Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study

Outcomes for children with relapsed or refractory acute myeloid leukaemia remain poor. The BCL-2 inhibitor, venetoclax, has shown promising activity in combination with hypomethylating agents and low-dose cytarabine in older adults for whom chemotherapy is not suitable with newly diagnosed acute mye...

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Bibliographic Details
Published in:The lancet oncology Vol. 21; no. 4; pp. 551 - 560
Main Authors: Karol, Seth E, Alexander, Thomas B, Budhraja, Amit, Pounds, Stanley B, Canavera, Kristin, Wang, Lei, Wolf, Joshua, Klco, Jeffery M, Mead, Paul E, Das Gupta, Soumyasri, Kim, Su Y, Salem, Ahmed Hamed, Palenski, Tammy, Lacayo, Norman J, Pui, Ching-Hon, Opferman, Joseph T, Rubnitz, Jeffrey E
Format: Journal Article
Language:English
Published: England Elsevier Ltd 01.04.2020
Elsevier Limited
Subjects:
Acute myeloid leukemia
Adolescent
Antineoplastic Combined Chemotherapy Protocols - administration & dosage
Bcl-2 protein
Bone marrow
Bridged Bicyclo Compounds, Heterocyclic - administration & dosage
Chemotherapy
Child
Child, Preschool
Children
Colitis
Cytarabine
Cytarabine - administration & dosage
Female
Fungal infections
Hematology
Hematology, Oncology, and Palliative Medicine
Humans
Idarubicin - administration & dosage
Intravenous administration
Invasiveness
Leukemia
Leukemia, Myeloid, Acute - drug therapy
Male
Neoplasm Recurrence, Local - drug therapy
Neutropenia
Neutrophils
Patients
Remission
Sepsis
Stem cells
Sulfonamides - administration & dosage
Transplants & implants
Young Adult
United States > US
ISSN:1470-2045, 1474-5488, 1474-5488
Online Access:Get full text
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Summary:Outcomes for children with relapsed or refractory acute myeloid leukaemia remain poor. The BCL-2 inhibitor, venetoclax, has shown promising activity in combination with hypomethylating agents and low-dose cytarabine in older adults for whom chemotherapy is not suitable with newly diagnosed acute myeloid leukaemia. We aimed to determine the safety and explore the activity of venetoclax in combination with standard and high-dose chemotherapy in paediatric patients with relapsed or refractory acute myeloid leukaemia. We did a phase 1, dose-escalation study at three research hospitals in the USA. Eligible patients were aged 2–22 years with relapsed or refractory acute myeloid leukaemia or acute leukaemia of ambiguous lineage with adequate organ function and performance status. During dose escalation, participants received venetoclax orally once per day in continuous 28-day cycles at either 240 mg/m2 or 360 mg/m2, in combination with cytarabine received intravenously every 12 h at either 100 mg/m2 for 20 doses or 1000 mg/m2 for eight doses, with or without intravenous idarubicin (12 mg/m2) as a single dose, using a rolling-6 accrual strategy. The primary endpoint was the recommended phase 2 dose of venetoclax plus chemotherapy and the secondary endpoint was the proportion of patients treated at the recommended phase 2 dose who achieved complete remission or complete remission with incomplete haematological recovery. Analyses were done on patients who received combination therapy. The study is registered with ClinicalTrials.gov (NCT03194932) and is now enrolling to address secondary and exploratory objectives. Between July 1, 2017, and July 2, 2019, 38 patients were enrolled (aged 3–22 years; median 10 [IQR 7–13]), 36 of whom received combination therapy with dose escalation, with a median follow-up of 7·1 months (IQR 5·1–11·2). The recommended phase 2 dose of venetoclax was found to be 360 mg/m2 (maximum 600 mg) combined with cytarabine (1000 mg/m2 per dose for eight doses), with or without idarubicin (12 mg/m2 as a single dose). Overall responses were observed in 24 (69%) of the 35 patients who were evaluable after cycle 1. Among the 20 patients treated at the recommended phase 2 dose, 14 (70%, 95% CI 46–88) showed complete response with or without complete haematological recovery, and two (10%) showed partial response. The most common grade 3–4 adverse events were febrile neutropenia (22 [66%]), bloodstream infections (six [16%]), and invasive fungal infections (six [16%]). Treatment-related death occurred in one patient due to colitis and sepsis. The safety and activity of venetoclax plus chemotherapy in paediatric patients with heavily relapsed and refractory acute myeloid leukaemia suggests that this combination should be tested in newly diagnosed paediatric patients with high-risk acute myeloid leukaemia. US National Institutes of Health, American Lebanese Syrian Associated Charities, AbbVie, and Gateway for Cancer Research.
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SEK participated in the design of the trial, took care of patients on the trial, analyzed data, and wrote the manuscript; JER was the principal investigator of the trial, took care of patients on the trial, analyzed data, and reviewed the manuscript; TBA, JW, NJL, C-HP participated in the design of the trial, took care of patients on the trial, and reviewed the manuscript; SBP and LW performed the statistical design and analysis and reviewed the manuscript; KC participated in the design of the trial, performed quality of life analyses, and reviewed the manuscript; AB, JMK, SDG, PEM, and JTO participated in the design of the trial, performed laboratory studies associated with the trial, and reviewed the manuscript; AHS performed pharmacokinetic analyses and reviewed the manuscript; SYK and TP reviewed the manuscript. SEK, JER, SBP, and LW had access to the complete trial database.
Contributors
ISSN:1470-2045
1474-5488
1474-5488
DOI:10.1016/S1470-2045(20)30060-7