Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. While both FLT3-ITD and FLT3-TKD mutations are common in AML with a normal karyotype, these mutations are also identified in AML with various karyotypic abnormalities. FLT3 -ITD is located within exon 14, corresponding to JMD,. 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. Xuan, L. et al. Sra. 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). Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens. Mali, R. S. et al. 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. Type I FLT3is are active against both the FLT3-ITD or TKD, type II inhibitors are only active against FLT3-ITD, not TKD. recently presented the first triplet combination of venetoclax, FLT3i (mainly gilteritinib or sorafenib), and decitabine from the FLT3mut subset of the prospective decitabine 10 days with venetoclax study (NCT03404193)54. Clin. By submitting a comment you agree to abide by our Terms and Community Guidelines. N. Engl. Remember me on this computer. DiNardo, C. D. et al. Mechanistically, FLT3-ITDs and FLT3-TKDs induce activation of transduction intermediates, including STAT5, AKT, and ERK1/2 ( 2 ). **If the C1 D14 bone marrow show >5% blastscontinue venetoclax, FLT3i till D21. 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. Elderly patients with AML have a distinct genetic landscape compared with the younger population. J. Med. Biol. All samples investigated in this study were obtained at the time of diagnosis. Welch John, S. et al. In a study that identified molecular mechanisms of resistance to gilteritinib, 32% of patients had emergent mutations in the RAS/MAPK pathway (K/NRAS), and 5% had emergent BCR/ABL1 fusions71. Naval Daver. Regrettably, patients with information on the IS of ITD available had received different treatments: intensive chemotherapy, n=37; non-intensive therapy, n=14; clinical trials, n=6; and best supportive care, n=2. FLT3-ITD length was compared between mutation and wild-type groups for each of the 39 genes using a MannWhitney test. The primary resistance mechanisms include specific FLT3-TKD mutations (either single TKD mutations or compound mutations within the FLT3-ITD allele), mutations in genes other than FLT3, activation of alternative signaling pathways in leukemic cells or the bone marrow microenvironment that confer resistance to FLT3i68. Blood Marrow Transplant 22, 12181226 (2016). ; Writingreview and editing, J.M.A., E.B., R.R.V., C.S., C.G., M.C.C., M.B.V., R.G., J.M.L., R.M.A., M.J.L., E.A., R.C., A.C., E.C., E.S.S., J.L., I.R., L.A., C.R.M., C.B.S., J.A.L.L., J.S., E.C., M.J.S., M.T.O., J.S.G., M.M., C.B., J.L.L.L., D.L., J.S., D.M.C., M.A.S. 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. In those patients with more than one ITD mutation, only the longest mutation was selected for statistical analysis (10 patients had>1 ITD mutation). Oran et al. Oncol. Pratz, K. W. et al. ABSTRACT. Am. Heart J. Suppl. FLT3-ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia and is associated with worse clinical outcome. Midostaurin has been approved and widely used in combination with induction and consolidation therapy in patients with newly diagnosed FLT3mut AML25. 120.000 new AML cases and over . 96 1993 2003, Article J. Med. CAS 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. In general, AML patients with intermediate-risk cytogenetics and with a FLT3-ITD mutation have a significantly poorer prognosis with an increased relapse risk and decreased . Secondary mutations as mediators of resistance to targeted therapy in leukemia. Rllig, C. et al. Leukemia 26, 23532359 (2012). The current European Leukemia Net (ELN) guidelines categorize FLT3 -ITDmut AML as favorable (NPM1mut with FLT3 wild-type Or NPM1mut with FLT3-ITD AR<0.5), intermediate (NPM1mut with FLT3-ITD AR>0.5 Or NPM1WT with FLT3-ITD AR<0.5), or adverse (NPM1WT with FLT3-ITD AR>0.5)18. 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 Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Analysis of FLT3-ITD insertion sites from 106 FLT3-ITD-positive AML patients. In another randomized phase III study comparing post-ASCT sorafenib maintenance (n=100) to non-maintenance (n=102), sorafenib demonstrated an improved 1-year OS (82.1% vs 68%, P=0.012) and a decreased 1-year cumulative incidence of relapse (7% vs 24.5%, P=0.001) in FLT3-ITDmut AML patients undergoing ASCT in CR143. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Which FLT3 Inhibitor for Treatment of AML? In the frontline setting, there was a sequential decrease in CRc rates (77%31%25%) and OS (16.76.01.4 months). However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. MRD detection in AML leverages cutoff points garnered from various detection methods include flow cytometry or real-time quantitative polymerase chain reaction (pCR). Patients with NPM1-/FLT3- showed complex karyotype (24%) and t(8;21) (8%). B MD Anderson Cancer Center Approach. Brinton, L. T. et al. Minetto, P. et al. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . 