Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy)

被引:0
|
作者
Ernst, Martijn P. T. [1 ,2 ]
Versluis, Jurjen [1 ,2 ]
Valk, Peter J. M. [1 ,2 ]
Bierings, Marc [3 ]
Tamminga, Rienk Y. J. [4 ]
Hooimeijer, Louise H. [4 ]
Doehner, Konstanze [5 ]
Gresele, Paolo [6 ]
Tawana, Kiran [7 ]
Langemeijer, Saskia M. C. [8 ]
van der Reijden, Bert A. [9 ]
Podgornik, Helena [10 ,11 ]
Sever, Matjaz [10 ,12 ]
Tvedt, Tor H. A. [13 ]
Vulliamy, Tom [14 ]
Fitzgibbon, Jude [15 ]
Dokal, Inderjeet [15 ]
Baliakas, Panagiotis [16 ]
Bastida, Jose M. [17 ]
Pohlkamp, Christian [18 ]
Haferlach, Torsten [18 ]
Larcher, Lise [19 ,20 ]
Soulier, Jean [19 ,20 ]
Schutgens, Roger E. G. [21 ,22 ]
Freson, Kathleen [23 ]
Duployez, Nicolas [24 ]
Loewenberg, Bob [1 ,2 ]
Ericson, Katrin [25 ]
Cammenga, Joerg [26 ]
Ripperger, Tim [27 ]
Raaijmakers, Marc H. G. P. [1 ,2 ]
机构
[1] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands
[2] Erasmus MC, Canc Inst, Rotterdam, Netherlands
[3] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands
[4] Univ Med Ctr Groningen, Beatrix Childrens Hosp, Groningen, Netherlands
[5] Ulm Univ, Dept Internal Med 3, Ulm, Germany
[6] Univ Perugia, Dept Med & Surg, Sect Internal & Cardiovasc Med, Perugia, Italy
[7] Addenbrookes Hosp, Dept Haematol, Cambridge, England
[8] Radboud UMC, Dept Hematol, Nijmegen, Netherlands
[9] Radboud UMC, Dept Lab, Nijmegen, Netherlands
[10] Univ Med Ctr Ljubljana, Dept Hematol, Ljubljana, Slovenia
[11] Univ Ljubljana, Fac Pharm, Ljubljana, Slovenia
[12] Univ Ljubljana, Fac Med, Ljubljana, Slovenia
[13] Oslo Univ Hosp, Dept Haematol, Oslo, Norway
[14] Queen Mary Univ London, Blizard Inst, Fac Med & Dent, London, England
[15] Queen Mary Univ London, Barts Canc Inst, Haemato Oncol, London, England
[16] Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Uppsala, Sweden
[17] Univ Salamanca USAL, Complejo Asistencial Univ Salamanca CAUSA, Dept Hematol, Inst Invest Biomed Salamanca IBSAL,Dept Hematol, Salamanca, Spain
[18] Munich Leukemia Lab, Munich, Germany
[19] Univ Paris Cite, Inserm, Paris, France
[20] Hop St Louis, APHP, Paris, France
[21] Univ Med Ctr Utrecht, Ctr Benign Haematol Thrombosis & Haemostasis, Van Creveldklin, Utrecht, Netherlands
[22] Univ Utrecht, Utrecht, Netherlands
[23] Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Leuven, Belgium
[24] Ctr Hosp Reg Univ Lille, Biol & Pathol Ctr, Biol & Pathol Ctr, F-59037 Lille, France
[25] RUNX1 Res Program, Santa Barbara, CA USA
[26] Lund Univ, Skane Univ Hosp & Mol Med & Gene Therapy, Dept Hematol, Lund, Sweden
[27] Hannover Med Sch, Dept Human Genet, Hannover, Germany
来源
HEMASPHERE | 2025年 / 9卷 / 01期
关键词
MUTATIONS; VARIANTS; PREDISPOSITION; PROPENSITY; LANDSCAPE; LINE; AML; RECOMMENDATIONS; EXPRESSION; MANAGEMENT;
D O I
10.1002/hem3.70057
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页数:13
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