Blood Marrow Transplant 22, 12181226 (2016). We thank the PETHEMA group for its participation in this study. Hypomethylating agent and venetoclax with FLT3 inhibitor triplet therapy in older/unfit patients with FLT3 mutated AML, Mechanisms of resistance to cancer therapy, Cancel Chyla, B. et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Provided by the Springer Nature SharedIt content-sharing initiative. The survival rates in patients 60 years of age were also similar across NPM1 mut /FLT3 wt, NPM1 mut /FLT3-ITD low, and NPM1 mut . 93, 213221 (2018). In order to improve the clinical condition of FLT3-ITD-positive patients, several FLT3 inhibitors have been developed showing variable results. 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. or reset password. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Eur. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. and P.M.; Project administration, J.M.A. N. Engl. Oran et al. Informed consent was a requisite for patients alive at the time of data lock (January 2019). 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. Seventeen patients underwent autologous hematopoietic progenitor transplantation, and forty-four patients underwent allogeneic hematopoietic progenitor transplantation (Table 1). FLT3ITD mutations in acute myeloid leukaemia - molecular FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. FLT3-ITD and NPM1 mutations were correlated, and the favorable prognostic impact of being FLT3-ITD negative and NPM1 mutation positive was evident only in patients aged 65 years or more. 3.3 TET2 in NPM1 mut /FLT3-ITD (), and CD34 and ID-Ara-C in NPM1 mut /FLT3 . PubMed Blood 97, 24342439 (2001). QuANTUM-R, a phase 3 randomized controlled trial, evaluated quizartinib monotherapy vs investigator choice salvage chemotherapy in R/R FLT3-ITDmut AML. 381, 17281740 (2019). 15 926 957, H Dhner DJ Weisdorf CD Bloomfield 2015 Acute myeloid leukemia N. Engl. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Blood 121, 27342738 (2013). Our treatment approach for FLT3mut AML in MD Anderson Cancer Center is as follows: in newly diagnosed patients who are eligible to receive intensive chemotherapy (Fig. Sorafenib is a first generation, type II multi-kinase FLT3i26 that demonstrated safety and efficacy (14/15 CR) in combination with the standard anthracycline/cytarabine induction therapy in newly diagnosed FLT3mut AML27. FLT3 Gene Mutation Profile and Prognosis in Adult Acute - PubMed 7, e724e736 (2020). McMahon, C. M. et al. Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine Patients treated with midostaurin had higher rates of anemia and skin rash compared to placebo and these were generally manageable with supportive care without necessitating dose reductions or interruptions in the majority of cases. These results led to the approval of gilteritinib monotherapy in the US and Europe in patients with R/R FLT3mut AML40. First, 161 AML patients with FLT3-ITD mutations treated with IC were analyzed using 39bp as the cutoff (<39bp; n=48,39bp; n=113). Prognostic significance of FLT3-ITD length in AML patients - Nature DiNardo, C. D. et al. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. J. Med. The impact of prognostic factors may change as the AML treatment landscape evolves. Patients diagnosed with acute promyelocytic leukemia (APL) were excluded. 135, 397402 (1986). Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. You are using a browser version with limited support for CSS. Internet Explorer). Sasaki, K. et al. In the treatment-naive setting, the median time to neutrophil and platelet recovery among responders was 45 and 30 days, respectively, suggesting cumulative myelosuppression is to be expected and further optimization of triplets schedules is ongoing55. Any variant allele frequency data were reported rarely. Unlike midostaurin, quizartinib monotherapy, even at lower doses demonstrated significant marrow remissions in R/R FLT3mut AML35,36,37. Due to the preliminary nature of the . As in previous works, we analyzed the clinical significance of FLT3-ITD length among fit patients treated with intensive regimens15,16. Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. The median OS was 2.4years (CI 05.5), 1.7years (CI: 04.4), 1.3years (CI 0.62.0), 1.5years (CI: 0.22.7), 0.9years (CI NC) and 2.3years (CI: 04.8), respectively. Jarno Kivioja, Disha Malani, Caroline A. Heckman, Iman Abou Dalle, Ahmad Ghorab, Gautam Borthakur, Frank G. Rcker, Ling Du, Konstanze Dhner, Feng-Ming Tien, Cheng-Hong Tsai, Hwei-Fang Tien, Kun-yin Qiu, Xiong-yu Liao, Dun-hua Zhou, Nikolaus Jahn, Ekaterina Jahn, Konstanze Dhner, Scientific Reports Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. Cancer 125, 37553766 (2019). Cite this article. Br. It's the most common genetic change in acute myeloid leukemia (AML), a type of leukemia that starts in the bone marrow and. A Conventional approach. Our real-life cohort was composed of 362 patients, most of whom were not included in clinical trials. Oncol. Similarly, a stratified analysis of FLT3-ITD length on the basis of 2010 ELN genetic risk was performed in 123 patients (intermediate-I group, ITD<39bp, n=31 and ITD39bp, n=68; intermediate-II group, ITD<39bp, n=5 and ITD39bp, n=10; and adverse group, ITD<39bp, n=2 and ITD39bp, n=7). (C) OS according to the FLT3-ITD length and allelic ratio. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain Prevalence of FLT3, NPM1 and CEBPA Mutations and Correlation to Clinical impact of change of FLT3 mutation status in acute myeloid 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. We currently recommend post-transplant maintenance with a FLT3i for at least 2 years (potentially indefinitely as there is limited data on the incidence of possible late relapses) in all FLT3mut AML. Patients with NPM1-/FLT3- showed complex karyotype (24%) and t(8;21) (8%). J. Haematol. Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. Characteristics and outcome of patients with core binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study. We further compared the survival of patients with FLT3-ITD and those with FLT3-D835 mutation in the Positive/Positive and Negative/Positive groups (Figure 3). Recurrent somatic internal tandem duplications (ITD) in the FMS-like tyrosine kinase 3 (FLT3) gene characterise approximately one third of patients with acute myeloid leukaemia (AML), and FLT3-ITD mutation status guides risk-adapted treatment strategies.The aim of this work was to characterise FLT3-ITD variant distribution in relation to molecular and clinical features, and overall survival in . Sorafenib plus intensive chemotherapy improves survival in patients with newly diagnosed, FLT3-internal tandem duplication mutation-positive acute myeloid leukemia. The sorafenib treatment arm had increased rates of adverse events, particularly diarrhea, bleeding, cardiac events, hand-foot-skin reaction, and rash but with no significant increase in the 30- or 60-day mortality between the two treatment arms. 5, 6 The FLT3 gene is a member of the class III receptor tyrosine kinase family, including c-kit, c-fms, and the platelet-derived growth factor receptors. This result is similar to the RATIFY study, in which 44% of patients lost FLT3 ITD under treatment with midostaurin 36. Differential impact of allelic ratio and insertion site in FLT3-ITDpositive AML with respect to allogeneic transplantation. 5 e336, S-B Liu 2019 Impact of FLT3-ITD length on prognosis of acute myeloid leukemia Haematologica 104 e9 e12, X Jiang 2018 Influence of FLT3-ITD mutation and length on the treatment response and prognosis in cytogenetically normal AML patients Blood 132 5245 5245, C Allen 2013 The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia Leukemia 27 1891 1901, X Quan J Deng 2020 Core binding factor acute myeloid leukemia: Advances in the heterogeneity of KIT, FLT3, and RAS mutations (Review) Mol. Castao-Bonilla, T., Alonso-Dominguez, J.M., Barragn, E. et al. Blood 130, 721 (2017). Prognostic analyses were performed using the 70bp cutoff in 161 AML patients with FLT3-ITD mutations treated with IC (<70bp; n=119,70bp; n=42). Mali, R. S. et al. Low relapse rate in younger patients 60 years old with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) treated with crenolanib and cytarabine/anthracycline chemotherapy. Among 14 R/R FLT3mut AML patients, the CRc rate was 64% with FLT3-PCR negativity in 88% of responders. Unfortunately, in our study, information on the site of insertion was not available in the whole cohort, and few patients harbored a TKD1 insertion.We did not carry out a statistical analysis of the insertion site given the heterogeneity in the treatment of patients analyzed and the small number of patients with an ITD inserted in the TKD1 domain. In our experienced cases FLT3-ITD mutation