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. Close Log In. Nevertheless, the short duration of remission with single-agent FLT3is in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3is remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML. Gale, R. E. et al. In the last 25years, advances in molecular techniques have allowed a greater understanding of the pathogenesis of AML and the subsequent development of targeted therapies and a more refined prognostic classification based on the genetic features of the disease2,3. AR is defined as the ratio of ITD-mutated alleles to wild-type allele (FLT3ITD/FLT3 wild-type)13. Although common methylation . and JavaScript. 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. Leukemia 10, 19111918 (1996). The median RFS was 1.2years (CI 0.22.2) and 0.77years (CI 0.51.1), respectively (P=0.06). These mutations arearranged in increasing order by FLT3-ITD length. Informed consent was a requisite for patients alive at the time of data lock (January 2019). FLT3-ITDs show great variation in size (ranging from 3 to more than 400 base pairs (bp)), insertion sites (ISs), allelic ratios (ARs) and the number of clones5. NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 Chinese patients with de novo acute myeloid leukemia. 7+37 days of cytarabine and 3 days of daunorubicin. https://doi.org/10.1038/s41598-021-00050-x. Alotaibi, A. S. et al. 16, 16911699 (2015). If C1 D28 marrow confirms remission and ANC<0.5 and/or platelet<50K consider interrupting FLT3i and using neupogen to enhance count recovery. or reset password. Mutations of the fms-tyrosine kinase ( FLT3) were first described in 1997 4 and account for the most frequent molecular mutations in AML. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. Ann Hematol. Complete response (CR) or complete responses with incomplete hematologic recovery (CRi) were defined according to current 2017 ELN guidelines8. Blood 135, 791803 (2020). 5 96 102, C Sargas 2020 Networking for advanced molecular diagnosis in acute myeloid leukemia patients is possible: The PETHEMA NGS-AML project Haematologica https://doi.org/10.3324/haematol.2020.263806, Article Hematology. 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. The median OS was 2.3years (CI: 1.03.6), 1.4years (CI: 1.01.8), 1.1years (CI: 0.81.3) and 1.0years (CI: 0.31.8), respectively (P=0.9). The NPM1/FLT3-ITD patients had normal karyotypes. PubMedGoogle Scholar. Expression and signal transduction of the FLT3 tyrosine kinase receptor. Gilteritinib was generally well tolerated but was associated with increased incidence of gastrointestinal side effects, most frequently diarrhea although nausea has been occasionally observed. Article Oncol. We used the 0.5 cutoff of the AR as recommended by the 2017 ELN guidelines8.These patients were divided on the basis of the FLT3-ITD AR into an FLT3-ITDLOWgroup (41%; n=58) and an FLT3-ITDHIGHgroup (59%; n=82). FLT3-TKD activating mutations also constitutively activate FLT311; however, they have not been associated with a consistent prognostic impact12. Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. Hematol. Burnett, A. K., Russell, N. H. & Hills, R. K. Group obotUKNCRIAMLS. However, whether these findings are specific to Ven + HMA therapy remains to be . PubMed Central Given the increasing importance that massive sequencing techniques are acquiring in the prognosis determination and therapeutic management of AML patients, we decided to study the possible correlation between the length or site of the insertion of the mutated ITD fragment and the mutational profile of these patients. FLT3 -ITD was a poor prognostic factor in both age groups, but the favorable prognostic impact of NPM1 was more evident in patients aged 65 years or more. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. https://doi.org/10.1038/s41408-021-00495-3, DOI: https://doi.org/10.1038/s41408-021-00495-3. 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. Cancer Res. No significant difference was found between acute myeloid leukemia patients with these Blood Cancer J. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). Abhishek Maiti, M. D. et al. 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. DiNardo, C. D. et al. J. Med. Lancet Oncol. We have no information on the treatment received by the remaining patients. Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models. Final results of the chrysalis trial: a first-in-human phase 1/2 dose-escalation, dose-expansion study of gilteritinib (ASP2215) in patients with relapsed/refractory acute myeloid leukemia (R/R AML). J. Hematol. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. This result is similar to the RATIFY study, in which 44% of patients lost FLT3 ITD under treatment with midostaurin 36. Oncogene 21, 25552563 (2002). Recently, a double-blind placebo-controlled study reported a trend toward improved OS but not EFS with sorafenib combined with intensive chemotherapy in the frontline setting, especially among those with high FLT3-ITDmut AR >0.730. The combination continues to enroll. 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. 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.. & Ley, C., Network CGAR. The median length of the ITD in four patients with SF3B1mutations was 15bp vs 48bp in patients without SF3B1 mutations (n=64) (P=0.012). Green indicates non-mutated genes, red indicates mutated genes and white indicates non-mutated genes. 