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Acute lymphoblastic leukemia

Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multicenter cohort study

Leukemia volume 34, pages 1741–1750 (2020)Cite this article

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Abstract

The rarity of mixed phenotype acute leukemia (MPAL) has precluded adequate data to incorporate minimal residual disease (MRD) monitoring into therapy. Fluidity in MPAL classification systems further complicates understanding its biology and outcomes; this includes uncertainty surrounding the impact of shifting diagnostic requirements even between iterations of the World Health Organization (WHO) classification. Our primary objective was to address these knowledge gaps. To do so, we analyzed clinicopathologic features, therapy, MRD, and survival in a centrally-reviewed, multicenter cohort of MPAL uniformly diagnosed by the WHO classification and treated with acute lymphoblastic leukemia (ALL) regimens. ALL induction therapy achieved an EOI MRD negative (<0.01%) remission in most patients (70%). EOI MRD positivity was predictive of 5-year EFS (HR = 6.00, p < 0.001) and OS (HR = 9.57, p = 0.003). Patients who cleared MRD by EOC had worse survival compared with those EOI MRD negative. In contrast to adults with MPAL, ALL therapy without transplantation was adequate to treat most pediatric patients. Earlier MRD clearance was associated with better treatment success and survival. Prospective trials are now necessary to validate and refine MRD thresholds within the pediatric MPAL population and to identify salvage strategies for those with poor predicted survival.

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Fig. 1: Survival from WHO2008-defined MPAL for those beginning with ALL therapy.
Fig. 2: MRD-stratified survival for MPAL following an ALL induction.
Fig. 3: MRD kinetics during ALL therapy on survival from MPAL.
Fig. 4: Association of MRD with event-free and overall survival for MPAL defined by WHO2016 update.

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Acknowledgements

Data were collated using the REDCAP database supported by NIH/NCATS, UL1TR001855, and UL1TR000130. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Author notes

  1. These authors contributed equally: Matthew J. Oberley, Sunil S. Raikar

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Matthew J. Oberley & Maurice R. G. O’Gorman

  2. Caris Life Sciences, Irving, TX, USA

    Matthew J. Oberley

  3. Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University and Children’s Healthcare of Atlanta, Atlanta, GA, USA

    Sunil S. Raikar & William G. Woods

  4. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania & the Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Gerald B. Wertheim

  5. Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Jemily Malvar, Richard Sposto & Etan Orgel

  6. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Richard Sposto

  7. Texas Children’s Cancer Center, Department of Pediatrics, Section of Hematology–Oncology, Baylor College of Medicine, Houston, TX, USA

    Karen R. Rabin

  8. Department of Pathology and Immunology, Baylor College of Medicine & Texas Children’s Hospital, Houston, TX, USA

    Jyotinder N. Punia

  9. Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Alix E. Seif & Viviane C. Cahen

  10. Children’s National Medical Center & George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Reuven J. Schore & Dragos C. Luca

  11. Department of Pediatrics, The Ohio State University & Nationwide Children’s Hospital, Columbus, OH, USA

    Terri Guinipero

  12. Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Maurice R. G. O’Gorman & Etan Orgel

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  1. Matthew J. Oberley
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Contributions

EO performed study conception and research design; MJO and GW conducted the hematopathology central review; JM and RS performed the statistical analysis; MJO, SSR, and EO wrote the paper first draft; All authors contributed case data, interpreted the analysis, and reviewed/edited paper.

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Correspondence to Etan Orgel.

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MJO is currently employed at Caris Life Sciences. There are no other conflicts of interest to report.

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Oberley, M.J., Raikar, S.S., Wertheim, G.B. et al. Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multicenter cohort study. Leukemia 34, 1741–1750 (2020). https://doi.org/10.1038/s41375-020-0741-0

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