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1357 Inherited Thrombocytopenias Predisposing to Hematologic Neoplasms. Experience of the Spanish Group for Inherited Platelet Disorders (GEAPC)

Program: Oral and Poster Abstracts
Session: 509. Bone Marrow Failure and Cancer Predisposition Syndromes: Congenital: Poster I
Hematology Disease Topics & Pathways:
Research, Bleeding and Clotting, bleeding disorders, Acquired Marrow Failure Syndromes, epidemiology, Bone Marrow Failure Syndromes, Inherited Marrow Failure Syndromes, Clinical Research, platelet disorders, Genetic Disorders, hematopoiesis, Diseases, thrombocytopenias, Biological Processes
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Jose Maria Bastida, MD, PhD1*, Ana Marín-Quílez2*, Ana Zamora2*, Maria Rocio Benito Sanchez, PhD3*, Agustín Rodriguez Alen4*, Teresa Sevivas5*, Pedro Luis Gómez-González2*, Lorena Díaz-Ajenjo3*, Nora Butta, PhD6*, Rosa M. Campos7*, Paola Escribano8*, Jorge Huertas-Aragoneses9*, Monica Lopez-Duarte10*, Antonio León11*, Angela Mompel12*, Raquel De Oña Navarrete, MD13*, Irene Peláez-Pleguezuelos14*, Fernando Jesús Ramos-Ortega, MD15*, Elena Sebastian16*, Claudia Serrano17*, Cristina Sierra-Aisa18*, Pablo Velasco, MD19, Laura Murillo19*, Rosa Vidal-Laso20*, Meritxell Nomdedeu, MD21*, Jordi Esteve Reyner, MD22*, Jesús María Hernández-Rivas, PhD23, Jose Rivera Pozo, PhD2* and Maria Luisa Lozano, MD, PhD24*

1Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, Salamanca, Spain
2Centro Regional de Hemodonación, Murcia, Spain
3Hospital Universitario De Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, Salamanca, Spain
4Servicio De HematologíA Y Hemoterapia, Hospital Virgen De La Salud, Compl, Toledo, ESP
5Complejo Hospitalario de Coimbra, Coimbra, Portugal
6IdiPAZ, Madrid, Spain
7Hospital Universitario de Jerez de la Frontera, Jerez de la Frontera, Spain
8Hospital General Río Carrión, Palencia, Spain
9Hospital Materno-Infantil Gregorio Marañón, Madrid, Spain
10University Hospital Marqués De Valdecilla - IDIVAL, Santander, ESP
11Hospital General de La Gomera, La Gomera, Spain
12Hospital General Universitario de Elche, Elche, Spain
13Hospital MD Anderson Cancer Center, Madrid, AL, ESP
14Hospital Universitario Virgen de las Nieves, Granada, Spain
15Hospital Universitario de León, León, Spain
16Hospital Infantil Universitario Niño Jesús, Madrid, ESP
17Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
18Hospital Universitario de Cruces, Barakaldo, Spain
19Hospital Universitario Vall d'Hebron, Barcelona, Spain
20Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
21Hematopoietic Cell Transplantation Unit, Hospital Clínic de Barcelona, ICHMO, Barcelona, Spain
22Hospital Clínic de Barcelona, Barcelona, Spain
23Department of Medicine, Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain
24Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, IMIB-Pascual Parrilla, CIBERER-ISCIII, Universidad de Murcia, Murcia, Spain


In inherited thrombocytopenic disorders (IT) associated with germline genetic variants in the transcription factors RUNX1 (RUNX1-RT) and ETV6 (ETV6-RT) or ankyrin 26 (ANKRD26-RT), bleeding is usually not clinically relevant. However, patients have a high risk (10-45%) of developing hematologic malignancies (HM). Genetic diagnosis at an early stage of life is essential for these patients and their families, as the underlying genotype determines the natural history of the disease and, consequently, its prognosis and clinical management. High-Throughput Sequencing (HTS) has greatly facilitated diagnosing and providing personalized medicine for these patients.


