Relapse Mechanisms in Children with Down Syndrome and Myeloid Leukemia

Children with Down syndrome (DS) achieve high cure rates with frontline therapy but are hypersensitive to cytarabine. Yet, relapse remains a major clinical challenge upon which event-free survival rates drop below 20%. To overcome toxicity while maintaining efficacy, ML-DS 2018 clinical trial replaced idarubicin, cytarabine, and etoposide (ML-DS 2006) with CPX-351, a liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio. To evaluate treatment response and relapse mechanisms, patient-derived xenografts (PDXs) were established from initial diagnosis and relapse samples across both trials. These models underwent comprehensive in vitro testing, confirming the CPX-351 efficacy. Orthogonal multi-omics integrative strategies (OMCIS) were applied to identify relapse-associated molecular alterations, while single-cell RNA sequencing (scRNA-seq) was used to detect chemoresistant subclones. By systematically comparing PDX samples from initial diagnosis and relapse, this study will identify key drivers of therapy resistance to uncover novel treatment vulnerabilities and support the development of more effective therapeutic strategies for relapsed ML-DS patients.

Publication History

Article published online:
09 May 2025