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Acute lymphoblastic leukemia

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

Leukemia volume 35, pages 1279–1290 (2021)Cite this article

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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.

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Fig. 1: CONSORT diagram: the flow of patients from enrollment to treatment assignment.
Fig. 2: Survival and cumulative incidence of events from study entry by risk group.
Fig. 3: Survival and cumulative incidence of events from post-induction treatment assignment by treatment arm.
Fig. 4: Survival according to results of FLT3 inhibitor laboratory correlative assays for patients treated with lestaurtinib (Arm C).

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Acknowledgements

The correlative laboratory studies were funded by grants NIH/NCI (K23 CA111728; PAB), Damon Runyon Cancer Research Foundation (CIA 30-06; PAB), Leukemia and Lymphoma Society (SCOR 7327–07 to DS and PAB, and LLS Scholar 2365–12 to PAB), and Children’s Cancer Foundation (PAB). The clinical trial was funded by grants to the children’s oncology group from the National Institutes of Health/National Cancer Institute (U10CA098543, U10CA098413, U10CA180886, and U10CA180899) and the St. Baldrick’s Foundation. Lestaurtinib was provided to study participants by Teva via a Collaborative Research and Development Agreement with the National Institutes of Health/National Cancer Institute/Cancer Therapy and Evaluation Program.

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Authors and Affiliations

  1. Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    Patrick A. Brown & Donald Small

  2. Department of Biostatistics, Colleges of Medicine, Public Health & Health Professions, University of Florida, Gainesville, FL, USA

    John A. Kairalla & Cindy Wang

  3. Center for Cancer and Blood Disorders, Children’s Hospital Colorado, Aurora, CO, USA

    Joanne M. Hilden & Lia Gore

  4. Texas Children’s Hospital, Houston, TX, USA

    ZoAnn E. Dreyer

  5. Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA

    Andrew J. Carroll

  6. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    Nyla A. Heerema

  7. Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Meenakshi Devidas

  8. U.S. Army Medical Research and Materiel Command, Fort Detrick, MD, USA

    Wanda L. Salzer

  9. Division of Pediatric Hematology/Oncology, University of Texas Southwestern School of Medicine, Dallas, TX, USA

    Naomi J. Winick

  10. Department of Pediatrics and Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA

    William L. Carroll & Elizabeth A. Raetz

  11. Departments of Pathology and Oncology, Johns Hopkins University, Baltimore, MD, USA

    Michael J. Borowitz

  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

    Mignon L. Loh

  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

    Stephen P. Hunger

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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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Correspondence to Patrick A. Brown.

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Conflict of interest

The authors report the following potential conflicts of interest: PAB: Scientific Advisory Committees for Novartis, Servier, Jazz, and Janssen. LG: Consultancy for Amgen, Novartis, Roche/Genentech; Equity Ownership for Amgen, Anchiano, Blueprint Medicines, Celgene, Clovis, Mirati, Sanofi Paris; Honoraria for Amgen, Roche/Genentech; Scientific Advisory Committee for Amgen; Data Safety and Monitoring Committee member for Novartis and Celgene. EAR: Research Funding from Pfizer; Data Safety and Monitoring Committee member for Celgene. MJB: Honoraria from Beckman Coulter. MLL: Scientific Advisory Committee for Medisix Therapeutics. SPH: Consultancy for Amgen, Bristol Myers Squibb,, and Novartis; Equity Ownership for Amgen; Honoraria for Jazz.

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Brown, P.A., Kairalla, J.A., Hilden, J.M. et al. FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children’s Oncology Group trial AALL0631. Leukemia 35, 1279–1290 (2021). https://doi.org/10.1038/s41375-021-01177-6

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