Outcomes of germ line testing for children with hematologic malignancies undergoing hematopoietic cell transplantation

Abstract Recent studies reveal that a growing proportion of children with hematologic malignancies (HM) harbor germ line pathogenic or likely pathogenic variants (PV) in cancer-predisposing genes (CPG). Identifying these children is critical because the information gained guides leukemia therapy, family testing, and selection of related donors for hematopoietic cell transplantation (HCT). Nevertheless, it remains unclear how often children with HM being considered for HCT undergo genetic evaluation and whether germ line data are used to guide clinical practice. To address this gap, we reviewed the records of 286 children who underwent ≥1 HCT for HM at St. Jude Children's Research Hospital between 1 January 2017 and 31 December 2023. We examined the timeline of genetic evaluation, prevalence of germ line PV, and impact of PV on HCT outcomes. Overall, 227 (79%) children met with a genetic counselor before their first HCT, 192 underwent testing, and 142 had results returned before the HCT. Thirty-six patients (19%) harbored a germ line CPG PV, among whom 12 (6%) had PV aligning with their HM diagnosis. Of 5 patients who received an HCT from a PV-positive relative, 1 patient developed donor-derived leukemia. We observed no significant differences in time to neutrophil engraftment, cumulative incidence of relapse, or overall survival between patients with and without PV, although the cohort was heterogeneous with respect to the underlying PV. Given the high prevalence of PV in children with HM, prompt referral to genetics is warranted to ensure timely counseling and germ line testing to detect a hereditary predisposition and inform donor selection for HCT.