Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results.
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Biomarkers, Tumor
/ genetics
Combined Modality Therapy
Female
Follow-Up Studies
Hematopoietic Stem Cell Transplantation
Humans
Leukemia, Myeloid, Acute
/ genetics
Male
Middle Aged
Mutagenesis, Insertional
Prognosis
Retrospective Studies
Survival Rate
Tandem Repeat Sequences
Transplantation, Homologous
fms-Like Tyrosine Kinase 3
/ genetics
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
21
05
2021
accepted:
03
06
2021
revised:
27
05
2021
pubmed:
29
7
2021
medline:
19
2
2022
entrez:
28
7
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34316017
doi: 10.1038/s41375-021-01323-0
pii: 10.1038/s41375-021-01323-0
pmc: PMC8727286
mid: NIHMS1755121
doi:
Substances chimiques
Biomarkers, Tumor
0
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
90-99Subventions
Organisme : NCI NIH HHS
ID : U24 CA196171
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180821
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180863
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233338
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180882
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180888
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233328
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233290
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA233331
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
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.
doi: 10.1200/JCO.2010.30.2554
pubmed: 21220609
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.
doi: 10.1056/NEJMoa1516192
pubmed: 27276561
pmcid: 4979995
Grimwade D, Ivey A, Huntly BJ. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood. 2016;127:29–41.
doi: 10.1182/blood-2015-07-604496
pubmed: 26660431
pmcid: 4705608
Bullinger L, Döhner K, Döhner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017;35:934–46.
doi: 10.1200/JCO.2016.71.2208
pubmed: 28297624
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.
doi: 10.1016/S1097-2765(03)00505-7
pubmed: 14759363
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.
doi: 10.1016/0092-8674(91)90010-V
pubmed: 1648448
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.
doi: 10.1073/pnas.91.2.459
pubmed: 7507245
pmcid: 42968
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.
doi: 10.1182/blood.V91.6.1947
pubmed: 9490677
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.
doi: 10.1038/sj.onc.1203354
pubmed: 10698507
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.
doi: 10.1182/blood.V96.12.3907
pubmed: 11090077
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.
doi: 10.1158/0008-5472.CAN-05-0422
pubmed: 16266983
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.
doi: 10.1182/blood-2007-11-125476
pubmed: 18483393
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.
doi: 10.1182/blood-2009-03-209999
pubmed: 19602710
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.
doi: 10.1182/blood.V98.6.1752
pubmed: 11535508
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.
doi: 10.1182/blood.V99.12.4326
pubmed: 12036858
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.
doi: 10.1182/blood-2007-08-109090
pubmed: 17957027
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.
doi: 10.1182/blood-2012-06-431122
pubmed: 23377436
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.
doi: 10.1182/blood-2014-05-578070
pubmed: 25270908
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.
doi: 10.1182/blood-2016-08-733196
pubmed: 27895058
pmcid: 5291965
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.
doi: 10.1111/cas.13835
pubmed: 30320942
pmcid: 6272103
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.
doi: 10.1182/blood-2007-11-126664
pubmed: 19144992
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.
doi: 10.1038/leu.2015.292
pubmed: 26487272
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.
doi: 10.1056/NEJMoa1614359
pubmed: 28644114
pmcid: 5754190
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.
doi: 10.1182/blood-2005-05-2164
pubmed: 16051734
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.
doi: 10.1038/s41375-019-0483-z
pubmed: 31089248
pmcid: 8075860
Gray RJ. A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141–54.
doi: 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.
doi: 10.1016/0197-2456(96)00075-X
pubmed: 8889347
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.
doi: 10.1182/blood-2006-10-053181
pubmed: 17387224
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.
doi: 10.1182/blood.2019002697
pubmed: 31826241
pmcid: 6993016
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.
doi: 10.1182/blood-2016-04-711820
pubmed: 28490572
pmcid: 5501146
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.
doi: 10.1158/2159-8290.CD-18-1453
pubmed: 31088841