Hematologic malignancies in pediatric patients with RUNX1-familial platelet disorder with associated myeloid...

Deleterious germ line RUNX1 variants cause familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and predisposition to hematologic malignancies (HM). We examined clinical and laboratory findings of pediatric (<19 years) patients with RUNX1-FPDMM enrolled in the National Institutes of Health RUNX1 Natural History Study. Pediatric patients have thrombocytopenia (131 ± 49 ×103/μL vs 314 ± 55 ×103/μL) and mild eosinophilia (372 ± 244/μL vs 165 ± 100/μL) similar to adults. Abnormal bleeding is less frequent in children than adults (32% vs 42%). Of 213 patients with RUNX1-FPDMM, 31 developed HM (13 pediatric, 19 adult; 1 had second malignancy). Lifetime HM risk is 42% (26%-55%). Median age of HM diagnosis is 36 years (range, 1-74). Pediatric patients have a 7.3% (3.5%-11%) cumulative incidence by age 18 years, 57.7-fold (27.7-86.6) higher than the general population, and are 3.4-fold more likely to develop HM by age 5 years than patients with Fanconi anemia. Unlike adult patients whose HM were all myeloid, pediatric patients develop a spectrum of HM but with a myeloid excess compared with the general pediatric population (62% vs 24%). Pediatric RUNX1-FPDMM HM is less likely than adult to have multiple somatic mutations (22% vs 67%), but more likely to have chromosome changes (67% vs 47%). We recommend prompt, universal cascade RUNX1 testing following a new diagnosis, regardless of age. Upon diagnosis, management of pediatric RUNX1-FPDMM should include a baseline bone marrow biopsy, once clinically acceptable, and peripheral blood evaluations. We recommend routine monitoring with quarterly blood counts and annual biopsy to monitor for changes and HM transformation. This trial was registered www.clinicaltrials.gov as #NCT03854318.