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.