Introduction
Therapeutic options for pediatric, adolescent and young adult (AYA) patients with relapsed/refractory acute myeloid leukemia (AML) are limited, and outcomes remain dismal; two-year relapse-free rates for these patients, even with current chemotherapeutic regimens and hematopoietic stem cell transplant (HSCT), are only 25%-30%.1-3 Relapsed/refractory acute lymphoblastic leukemia (ALL) has also remained challenging to treat in children and AYA, with survival rates lagging significantly behind those observed at initial diagnosis. Although there have been improvements in outcomes over the past several decades, only ∼50% of children and AYA with first relapse of ALL experience long term survival, and outcomes are even worse with second or later relapses.4 Novel therapeutic strategies are thus needed to improve outcomes in pediatric/AYA patients with relapsed/refractory (advanced) hematologic malignancies.
Venetoclax, a potent, highly selective, orally available inhibitor of the anti-apoptotic protein B-cell lymphoma-2 (BCL-2), has emerged as one such promising agent. Venetoclax in combination with low-dose cytarabine or hypomethylating agents is Food and Drug Administration-approved for adults with newly diagnosed chronic lymphocytic leukemia and AML, based on results supporting its safety and efficacy in elderly adults deemed unfit for cytotoxic chemotherapy.5-7 Several studies also suggest these combinations may be effective salvage regimens for adults with relapsed or refractory AML, even in heavily pre-treated populations.8-10
Venetoclax is currently the subject of several ongoing phase I/II clinical trials evaluating its safety and efficacy in pediatric/AYA patients with relapsed or refractory AML (NCT03194932) and in other malignancies (NCT03236857). A phase I dose-escalation study of venetoclax in combination with cytarabine with or without idarubicin in pediatric patients with relapsed/ refractory AML or ambiguous lineage leukemia supported the safety and efficacy of venetoclax and conventional chemotherapy in this population.11Another phase I dose escalation study demonstrated venetoclax with chemotherapy and low-dose navitoclax, a BCL-XL/BCL-2 inhibitor, is a safe and promising combination in pediatric and adult patients with advanced ALL and lymphoblastic lymphoma.12
Aside from these early-phase trials, the published literature to date concerning venetoclax in pediatric/AYA patients with hematologic malignancies consists of a few single-institution reports that support the safety and efficacy of venetoclax in combination with cytotoxic chemotherapy in pediatric patients with ALL13 and AML14 and in combination therapy with azacitidine in pediatric patients with MDS or AML unfit for standard chemotherapy.15
While these reports are encouraging, more robust data are needed to guide clinicians in the safe and efficacious use of venetoclax combination therapy across a range of pediatric hematologic malignancies. We therefore retrospectively reviewed our institutional experience of venetoclax use in pediatric/AYA patients at the University of California San Francisco (UCSF) Benioff Children’s Hospitals and report on 13 pediatric and AYA patients with hematologic malignancies who received venetoclax combination therapy outside of a clinical trial between 2016 and 2022. We report on exceptional responders and previously unreported toxicities.