Molecular Risk Markers Define Risk of Relapse in Myeloid Leukemia of Down syndrome Beyond Measurable Residual Disease Open Access

• Intensification of chemotherapy for ML-DS based on positive MRD did not improve survival but increased the risk for neutropenia and sepsis.

• Proposed molecular were prognostic in patients with ML-DS regardless of MRD supporting their evaluation as new risk stratification in ML-DS.

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 to 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 (COG) study AAML1531 introduced the use of minimal residual disease measured by multi-parameter flow cytometry at the end of the first course of induction therapy (EOI-1 MRD) for risk stratification of treatment intensity. Of 280 ML-DS patients 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 to MRD-positive patients treated with reduced intensity therapy in predecessor study AAML0431(80.5 + 12.4% vs. 76%, p=0.247) or overall survival (80.5 + 12.4% vs. 76.2 + 18.6%, p=0.819), 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 AAML1531 HR patients with any high risk molecular marker compared to 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. https://clinicaltrials.gov/study/NCT02521493