94, 984991 (2019). S.V. Timothy, J. Cancer 51 910 924, AT Cohen S Goto K Schreiber C Torp-Pedersen 2015 Why do we need observational studies of everyday patients in the real-life setting? However, the median OS was 19.2 months in FLT3-TKDmut AML (19.2 months), but only 11.5 months in FLT3-ITDmut patients65. 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. 368, 20592074 (2013). Among the FLT3mut patients, response rates were numerically higher (33%) and remission duration was longer (31 versus 16 weeks, P=0.09) in those who were naive to treatment with FLT3 inhibitors compared with those who had been exposed to prior FLT3 inhibitors. Cancer Cell 1, 433443 (2002). Favorable relapse risk and OS were seen in NPM1mut with FLT3 wild-type; intermediate prognosis in FLT3-ITDmut with concurrent NPM1mut, and adverse prognosis in FLT3-ITDmut with NPM1 wild-type patients16. In fact, every quartile increase in FLT3-ITD AR (from 0.01 to 0.20, 0.20 to 0.53, 0.53 to 0.80, 0.80 to 1.19) was associated with worsening complete remission (CR) rates, RFS, and OS, highlighting the prognostic value of AR. Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia. It is important to note that none of these patients received a FLT3 inhibitor (FLT3i) during induction, consolidation, or post-ASCT. An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown).A stratified analysis of FLT3-ITD length on the basis ofthe AR was performed in 140 patients (AR<0.5 and ITD<39bp, n=17; AR<0.5 and ITD39bp, n=41; AR>0.5 and ITD<39bp, n=23; AR>0.5 and ITD39bp, n=59). CR or CRi was achieved in 70% of the patients in both groups (P=0.9). Flow diagram showing all AML patients with FLT3-ITD mutations in the study period between 2003 and 2019 on the basis of genetic data and treatment administered. 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 . A subsequent randomized phase IIb trial evaluated lower doses, 30 or 60mg of quizartinib daily, in patients with R/R FLT3-ITDmut AML. PubMed 93, E202E205 (2018). Haematologica (2021). Nature 485, 260263 (2012). SORAML, a randomized placebo-controlled trial evaluated the efficacy and tolerability of 3+7 induction-consolidation with or without sorafenib in patients 60 years with newly diagnosed AML, irrespective of a FLT3mut (only 34% had FLT3mut). Authors and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. However, other studies did not find significantly worse clinical outcomes in patients with non-JMD ITD mutations24,25. 21, 12011212 (2020). Enter the email address you signed up with and we'll email you a reset link. The addition of sorafenib to standard AML treatment results in a substantial reduction in relapse risk and improved survival. Fishers exact test was employed to correlate the ITD insertion site and mutational status. 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). The origin and evolution of mutations in acute myeloid leukemia. Samples from 118 of the 362 AML patients with FLT3-ITDmutations were analyzed with an NGS panel of 39 genes (see Supplementary Fig. S2) in PETHEMA centralized diagnostic laboratories as previously described33. Oncol. Front. 31, 3681 (2013). Google Scholar. TM,transmembrane domain; JMD, juxtamembrane domain; JMD-B, binding motif; JMD-S, switch motif; JMD-Z, zipper motif; HR, hinge region; TKD1, tyrosine kinase domain 1; B1, beta1-sheet; NBL, nucleotide binding loop; B2, beta2-sheet; and TKD2, tyrosine kinase domain 2. Blood Cancer J. 377, 454464 (2017). Brinton, L. T. et al. The choice of treatment backbone depends on the patients ability to successfully tolerate intensive chemotherapy. evaluated midostaurin with azacitidine in patients with both newly diagnosed and R/R AML regardless of FLT3 mutational status. 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. Cortes, J. E. et al. 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. Ann Hematol. Acute myeloid leukemia, Version 3.2019, NCCN clinical practice guidelines in oncology. FLT3 plays a role in cell survival, proliferation and differentiation of hematopoietic progenitor cells. Article However, previous studies have shown that FLT3/ITD mutation was not an independent adverse prognostic factor in DEK/CAN-positive AML patients. In patients with FLT3mut AML unsuitable for intensive chemotherapy, azacitidine with venetoclax demonstrated encouraging CR/CRi rates (5570%) and a median OS of 13.3 months64 which prompted the inclusion of this combination approach as part of NCCN AML guidelines (Fig. Blood Marrow Transplant 22, 12181226 (2016). Regarding the ITD insertion site, Kayseret al22,23 observed that adult AML patients with an ITD in the beta-1 sheet had significantly inferior OS and DFS compared to those with ITDs located in other regions. These observations have made FLT3 an attractive drug target. Using the same response criteria, the CRc rate was 85.4% (n=35/41) which compared favorably to 52% with gilteritinib alone in the ADMIRAL study. Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. Kadia, T. et al. F fludarabine, I idarubicin, CL cladribine, A cytarabine 1.52g/m2, HMA hypomethylating agent, CR complete remission, ECOG PS Eastern Cooperative Oncology Group Performance Status, CG cytogenetics, MRD measurable residual disease, SCT stem cell transplant, HiDAC high-dose cytarabine, CBC complete blood count. Lancet Oncol. We analyzed 118 patients (median age at diagnosis 58.3, range 14.3&ndash . 