Natural History Study of Patients with Familial Platelet Disorder with Myeloid Malignancy.

Deleterious germline RUNX1 variants cause the autosomal dominant disease familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet functional defects and predisposition to hematologic malignancies (HMs). We launched a FPDMM natural history study and, from January 2019-December 2021, enrolled 214 participants, including 111 patients with 39 different RUNX1 variants from 45 unrelated families. Of those with available data, 91% (70/77) had thrombocytopenia, 100% (18/18) had abnormal platelet aggregometry, 46% (16/35) had platelets with decreased dense granules, and 51% (28/55) had abnormal bleeding scores. Histologic evaluation of non-malignant bone marrows showed increased number of megakaryocytes in 22% (12/55) patients, dysmegakaryopoiesis in 76% (42/55), and reduced cellularity for age in 55% adult (30/55) and 81% pediatric (17/21) cases. 19 of 111 (17%) enrolled patients were diagnosed with HMs, including myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia and smoldering myeloma. 18 of the 19 patients with HM were relapsed or refractory to upfront therapy and referred for hematopoietic stem cell transplantation. In addition, 62% (28/45) of families have at least one member who has developed HMs. Moreover, 93% (42/45) of patients had allergic and 80% (24/30) had gastrointestinal symptoms. Our results highlight the importance of a multidisciplinary approach, early malignancy detection, and wider awareness of inherited disorders. This actively accruing, longitudinal study will genotype and phenotype more patients with FPDMM, which may lead to better understanding of the disease pathogenesis and clinical course, which may then inform preventative and therapeutic interventions.