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LYMPHOMA

A dose substitution of anthracycline intensity with dose-dense rituximab in children and adolescents with good-risk mature B-cell lymphoma

Leukemia volume 35, pages 2994–2997 (2021)Cite this article

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The most common chemotherapy backbone for children with mature B-non Hodgkin lymphoma (B-NHL), Burkitt’s lymphoma (BL), and diffuse large B-cell lymphoma includes short intensive therapy including steroids, high dose methotrexate, fractionated cyclophosphamide, anthracycline, and intrathecal prophylaxis/treatment, which we established based on the French-American-British (FAB) (FAB LMB 96) studies in the mid-1990s [1,2,3]. While the cure rate with this approach in good risks patients is high (≥95% 5 year event free survival [EFS]), there is a substantial burden of short-term toxicity (i.e., hospitalization for febrile neutropenia and grade III/IV mucositis) and long-term toxicity including rates of second malignancies [1,2,3,4,5]. Anthracycline cumulative exposure (dose intensity) is a major risk factor for cardiovascular long-term morbidity [6]. The FAB intermediate risk treatment schema requires 9 intrathecal injections, procedural conscious sedations and diagnostic lumbar punctures, which are a risk factor for late neurocognitive deficits [3, 7].

We demonstrated the feasibility of adding dose-dense rituximab (two doses per induction cycles 48 h apart) to advanced stage III/IV, FAB group B and all group C mature B-NHL patients without modification of the chemotherapy backbones [8, 9]. We demonstrated rituximab to be safe and associated with an increased EFS in both advanced mature B-NHL cohorts over historical controls [8, 9]. In this study we determined whether an anthracycline dose intensity reduction of ~60% (50 mg/m2/total dose) with the addition of six doses of dose-dense rituximab would yield similar EFS to patients treated historically with FAB Group B therapy (120–180 mg/m2/anthracycline) in good-risk patients (stage II and stage III with levels of lactic acid dehydrogenase below 2 times upper normal limits [<2 ULN]) who were recently diagnosed with mature B-NHL [3, 8]. Secondarily, we investigated the use of a long-acting liposomal cytarabine for intrathecal prophylaxis to determine the safety of reducing the number of intrathecal prophylactic treatments in this childhood good-risk mature B-NHL population [10].

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Fig. 1: Consort diagram and EFS/OS.

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Acknowledgements

This manuscript is supported by a grant from Pediatric Cancer Research Foundation (PCRF), Pediatric Cancer Foundation (PCF), and Leadiant Biosciences, Inc. (MC). The authors would like to thank the patients and their families who participated in the trial. We would also like to thank Virginia Davenport, RN, and Erin Morris, RN for their editorial assistance and the Data Safety Monitoring Committee: Oussama Abla, MD, Michelle Hermiston, MD, Sharon Bergeron, RN, and Joseph Laver, MD.

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Authors and Affiliations

  1. Department of Pediatric Hematology/Oncology, Medical City Children’s Hospital, Dallas, TX, USA

    Stan Goldman

  2. Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, NY, USA

    Matthew Barth

  3. Department of Tropical Medicine, Medical Microbiology & Pharmacology, University of Hawaii, Honolulu, HI, USA

    Bruce Shiramizu, Melissa Agsalda-Garcia & Tiffany Shieh

  4. Department of Biostatistics, New York Medical College, Valhalla, NY, USA

    Qiuhu Shi

  5. Department of Pediatrics, New York Medical College, Valhalla, NY, USA

    Jessica Hochberg, Liana Klejmont, Lauren Harrison, Jackie Basso, Yaya Chu & Mitchell Cairo

  6. Department of Pathology, New York Medical College, Valhalla, NY, USA

    Humayun Islam & Mitchell Cairo

  7. Department of Radiology, New York Medical College, Valhalla, NY, USA

    Perry Gerard

  8. Levine Children’s Hospital, Charlotte, NC, USA

    Javier Oesterheld

  9. Cook Children’s Medical Center, Fort Worth, TX, USA

    Kenneth Heym

  10. Children’s Hospital Orange County, Irvine, CA, USA

    Ivan Kirov

  11. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Richard Drachtman

  12. Medical College of Wisconsin, Milwaukee, WI, USA

    Paul Harker-Murray

  13. Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT, USA

    Sherrie Perkins & Rodney R. Miles

  14. Department of Medicine, New York Medical College, Valhalla, NY, USA

    Mitchell Cairo

  15. Department of Microbiology & Immunology, New York Medical College, Valhalla, NY, USA

    Mitchell Cairo

  16. Cell Biology & Anatomy, New York Medical College, Valhalla, NY, USA

    Mitchell Cairo

Authors
  1. Stan Goldman
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  18. Paul Harker-Murray
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  19. Sherrie Perkins
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  20. Rodney R. Miles
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  21. Mitchell Cairo
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Contributions

SG and MSC conceived and designed the study; SG, LH, MB, QS, YC, and MC collected the data and SG, MB, QS, YC, and MC analyzed and interpreted the data; and SG, QS, LH, and MC wrote the manuscript. All authors reviewed, revised and approved the final draft of the manuscript prior to submission.

Corresponding author

Correspondence to Mitchell Cairo.

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Conflict of interest

MC is on the advisory board for Jazz Pharmaceuticals and Nektar Therapeutics and the speaker bureau for Jazz Pharmaceuticals, Servier Pharmaceuticals, Sanofi Pharmaceuticals and Amgen, Inc. SG is on the speaker bureau for Jazz Pharmaceuticals. All other authors declare no conflict of interest.

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Presented in part at the Sixth International Symposium on Childhood, Adolescent and Young Adult non-Hodgkin lymphoma, 2018, Rotterdam, Netherlands.

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Goldman, S., Barth, M., Shiramizu, B. et al. A dose substitution of anthracycline intensity with dose-dense rituximab in children and adolescents with good-risk mature B-cell lymphoma. Leukemia 35, 2994–2997 (2021). https://doi.org/10.1038/s41375-021-01256-8

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