FLT3 mutations in acute myeloid leukemia: a review focusing on Blood 125, 32363245 (2015). Netw. J. Hematol. PubMedGoogle Scholar. Metzelder, S. et al. A stratified analysis of FLT3-ITD length by 2010 ELN genetic risk was performed in 123 patients (intermediate-I group, ITD<70bp, n=75 and ITD70bp, n=24; intermediate-II group, ITD<70bp, n=14 and ITD70bp, n=1; and adverse group, ITD<70bp, n=6 and ITD70bp, n=3). Password. Informed consent was a requisite for patients alive at the time of data lock (January 2019). Oncol. 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. All four patients with ITD insertions in TKD1 had mutations in DNTM3A, compared with 39 out of 96 patients (41%) with ITD insertions in the JMD domain (P=0.031). 17, 721749 (2019). However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. Type I FLT3is are active against both the FLT3-ITD or TKD, type II inhibitors are only active against FLT3-ITD, not TKD. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Article Ravandi, F. et al. In our cohort, FLT3-ITD was located in the JMD domain (JMD-B, JMD-S, JMD-Z and HR) in 98 patients and in the TKD1 domain (B1, NBL and B2) in four patients. Libura, M. et al. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. (4) Only five patients in our cohort received treatment with midostaurin (2 in induction and 3 in consolidation treatment); therefore, we were not able to draw conclusions regarding the prognostic impact of the length of the ITD as described in previous studies29,30. Off-target resistance includes clonal evolution during FLT3i therapy even when FLT3-ITDmut clone is lost70. Among those with NPM1 wild-type, all FLT3-ITDmut patients had an increased risk of relapse and inferior OS, regardless of the AR17. In the meantime, to ensure continued support, we are displaying the site without styles Because the comutation of DNMT3A (DNMT3A(mut)) has been suggested to negatively influence prognosis in AMLNPM1, we analyzed the impact of DNMT3A(mut) in FLT3-ITD subsets (absent, low, and high ratios). The Spanish group evaluated intermediate-risk AML patients treated with intensive chemotherapy. The two leading types of FLT3 mutations found in AML include internal tandem duplications in the juxtamembrane domain (ITD, 17-34%) and mutations in the tyrosine kinase domain (TKD) activation loop (~7%) ( 1 ). We also performed an ROC curve analysis for OS prediction excluding those 10 patients with more than 1 ITD insertion and obtained an AUC of 0.521. Nevertheless, in three patients, similar VAFs (<5% difference) were detected, which might indicate that these mutations occurred at the same timepoint as the FLT3 mutation.No significant differences were found between the ITD length and the mutational status of any of the remaining genes (Fig. and P.M; Writingoriginal draft, T.C. Administration of the triplet is associated with prolonged cytopenias, requiring close monitoring and experience with venetoclax based combinations. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITDmutated, relapsed or refractory AML. QTc prolongation >500ms emerged as a significant adverse event36. * Genes with a P value<0.05 in the MannWhitney test correlating mutational status with ITD length. A Conventional approach. (C) OS according to the FLT3-ITD length and allelic ratio. The CRc rates with quizartinib were similar to prior studies (48.2%), and 32% patients on the quizartinib arm underwent ASCT compared with 11% with salvage chemotherapy. 1,2 Real-time pCR, which has . The UKMRC group evaluated the presence of NPM1 co-mutations in young adult patients with AML. Brinton, L. T. et al. Abstract 44: CG806, a first-in-class FLT3/BTK inhibitor, exhibits Regardless of the regimen intensity, all clinical trial participants were grouped in a separate treatment category (n=15). Br. Blood 127, 360362 (2016). Green indicates non-mutated genes, red indicates mutated genes and white indicates non-mutated genes. As Dr. Erba explained, patients with FLT3 -ITD-positive AML represent a particularly poor prognostic group. Authors S1. An FLT3/ITD mutation was present in 27% of the patients and was associated with leukocytosis and a high percentage of bone marrow blast cells (P <.001 for both). 19, 889903 (2018). DiNardo, C. D. et al. Oncol. FLT3-ITD length was compared between mutation and wild-type groups for each of the 39 genes using a MannWhitney test. Clinical outcome stratified according to the FLT3-ITD length (cutoff 70bp) for all patients treated with intensive chemotherapy. Perl, A. E. et al. Sorafenib with azacitidine combination reported an overall response rate (ORR) of 78% (n=27) in the frontline patients not eligible for intensive induction31 and an ORR of 46% with an acceptable safety profile in R/R FLT3-ITDmut 32 which led to the inclusion of sorafenib with azacitidine combination as a 2B guideline in National Comprehensive Cancer Network (NCCN) for R/R FLT3-ITDmut AML33. Type I FLT3is like gilteritinib are less prone to develop secondary mutations in the TKD, although the gatekeeper F691M can confer resistance to gilteritinib71. 1B) we add a second generation FLT3i to the intensive induction backbone of cladribine or fludarabine with cytarabine and idarubicin (CLIA or FIA, respectively) as published previously by our group61,62. recently showed that ASCT in CR1 improved RFS and OS independent of the FLT3-ITDmut AR or NPM1mut status in patients with FLT3-ITDmut AML20. Blood 130, 721 (2017). Quizartinib demonstrated an OS of 6.2 months compared with 4.7 months with salvage chemotherapy (hazard ratio 0.76 and P=0.02). Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in acute myeloid leukemia Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in acute myeloid leukemia Blood Adv. and JavaScript. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in 13, 132 (2020). Fig. Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD).Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). and JM.A. 17 D2 D8, H-S Kim S Lee JH Kim 2018 Real-world evidence versus randomized controlled trial: Clinical research based on electronic medical records J Korean Med Sci 33 e213, RF Schlenk 2014 Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation Blood 124 3441 3449, I Abou Dalle 2020 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 Blood Cancer J. Figure legend Overall survival of patients with AML following frontline venetoclax plus hypomethylating agent Previously published cutoffs of ITD length, reported in more than one publication(i.e., 39bp and 70bp), were tested to check their applicability in our cohort. Therefore, there is a lack of consensus regarding the prognostic importance of the ITD IS and the subdomains that confer this adverse outcome. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. It is mutated in about 1/3 of acute myeloid leukemia (AML) patients, either by internal tandem duplications (ITD) of the juxtamembrane domain or by point mutations usually involving the kinase domain (KD). Cell 150, 264278 (2012). Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. These mutations arearranged in increasing order by FLT3-ITD length. The length of the 362 ITDs ranged from 3 to 201bp, with a median ITD length of 48bp.The distribution of ITD length can be observed in Supplementary Fig. Although common methylation . Internet Explorer). and P.M.; Supervision, J.M.A. The MORPHO phase III placebo-controlled trial evaluating post-transplant maintenance with gilteritinib in FLT3mut AML recently completed accrual and results are eagerly awaited (NCT02997202). Google Scholar. The median OS was 1.3years (CI 0.71.9) and 1.4years (CI 1.01.8), respectively (P=0.8). FLT3 -ITD has a poor prognostic impact in patients with AML at diagnosis. Google Scholar. In the frontline setting, there was a sequential decrease in CRc rates (77%31%25%) and OS (16.76.01.4 months). FLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. We currently recommend the incorporation of FLT3is and ASCT in CR1 in all ASCT eligible patients with a FLT3-ITDmut AML, irrespective of the AR and/or NPM1 co-mutation status. Abhishek Maiti, M. D. et al. FLT3 -TKD mutations are point mutations in the activation loop of FLT3, mainly represented by codon D835 or deletion of codon I836, which leads to a loss of auto-inhibition [ 18 ]. Heart J. Suppl. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. 21, 12011212 (2020). Larger studies of ITD size, although they did not employ these cutoffs, did not find prognostic power of this measure, which corroborates our results. 100, 184198 (2008). Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Among patients treated with gilteritinib, the median overall survival was similar among those with FLT3 ITD mutations alone (9.3 months) and those with FLT3 TKD mutations alone (8.0 months). Which FLT3 Inhibitor for Treatment of AML? Cancer Discov. Citation 56 The new FLT3 inhibitors, G-749 and ASP2215, have been proved to cause strong inhibition of FLT3 phosphorylation and increase the ability to overcome drug resistance in preclinical trials, but further studies are needed to evaluate their . Ohanian, M. et al. J. Hematol. 96 1993 2003, Article We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. PubMed As in previous works, we analyzed the clinical significance of FLT3-ITD length among fit patients treated with intensive regimens15,16. Acute myeloid leukemia patient with FLT3-ITD and NPM1 double mutation Although poor prognosis in AML is only associated with FLT3-ITD, all activating FLT3 mutations can contribute to leukemogenesis and are thus potential targets for therapeutic interventions. Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 gene ( FLT3) confer a poor prognosis in adult AML. Emergence of BCR-ABL1 fusion in AML post-FLT3 inhibitor-based therapy: a potentially targetable mechanism of resistancea case series. AbuDuhier, F. et al. The FLT3-ITD AR was available in 140 intensively treated patients. None of the studies has carried out an internal ITD length cutoff validation by dividing the patients into a training cohort and a validation cohort, which, given the arbitrary selection of the cutoffs used, would be necessary. Background and aims: To explore the relationship between FLT3 (encoding Fms related tyrosine kinase 3) internal tandem duplication (ITD) mutations with the prognosis of acute promyelocytic leukemia. Clin. In older patients not eligible for intensive therapy, patients with primary refractory disease or early relapse with a persistent FLT3 mutation we would suggest gilteritinib based therapy. 5).The study protocol was conducted following the guidelines of the Declaration of Helsinki and approved by the Ethics Committee for Clinical Research of the Hospital UniversitarioFundacin Jimnez Daz (PIC169-18_FJD).
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