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 82 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
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Abstract	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.
AbstractList	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 [plus or minus] 6%) vs. chemotherapy only (n = 54, 39 [plus or minus] 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 [plus or minus] 10%/28 [plus or minus] 7% (p = 0.009) and for FLTi EVS, EFS for sensitive/resistant was 52 [plus or minus] 8%/5 [plus or minus] 5% (p < 0.001). Seventeen patients were both inhibited and sensitive, with an EFS of 88 [plus or minus] 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. 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. 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.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. 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.
Audience	Academic
Author	Loh, Mignon L. Devidas, Meenakshi Small, Donald Carroll, Andrew J. Dreyer, ZoAnn E. Hilden, Joanne M. Heerema, Nyla A. Carroll, William L. Borowitz, Michael J. Gore, Lia Salzer, Wanda L. Winick, Naomi J. Kairalla, John A. Hunger, Stephen P. Wang, Cindy Raetz, Elizabeth A. Brown, Patrick A.
AuthorAffiliation	10 Department of Pediatrics and Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA 2 Department of Biostatistics, Colleges of Medicine, Public Health & Health Professions, University of Florida, Gainesville, FL, USA 9 Division of Pediatric Hematology/Oncology, University of Texas Southwestern School of Medicine, Dallas, TX, USA 6 The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 5 Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA 11 Departments of Pathology and Oncology, Johns Hopkins University, Baltimore, MD, USA 13 Department of Pediatrics and the Center for Childhood Cancer Research, Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA 3 Center for Cancer and Blood Disorders, Children’s Hospital Colorado, Aurora, CO, USA 4 Texas Children’s Hospital, Houston, TX, USA 1 Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Ho
AuthorAffiliation_xml	– name: 8 U.S. Army Medical Research and Materiel Command, Fort Detrick, MD, USA – name: 5 Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA – name: 2 Department of Biostatistics, Colleges of Medicine, Public Health & Health Professions, University of Florida, Gainesville, FL, USA – name: 6 The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA – name: 11 Departments of Pathology and Oncology, Johns Hopkins University, Baltimore, MD, USA – name: 13 Department of Pediatrics and the Center for Childhood Cancer Research, Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA – name: 10 Department of Pediatrics and Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA – name: 9 Division of Pediatric Hematology/Oncology, University of Texas Southwestern School of Medicine, Dallas, TX, USA – name: 7 Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN, USA – name: 1 Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA – name: 4 Texas Children’s Hospital, Houston, TX, USA – name: 3 Center for Cancer and Blood Disorders, Children’s Hospital Colorado, Aurora, CO, USA – name: 12 Department of Pediatrics, Benioff Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/33623141$$D View this record in MEDLINE/PubMed
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 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.
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PublicationTitle	Leukemia
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Snippet	Infants with KMT2A ‐rearranged acute lymphoblastic leukemia ( KMT2A -r ALL) have a poor prognosis. KMT2A -r ALL overexpresses FLT3, and the FLT3 inhibitor... Infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) have a poor prognosis. KMT2A-r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i)... Infants with KMT2A‐rearranged acute lymphoblastic leukemia (KMT2A-r ALL) have a poor prognosis. KMT2A-r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i)...
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StartPage	1279
SubjectTerms	631/67/1059/602 631/67/1990/283/2125 82 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
Title	FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children’s Oncology Group trial AALL0631
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Volume	35
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