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 "For patients with AML, the 5-year survival rate is only about 29%," said Dr. Erba. 4). Phase 3, Multicenter, Open-label Study of Gilteritinib, Gilteritinib plus Azacitidine, or Azacitidine Alone in Newly Diagnosed FLT3-Mutated (FLT3mut+) Acute Myeloid Leukemia (AML) Patients Ineligible for Intensive Induction Chemotherapy (ASH, 2020). However, emerging data does suggest that patients with FLT3-ITDmut AR<0.5 and NPM1 co-mutation without concurrent high-risk mutations such as DNMT3A, TP53, TET2, or high-risk cytogenetics may be a more favorable subset, who may be considered for induction, consolidation followed by maintenance therapy without ASCT on a case by case basis if they achieve early MRD negativity using a highly sensitive MRD assay. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. We have no explanation regarding the reduced number of patients with an FLT3-ITD inserted in TKD1 found in our cohort. Therefore, in patients not eligible for intensive chemotherapy at MDACC, we prefer a combination of HMA with venetoclax and FLT3i (gilteritinib) over an HMA with venetoclax doublet (Fig. Commun. 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. Lymphoma 54 145 152, S Schnittger 2012 Diversity of the juxtamembrane and TKD1 mutations (Exons 1315) in the FLT3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data Genes Chromosom. PCR with fluorescently labeled primers followed by capillary electrophoresis for FLT3-ITD was performed as described elsewhere31. Burchert, A. et al. Altman, J. K. et al. The favorable prognostic molecular mutations, such as NPM-1 and CEBPA, are uncommon in elderly AML . Increase in bilirubin and transaminase can be seen with giltertiinib but are usually self-resolving and transient. Informed consent was a requisite for patients alive at the time of data lock (January 2019). Rydapt Prescribing Information. Yalniz, F. et al. In sensitivity analysis, no significant . Am. (A) Overall survival. and JM.A. Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 gene ( FLT3) confer a poor prognosis in adult AML. DNA quantification was performed with a Nanodrop (Thermo Fisher Scientific, Waltham,MA) or Qubitfluorometer (Thermo Fisher Scientific, Waltham, MA). Wang, E. S. et al. Front. 2013 220 226, H Dhner 2017 Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel Blood 129 424 447, F Breitenbuecher 2009 Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor Blood 113 4074 4077, S Liu 2018 Pattern and prognostic value of FLT3-ITD mutations in Chinese de novo adult acute myeloid leukemia Cancer Sci. 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. Lancet Haematol. Lymphoma 59 2273 2286, S Schnittger 2002 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, M Levis 2013 FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? The presence of FLT3-ITD mutation correlates with a high leukemic burden with increased risk of relapse and is recognized to be a driver mutation in patients with AML ( 5 ). In the absence of clinical trial options: among patients eligible for intensive chemotherapy who had a prior remission >1012 months, we would prefer a regimen incorporating intensive therapy (FLAG-Ida, CLAG-M, CLIA, MEC) in combination with a FLT3 inhibitor with an intent to achieve a rapid and hopefully deep remission and transition patients to ASCT followed by post-ASCT maintenance. CBF translocations have been associated with FLT3-ITD mutations in very few patients, and there is no clear information regarding their ELN prognostication18,19,20. Quizartinib with Decitabine+/Venetoclax is Highly Active in Patients (Pts) with FLT3-ITD Mutated (mut) Acute Myeloid Leukemia (AML): Clinical Report and Signaling Cytof Profiling from a Phase IB/II Trial (ASH, 2020). Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Blood Cancer Discov. 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. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3internal tandem duplication status. Midostaurin is a type I FLT3i active against PDGFR, KIT, SRC, and other RTKs22,23. ISSN 2044-5385 (online), FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm, https://doi.org/10.1038/s41408-021-00495-3, Targeting FLT3 mutations in AML: review of current knowledge and evidence, Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib, Gilteritinib activity in refractory or relapsed FLT3-mutated acute myeloid leukemia patients previously treated by intensive chemotherapy and midostaurin: a study from the French AML Intergroup ALFA/FILO, Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial, 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, FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions, Risk stratification using FLT3 and NPM1 in acute myeloid leukemia patients autografted in first complete remission, European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia, Impact of FLT3-ITD allele ratio and ITD length on therapeutic outcome in cytogenetically normal AML patients without NPM1 mutation, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf2017, http://creativecommons.org/licenses/by/4.0/, Feasibility of autologous peripheral blood stem cell mobilization and harvest in adult patients with FLT3-mutated acute myeloid leukemia receiving chemotherapy combined with midostaurin: a single-center experience, Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy. Kiyoi, H. et al. Variant allele frequency (VAF) is the ratio of ITD-mutated alleles to ITD-mutated+wild-type alleles (FLT3ITD/FLT3ITD+FLT3 wild-type)14. Cite this article. In the meantime, to ensure continued support, we are displaying the site without styles Progr. