flt3 itd mutation prognosis
The LACEWING phase III randomized trial evaluated gilteritinib with azacitidine vs azacitidine monotherapy (NCT02752035) in patients with newly diagnosed FLT3mut AML not eligible for intensive induction chemotherapy. Presented in part at the 42nd Annual Meeting of the American Society of Hematology, December 15, 2000, San Francisco, CA (abstract 2334). The number, area and length of mutant peaks on capillary electrophoresis were analyzed using GeneMapper analysis software (Applied Biosystems, Foster City, CA). Besides FLT3-ITD MRD, only a high white blood cell count and late CR appeared to be independently associated with relapse and OS. Welch John, S. et al. Patients diagnosed with acute promyelocytic leukemia (APL) were excluded. We aimed to assess the prognostic impact of these variables on the complete remission (CR) rates, overall survival (OS) and relapse-free survival (RFS) of AML patients withFLT3-ITDmutations. 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 and P.M.; Methodology, T.C., 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. To obtain F.R. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). Strati et al. evaluated the impact of AR in 323 patients with newly diagnosed FLT3-ITDmut AML. 10 1 10, K Dhner 2020 Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia Blood 135 371 380, C Thiede 2002 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, KM Murphy 2003 Detection of FLT3 Internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay J. Mol. ITD amplicons with a size greater than that of the wild type (3281 bases) were interpreted as positive for the FLT3-ITD mutation. https://doi.org/10.1038/s41408-021-00495-3, DOI: https://doi.org/10.1038/s41408-021-00495-3. Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Conceptualization, T.C., J.M.A., E.B. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. 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. Perl, A. E. et al. Smith, C. C. et al. Stone, R. M. et al. However, whether these findings are specific to Ven + HMA therapy remains to be . Gilteritinib decreased the risk of death by 36% compared with salvage chemotherapy, with a median OS of 9.3 months vs 5.6 months (P<0.001), and a superior CR+CRh rate (34% vs 15.3%). In the R/R setting, the CRc rate was 64% (n=18/28) with a median OS of 12.0 months, with responses observed even in prior FLT3i exposed patients48. Blood Cancer J. The NPM1/FLT3-ITD patients had normal karyotypes. 120.000 new AML cases and over . T.C. 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 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. Blood 135, 791803 (2020). 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. The authors declare no competing interests. prospectively evaluated decitabine and quizartinib (doublet) with or without venetoclax (triplet) in patients with newly diagnosed and R/R FLT3-ITDmut AML. 2). **If the C1 D14 bone marrow show >5% blastscontinue venetoclax, FLT3i till D21. Molecular landscape and prognostic impact of FLT3-ITD - Nature S2) in PETHEMA centralized diagnostic laboratories as previously described33. Among 16 patients with newly diagnosed FLT3mut AML not eligible for intensive induction, the CRc rate was 88% with FLT3-PCR negativity in 100% of responders and a projected 2-year OS of >80%. Biao Wang, X. Hua, Jihong Zhang, Weiying Gu . Article Full article: The importance of FLT3 mutational analysis in acute Acta Haematol. and JM.A. N. Engl. Minetto and colleagues retrospectively evaluated the efficacy of fludarabine, high-dose cytarabine, and idarubicin (FAI) in 149 newly diagnosed FLT3-ITDmut and/or NPM1mut AML (only FLT3-ITDmut=29; FLT3-ITDmut NPM1mut=59, only NPM1mut=61). 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. The non-intensive chemotherapy group received FLUGA (fludarabine+Ara-C), n=22; azacytidine, n=15; and decitabine, n=5, and one patient was treated with IDA-FLAG-Lite. 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. Secondary resistance to FLT3i could be either on-target (changes in the FLT3) or off-target (constitutive activation of non-FLT3-dependent oncogenic pathways). Blood 93, 30743080 (1999). FLT3 Mutations in R/R Acute Myeloid Leukemia (AML) - XOSPATA Staurosporine, a potent inhibitor of phospholipid Ca++ dependent protein kinase. Ravandi, F. et al. 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.. Alotaibi, A. S. et al. FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML. Blood 127, 360362 (2016). J. Med. Minetto, P. et al. or reset password. If material is not included in the articles Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Fig. 