Molecular risk markers define risk of relapse in myeloid leukemia of Down syndrome beyond measurable residual disease

Myeloid leukemia of Down syndrome (ML-DS) is a distinct form of pediatric acute myeloid leukemia (AML) that responds to reduced-intensity chemotherapy, as compared with non-DS AML that requires intensive chemotherapy and often stem cell transplant. While most patients with ML-DS have a favorable prognosis, outcomes for those with refractory or relapsed disease are dismal. Children's Oncology Group study AAML1531 introduced the use of measurable residual disease by multiparameter flow cytometry at the end of the first course of induction therapy (EOI-1 MRD) for risk stratification of treatment intensity. Of 280 patients with ML-DS who were enrolled, 41 were classified as high risk (HR) due to positive EOI-1 MRD, and treated with intensified chemotherapy similar to that used for pediatric non-DS AML. Treatment intensification did not improve the 2-year event-free survival compared with patients who were MRD-positive treated with reduced-intensity therapy in the predecessor study AAML0431 (80.5% ± 12.4% vs 76%; P = .247) or overall survival (80.5% ± 12.4% vs 76.2% ± 18.6%; P = .819), but significantly increased the frequency of febrile neutropenia and sepsis events. While stratification of treatment intensity based on MRD was not beneficial, molecular markers of relapse risk proposed by the Japan Children's Cancer Group for ML-DS (alterations of CDKN2A, ZBTB7A, JAK2, TP53) proved prognostic. Relapse risk was 50% in patients who were HR from AAML1531 with any high-risk molecular marker compared with 6.7% in those without. Similar relapse results were obtained in the MRD-negative AAML1531 group, suggesting molecular risk markers can predict outcome and thus be used to stratify therapy in ML-DS. This trial was registered at www.clinicaltrials.gov as #NCT02521493.

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Journal
Blood Advances
Published
2025-10-22
DOI
https://doi.org/10.1182/bloodadvances.2025017837
Primary Topic
Acute Myeloid Leukemia Research
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article
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article

Molecular risk markers define risk of relapse in myeloid leukemia of Down syndrome beyond measurable residual disease

E Anders Kolb, Jeffrey W. Taub, Susana C. Raimondi, Reuven J. Schore et al.
Blood Advances
Acute Myeloid Leukemia Research
article

Molecular risk markers define risk of relapse in myeloid leukemia of Down syndrome beyond measurable residual disease

E Anders Kolb, Jeffrey W. Taub, Susana C. Raimondi, Reuven J. Schore, Rhonda E. Ries, Anupam Verma, Shelton A. Viola, Johann Hitzler, Betsy Hirsch, Jason N. Berman, Todd M. Cooper, Karen M. Chisholm, Soheil Meshinchi, Amy Beckman, Michael R. Loken, Todd A. Alonzo, Alan S. Gamis, Lisa Eidenschink Brodersen, Yicheng Wang, Xiaotu Ma
article en

Abstract

Myeloid leukemia of Down syndrome (ML-DS) is a distinct form of pediatric acute myeloid leukemia (AML) that responds to reduced-intensity chemotherapy, as compared with non-DS AML that requires intensive chemotherapy and often stem cell transplant. While most patients with ML-DS have a favorable prognosis, outcomes for those with refractory or relapsed disease are dismal. Children's Oncology Group study AAML1531 introduced the use of measurable residual disease by multiparameter flow cytometry at the end of the first course of induction therapy (EOI-1 MRD) for risk stratification of treatment intensity. Of 280 patients with ML-DS who were enrolled, 41 were classified as high risk (HR) due to positive EOI-1 MRD, and treated with intensified chemotherapy similar to that used for pediatric non-DS AML. Treatment intensification did not improve the 2-year event-free survival compared with patients who were MRD-positive treated with reduced-intensity therapy in the predecessor study AAML0431 (80.5% ± 12.4% vs 76%; P = .247) or overall survival (80.5% ± 12.4% vs 76.2% ± 18.6%; P = .819), but significantly increased the frequency of febrile neutropenia and sepsis events. While stratification of treatment intensity based on MRD was not beneficial, molecular markers of relapse risk proposed by the Japan Children's Cancer Group for ML-DS (alterations of CDKN2A, ZBTB7A, JAK2, TP53) proved prognostic. Relapse risk was 50% in patients who were HR from AAML1531 with any high-risk molecular marker compared with 6.7% in those without. Similar relapse results were obtained in the MRD-negative AAML1531 group, suggesting molecular risk markers can predict outcome and thus be used to stratify therapy in ML-DS. This trial was registered at www.clinicaltrials.gov as #NCT02521493.

Blood AdvancesVol. 10(5)
Ontario Institute for Cancer Research (CA), Children's Oncology Group (CH), University of Southern California (US), Seattle Children's Hospital (US), University of Minnesota (US), Naval Medical Center Portsmouth (US), St. Jude Children's Research Hospital (US), Alfred I. duPont Hospital for Children (US), Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA), Children's Mercy Hospital (US), Children's Hospital of Philadelphia (US), Children's National (US), George Washington University (US), University of Washington (US), Children's Hospital of Eastern Ontario (CA), Agricultural Research Institute of Ontario (CA), University of Minnesota System (US), Hospital for Sick Children (CA), Fred Hutch Cancer Center (US), The Barbara Ann Karmanos Cancer Institute (US), Seattle Children's Hospital (US), Center for Cancer and Blood Disorders (US), Michigan United (US), Anthem (United States) (US), Virginia Cancer Specialists (US), Mercy Hospital (US), Children's Hospital of Michigan (US), Children's Oncology Group (US), California Library Association (US)
National Institutes of Health
Openalex Percentile: Top 62%
Acute Myeloid Leukemia Research
DOIOpen Access PDFOpenAlex
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