Venetoclax in combination with cytarabine with or without idarubicin or azacitidine in children, adolescents, and young adults with relapsed or refractory acute myeloid leukaemia (VENAML): a multicentre, phase 1 expansion study.
In this multicentre phase 1 expansion study, 25 of 44 children, adolescents, and young adults with relapsed or refractory AML treated at the recommended phase 2 dose of venetoclax plus cytarabine-based therapy achieved complete response with or without haematological recovery after one cycle, with frequent severe toxicities and two grade 5 events.
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In this multicentre phase 1 expansion study, 25 of 44 children, adolescents, and young adults with relapsed or refractory AML treated at the recommended phase 2 dose of venetoclax plus cytarabine-based therapy achieved complete response with or without haematological recovery after one cycle, with frequent severe toxicities and two grade 5 events.
Research significance
The clinical results support the hypothesis that adding venetoclax to high-dose cytarabine-based regimens can induce remissions, including measurable-residual-disease-negative responses, in some young patients with relapsed or refractory AML; whether venetoclax improves survival or outcomes over chemotherapy alone remains an inference requiring randomized testing.
Source abstract
BACKGROUND: The prognosis for paediatric patients with relapsed or refractory acute myeloid leukaemia remains poor. Although encouraging, published paediatric data on venetoclax combined with intensive chemotherapy are scarce. We aimed to refine efficacy and toxicity estimates from the previously published dose-escalation phase of this study. METHODS: This multicentre, phase 1 study included two phases, an initial dose-escalation phase to identify the primary endpoint of recommended phase 2 dose (RP2D; previously reported), followed by an expansion cohort phase, the results of which are reported here. Paediatric patients (aged 2-24 years) with relapsed or refractory acute myeloid leukaemia from three US research hospitals were included. Patients had at least 5% blasts in the bone marrow by morphology or at least 1% blasts by flow cytometry. Treatment varied across cohorts. Patients received oral venetoclax 360 mg/m2 (maximum 600 mg) daily for 27 days after a 50% dose reduction on day 1 and intravenous cytarabine 1000 mg/m2 per dose every 12 h for eight doses on days 8-11 (cohort A), with intravenous idarubicin (12 mg/m2 on day 8; cohort B) and dexrazoxane or intravenous azacitidine (75 mg/m2 on days 1-7; cohort C). Here, we report results for all patients treated at the RP2D, including patients treated in the expansion cohort phase (cohort A and B) and patients in cohort C added by protocol amendment (Oct 13, 2020). This final report describes the key secondary endpoint of the rates of complete response with or without haematological recovery at the RP2D. Analyses were on the intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT03194932) and is completed. FINDINGS: From July 1, 2017, to July 22, 2022, 61 patients were enrolled and 44 patients were subsequently included and treated at the RP2D (21 [48%] female, 23 [52%] male; 22 [50%] in cohort A, 15 [34%] in cohort B, and seven [16%] in cohort C). The median follow-up was 5·3 years (IQR 4·2-6·3). After 1 cycle, 25 (57% [95% CI 41-72]) patients had a complete response with or without haematological recovery; 19 were negative for measurable residual disease. Common grade 3 or 4 adverse events included febrile neutropenia (23 [52%]), gastrointestinal disorders (14[32%]]) including colitis (four [9%]), and infections (11 [25%]). There were two grade 5 adverse events due to sepsis and multiorgan failure. INTERPRETATION: Venetoclax with high-dose cytarabine is active with acceptable safety in paediatric patients with relapsed or refractory AML. These findings support ongoing research of venetoclax with high-dose cytarabine in this population, including the randomised paediatric phase 3 trial (NCT05183035). FUNDING: US National Institutes of Health (NIH), American Lebanese Syrian Associated Charities (ALSAC), AbbVie, Gateway for Cancer Research.