Combinatorial BCL-2 Inhibition for ALL of the Leukemias: The Sum Is More Than the Parts

Clinical care of adult patients with acute myeloid leukemia (AML) or chronic lymphocytic leukemia have been revolutionized by the successful actualization of venetoclax-based therapeutic regimens in the past five years.^1–4  Inspired by this success, investigators have begun to elucidate the potential biologic dependencies of other difficult-to-treat leukemias on apoptosis pathways and the therapeutic possibility of apoptosis regulatory protein inhibition. In recent years, preclinical studies have identified the critical role of apoptosis proteins BCL-2, BCL-xL, and/or MCL-1 in acute lymphoblastic leukemia (ALL) and reported preferential sensitivity of specific high-risk B-cell ALL (B-ALL) and T-cell ALL (T-ALL) subtypes to venetoclax and other inhibitors.^5–9  Recent publications have also reported the ability of BCL-2 inhibition to re-sensitize leukemia cells to chemotherapy that have clear translational implications for patients with relapsed/refractory (R/R) disease.¹⁰  Currently, there are 11 active clinical trials in the United States evaluating single-agent or combination venetoclax therapy, specifically in patients with R/R or de novo ultra–high-risk ALL, including three studies that include pediatric participation (ClinicalTrials.gov search) performed November 1, 2021, confirming the significant interest in BCL-2 inhibition also in these patient populations.

In a recently completed phase I study (NCT03181126), Dr. Vinod Pullarkat and colleagues report impressive and seemingly synergistic success of “next-generation” apoptosis co-targeting via the BCL-2 inhibitor venetoclax and the dual BCL-2/BCL-xL inhibitor navitoclax in combination with conventional chemotherapy in adults and children with R/R ALL or lymphoblastic lymphoma (LL).¹¹  Dose-limiting thrombocytopenia due to BCL-xL inhibition has emerged as a major toxicity of navitoclax therapy in patients.¹²  As an alternative approach, the investigators tested the hypothesis that combining venetoclax with lower-dose navitoclax could mitigate drug-induced thrombocytopenia while facilitating successful antileukemia efficacy in patients. The study team first explored and identified the maximally tolerated dose of navitoclax (50 mg daily for weight ≥ 45 kg, 25 mg daily for weight < 45 kg administered days 3-28) in combination with 400 mg adult-equivalent daily dosing of venetoclax and reinduction chemotherapy composed of peg-asparaginase and/or vincristine and dexamethasone. Additional therapy with tyrosine kinase inhibition was permitted for patients with BCR-ABL1–rearranged or BCR-ABL1–like ALL. Importantly, combination therapy at optimized navitoclax dosing was well-tolerated and induced 75 percent (9 of 12) and 54 percent (19 of 35) complete remission (CR) rates in enrolled children and adults, respectively, with negative measurable residual disease (MRD) in 16 patients. These responses exceed historic remission rates for patients with multiply R/R ALL and LL and provide enthusiasm for future further clinical investigation in phase II and phase III clinical trials.^13–15 

In correlative biology assays, this phase I study also attempted to elucidate potential biomarkers of venetoclax/navitoclax treatment response or failure via BH3 profiling and gene expression analysis. Robust biomarker definition has been an elusive goal to date in AML studies in which higher BCL-2 expression in leukemia cells has not necessarily correlated with greater clinical response to venetoclax and vice-versa.^16–18  Analysis of a subset of primary patient specimens (n=9, B-ALL; n=11, T-ALL) in the present study revealed heterogeneous baseline dependencies upon BCL-2 and BCL-xL proteins and BCL2, BCL2L1, and MCL1 expression levels. While some patients’ ALL cells retained their initial profiles, other specimens were observed to switch from BCL-2 to BCL-xL or BCL-2/BCL-xL dependencies following venetoclax/navitoclax therapy. However, no clear dependency patterns were identified that correlated with treatment response or resistance, furthering the mystery of venetoclax (and navitoclax) biomarkers now also in ALL.

While the advent of U.S. Food and Drug Administration–approved antibody-based and cellular immunotherapies has markedly changed the therapeutic landscape of patients with R/R B-ALL, treatment failures and antigen-loss relapses have emerged as major barriers to long-term cure. Immunotherapeutic options are also presently quite limited for patients with R/R T-ALL, who have very poor rates of second CR and overall survival. Successful actualization of venetoclax/navitoclax–based regimens such as in this phase I trial thus provide tantalizing hope for a tolerable, potentially highly effective “best therapy” that may provide additional options for patients with high-risk leukemias and could eventually be moved forward to frontline regimens.