Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Abstract

Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-X_L/BCL2 inhibitor, may allow targeting of both BCL2 and BCL-X_L without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population. SIGNIFICANCE: In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histologic and genomic subtypes and in those who failed available therapies including stem cell transplant.See related commentary by Larkin and Byrd, p. 1324.This article is highlighted in the In This Issue feature, p. 1307.

Figure 1.

Kaplan-Meier plot of overall survival. Overall survival was defined as the number of months from the date of first dose to the date of death. Abbreviations: B-ALL, B-cell acute lymphoblastic leukemia; LL, lymphoblastic lymphoma; T-ALL, T-cell acute lymphoblastic leukemia.

Figure 2.

Subtype analysis and response. A, Subtype profiles in patients with B-ALL and T-ALL. B, Subtypes assessed based on response. Abbreviations: B-ALL, B-cell acute lymphoblastic leukemia; BCL-2, B-cell lymphoma 2; BCL2L1, BCL2 like 1; CRi, complete remission with incomplete marrow recovery; CRp, complete remission without platelet recovery; ETP-ALL, early T-cell precursor acute lymphoblastic leukemia; MCL-1, myeloid cell leukemia 1; NR, not reached; Ph, Philadelphia chromosome; T-ALL, T-cell acute lymphoblastic leukemia.