FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children’s Oncology Group trial AALL0631

Infants with KMT2A ‐rearranged acute lymphoblastic leukemia ( KMT2A -r ALL) have a poor prognosis. KMT2A -r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i) lestaurtinib potentiates chemotherapy‐induced cytotoxicity in preclinical models. Children’s Oncology Group (COG) AALL0631 tested whether...

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Published in:Leukemia Vol. 35; no. 5; pp. 1279 - 1290
Main Authors: Brown, Patrick A., Kairalla, John A., Hilden, Joanne M., Dreyer, ZoAnn E., Carroll, Andrew J., Heerema, Nyla A., Wang, Cindy, Devidas, Meenakshi, Gore, Lia, Salzer, Wanda L., Winick, Naomi J., Carroll, William L., Raetz, Elizabeth A., Borowitz, Michael J., Small, Donald, Loh, Mignon L., Hunger, Stephen P.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.05.2021
Nature Publishing Group
Subjects:
631/67/1059/602
631/67/1990/283/2125
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96/95
Acute lymphoblastic leukemia
Acute lymphocytic leukemia
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Cancer
Cancer in children
Cancer Research
Carbazoles - therapeutic use
Chemotherapy
Children
Critical Care Medicine
Cytotoxicity
Drug therapy
Female
fms-Like Tyrosine Kinase 3 - antagonists & inhibitors
Furans
Genetic aspects
Hematology
Histone-Lysine N-Methyltransferase - metabolism
Humans
Infant
Infants
Inhibitors
Intensive
Internal Medicine
Leukemia
Lymphatic leukemia
Male
Medical prognosis
Medicine
Medicine & Public Health
Methods
Myeloid-Lymphoid Leukemia Protein - metabolism
Oncology
Pediatric research
Pharmacodynamics
Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Protein Kinase Inhibitors - therapeutic use
Toxicity
United States
ISSN:0887-6924, 1476-5551, 1476-5551
Online Access:Get full text
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Summary:Infants with KMT2A ‐rearranged acute lymphoblastic leukemia ( KMT2A -r ALL) have a poor prognosis. KMT2A -r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i) lestaurtinib potentiates chemotherapy‐induced cytotoxicity in preclinical models. Children’s Oncology Group (COG) AALL0631 tested whether adding lestaurtinib to post‐induction chemotherapy improved event-free survival (EFS). After chemotherapy induction, KMT2A -r infants received either chemotherapy only or chemotherapy plus lestaurtinib. Correlative assays included FLT3i plasma pharmacodynamics (PD), which categorized patients as inhibited or uninhibited, and FLT3i ex vivo sensitivity (EVS), which categorized leukemic blasts as sensitive or resistant. There was no difference in 3-year EFS between patients treated with chemotherapy plus lestaurtinib ( n  = 67, 36 ± 6%) vs. chemotherapy only ( n  = 54, 39 ± 7%, p  = 0.67). However, for the lestaurtinib-treated patients, FLT3i PD and FLT3i EVS significantly correlated with EFS. For FLT3i PD, EFS for inhibited/uninhibited was 59 ± 10%/28 ± 7% ( p  = 0.009) and for FLTi EVS, EFS for sensitive/resistant was 52 ± 8%/5 ± 5% ( p  < 0.001). Seventeen patients were both inhibited and sensitive, with an EFS of 88 ± 8%. Adding lestaurtinib did not improve EFS overall, but patients achieving potent FLT3 inhibition and those whose leukemia blasts were sensitive FLT3-inhibition ex vivo did benefit from the addition of lestaurtinib. Patient selection and PD-guided dose escalation may enhance the efficacy of FLT3 inhibition for KMT2A -r infant ALL.
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Author contributions PAB and DS conceived of the clinical trial and correlative laboratory studies; PAB conducted the correlative laboratory studies; PAB, SPH, WLC, MD, JAK, JMH, ZED, LG, WLS, NJW, EAR, and MLL designed and executed the clinical trial; AJC and NAH performed a central review of cytogenetics and FISH data for risk stratification; MJB performed immunophenotyping for eligibility; JAK and CW performed statistical analyses. PAB and JAK wrote the paper. All authors reviewed, edited, and approved the paper.
ISSN:0887-6924
1476-5551
1476-5551
DOI:10.1038/s41375-021-01177-6