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). Mali, R. S. et al. Upon achieving CR, the decision for ASCT is based on the risk-benefit assessment for ASCT. The FLT3-ITD AR was available in 140 intensively treated patients. Accumulating evidence have shown improved outcomes in FLT3-ITDmut patients receiving induction with higher dose anthracyclines57, cladribine58, or fludarabine added to induction backbone21, and incorporating FLT3i with induction (either first or second generation) in FLT3mut AML24,44,59,60 (Fig. and P.M.; Data curation, J.M.A. 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. 90, 276281 (2015). 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. Google Scholar. 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). Of note, we tested 3 different ITD length thresholds, and to be considered significant, the P value should be<0.025. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated Oncol. 61, 72337239 (2001). Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. The first-generation FLT3is lack specificity for FLT3 and inhibit multiple downstream RTKs that may result in more off-target toxicities. Cladribine combined with idarubicin and Ara-C (CLIA) as a frontline and salvage treatment for young patients (65 yrs) with acute myeloid leukemia. 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%. Linch, D. C., Hills, R. K., Burnett, A. K., Khwaja, A. Among 161 intensively treated patients, 123 had the cytogenetic and molecular information required to calculate the 2010 ELN classification21. FLT3 Mutations: Biology and Treatment | Hematology, ASH Education Prognostic impact analyses of FLT3-ITD length were performed among patients treated with upfront IC regimens. Complete response (CR) or complete responses with incomplete hematologic recovery (CRi) were defined according to current 2017 ELN guidelines8. FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. and JavaScript. 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. Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine We also analyzed the mutational profile of 118 FLT3-ITD AML patients with an NGS panel of 39 genes and correlated mutational status with the length and IS of ITD. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain Res. Blood 136, 2223 (2020). FLT 3-ITD mutations typically were determined using polymerase chain reaction and fragment analyses. DiNardo, C. D. et al. Levis turned to FLT3-ITD mutations in acute myeloid leukemia (AML) to highlight the challenges with targeted therapy. Statistically significant results were not observed for any other gene in this analysis. Therefore, the value obtained is not significant, although it shows a slight trend toward being significant. Heart J. Suppl. Log in with Facebook Log in with Google. 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. Blood 121, 46554662 (2013). We observed a low frequency of NPM1 mutation (10.1%), which correlated with the good prognosis of this mutation. This study shows that the size of FLT3-ITD mutations has no prognostic impact in terms of survival, relapse or CR rate among newly diagnosed AML patients treated with first-line intensive regimens. Nevertheless, there are numerous and contradictory manuscripts regarding the prognostic importance of the length and insertion site of the ITD fragment. Perl, A. E. et al. Andrew, H. et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. 1 FLT3 gene is one of the most frequently mutated genes in acute myeloid leukemia (AML), and is reported in 25-30% of AML patients. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Clinical heterogeneity under induction with different dosages of 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 . 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). Article volume11, Articlenumber:104 (2021) 93, 11361141 (2018). Relapse-free survival (RFS) was calculated from the date of achieving CR/CRi until the date of relapse (death without relapse or relapse were consideredevents)8. Although activity was seen, the response rates were overall modest with this combination and the combination of HMA with midostaurin is not one that we routinely use or recommend for frontline FLT3-mutated AML47. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. Leukemia 10, 19111918 (1996). Higher daunorubicin exposure benefits FLT3 mutated acute myeloid leukemia. CAS FLT3-ITD Mutation in MDS Patients Is Associated with Early 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. It should be noted that MDS-MLD and -EB-1 patients with low and intermediate risk in IPSS-R were included in FLT3-ITD mutation group, and showed poor prognosis. J. Clinl. fms3flt3-itdaml molm13baf3-flt3-itd p-erkp-akt . Among patients treated with azacitidine and quizartinib in the frontline setting, the CRc rate was 78% (n=7/9) with a median OS of 21.1 months. PubMed Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. 