and a historical cohort. The analysis confirmed superior survival compared with historical chemotherapy-only controls, strengthening the evidence that the addition of venetoclax was the key driver of the improved outcomes.

Safety Profile: Managing Adverse Events

The enhanced efficacy of the venetoclax combination did not introduce an unmanageable toxicity burden. As is common with intensive ALL therapy, the most frequently observed Grade ≥ 3 adverse events were primarily hematologic toxicities and infections. These events require diligent monitoring and supportive care but are familiar to clinicians managing this patient population. Critically, the study found that the incidence of these severe adverse events was comparable to that of the historical cohort that received chemotherapy alone. This finding suggests that incorporating venetoclax intensifies the anti-leukemic effect without a corresponding increase in severe toxicity, resulting in a regimen with a manageable safety profile.

Clinical Implications: Enhancing Outcomes in ND Ph-Negative ALL

This phase 2 study provides compelling evidence for incorporating venetoclax into the first-line treatment of newly diagnosed Philadelphia chromosome-negative ALL in adolescents and adults. The findings demonstrate that this combination therapy significantly improves measurable residual disease (MRD) response, with 73.0% of responders achieving MRD negativity, a key predictor of long-term success. Furthermore, the regimen significantly improves survival outcomes, as evidenced by 2-year overall and disease-free survival rates of 78.5% and 76.7%, respectively, and a confirmed survival advantage over historical chemotherapy-only controls. Because these benefits were achieved with a manageable safety profile comparable to standard chemotherapy, the addition of venetoclax represents a clinically meaningful strategy for improving both the depth of remission and the likelihood of durable survival for these patients.

References

1. Kowalczyk A, Zarychta J, Zawitkowska J, Lejman M. The use of venetoclax in the treatment of acute lymphoblastic leukemia-a systematic review.. Therapeutic advances in medical oncology. 2026. doi:10.1177/17588359251403912

2. Valtis YK, Geyer M, Torres M, et al. Venetoclax in Combination with Pediatric-Inspired Chemotherapy in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia: Results of a Phase I Trial. Blood. 2023. doi:10.1182/blood-2023-181122

3. Li M, Cui Q, Li X, et al. Chemotherapy-Free Induction with Venetoclax and Azacitidine, Followed By Tandem CD19/CD22 CAR-T Cell Therapy As First-Line Treatment in Newly Diagnosed High-Risk Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Prospective, Single-Center, Single-Arm, Phase 2 Trial. Blood. 2024. doi:10.1182/blood-2024-207017

4. Leonard JT, Cook R, Newell LF, et al. A Phase I/II Study to Investigate the Addition of Venetoclax to Dasatinib and Steroids in Patients with Newly Diagnosed or Relapsed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL): The Venda Trial, in Progress. Blood. 2023. doi:10.1182/blood-2023-188313

5. Fransecky L, Fiedler W, Röllig C, et al. Venetoclax and Blinatumomab for adult patients with relapsed/refractory or MRD positive Ph-negative B-cell precursor ALL: phase I part of the GMALL-BLIVEN trial.. Annals of hematology. 2026. doi:10.1007/s00277-026-06883-8

6. Oran B, Thall PF, Ramdial J, et al. Phase II trial of venetoclax in combination with azacitidine as maintenance therapy for acute lymphoblastic leukemia following allogeneic stem cell transplantation. Blood. 2025. doi:10.1182/blood-2025-2515

7. Cao H, Chen L, Wan C, et al. Venetoclax Combined with Azacitidine Was Effective and Safe for Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma: Preliminary Results of a Phase 2, Multicenter Trial. Blood. 2023. doi:10.1182/blood-2023-179733

8. Palmisiano ND, Lee J, Claxton DF, et al. A phase 1 trial of venetoclax in combination with liposomal vincristine in patients with relapsed or refractory B-cell or T-cell acute lymphoblastic leukemia: Results from the ECOG-ACRIN EA9152 protocol.. EJHaem. 2024. doi:10.1002/jha2.991

9. Gong X, Liu Y, Fang Q, et al. Venetoclax Plus Pediatric Regimen in Adolescents and Adults with Ph-Negative Acute Lymphoblastic Leukemia.. Blood. 2026. doi:10.1182/blood.2026033577