دورية أكاديمية
Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results.
العنوان: | Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results. |
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المؤلفون: | Rücker FG; Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany., Du L; Novartis Pharmaceuticals, Cambridge, MA, USA., Luck TJ; Department of Hematology, Oncology and Tumor Immunology, Charité University, Berlin, Germany., Benner A; Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany., Krzykalla J; Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany., Gathmann I; Novartis Pharmaceuticals, Basel, Switzerland., Voso MT; Department of Biomedicine and Prevention, Università di Roma 'Tor Vergata', Rome, Italy., Amadori S; Department of Biomedicine and Prevention, Università di Roma 'Tor Vergata', Rome, Italy., Prior TW; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Brandwein JM; Department of Medicine, University of Alberta, Edmonton, AB, Canada., Appelbaum FR; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Medeiros BC; Division of Hematology, Stanford Comprehensive Cancer Center, Stanford University, Stanford, CA, USA., Tallman MS; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA., Savoie L; University of Calgary, Calgary, AB, Canada., Sierra J; Hematology Department, Hospital de la Santa Creu i Sant Pau and Jose Carreras Leukemia Research Institute, Autonomus University of Barcelona, Barcelona, Spain., Pallaud C; Novartis Pharmaceuticals, Basel, Switzerland., Sanz MA; Hospital Universitario la Fe, Hematology Department, Department of Medicine, University of Valencia, Valencia, Spain., Jansen JH; Radboud Institute Molecular Studies, Radboud University Medical Center, Nijmegen, The Netherlands., Niederwieser D; Hematology and Oncology, University of Leipzig, Leipzig, Germany., Fischer T; Department of Hematology and Oncology, Center of Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany., Ehninger G; Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany., Heuser M; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany., Ganser A; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany., Bullinger L; Department of Hematology, Oncology and Tumor Immunology, Charité University, Berlin, Germany., Larson RA; Department of Medicine and Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA., Bloomfield CD; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Stone RM; Department of Medical Oncology, Dana-Farber/Partners CancerCare, Boston, MA, USA., Döhner H; Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany., Thiede C; Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany., Döhner K; Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany. konstanze.doehner@uniklinik-ulm.de. |
المصدر: | Leukemia [Leukemia] 2022 Jan; Vol. 36 (1), pp. 90-99. Date of Electronic Publication: 2021 Jul 28. |
نوع المنشور: | Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Publishing Group, Specialist Journals Country of Publication: England NLM ID: 8704895 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5551 (Electronic) Linking ISSN: 08876924 NLM ISO Abbreviation: Leukemia Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 2000- : London : Nature Publishing Group, Specialist Journals Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987- |
مواضيع طبية MeSH: | Mutagenesis, Insertional* , Tandem Repeat Sequences*, Antineoplastic Combined Chemotherapy Protocols/*therapeutic use , Biomarkers, Tumor/*genetics , Leukemia, Myeloid, Acute/*pathology , fms-Like Tyrosine Kinase 3/*genetics, Combined Modality Therapy ; Female ; Follow-Up Studies ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/therapy ; Male ; Middle Aged ; Prognosis ; Retrospective Studies ; Survival Rate ; Transplantation, Homologous |
مستخلص: | In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3-ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3-ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n = 251, 55%), JMD and TKD1 (JMD/TKD1; n = 117, 26%), and TKD1sole (n = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3-ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin. (© 2021. The Author(s).) |
References: | Marcucci G, Haferlach T, Döhner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol. 2011;29:475–86. Erratum in: J Clin Oncol. 2011;29(13):1798. (PMID: 10.1200/JCO.2010.30.255421220609) Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21. (PMID: 10.1056/NEJMoa1516192272765614979995) Grimwade D, Ivey A, Huntly BJ. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood. 2016;127:29–41. (PMID: 10.1182/blood-2015-07-604496266604314705608) Bullinger L, Döhner K, Döhner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017;35:934–46. (PMID: 10.1200/JCO.2016.71.220828297624) Griffith J, Black J, Faerman C, Swenson L, Wynn M, Lu F, et al. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell. 2004;13:169–78. (PMID: 10.1016/S1097-2765(03)00505-714759363) Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell. 1991;65:1143–52. (PMID: 10.1016/0092-8674(91)90010-V1648448) Small D, Levenstein M, Kim E, Carow C, Amin S, Rockwell P, et al. STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci USA. 1994;91:459–63. (PMID: 10.1073/pnas.91.2.459750724542968) Gotze KS, Ramirez M, Tabor K, Small D, Matthews W, Civin CI. Flt3high and Flt3low CD34+ progenitor cells isolated from human bone marrow are functionally distinct. Blood. 