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Acute lymphoblastic leukemia

Randomized assessment of delayed intensification and two methods for parenteral methotrexate delivery in childhood B-ALL: Children’s Oncology Group Studies P9904 and P9905

Leukemia volume 34, pages 1006–1016 (2020)Cite this article

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Abstract

The delayed intensification (DI) enhanced outcome for patients with acute lymphoblastic leukemia (ALL) treated on BFM 76/79 and CCG 105 after a prednisone-based induction. Childrens Oncology Group protocols P9904/9905 evaluated DI via a post-induction randomization for eligible National Cancer Institute (NCI) standard (SR) and high-risk (HR) patients. A second randomization compared intravenous methotrexate (IV MTX) as a 24- (1 g/m2) vs. 4-h (2 g/m2) infusion. NCI SR patients received a dexamethasone-based three-drug and NCI HR/CNS 3 SR patients a prednisone-based four-drug induction. End induction MRD (minimal residual disease) was obtained but did not impact treatment. DI improved the 10-year continuous complete remission (CCR) rate; 75.5 ± 2.5% vs. 81.8 ± 2.2% p = 0.002, whereas MTX administration did not; 4-h 80.8 ± 1.9%; 24-h 81.4 ± 1.9% (p = 0.7780). Overall survival (OS) at 10 years did not differ with DI: 91.4 ± 1.6% vs. 90.9 ± 1.7% (p = 0.25) without but was higher with the 24-h MTX infusion; 4-h 91.1 ± 1.4%; 24-h 93.9 ± 1.2% (p = 0.0209). MRD predicted outcome; 10-year CCR 87.7 ± 2.2 and 82.1 ± 2.5% when MRD was <0.01% with/without DI (p = 0.007) and 54.3 ± 8% and 44 ± 8% for patients with MRD ≥ 0.01% with/without DI (p = 0.11). DI improved CCR for patients with B-ALL with and without end induction MRD.

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Funding

U10 CA98543, U10 CA98413, U10 CA180886, and U10 CA180899 from the National Institutes of Health, and by St. Baldrick’s Foundation.

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Authors and Affiliations

  1. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Naomi Winick

  2. Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA

    Paul L. Martin

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

    Meenakshi Devidas

  4. Department of Health Outcomes and Policy, College of Medicine, University of Florida, Gainesville, FL, USA

    Jonathan Shuster

  5. Department of Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Michael J. Borowitz

  6. Department of Pediatrics, University of North Texas Health Science Center, Fort Worth, TX, USA

    W. Paul Bowman

  7. Maine Children’s Cancer Program, Scarborough, ME, USA

    Eric Larsen

  8. Department of Pediatrics, University of Mississippi, Jackson, MS, USA

    Jeanette Pullen

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

    Andrew Carroll

  10. Cancer Center and Departments of Internal Medicine and Pathology, University of New Mexico, Albuquerque, NM, USA

    Cheryl Willman

  11. 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

  12. Department of Pediatrics and The Perlmutter Cancer Center, New York University Medical Center, New York, NY, USA

    William L. Carroll

  13. Department of Pediatrics, Midwest Center for Cancer and Blood Disorders, Medical College of Wisconsin, Milwaukee, WI, USA

    Bruce M. Camitta

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Correspondence to Naomi Winick.

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Conflict of interest

Dr. Hunger received consulting fees from Novartis and honoraria from Jazz Pharmaceuticals. He owns common stock in Amgen and Merck; Dr. Borowitz received honoraria from Shire Pharmaceuticals, Jazz Pharmaceuticals, and Amgen. Drs. Winick, Martin, Devidas, Shuster, Bowman, Larsen, Pullen, Carroll, Willman, Carroll, and Camitta declare no competing financial interests.

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Winick, N., Martin, P.L., Devidas, M. et al. Randomized assessment of delayed intensification and two methods for parenteral methotrexate delivery in childhood B-ALL: Children’s Oncology Group Studies P9904 and P9905. Leukemia 34, 1006–1016 (2020). https://doi.org/10.1038/s41375-019-0642-2

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