Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy)
Abstract 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...
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2025-01-01
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| Online Access: | https://doi.org/10.1002/hem3.70057 |
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| author | Martijn P. T. Ernst Jurjen Versluis Peter J. M. Valk Marc Bierings Rienk Y. J. Tamminga Louise H. Hooimeijer Konstanze Döhner Paolo Gresele Kiran Tawana Saskia M. C. Langemeijer Bert A. Van der Reijden Helena Podgornik Matjaz Sever Tor H. A. Tvedt Tom Vulliamy Jude Fitzgibbon Inderjeet Dokal Panagiotis Baliakas José M. Bastida Christian Pohlkamp Torsten Haferlach Lise Larcher Jean Soulier Roger E. G. Schutgens Kathleen Freson Nicolas Duployez Bob Löwenberg Katrin Ericson Jörg Cammenga Tim Ripperger Marc H. G. P. Raaijmakers |
| author_facet | Martijn P. T. Ernst Jurjen Versluis Peter J. M. Valk Marc Bierings Rienk Y. J. Tamminga Louise H. Hooimeijer Konstanze Döhner Paolo Gresele Kiran Tawana Saskia M. C. Langemeijer Bert A. Van der Reijden Helena Podgornik Matjaz Sever Tor H. A. Tvedt Tom Vulliamy Jude Fitzgibbon Inderjeet Dokal Panagiotis Baliakas José M. Bastida Christian Pohlkamp Torsten Haferlach Lise Larcher Jean Soulier Roger E. G. Schutgens Kathleen Freson Nicolas Duployez Bob Löwenberg Katrin Ericson Jörg Cammenga Tim Ripperger Marc H. G. P. Raaijmakers |
| author_sort | Martijn P. T. Ernst |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-1284875afea343b4ae41274a7b3bfdf3 |
| institution | OA Journals |
| issn | 2572-9241 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
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| series | HemaSphere |
| spelling | doaj-art-1284875afea343b4ae41274a7b3bfdf32025-08-20T02:27:22ZengWileyHemaSphere2572-92412025-01-0191n/an/a10.1002/hem3.70057Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy)Martijn P. T. Ernst0Jurjen Versluis1Peter J. M. Valk2Marc Bierings3Rienk Y. J. Tamminga4Louise H. Hooimeijer5Konstanze Döhner6Paolo Gresele7Kiran Tawana8Saskia M. C. Langemeijer9Bert A. Van der Reijden10Helena Podgornik11Matjaz Sever12Tor H. A. Tvedt13Tom Vulliamy14Jude Fitzgibbon15Inderjeet Dokal16Panagiotis Baliakas17José M. Bastida18Christian Pohlkamp19Torsten Haferlach20Lise Larcher21Jean Soulier22Roger E. G. Schutgens23Kathleen Freson24Nicolas Duployez25Bob Löwenberg26Katrin Ericson27Jörg Cammenga28Tim Ripperger29Marc H. G. P. Raaijmakers30Department of Hematology Erasmus University Medical Center and Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Hematology Erasmus University Medical Center and Erasmus MC Cancer Institute Rotterdam The NetherlandsDepartment of Hematology Erasmus University Medical Center and Erasmus MC Cancer Institute Rotterdam The NetherlandsPrincess Máxima Center for Pediatric Oncology Utrecht The NetherlandsBeatrix Children's Hospital University Medical Center Groningen The NetherlandsBeatrix Children's Hospital University Medical Center Groningen The NetherlandsDepartment of Internal Medicine III Ulm University Ulm GermanyDepartment of Medicine and Surgery, Section of Internal and Cardiovascular Medicine University of Perugia Perugia ItalyDepartment of Haematology Addenbrooke's Hospital Cambridge UKDepartment of Hematology Radboud UMC Nijmegen The NetherlandsDepartment of Laboratory Radboud UMC Nijmegen The NetherlandsDepartment of Hematology University Medical Centre Ljubljana Ljubljana SloveniaDepartment of Hematology University Medical Centre Ljubljana Ljubljana SloveniaDepartment of Haematology Oslo University Hospital Oslo NorwayBlizard Institute, Faculty of Medicine and Dentistry Queen Mary University of London London UKHaemato‐Oncology, Barts Cancer Institute Queen Mary University of London London UKHaemato‐Oncology, Barts Cancer Institute Queen Mary University of London London UKDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala University Uppsala SwedenDepartment of Hematology Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomedica de Salamanca (IBSAL), Universidad de Salamanca (USAL) Salamanca SpainMunich Leukemia Laboratory Munich GermanyMunich Leukemia Laboratory Munich GermanyUniversité Paris Cité, Inserm and Hôpital Saint‐Louis, APHP Paris FranceUniversité Paris Cité, Inserm and Hôpital Saint‐Louis, APHP Paris FranceCenter for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht and University Utrecht The NetherlandsDepartment of Cardiovascular Sciences, Center for Molecular and Vascular Biology University of Leuven Leuven BelgiumLaboratory of Hematology Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille Lille FranceDepartment of Hematology Erasmus University Medical Center and Erasmus MC Cancer Institute Rotterdam The NetherlandsThe RUNX1 Research Program Santa Barbara California USADepartment of Hematology, Skåne University Hospital and Molecular Medicine and Gene Therapy Lund University Lund SwedenDepartment of Human Genetics Hannover Medical School Hannover GermanyDepartment of Hematology Erasmus University Medical Center and Erasmus MC Cancer Institute Rotterdam The NetherlandsAbstract 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.https://doi.org/10.1002/hem3.70057 |
| spellingShingle | Martijn P. T. Ernst Jurjen Versluis Peter J. M. Valk Marc Bierings Rienk Y. J. Tamminga Louise H. Hooimeijer Konstanze Döhner Paolo Gresele Kiran Tawana Saskia M. C. Langemeijer Bert A. Van der Reijden Helena Podgornik Matjaz Sever Tor H. A. Tvedt Tom Vulliamy Jude Fitzgibbon Inderjeet Dokal Panagiotis Baliakas José M. Bastida Christian Pohlkamp Torsten Haferlach Lise Larcher Jean Soulier Roger E. G. Schutgens Kathleen Freson Nicolas Duployez Bob Löwenberg Katrin Ericson Jörg Cammenga Tim Ripperger Marc H. G. P. Raaijmakers Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy) HemaSphere |
| title | Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy) |
| title_full | Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy) |
| title_fullStr | Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy) |
| title_full_unstemmed | Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy) |
| title_short | Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy) |
| title_sort | disease characteristics and outcomes of acute myeloid leukemia in germline runx1 deficiency familial platelet disorder with associated myeloid malignancy |
| url | https://doi.org/10.1002/hem3.70057 |
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