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

Abstract RUNX1 is a transcription factor crucial for normal hematopoiesis. Deleterious germline RUNX1 variants cause Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM), an autosomal dominant disorder characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematologic malignancies (HM). Since 2019, we have conducted a longitudinal natural history study of RUNX1-FPDMM (NCT03854318) in order to characterize clinical features, assess risks of malignant transformation, and formulate recommendations for clinical care and management. Our previous reports from the natural history study primarily focused on adult patients due to the small number of pediatric patients enrolled. However, we have expanded our cohort to 213 enrolled patients with pathogenic/likely pathogenic RUNX1 variants. Of these, 206 are alive (71 pediatric, 135 adults), 7 are deceased (2 pediatric, 5 adults). “Pediatric” is defined as <19 years old, whereas “adult” is ≥19 years old. To our knowledge, this is the largest cohort of pediatric RUNX1-FPDMM patients, which has enabled us to examine the findings of these patients more closely. Previously, it was found that adult RUNX1-FPDMM patients have significantly lower platelet counts and about half have abnormal ISTH-BAT bleeding scores compared to controls. From our analysis we found that his holds true when comparing pediatric RUNX1-FPDMM patients to controls. More importantly, whereas the median age of onset of hematologic malignancy (HM) in RUNX1-FPDMM is 35 years old for all patients, the age of HM diagnosis follows a bimodal distribution, with peaks in the first decade of life and again in the fifth and sixth decades. Indeed, pediatric patients aged 0 to 10 have an increased risk of developing HM. In our cohort, 31/213 (14%) patients had HM, 6 of whom are deceased. Thirteen (41%) were diagnosed as children; 19 (59%) as adults (one had a second HM after childhood). We examined genomic features of pediatric and adult patients with HM. The majority of both exhibit somatic changes (77.8% in pediatric, 93.3% in adult). For pediatric patients, most are structural chromosomal abnormalities (66.7%; 6/9 individuals) not sequence changes (33.3%; 3/9 individuals). Conversely, for adults, most changes are sequence (73.3%; 11/15 individuals), compared with 46.7% (7/15 individuals) chromosomal. Furthermore, of the 182 patients (65 pediatric, 117 adults) without HM, 40 have clonal hematopoiesis (3/65, 4.6% pediatric; 37/117 32% adult). Together, these data suggest the acquisition of clonal mutations, does not precede HM progression in pediatric RUNX1-FPDMM, unlike adults. To characterize pediatric HM risk, we conducted survival analyses. In RUNX1-FPDMM, there is a cumulative HM incidence (CI) of 7.3% (3.5-11%) by 18 years old compared with 0.126% that for the general US population. We compared the disease (malignancy)-free survival (DFS) and CI for RUNX1-FPDMM with that of 193 Fanconi anemia (FA) patients from the NCI IBMFS Cohort Study (NCT00027274). At birth, FA has an annual hazard rate comparable to that of the general population, which increases in older childhood. RUNX1-FPDMM patients have a very high risk as early as 1 year old. During the pediatric period, RUNX1-FPDMM patients are at a 50-fold increased risk of HM compared with the general population, comparable to that of FA, but with an earlier accumulation of that risk prior to 5 years old. Currently, no guidelines exist regarding the initiation and frequency of monitoring for pediatric RUNX1-FPDMM patients; however, examination of illustrative pediatric cases holds to inform best practices for patients with RUNX1-FPDMM. These cases demonstrate that the early diagnosis, and prompt initiation of clinical monitoring (regular, complete blood counts and bone marrow (BM) biopsies) can detect disease transformation early on. Furthermore, newborns with severe thrombocytopenia and pediatric patients with family members with confirmed or suspected RUNX1-FPDMM should be tested for RUNX1 variants as soon as possible due to the risk of HM in the pediatric ages.Based on these findings, we recommend that the clinical management of pediatric RUNX1-FPDMM patients should include, early diagnostic molecular confirmation, baseline BM biopsy as soon as reasonably possible, and regular blood and BM testing to monitor for changes and transformation to HM throughout their lives.