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. Smith, C. C. et al. Of note, we tested 3 different ITD length thresholds, and to be considered significant, the P value should be<0.025. 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. At a median follow-up of 42 months, sorafenib demonstrated a 2-year estimated RFS of 85% and OS of 90.5% compared with 53.3% (P=0.002), and 66.2% with placebo, respectively (P=0.007). PubMed Blood 121, 46554662 (2013). Perl, A. E. et al. Administration of the triplet is associated with prolonged cytopenias, requiring close monitoring and experience with venetoclax based combinations. The randomized phase III ADMIRAL trial evaluated gilteritinib vs investigator choice salvage chemotherapy in patients with R/R FLT3mut AML. J. Hematol. However, a subsequent UKMRC study of 1600 patients with cytogenetic intermediate-risk AML showed that relapse risk did not differ based on the FLT3-ITDmut AR, and that the cumulative incidence of relapse in patients with NPM1mut was increased with a concurrent FLT3-ITDmut irrespective of the AR19. The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in a credit line to the material. Yamatani, K. et al. The AUC of the ROC curve of the ITD length for OS prediction was 0.504, and no differences were found when applying any of the thresholds for OS, RFS or CR rate. Zhang, W. et al. Blood 114, 29842992 (2009). In patients with relapsed or refractory FLT3mut AML (Fig. The AR was determined by fragment length analysis and calculated as previously described32. Multivariate analysis showed that age < 65 years, FLT3-ITD and CEBPA bZIP in-frame mutation were independent prognostic factors. Get the most important science stories of the day, free in your inbox. However, previous studies have shown that FLT3/ITD mutation was not an independent adverse prognostic factor in DEK/CAN-positive AML patients. Slider with three articles shown per slide. The FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) is one of the most frequent mutations found in acute myeloid leukemia (AML) patients, with a frequency of 20-30%. This value highlights the scarce prognostic value of the measure. The median OS was 1.3years (CI 0.71.9) and 1.4years (CI 1.01.8), respectively (P=0.8). FLT3-ITD allelic ratio and HLF expression predict FLT3 inhibitor efficacy in adult AML, 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, Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results, Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission, Poor outcome of pediatric patients with acute myeloid leukemia harboring high FLT3/ITD allelic ratios, Mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia, Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial, Impact of FLT3-ITD allele ratio and ITD length on therapeutic outcome in cytogenetically normal AML patients without NPM1 mutation, Mutational spectrum and prognosis in NRAS-mutated acute myeloid leukemia, https://doi.org/10.3324/haematol.2020.263806, http://creativecommons.org/licenses/by/4.0/. In the frontline setting (n=4), the CRc rate with the triplet was 100% with FLT3-PCR negativity in all four patients56. 100, 184198 (2008). While the seven patients treated with the doublet had a CRc rate of 57% (n=4/7) and a median OS of 5.7 months, the fifteen R/R FLT3mut AML patients treated with the triplet had a CRc rate of 81% (n=11) with a projected 1-year OS of 60%. Mutations of FLT3 are found in approximately 30% of newly diagnosed AML patients and appear either as ITDs ( 25%) or point mutations in the tyrosine kinase domain (TKD) (710%)4. In the randomized phase III RATIFY trial of midostaurin combined with cytarabine and daunorubicin (3+7) induction and consolidation, midostaurin improved OS compared to placebo in patients <60years of age with newly diagnosed FLT3 (ITD and/or TKD) AML24, regardless of AR (0.7 or 0.7) or the type of mutation (ITD or TKD). FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) is one of the most frequent mutations found in AML patients. Among 14 R/R FLT3mut AML patients, the CRc rate was 64% with FLT3-PCR negativity in 88% of responders. (B) Relapse-free survival. Castao-Bonilla, T., Alonso-Dominguez, J.M., Barragn, E. et al. evaluated midostaurin with azacitidine in patients with both newly diagnosed and R/R AML regardless of FLT3 mutational status. The median OS was 1.7years (CI 04.0), 1.7years (CI NC), 1.3years (CI 0.32.3), 1.5years (CI NC), 1.2years (CI: 0.52.0) and 2.4years (CI NC), respectively.
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