The aim of this study was to evaluate the frequency, clinical characteristics, platelet phenotype and molecular alterations of patients with IT predisposing to HM, within the series of IT patients recruited by the Spanish Group of Inherited Platelet Disorders (GEAPC).


Since 2008, we have enrolled 296 patients (174 families) suspected of having any type of IT. They were selected according to their clinical and biological background. Bleeding (bleeding score (BS); ISTH-BAT), complete blood count and smear, and in many patients platelet phenotyping (platelet aggregation (LTA), cytometry, microscopy, etc.) were performed. Sanger sequencing of candidate genes (until 2014) or HTS was used for genetic diagnosis of patients. Candidate genetic variants were classified in accordance with the ACMG/AMP criteria, also taking into account the adapted specifications for RUNX1.


Genetic diagnosis was obtained in 208 patients (76.3%) (135 families), identifying 26 different types of IT. Thirty patients (17 families) had RUNX1-RT (14.4%), 16 (5 families) had ANKRD26-RT (7.7%) and 7 cases (4 families) had ETV6-RT (3.4%).

In patients with RUNX1-RT, the median age at identification of cytopenia and at genetic diagnosis was 17 (0-56) and 27 (1-71) years, respectively. Mild-to-moderate thrombocytopenia (95x109 pl/L (15-142)) and mild bleeding (BS=2(0-12)) was observed in 89% of these patients. Of the 13 patients evaluated, 83.3% had a reduced LTA at 2µg/ml collagen and 80% had low levels of glycoprotein Ia (collagen receptor). We identified 15 different variants in RUNX1 (8 novel); 47% missense, 30% nonsense, 12% large deletions, 6% splicing and 6% frameshift. Sixty-five percent of the variants were classified as pathogenic (PV), 6% as likely pathogenic (LPV), and 29% of uncertain significance (VUS). In 7 cases the variant was de novo. Ten patients (33.3%) developed HM (median age 49 years) (Table 1). Of these, 53% had at least one family member with HM (AML, 53.5%; MDS, 10.7%; CML, 7.1%; AML-post-MDS, 3.6%) or solid tumor (breast cancer, 14.2% [50% BRCA2+]; prostate, 7.1%; stomach, 3.6%).

In 16 cases with ANKRD26-RT, thrombocytopenia was identified at age 16 (0-60 years), while the genetic diagnosis was made at age 36 (0-79 years). In all cases the thrombocytopenia was moderate [median: 53.5x109 pl/L (8-119)], mostly asymptomatic (BS=1.5(0-12)) and not associated with platelet dysfunction (5 cases studied). We detected 3 different variants in the 5'UTR of ANKRD26 (1 LPV, 2 VUS). One patient had a de novo variant. Twenty-five percent developed neoplasia (3 HM cases; 1 breast cancer) at 42 years of age (median). Two of 5 families had a history of HM (MDS or AML) (Table 1).

The ETV6-RT patients were genetically diagnosed at the age of 30 (3-59) years, while thrombocytopenia, moderate [97 x 109 cells/L (8-119)] and not associated with a bleeding diathesis (BS=0 (0-4)), was detected at the age of 12 (2-33) years. In one case, a defect in LTA, activation and platelet dense granule number was detected in platelet function studies. In this group we identified 4 different ETV6 missense variants (2 PV and 2 LPV/VUS). One patient developed B-ALL at the age of 12 years (Table 1).


Inherited thrombocytopenia that predisposes to HM is the most common form of IT in this Spanish cohort (25.5% of cases [19% of families]). We found an excessive delay (10-20 years) in the genetic diagnosis of patients with respect to the age of identification of the cytopenia. The high rate of development of HM of 28% reinforces the critical importance of early genetic diagnosis of these IT in order to apply optimal surveillance and clinical management aimed at early detection of their evolution to neoplasm.

Disclosures: Butta: Novo Nordisck, Novartis: Speakers Bureau; Takeda, Novo Nordisck: Research Funding. Hernández-Rivas: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

*signifies non-member of ASH