Clinical responses in pediatric patients with relapsed/refractory leukemia treated with azacitidine and venetoclax

Abstract

Clinical responses in pediatric patients with relapsed/refractory leukemia treated with azacitidine and venetoclaxDespite optimization and escalation of risk-based chemotherapy regimens, children with relapsed or chemotherapyrefractory acute leukemias, particularly acute myeloid leukemia (AML), remain difficult to cure. 1,2Traditional intensive cytotoxic chemotherapy salvage regimens require extended inpatient hospitalization due to infectious risk during severe myelosuppression and are accompanied by therapy-related morbidity and deleterious impact upon quality-of-life. 3,4The combination of the hypomethylating agent azacitidine with venetoclax, an oral selective BH3mimetic inhibitor of the anti-apoptotic protein B-cell lymphoma 2 (BCL-2), is effective at remission induction in elderly or intensive induction chemotherapy-ineligible adults with previously-untreated AML and is Food and Drug Administration-approved for this indication. 5,6The recent VENAML phase I clinical trial demonstrated safety and activity of venetoclax combined with idarubicin and/or highdose cytarabine in children and adolescents/young adults (AYAs) with relapsed refractory AML (clinicaltrials gov.Identifier: NCT03194932). 7However, clinical experience with the azacitidine/venetoclax regimen in children has been limited to small case series. 8,9Herein, we report clinical characteristics and outcomes of 37 pediatric patients with relapsed/refractory acute leukemias treated at our institution with commercially-available azacitidine/venetoclax therapy.We analyzed data from patients aged 0-21 years with multiply-relapsed/refractory acute lymphoblastic leukemia (ALL), AML, or mixed-phenotype acute leukemia (MPAL) treated with azacitidine/venetoclax without or with the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) at the Children's Hospital of Philadelphia from January 1 st , 2018 to March 31 st , 2022.Institutional Review Board exemption was obtained for retrospective chart review.Clinical data were abstracted from electronic medical records on baseline patient demographics, leukemia-associated immunophenotyping and genetic characteristics, therapy administration, clinical response, and post-azacitidine/venetoclax outcomes with clinical follow-up through June 30, 2022.Azacitidine 100 mg/m 2 daily was given intravenously on days 1-5 of each 28-day cycle.Venetoclax was given once daily as oral tablets (swallowed intact or crushed) with 3day 'ramp-up' dosing during cycle 1 to minimize tumor lysis syndrome (TLS) risk with body surface area-adjusted adult exposure-equivalent dosing (AED) of 200 mg (day 1),

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