1998;91:1947–58. (PMID: 10.1182/blood.V91.6.19479490677) Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito H, et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene. 2000;19:624–31. (PMID: 10.1038/sj.onc.120335410698507) Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Müller C, et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood. 2000;96:3907–14. (PMID: 10.1182/blood.V96.12.390711090077) Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwäble J, et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res. 2005;65:9643–50. (PMID: 10.1158/0008-5472.CAN-05-042216266983) Breitenbuecher F, Schnittger S, Grundler R, Markova B, Carius B, Brecht A, et al. Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor. Blood. 2009;113:4074–77. (PMID: 10.1182/blood-2007-11-12547618483393) Kayser S, Schlenk RF, Londono MC, Breitenbuecher F, Wittke K, Du J, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114:2386–92. (PMID: 10.1182/blood-2009-03-20999919602710) Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1752–59. (PMID: 10.1182/blood.V98.6.175211535508) Thiede C, Steudel C, Mohr B, Schaich M, Schäkel U, Platzbecker U, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–35. (PMID: 10.1182/blood.V99.12.432612036858) Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111:2776–84. (PMID: 10.1182/blood-2007-08-10909017957027) Pratcorona M, Brunet S, Nomdedéu J, Ribera JM, Tormo M, Duarte R, et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Blood. 2013;121:2734–38. (PMID: 10.1182/blood-2012-06-43112223377436) Schlenk RF, Kayser S, Bullinger L, Kobbe G, Casper J, Ringhoffer M, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014;124:3441–49. (PMID: 10.1182/blood-2014-05-57807025270908) Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47. (PMID: 10.1182/blood-2016-08-733196278950585291965) Liu SB, Qiu QC, Bao XB, Ma X, Li HZ, Liu YJ, et al. Pattern and prognostic value of FLT3-ITD mutations in Chinese de novo adult acute myeloid leukemia. Cancer Sci. 2018;109:3981–92. (PMID: 10.1111/cas.13835303209426272103) Breitenbuecher F, Markova B, Kasper S, Carius B, Stauder T, Böhmer FD, et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML. Blood. 2009;113:4063–73. (PMID: 10.1182/blood-2007-11-12666419144992) Arreba-Tutusaus P, Mack TS, Bullinger L, Schnöder TM, Polanetzki A, Weinert S, et al. Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo. Leukemia. 2016;30:1220–25. (PMID: 10.1038/leu.2015.29226487272) Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377:454–64. (PMID: 10.1056/NEJMoa1614359286441145754190) Döhner K, Schlenk RF, Habdank M, Scholl C, Rücker FG, Corbacioglu A, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106:3740–6. (PMID: 10.1182/blood-2005-05-216416051734) Blätte TJ, Schmalbrock LK, Skambraks S, Lux S, Cocciardi S, Dolnik A, et al. getITD for FLT3-ITD-based MRD monitoring in AML. Leukemia. 2019;33:2535–39. (PMID: 10.1038/s41375-019-0483-z310892488075860) Gray RJ. A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141–54. (PMID: 10.1214/aos/1176350951) Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials. 1996;17:343–6. (PMID: 10.1016/0197-2456(96)00075-X8889347) Cox DR. Regression models and life-tables. J R Stat Soc Ser B Stat Methodol. 1972;34:187–220. Vempati S, Reindl C, Kaza SK, Kern R, Malamoussi T, Dugas M, et al. Arginine 595 is duplicated in patients with acute leukemias carrying internal tandem duplications of FLT3 and modulates its transforming potential. Blood. 2007;110:686–94. (PMID: 10.1182/blood-2006-10-05318117387224) Döhner K, Thiede C, Jahn N, Panina E, Gambietz A, Larson RA, et al. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia. Blood. 2020;135:371–80. (PMID: 10.1182/blood.2019002697318262416993016) Smith CC, Paguirigan A, Jeschke GR, Lin KC, Massi E, Tarver T, et al. Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis. Blood. 2017;130:48–58. (PMID: 10.1182/blood-2016-04-711820284905725501146) McMahon CM, Ferng T, Canaani J, Wang ES, Morrissette JJD, Eastburn DJ, et al. Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Cancer Discov. 2019;9:1050–63. (PMID: 10.1158/2159-8290.CD-18-145331088841) |
معلومات مُعتمدة: | U10 CA180821 United States CA NCI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; U10 CA180863 United States CA NCI NIH HHS; U24 CA196171 United States CA NCI NIH HHS; U10 CA180888 United States CA NCI NIH HHS; UG1 CA233328 United States CA NCI NIH HHS; UG1 CA233290 United States CA NCI NIH HHS; UG1 CA233331 United States CA NCI NIH HHS; U10 CA180882 United States CA NCI NIH HHS; UG1 CA233338 United States CA NCI NIH HHS |
المشرفين على المادة: | 0 (Biomarkers, Tumor) EC 2.7.10.1 (FLT3 protein, human) EC 2.7.10.1 (fms-Like Tyrosine Kinase 3) |
تواريخ الأحداث: | Date Created: 20210728 Date Completed: 20220218 Latest Revision: 20240211 |
رمز التحديث: | 20240211 |
مُعرف محوري في PubMed: | PMC8727286 |
DOI: | 10.1038/s41375-021-01323-0 |
PMID: | 34316017 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1476-5551 |
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DOI: | 10.1038/s41375-021-01323-0 |