Impact of numerical variation, allele burden, mutation length and co-occurring mutations on the efficacy of tyrosine kinase inhibitors in newly diagnosed FLT3- mutant acute myeloid leukemia.
Adolescent
Adult
Aged
Aged, 80 and over
Alleles
Cytogenetics
Female
Humans
Leukemia, Myeloid, Acute
/ diagnosis
Male
Middle Aged
Mutation
/ drug effects
Nucleophosmin
Prognosis
Protein Kinase Inhibitors
/ therapeutic use
Survival Analysis
Treatment Outcome
Young Adult
fms-Like Tyrosine Kinase 3
/ genetics
Journal
Blood cancer journal
ISSN: 2044-5385
Titre abrégé: Blood Cancer J
Pays: United States
ID NLM: 101568469
Informations de publication
Date de publication:
04 05 2020
04 05 2020
Historique:
received:
01
10
2019
accepted:
17
02
2020
revised:
07
01
2020
entrez:
6
5
2020
pubmed:
6
5
2020
medline:
5
5
2021
Statut:
epublish
Résumé
FLT3-ITD mutations in newly diagnosed acute myeloid leukemia (AML) are associated with worse overall survival (OS). FLT3-ITD diversity can further influence clinical outcomes. Addition of FLT3 inhibitors to standard chemotherapy has improved OS. The aim of this study is to evaluate the prognostic impact of FLT3 diversity and identify predictors of efficacy of FLT3 inhibitors. We reviewed prospectively collected data from 395 patients with newly diagnosed FLT3-ITD mutant AML. 156 (39%) patients received FLT3 inhibitors combined with either high or low intensity chemotherapy. There was no statistically significant difference in clinical outcomes among patients treated with FLT3 inhibitors based on FLT3 numerical variation (p = 0.85), mutation length (p = 0.67). Overall, the addition of FLT3 inhibitor to intensive chemotherapy was associated with an improved OS (HR = 0.35, 95% CI: 0.24-0.5, p = 0.0005), but not in combination with lower intensity chemotherapy (HR = 0.98, 95%CI: 0.7-1.36, p = 0.85). A differential effect of FLT3 inhibitor on OS was more pronounced in younger patients with FLT3 allelic ratio ≥0.5 (HR = 0.41, 95% CI: 0.25-0.66, p < 0.001), single ITD mutation (HR = 0.55, 95% CI: 0.34-0.88, p = 0.01), diploid cytogenetics (HR = 0.52, 95% CI: 0.35-0.76, p = 0.001), NPM1 co-mutation (HR = 0.35, 95% CI: 0.19-0.67, p = 0.001). Our analysis identifies predictors of survival among diverse FLT3 related variables in patients treated with FLT3 inhibitor.
Identifiants
pubmed: 32366841
doi: 10.1038/s41408-020-0318-1
pii: 10.1038/s41408-020-0318-1
pmc: PMC7198530
doi:
Substances chimiques
NPM1 protein, human
0
Protein Kinase Inhibitors
0
Nucleophosmin
117896-08-9
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
48Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Références
Nakao, M. et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 10, 1911–1918 (1996).
pubmed: 8946930
Kottaridis, P. D. 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 98, 1752–1759 (2001).
doi: 10.1182/blood.V98.6.1752
Thiede, C. 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 99, 4326–4335 (2002).
doi: 10.1182/blood.V99.12.4326
Schnittger, S. et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 100, 59–66 (2002).
doi: 10.1182/blood.V100.1.59
Grafone, T., Palmisano, M., Nicci, C. & Storti, S. An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment. Oncol. Rev. 6, e8 (2012).
doi: 10.4081/oncol.2012.e8
Griffith, J. et al. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol. Cell 13, 169–178 (2004).
doi: 10.1016/S1097-2765(03)00505-7
Frohling, S. et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 100, 4372–4380 (2002).
doi: 10.1182/blood-2002-05-1440
Dohner, H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129, 424–447 (2017).
doi: 10.1182/blood-2016-08-733196
O’Donnell, M. R. et al. Acute Myeloid Leukemia, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 15, 926–957 (2017).
doi: 10.6004/jnccn.2017.0116
Gale, R. E. 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 111, 2776–2784 (2008).
doi: 10.1182/blood-2007-08-109090
Stirewalt, D. L. et al. Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood 107, 3724–3726 (2006).
doi: 10.1182/blood-2005-08-3453
Kusec, R. et al. More on prognostic significance of FLT3/ITD size in acute myeloid leukemia (AML). Blood 108, 405–406 (2006).