2014;19(6):324-8. Administration of the triplet is associated with prolonged cytopenias, requiring close monitoring and experience with venetoclax based combinations. The favorable prognostic molecular mutations, such as NPM-1 and CEBPA, are uncommon in elderly AML . To obtain The insertion site of FLT3-ITD was available in 106 of 118 patients (Fig. T.C. Blood 93, 30743080 (1999). A total of 164 patients diagnosed with AML-NPM1 included in 2 consecutive CETLAM protocols and with DNMT3A and FLT3 status available were studied. Google Scholar. 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 . On the other hand, we obtained a value (0.52) that was close to significant in the analysis of the prognostic impact of the FLT3-ITD AR according to the 2017 ELN cutoff8. Patients were classified into four therapeutic groups according to the first-line approach: intensive chemotherapy (IC), n=161; non-intensive therapy, n=43; clinical trial, n=15; and best supportive care (BSC) only, n=7. The median OS was 1.0years [CI not calculable (NC)], 2.3years (CI: 1.23.5), 1.6years (CI: 0.62.6) and 1.0years (CI: 0.81.2), respectively (P=0.9). CAS 28, 1856 (2010). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. Our results, alongside those of other non-significant reports, lead us to believe that FLT3-ITD length has neither prognostic value nor possible clinical application. fms3flt3-itdaml molm13baf3-flt3-itd p-erkp-akt . The median OS was 1.3years (CI 0.71.9) and 1.4years (CI 1.01.8), respectively (P=0.8). Intensive chemotherapy regimens were administered to 161 patients (idarubicin+cytarabine; 3+7, n=151 and 2+5, n=8; IDA-FLAG (fludarabine+Ara-C+idarubicin), n=1 and FLAG, n=1). Article QTc prolongation >500ms emerged as a significant adverse event36. FLT3 activating mutations ( FLT3mut) may involve either the juxta membrane domain [internal tandem duplication mutations ( FLT3 -ITD)] 4 or the tyrosine kinase domain ( FLT3 -TKD) 5, 6.. evaluated the impact of AR in 323 patients with newly diagnosed FLT3-ITDmut AML. S1. Upregulation of Bcl-2 confers resistance to FLT3 inhibition in FLT3-ITD AML with secondary acquired mutations. Among 38 patients with FLT3mut AML who received gilteritinib 120mg daily, the CRc rate was 81.6% (n=31) including 39.5% CR and median OS was not reached at a median follow-up of 35.8 months. 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. Hematology Department, Hospital Universitario Fundacin Jimnez Daz, Avenida Reyes Catlicos, 2, 28040, Madrid, Spain, Tamara Castao-Bonilla,Juan M. Alonso-Dominguez,Carlos Blas&Jose L. Lpez-Lorenzo, Instituto de Investigacin Sanitaria (IIS-FJD), Hospital Universitario Fundacin Jimnez Daz, Madrid, Spain, Tamara Castao-Bonilla,Juan M. Alonso-Dominguez,Carlos Blas,Jose L. Lpez-Lorenzo,Daniel Lainez-Gonzalez&Juana Serrano, Hematology Department, Hospital Universitario La Fe de Valencia, Valencia, Spain, Eva Barragn,Rebeca Rodrguez-Veiga,Claudia Sargas,David Martnez-Cuadrn,Miguel A. Sanz&Pau Montesinos, Hematology Department, Hospital General de Alicante, Alicante, Spain, Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain, Hematology Department, Hospital General de Castelln, Castelln, Spain, Hematology Department, Hospital Universitario Doce de Octubre, Complutense University, CNIO, Madrid, Spain, Molecular Biology Department, Cimalab Diagnosis, Clnica Universitaria de Navarra, Navarra, Spain, Hematology Department, Hospital Universitario Clnico San Carlos, Medicine Department, UCM, Madrid, Spain, Hematology Department, Hospital Universitario de Valladolid, Valladolid, Spain, Hematology Department, Hospital Universitario Ro Hortega, Valladolid, Spain, Hematology Department, Hospital Universitario Virgen del Roco, Instituto de Biomedicina de Sevilla (IBIS/CISC/CIBERON), Sevilla, Spain, Hematology Department, Hospital Universitario de Burgos, Burgos, Spain, Hematology Department, Hospital Ntra. The AR was determined by fragment length analysis and calculated as previously described32. prospectively evaluated decitabine and quizartinib (doublet) with or without venetoclax (triplet) in patients with newly diagnosed and R/R FLT3-ITDmut AML. FLT3-ITD fragment length analysis was performed in seven centralized PETHEMA laboratories. A randomized, placebo-controlled phase III study of 3+7 with quizartinib (QuANTUM-First; NCT02668653) in patients with newly diagnosed FLT3-ITDmut AML eligible for induction therapy recently completed accrual. Patients with an ITD fragment39bp or70bp had a significant reduction in OS and RFS in some of these studies, but we were unable to validate these findings11,15,16,17. N. Engl. The median RFS was 1.2years (CI 0.22.2) and 0.77years (CI 0.51.1), respectively (P=0.06). J. Clinl. To obtain 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. CAS The size of our cohort was larger than those of the studies published using these cutoffs. The phase III RATIFY study (CALGB 10603), for example, looked at the addition of the tyrosine kinase inhibitor midostaurin to intensive chemotherapy in newly-diagnosed AML with FLT3 mutations (either ITD or TKD) and showed an overall survival (OS) benefit with midostaurin compared to placebo (74.7 vs. 25.6 months, respectively) . PubMed Central Naval Daver, Richard F. Schlenk, Mark J. Levis, Alexander E. Perl, Naoko Hosono, Jessica K. Altman, Pierre-Yves Dumas, Emmanuel Raffoux, Christian Rcher, Richard A. Larson, Sumithra J. Mandrekar, Richard M. Stone, Iman Abou Dalle, Ahmad Ghorab, Gautam Borthakur, Ahmad I. Antar, Zaher K. Otrock, Ali Bazarbachi, Roni Shouval, Myriam Labopin, Arnon Nagler, Blood Cancer Journal