Rescuing of the Chemotherapy Sensitivity in Relapsed/Refractory, Pediatric Acute Lymphoblastic Leukemia (r/r ALL) through the Combination of Navitoclax (NAV) and Venetoclax (VEN): Results of Compassionate Use across Four European Countries

Despite improving survival rates of children and young adults with relapsed/refractory ALL, a significant number of patients still dies from relapsed and refractory (R/R) disease. This calls for combinations of new drugs to reinduce complete remissions (CR) and offer the possibility of long-term survival through consolidation with either allogeneic hematopoietic stem cell transplantation (allo-HSCT) or chimeric antigen receptor (CAR)-T cells. Whereas immunotherapies, including CAR-T cells, have increased the proportion of patients with B-ALL who are cured, the results for T-ALL are preliminary and data of long-term outcome in larger patient cohorts are not available yet. In addition, CAR T cells are associated with significantly improved survival if administered with low disease burden, a result that may be difficult to achieve in patients with advanced disease. B-cell lymphoma (BCL) family proteins have a key role in regulating the apoptotic response of blasts to the chemotherapy-induced damage. A Phase I study suggested that the combination of the BCL2 and BCL-X_L/BCL2 inhibitors (VEN and NAV, respectively) with conventional chemotherapy could revert the resistance observed in r/r leukemia patients.

We retrospectively collected safety and efficacy data of VEN/NAV combined with chemotherapy in pediatric patients and young adults with r/r ALL treated under compassionate use in 5 European centers. Between 08/2021 and 04/2024, 30 children/young adults with B-ALL (n=17) or T-ALL (n=13) were treated. Eight B-ALL patients and 12 with T-ALL were male, the median age was 7 (range 3-19) and 10 (3-17), respectively. All patients were heavily pretreated, having received a median of 3 previous lines of therapy in both cohorts (range: 2-7, B-ALL; 1-5, T-ALL); 9 B-ALL patients and 5 T-ALL relapsed after allo-HSCT. Extramedullary sites were involved in 12/17 patients with B-ALL (including 3 CNS) and 4/13 T-ALL (4 CNS). Unfavorable cytogenetics characteristics were present in 6/17 B-ALL patients and 4/13 T-ALL patients.

NAV and VEN were administered continuously over 28 days in combination with different chemotherapy backbones. In B-ALL patients, dexamethasone and vincristine were administered in 15/17 children (alone – 8/15; in combination with PEG-asparaginase – 5/15; or with anthracyclines – 2/15). In patients with T-ALL, the chemotherapy backbones were more heterogeneous including citarabine in 8/13, daratumumab in 5/13, tyrosine kinase inhibitors in 4/13 and decitabine in 3/13 patients. The median number of NAV/VEN cycles administered was 1 (0.3 – 3). The main reasons for treatment discontinuation were: treatment failure (44.4%), consolidation with allo-HSCT/CAR-T cells (48.1%) or prolonged severe hematological toxicity (7.4%).

The most common toxicity was hematologic: overall, 93% of the patients developed grade 3-4 neutropenia, 67% grade 3-4 anemia and 81.5% grade 3-4 thrombocytopenia. Two patients developed bacterial sepsis during treatment-induced aplasia. Other severe toxicities were: paralytic ileus (14.8%), salt wasting tubulopathy (11.1%) and pancreatitis (7.4%). No fatal adverse event was recorded.

The overall response rate was 71% for the B-ALL cohort (12/17 patients) and 50% for the T-ALL cohort. In particular, in the B-ALL patients, 11/16 patients obtained CR in the BM (1 patient had EM isolated disease) and 10/12 in the EM compartment. Amongst T-ALL patients, 12/13 children were evaluable for response and 5/12 (42%) demonstrated CR in the bone marrow. Twelve patients in the B-ALL cohort and 4/12 in the T-ALL cohort received further consolidation with allo-HSCT and/or CAR-T cells. Five B-ALL patients and 2 T-ALL patients are alive and maintain the response, with a median follow-up of 24 months and 25 months, respectively. All patients who did not receive consolidation ultimately relapsed and died of disease.

Our experience underlines the strong potential of the combination of VEN/NAV with conventional chemotherapy to reinduce complete remission in heavily pretreated and refractory pediatric/young adult patients with either B- or T-ALL, offering a bridge to consolidative strategies that induce long term remission of these patients. The approach deserves further investigation of its full potential in a prospective clinical trial and in less advanced disease cohorts of patients, despite the recent announcement of discontinuation of development of NAV by the Company.