in MDS showed shorter duration to AML transformation and very poor prognosis. FLT3 mutations in acute myeloid leukemia: a review focusing on Andrew, H. et al. Acta Haematol. Finally, a different report showed worse clinical outcomes in terms of OS and DFS in the TKD1 group. Internet Explorer). This work was supported in part by the MD Anderson Cancer Centre Support Grant (CCSG) CA016672, the MD Anderson Cancer Center Leukemia SPORE CA100632, the Charif. This work is submitted in partial fulfillment of the requirement for the PhD. Staurosporine, a potent inhibitor of phospholipid Ca++ dependent protein kinase. PubMed CR or CRi was achieved in 70% of the patients in both groups (P=0.9). Sra. Ravandi, F. et al. FLT3 -ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. Despite the current availability of the FLT3 inhibitor midostaurin, there is an unmet need for improved treatment options. FLT3-ITD mutation is one of the most commonly identified gene mutations in AML while being an infrequent mutation in MDS and acute lymphocytic leukemia. NGS, next-generation sequencing. 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. Blood 130, 566 (2017). Kottaridis, P. D. et al. Stone, R. M. et al. 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). 1). Google Scholar. Oncol. The data described in the literature alongside the results that we have obtained regarding ITD mutation lead us to believe that future studies should focus on the functional characterization of the protein products of the mutated genes. SORMAIN, a placebo-controlled randomized phase II trial evaluated post-transplant sorafenib maintenance in patients with FLT3-ITDmut AML with RFS post-ASCT as the primary endpoint. Hematology. DNA was extracted using automated or manual DNA extraction kits following the manufacturers recommendations. DiNardo, C. D. et al. Activating FLT3 Mutants Show Distinct Gain-of-Function - PLOS Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. 9, 10501063 (2019). Google Scholar. Blood Cancer J. is a PhD candidate at Universidad Autnoma de Madrid (UAM). and JM.A. 10, 588876- (2020). Slider with three articles shown per slide. Yamatani, K. et al. A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. and P.M.; Data curation, J.M.A. Gilteritinib with venetoclax (NCT03625505) was evaluated in 41 patients with heavily pretreated R/R FLT3mut AML (median salvage 2, 65% previously exposed to FLT3i)40,53. Lancet Haematol. Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/refractory FLT3-mutated Acute Myeloid Leukemia in the Expansion Cohort of a Phase 1b Study (ASH, 2020). (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. Cladribine added to daunorubicin-cytarabine induction prolongs survival of FLT3-ITD+ normal karyotype AML patients. Type I FLT3is like gilteritinib are less prone to develop secondary mutations in the TKD, although the gatekeeper F691M can confer resistance to gilteritinib71. However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. J. Hematol. Among 362 patients, NGS was performed in 118 patients using a panel of 39 genes. By submitting a comment you agree to abide by our Terms and Community Guidelines. Weisberg, E. et al. A comparable decrease in CRc rates (45%21%10%) and OS (7.94.04.1 months) was observed with sequential FLT3i-based therapies in the R/R AML setting73. FLT3-ITD Mutation and FLT3 Ligand Plasma Level Were Not Associated wit ___ Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. In patients with newly diagnosed AML, FLT3-ITDmut is a poor prognostic factor in terms of relapse-free (RFS) and overall survival (OS)7,8,9,10. de Sonsoles de vila-Complejo Asistencial vila, vila, Spain, Hematology Department, Hospital General de Albacete, Albacete, Spain, Hematology Department, Hospital Universitario de Gran Canaria Doctor Negrn, Las Palmas de Gran Canaria, Spain, Carlos Rodrguez-Medina&Cristina Bilbao-Syeiro, Hematology Department, Hospital General Ciudad de Jan, Jan, Spain, UGC de Hematologia, Hospital U. Reina Sofia, IMIBIC, UCO, Cordoba, Crdoba, Spain, Josefina Serrano&Joaqun Snchez-Garca, Hematology Department, Hospital Comarcal del Bierzo, Len, Spain, Hematology Department, Hospital Universitario Doctor Peset, Valencia, Spain, Hematology Department, Hospital Clnico Universitario Lozano Blesa, Zaragoza, Spain, Hematology Department, Complejo Hospitalario de Navarra, Navarra, Spain, You can also search for this author in