Bone marrow surveillance of pediatric cancer survivors identifies clones that predict therapy-related leukemia.

Overview

abstract

PURPOSE: Therapy-related myelodysplastic syndrome and acute leukemias (t-MDS/AL) are a major cause of non-relapse mortality amongst pediatric cancer survivors. While the presence of clonal hematopoiesis (CH) in adult patients at cancer diagnosis has been implicated in t-MDS/AL, there is limited published literature describing t-MDS/AL development in children. EXPERIMENTAL DESIGN: We performed molecular characterization of 199 serial bone marrow samples from 52 patients treated for high-risk neuroblastoma, including 17 with t-MDS/AL (transformation), 14 with transient cytogenetic abnormalities (transient), and 21 without t-MDS/AL or cytogenetic alterations (neuroblastoma-treated control). We also evaluated for CH in a cohort of 657 pediatric solid tumor patients. RESULTS: We detected at least one disease-defining alteration in all cases at t-MDS/AL diagnosis, most commonly TP53 mutations and KMT2A rearrangements, including involving two novel partner genes (PRDM10, DDX6). Backtracking studies identified at least one t-MDS/AL-associated mutation in 13/17 patients at a median of 15 months before t-MDS/AL diagnosis (range 1.3-32.4). In comparison, acquired mutations were infrequent in the transient and control groups (4/14, 1/21 respectively). The relative risk for development of t-MDS/AL in the presence of an oncogenic mutation was 8.8 for transformation patients compared to transient. Unlike CH in adult oncology patients, TP53 mutations were only detectable after initiation of cancer therapy. Lastly, only 1% of pediatric solid tumor patients evaluated had CH involving myeloid genes. CONCLUSIONS: These findings demonstrate the clinical relevance of identifying molecular abnormalities in predicting development of t-MDS/AL and should guide the formation of intervention protocols to prevent this complication in high-risk pediatric patients.