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). As in previous works, we analyzed the clinical significance of FLT3-ITD length among fit patients treated with intensive regimens15,16. 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. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. ___ Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The insertion site of FLT3-ITD was available in 106 of 118 patients (Fig. Sci Rep 11, 20745 (2021). Lancet Oncol. 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. 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. Blood 135, 791803 (2020). 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. and P.M.; Visualization, T.C., J.M.A., D.L., J.S. Google Scholar. Resistance Mutations Present an Ongoing Challenge in Aggressive FLT3 -ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. Arsenic trioxide (ATO, As2O3) has been proven effective in treating acute promyelocytic leukemia (APL) and has shown activity in some cases of refractory and . S2) in PETHEMA centralized diagnostic laboratories as previously described33. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia. 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). Enter the email address you signed up with and we'll email you a reset link. Hematology. More recently, the emergence of BCR-ABL1-positive clone was shown as a resistance mechanism to multiple FLT3is72. Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 gene ( FLT3) confer a poor prognosis in adult AML. 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). 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). Quizartinib is also being evaluated in combination with CPX-351 (NCT04209725) and with CLIA (NCT04047641) in treatment naive and R/R FLT3mut AML. Cite this article. However, the median OS was 19.2 months in FLT3-TKDmut AML (19.2 months), but only 11.5 months in FLT3-ITDmut patients65. 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 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. Blood 134, 2564 (2019). FLT3-ITD has been strongly associated with a bad prognosis, leukocytosis, high blast counts, increased risk of relapse and shorter overall survival. PubMed Central CAS Levis turned to FLT3-ITD mutations in acute myeloid leukemia (AML) to highlight the challenges with targeted therapy. and P.M.; Resources, 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.M.C., M.A.S. F.R. In sensitivity analysis, no significant . N. Engl. CAS volume11, Articlenumber:20745 (2021) Internet Explorer). 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. Our real-life cohort was composed of 362 patients, most of whom were not included in clinical trials. J. Natl Cancer Inst. Google Scholar, MM Patnaik 2018 The importance of FLT3 mutational analysis in acute myeloid leukemia Leuk. FLT3-ITD Mutation and FLT3 Ligand Plasma Level Were Not Associated wit 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. Among 729 AML patients with FLT3-ITD mutations included in the PETHEMA AML epidemiologic registry between 2003 and 2019, FLT3-ITD length was available in 362: 188 males and 174 females; median age of 60.8years (range 17.191.4years). The Programa Espaol de Tratamientos en Hematologa (PETHEMA) AML epidemiologic registry (NCT02607059) includes patients diagnosed with AML, regardless of the treatment administered. 61, 72337239 (2001). The BSC group included 7 patients receiving transfusions and other supportive measures. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). (B) Relapse-free survival. We found a statistically significant correlation among SF3B1, WT1 and EZH2 mutations and ITD length. Analysis of NPM1 and FLT3 Mutations in Patients with Acute Myeloid Blood 97, 24342439 (2001). CAS J. Hematol. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITDmutated, relapsed or refractory AML. After post-remission therapy with either consolidation (high-dose cytarabine-based) or allogeneic stem cell transplant (ASCT), AR 0.51 and FLT3-ITD insertion site in TKD1 were associated with an unfavorable RFS (P=0.0008) and OS (P=0.004)15. We tried to validate the thresholds of ITD length previously published (i.e., 39bp and 70bp) in intensivelytreated AML patients (n=161). Libura, M. et al. 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. 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/. First, 161 AML patients with FLT3-ITD mutations treated with IC were analyzed using 39bp as the cutoff (<39bp; n=48,39bp; n=113). Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in Acute Myeloid Leukemia Patients in Eastern Algeria . 93, 11361141 (2018). Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. In the meantime, to ensure continued support, we are displaying the site without styles N. Engl. It is important to acknowledge the diverse mechanisms of FLT3i resistance after different FLT3is, and it is essential to proactively evaluate for these mechanisms at the time of FLT3i failure to optimize subsequent therapy. Article QTc prolongation >500ms emerged as a significant adverse event36. Tallman, M. S. et al. Blood Marrow Transplant 22, 12181226 (2016). Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. These observations have made FLT3 an attractive drug target. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . 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. 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 . Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia. Yilmaz et al. Hypomethylating agent and venetoclax with FLT3 inhibitor triplet therapy in older/unfit patients with FLT3 mutated AML, Mechanisms of resistance to cancer therapy, Cancel A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid Although the label indication for gilteritinib is as a single agent we have never used it as a single agent but always in combination with either HMA alone, venetoclax alone or as a triplet with HMA and venetoclax. We identified 1572 adult (age 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or . 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. More studies will be necessary to confirm these results and to shed light on the possible physiopathologic relationship. Remarkably, the NPM1 mutation status and the FLT3-ITD allelic ratio at diagnosis lost their prognostic value for relapse and survival when FLT3-ITD MRD was taken into account . The Spanish group evaluated intermediate-risk AML patients treated with intensive chemotherapy. The . Juan M. Alonso-Dominguez. 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. 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). Correspondence to Due to this, the development of tyrosine kinase inhibitors (TKI) blocking FLT3-ITD became a rational therapeutic concept. 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