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). Google Scholar. Cancer Netw. J. Hematol. The area under the ROC curve (AUC) for OS prediction was 0.504. 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). Figure legend Overall survival of patients with AML following frontline venetoclax plus hypomethylating agent Changes in FLT3 mutation status can occur during the course of disease, but the clinical impact of a change is unclear. J. Hematol. Interestingly, FLT3-ITD mutation, which has an adverse prognosis is found in up to one-third of younger patients but only 15-18% in >65 years. In the meantime, to ensure continued support, we are displaying the site without styles Regardless of prior FLT3i therapy, gilteritinib-treated patients had CRc rates >40%, however, the median OS with single-agent gilteritinib was 6.5 vs 9.6 months in prior FLT3i exposed (n=31) vs naive patients (n=216) with FLT3mut R/R AML74. 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. Multivariate analysis showed that age < 65 years, FLT3-ITD and CEBPA bZIP in-frame mutation were independent prognostic factors. (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. FLT3 Gene Mutation Profile and Prognosis in Adult Acute - PubMed and P.M.; Visualization, T.C., J.M.A., D.L., J.S. CAS 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. Hematol. Acute myeloid leukemia patient with FLT3-ITD and NPM1 double mutation No statistically significant differences were found (P=0.8) (Fig. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. The addition of sorafenib to standard AML treatment results in a substantial reduction in relapse risk and improved survival. Pratz, K. W. et al. 2-Aminopyrimidine derivatives as selective dual inhibitors of JAK2 and Due to the preliminary nature of the . Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens. and P.M. Regardless of the regimen intensity, all clinical trial participants were grouped in a separate treatment category (n=15). Mechanistically, FLT3-ITDs and FLT3-TKDs induce activation of transduction intermediates, including STAT5, AKT, and ERK1/2 ( 2 ). A detailed analysis of all patients showed ITD integrations in the JMD-B, amino acids 572 to 578, in six patients; the JMD-S, amino acids 579 to 592, in 42 patients; the JMD-Z, amino acids 593 to 603, in 43 patients; the HR, amino acids 604 to 609, in seven patients; the B1 of TKD1, amino acids 610 to 615, in one patient; the NBL, amino acids 616 to 623, in two patients; and the B2, amino acids 624 to 630, in one patient. 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. Among 14 R/R FLT3mut AML patients, the CRc rate was 64% with FLT3-PCR negativity in 88% of responders. However, these studies did not apply previously validated ITD length cutoffs obtained in other smaller series11,15,16,17. 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. Provided by the Springer Nature SharedIt content-sharing initiative. Rydapt Prescribing Information. Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in Am. Full article: Advances in the drug therapies of acute myeloid leukemia Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models. FLT3-ITD Mutation and FLT3 Ligand Plasma Level Were Not Associated wit 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. Prognostic significance of FLT3-ITD length in AML patients - Nature Pratcorona, M. et al. Analysis of NPM1 and FLT3 Mutations in Patients with Acute Myeloid The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Upregulation of Bcl-2 confers resistance to FLT3 inhibition in FLT3-ITD AML with secondary acquired mutations. We evaluate these patients on a case by case basis and may consider maintenance with 45 consolidation cycles of CLIA or FAI with FLT3i followed by FLT3i+/HMA maintenance for two years vs ASCT based on donor availability, age, performance status, MRD negativity, and patient preference. 28, 1856 (2010). 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. Enter the email address you signed up with and we'll email you a reset link. which included NPM1 mut /FLT3-ITD high AR cases. "FLT3 is a particularly nasty version of the disease," Levis said. In summary, in our population of 161 intensively treated FLT3-ITD AML patients, we did not validate any of the previously published recurrent thresholds of ITD length obtained from smaller series. The AR was determined by fragment length analysis and calculated as previously described32. Google Scholar. Request PDF | Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain mutation in cytogenetically normal acute myeloid leukemia: a Hokkaido Leukemia Net study | Mutation status of FLT3 . Juan M. Alonso-Dominguez. 