doi: 10.1182/blood-2005-12-5128
Kim, Y. et al. Quantitative fragment analysis of FLT3-ITD efficiently identifying poor prognostic group with high mutant allele burden or long ITD length. Blood Cancer J. 5, e336 (2015).
doi: 10.1038/bcj.2015.61
Schlenk, R. F. et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood 124, 3441–3449 (2014).
doi: 10.1182/blood-2014-05-578070
Fischer, M. et al. Impact of FLT3-ITD diversity on response to induction chemotherapy in patients with acute myeloid leukemia. Haematologica. 102, e129–e31. (2017).
doi: 10.3324/haematol.2016.157180
Daver, N., Schlenk, R. F., Russell, N. H. & Levis, M. J. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia 33, 299–312 (2019).
doi: 10.1038/s41375-018-0357-9
Stone, R. M. et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 Mutation. The New Engl. J. Med. 377, 454–64. (2017).
doi: 10.1056/NEJMoa1614359
Levis, M. Midostaurin approved for FLT3-mutated AML. Blood 129, 3403–3406 (2017).
doi: 10.1182/blood-2017-05-782292
Schlenk, R. F. et al. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood 133, 840–851 (2019).
doi: 10.1182/blood-2018-08-869453
Uy, G. L. et al. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 1, 331–340 (2017).
doi: 10.1182/bloodadvances.2016003053
Chang, E. et al. The combination of FLT3 and DNA methyltransferase inhibition is synergistically cytotoxic to FLT3/ITD acute myeloid leukemia cells. Leukemia 30, 1025–1032 (2016).
doi: 10.1038/leu.2015.346
Ohanian, M. et al. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. Am. J. Hematol. 93, 1136–1141 (2018).
doi: 10.1002/ajh.25198
Macdonald, D. A. et al. A phase I/II study of sorafenib in combination with low dose cytarabine in elderly patients with acute myeloid leukemia or high-risk myelodysplastic syndrome from the National Cancer Institute of Canada Clinical Trials Group: trial IND.186. Leuk. Lymphoma 54, 760–766 (2013).
doi: 10.3109/10428194.2012.737917
Bowen, D. et al. AC220 (Quizartinib) can be safely combined with conventional chemotherapy in older patients with newly diagnosed acute myeloid leukaemia: experience from the AML18 pilot trial. Blood 122, 622 (2013).
doi: 10.1182/blood.V122.21.622.622
Swaminathan, M. et al. The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients (Pts) with FLT3-ITD mutated myeloid leukemias: interim report of a phase I/II trial. Blood 130(Suppl 1), 723 (2017).
Borthakur, G. et al. Impact of numerical variation in FMS-like tyrosine kinase receptor 3 internal tandem duplications on clinical outcome in normal karyotype acute myelogenous leukemia. Cancer 118, 5819–5822 (2012).
doi: 10.1002/cncr.27571
Schranz, K. et al. Clonal heterogeneity of FLT3-ITD detected by high-throughput amplicon sequencing correlates with adverse prognosis in acute myeloid leukemia. Oncotarget 9, 30128–30145 (2018).
doi: 10.18632/oncotarget.25729
Liu, S. B. et al. Impact of FLT3-ITD length on prognosis of acute myeloid leukemia. Haematologica 104, e9–e12 (2019).
doi: 10.3324/haematol.2018.191809
Pratcorona, M. 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 121, 2734–2738 (2013).
doi: 10.1182/blood-2012-06-431122
Pratz, K. W. et al. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood 115, 1425–1432 (2010).
doi: 10.1182/blood-2009-09-242859
Chen, F., Ishikawa, Y., Akashi, A., Naoe, T. & Kiyoi, H. Co-expression of wild-type FLT3 attenuates the inhibitory effect of FLT3 inhibitor on FLT3 mutated leukemia cells. Oncotarget 7, 47018–47032 (2016).
pubmed: 27331411
pmcid: 5216920
Döhner, K. et al. Prognostic Impact of NPM1/FLT3-ITD genotypes from randomized patients with acute myeloid leukemia (AML) treated within the international ratify study. Blood 130(Suppl 1), 467 (2017).
Knapper, S. et al. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. Blood 129, 1143–1154 (2017).
doi: 10.1182/blood-2016-07-730648
Rücker, F. G. et al. Prognostic impact of insertion site in acute myeloid leukemia (AML) with FLT3 internal tandem duplication: results from the ratify study (Alliance 10603). Blood 132(Suppl 1), 435 (2018).
doi: 10.1182/blood-2018-99-116149
Arreba-Tutusaus, P. et al. Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo. Leukemia 30, 1220–1225 (2016).
doi: 10.1038/leu.2015.292