Deleterious germline 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 old) RUNX1-FPDMM patients enrolled in the NIH RUNX1 Natural History Study. Pediatric patients have thrombocytopenia (131,000±49,000/µL vs 314,000±55,000/µL) and mild eosinophilia (372±244/µL vs 165±100/µL) similar to adult patients. Abnormal bleeding is less frequent in children than adults (32% vs. 42%). Of 213 RUNX1-FPDMM patients, 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 (1-74) years. Pediatric patients have a 7.3% (3.5-11%) cumulative incidence by 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 5 years than patients with Fanconi anemia. Unlike adult patients whose HM were all myeloid, pediatric patients develop a spectrum of HM subtypes, 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 complete blood counts and annual bone marrow biopsies to monitor for changes and transformation to HM. (NCT03854318).

RUNX1-familial platelet disorder with associated myeloid malignancy (RUNX1-FPDMM) is caused by heterozygous germline variants of RUNX1. With the broader application of next-generation sequencing (NGS)-based gene panel analysis in individuals presenting with benign hematologic abnormalities such as thrombocytopenia, pathogenic RUNX1 variants were more frequently identified, independent of a hematologic malignancy. This study aimed to describe the clinical and genetic characteristics of individuals with pathogenic germline RUNX1 variants, with a particular focus on platelet function and diagnostic challenges. We retrospectively analyzed 10 individuals from 6 families with genetically confirmed RUNX1-FPDMM. Platelet counts and function were evaluated using light transmission aggregometry (LTA) and flow cytometry (FC). For genetic analysis, NGS-based panel sequencing for inherited platelet disorders, Sanger sequencing, karyotyping, fluorescence in situ hybridization (FISH), and microarray analysis were performed. Platelet counts ranged between 40 and 208 G/L. In all six tested individuals, LTA revealed impaired aggregation in response to collagen, adenosine diphosphate (ADP), and epinephrine. FC analysis identified a pronounced granule secretion defect in three of the eight tested individuals. Disease-causing RUNX1 variants included whole-gene or intragenic deletions, one missense, two not previously reported non-sense variants, and a mosaic RUNX1 loss most probably due to the loss of a derivative chromosome 21. One patient has developed acute myeloid leukemia (AML), and another was diagnosed with RUNX1-FPDMM due to thrombocytopenia onset following T-lymphoblastic lymphoma. RUNX1-FPDMM is a challenging disease due to its associated increased risk for hematologic malignancies, mainly myelodysplastic syndrome (MDS) or AML. Genetic diagnosis in individuals with thrombocytopenia or functional platelet defects of unknown origin is crucial to offer structured surveillance and patient education. Increased risk of bleeding due to qualitative platelet function defects, particularly granule secretion abnormalities, must be considered when managing patients, especially prior to invasive procedures.

Hereditary hematopoietic malignancies (HHMs) were once considered extremely rare. As diagnostic testing indications and methods have evolved, deleterious germline variants associated with increased risk of developing hematopoietic malignances are recognized increasingly. The purpose of this review is to summarize recent advances in knowledge, diagnostic, and treatment approaches for several well-known HHM predisposition disorders. Patients often lack classic signs and symptoms typically associated with HHMs, may present at any age, and may not have a suggestive family history. Early identification of causative variants allows for timely anticipatory guidance for patients and family members and has important implications for optimizing treatment decisions. HHMs are not rare. With expanded genetic testing along with appropriate germline tissue selection and ancillary testing, predisposition variants can be identified early and inform appropriate surveillance and treatment decisions for patients and their families.

Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM, FPD/AML, RUNX1-FPD), caused by monoallelic deleterious germline RUNX1 variants, is characterized by bleeding diathesis and predisposition for hematologic malignancies, particularly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical data on FPDMM-associated AML (FPDMM-AML) are limited, complicating evidence-based clinical decision-making. Here, we present retrospective genetic and clinical data of the largest cohort of FPDMM patients reported to date. We describe 159 European patients (from 94 families) of whom 134 were evaluable for the development of malignant disease. Sixty developed a hematologic malignancy (44.8%), most frequently AML (36/134, 26.9%) or MDS (18/134, 13.4%). Somatic alterations of RUNX1 by gene mutation (48%) and chromosome 21 aberrations (14.3%) were the most common somatic genetic aberrations in FPDMM-AML, followed by FLT3-ITD mutations (24.1%). Somatic RUNX1 and FLT3-ITD mutations were not detected in FPDMM-associated MDS, suggesting important contributions to leukemic transformation. Remission-induction chemotherapy resulted in complete remission in 80% of FPDMM-AML patients with a 5-year overall survival (OS) of 50.4%. Survival outcome was non-inferior compared to a large cohort of newly diagnosed adult RUNX1-mutated AML (5-year OS 36.6%, p = 0.5), with relatively infrequent concurrent adverse risk somatic aberrations (ASXL1 mutation, monosomal karyotype, monosomy 5/del 5q) in FPDMM-AML. Collectively, data support the notion that step-wise leukemic evolution in FPDMM is associated with distinct genetic events and indicate that a substantial subset of FPDMM-AML patients achieves prolonged survival with conventional AML treatment, including allogeneic stem cell transplant. These findings are anticipated to inform personalized clinical decision-making in this rare disorder.

Deleterious germ line RUNX1 variants cause the autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematologic malignancies (HMs). We launched a FPDMM natural history study and, from January 2019 to December 2021, enrolled 214 participants, including 111 patients with 39 different RUNX1 variants from 45 unrelated families. Seventy of 77 patients had thrombocytopenia, 18 of 18 had abnormal platelet aggregometry, 16 of 35 had decreased platelet dense granules, and 28 of 55 had abnormal bleeding scores. Nonmalignant bone marrows showed increased numbers of megakaryocytes in 12 of 55 patients, dysmegakaryopoiesis in 42 of 55, and reduced cellularity for age in 30 of 55 adult and 17 of 21 pediatric cases. Of 111 patients, 19 were diagnosed with HMs, including myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, and smoldering myeloma. Of those 19, 18 were relapsed or refractory to upfront therapy and referred for stem cell transplantation. In addition, 28 of 45 families had at least 1 member with HM. Moreover, 42 of 45 patients had allergic symptoms, and 24 of 30 had gastrointestinal (GI) 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 a better understanding of the disease pathogenesis and clinical course, which may then inform preventive and therapeutic interventions. This trial was registered at www.clinicaltrials.gov as #NCT03854318.