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). (B) Relapse-free survival. We have no information on the treatment received by the remaining patients. evaluated midostaurin with azacitidine in patients with both newly diagnosed and R/R AML regardless of FLT3 mutational status. J. Med. Blood 136, 3233 (2020). Kayser, S. et al. Differential impact of allelic ratio and insertion site in FLT3-ITDpositive AML with respect to allogeneic transplantation. CNS Relapse in Acute Promyeloctyic Leukemia - academia.edu PubMed E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for KIT+ . FLT3 -ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. Astellas Reports XOSPATA (gilteritinib) in combination with azacitidine did not meet endpoint of overall survival in newly diagnosed flt3 mutation-positive acute myeloid leukemia patients ineligible for intensive induction chemotherapy (2020). Some studies showed a reduced CR rate, while others analyzing the IS in the same region found differences in OS. Molecular Diagnostics | FLT3 (ITD and TKD) Mutation Detection Expression and signal transduction of the FLT3 tyrosine kinase receptor. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. 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 ]. Remember me on this computer. or. We found a statistically significant correlation among SF3B1, WT1 and EZH2 mutations and ITD length. Kiyoi, H. et al. DiNardo, C. D. et al. (2) Larger studies analyzing ITD length also found no significant results14,23,28. Blood 136, 1617 (2020). Daver, N. et al. Zhu, R., Li, L., Nguyen, B., Duffield, A. S. & Small, D. Gilteritinib and venetoclax synergize to eliminate FLT3/ITD+ leukemia cells through BIM. CAS Blood 136, 810 (2020). We believe that triplets may be the optimal way to use FLT3i to improve long-term survival and cure rates in older patients, able to tolerate this approach. In the FLT3-ITDLOW group of patients, the median OS was 2.3years (CI: 1.13.6), and in the FLT3-ITDHIGH group of patients, the median OS was 1.1years (CI: 0.71.5). Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. The insertion site of FLT3-ITD was available in 106 of 118 patients (Fig. Prognostic significance of baseline FLT3-ITD mutant allele level in acute myeloid leukemia treated with intensive chemotherapy with/without sorafenib. Patterns of resistance differ in patients with acute myeloid leukemia treated with type I versus type II FLT3-inhibitors. 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. A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. Elderly patients with AML have a distinct genetic landscape compared with the younger population. To test the prognostic significance of the ITD length and its clinical applicability, we used recurrent previously published cutoffs, which were analyzed in series ranging from 28 to 100 intensively treated patients. Activating FLT3 Mutants Show Distinct Gain-of-Function Phenotypes In Ann Hematol. 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. 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. Type I FLT3is are active against both the FLT3-ITD or TKD, type II inhibitors are only active against FLT3-ITD, not TKD. Whitman, S. P. et al. Cite this article. The PubMed database, the Cochrane Library, conference proceedings, the EMBASE databases, and references of published trials and review articles were searched. Taking into account the great number of comparisons performed, we cannot assume a real relationship between these mutations. Souki Cancer Research Fund and generous philanthropic contributions to the MD Anderson Moon Shots Program. Oran et al. Management of Newly Diagnosed Acute Myeloid Leukemia in Older Adults 3 A Survival curves stratified by the presence or absence of FLT3 -ITD and NPM1 mutation for patients younger than 65 years. N. Engl. AR,allelic ratio. Blood 100, 43724380 (2002). Impact of FLT3-ITD length on prognosis of acute myeloid leukemia Jain, P. et al. Which FLT3 Inhibitor for Treatment of AML? 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). Two randomized trials are evaluating the addition of gilteritinib vs midostaurin to induction and consolidation therapy in patients with newly diagnosed FLT3mut AML44 (NCT04027309, NCT03836209). Alotaibi, A. S. et al. FLT3 -ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. FLT3-TKD activating mutations also constitutively activate FLT311; however, they have not been associated with a consistent prognostic impact12. Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability. 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). 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. 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). Gilteritinib, a second-generation type I FLT3i demonstrated tolerability with CRc rates of 4555% in patients with R/R FLT3 (ITD or TKD)mut AML38,39. 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.