Natural history study of patients with familial platelet disorder with associated myeloid malignancy

Author:

Cunningham Lea12,Merguerian Matthew13ORCID,Calvo Katherine R.4,Davis Joie1,Deuitch Natalie T.1ORCID,Dulau-Florea Alina4,Patel Nisha4,Yu Kai1,Sacco Keith5ORCID,Bhattacharya Sumona6,Passi Monica6,Ozkaya Neval7,De Leon Seila4ORCID,Chong Shawn1,Craft Kathleen1,Diemer Jamie1,Bresciani Erica1,O’Brien Kevin8,Andrews Elizabeth J.12,Park Nguyen8,Hathaway Londa9,Cowen Edward W.9ORCID,Heller Theo10ORCID,Ryan Kerry11,Barochia Amisha11ORCID,Nghiem Khanh4,Niemela Julie4,Rosenzweig Sergio4,Young David J.12ORCID,Frischmeyer-Guerrerio Pamela A.5,Braylan Raul4,Liu Paul P.1ORCID

Affiliation:

1. 1Oncogenesis and Development Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

2. 2Immune Deficiency Cellular Therapy Program, National Cancer Institute, National Institutes of Health, Bethesda, MD

3. 3Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD

4. 4Department of Laboratory Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD

5. 5Laboratory of Allergic Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

6. 6Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

7. 7Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD

8. 8Office of Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

9. 9Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD

10. 10Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

11. 11Laboratory of Asthma and Lung Inflammation, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD

12. 12Laboratory of Molecular Hematopoiesis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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