Internet Explorer). The choice of treatment backbone depends on the patients ability to successfully tolerate intensive chemotherapy. Slider with three articles shown per slide. 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. You are using a browser version with limited support for CSS. 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. 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 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. Educ. Changes in FLT3 mutation status can occur during the course of disease, but the clinical impact of a change is unclear. Am. 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. It's the most common genetic change in acute myeloid leukemia (AML), a type of leukemia that starts in the bone marrow and. Brinton, L. T. et al. In patients with concurrent NPM1mut, the OS and relapse risk were comparable between FLT3 wild-type and FLT3-ITDmut AR <0.5, but worse when AR 0.5. 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. The role of ASCT in patients with FLT3-ITDmut AR<0.50 with concomitant NPM1mut in the absence of concomitant high-risk features such as DNMT3A, TP53, or RUNX1 co-mutations, adverse cytogenetics, therapy-related or secondary AML, who achieve MRD negativity by high-sensitivity PCR (ideally for NPM1mut), or patients with FLT3-TKDmut is an area of ongoing debate. CAS Type I FLT3is like gilteritinib are less prone to develop secondary mutations in the TKD, although the gatekeeper F691M can confer resistance to gilteritinib71. Pulmonary infiltration and acute pneumonitis-like picture are rare (<1%) but noted side effects of midostaurin that treating physicians should be aware of. 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. Quizartinib is also being evaluated in combination with CPX-351 (NCT04209725) and with CLIA (NCT04047641) in treatment naive and R/R FLT3mut AML. 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. Yalniz, F. et al. A Conventional approach. S2) in PETHEMA centralized diagnostic laboratories as previously described33. J. Med. 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. Oncol. and P.M.; Visualization, T.C., J.M.A., D.L., J.S. 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. 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. or. Blood 136, 810 (2020). The AR was determined by fragment length analysis and calculated as previously described32. Additionally, different subdomains of TKD1 (HR or beta1-sheet) have been highlighted as those conferring an adverse outcome10. Intensive fludarabine, high dose cytarabine and idarubicin-based induction for younger NPM1-mutated AML patient: overcoming the negative prognosis of FLT3-ITD mutation. Taking into account the great number of comparisons performed, we cannot assume a real relationship between these mutations. FLT3 -ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. We thank the PETHEMA group for its participation in this study. 3). Slider with three articles shown per slide. and P.M.; Supervision, J.M.A. 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. 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. We aimed to study the FLT3 gene mutation profile and prognosis in 139 adult Iranian patients with newly diagnosed AML. Perl, A. E. et al. 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. Correspondence to 16, 16911699 (2015). 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). 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. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Schneider F, Hoster E, Schneider S, Dufour A, Benthaus T, Kakadia PM, et al. 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. Blood 136, 3233 (2020). 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. 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. Fig. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. 3). Google Scholar. Mutations of SF3B1, EZH2 and WT1 seem to be a more ancestral event than FLT3 mutations, as expected, given the VAF of the genes. FLT3 mutations occur in more than 30% of patients with acute myeloid leukemia (AML) and are associated with short relapse-free and overall survival, including internal tandem duplication (ITD) and point mutations within the tyrosine kinase domain (TKD) [1, 2].To date, multiple FLT3 kinase inhibitors have been developed and some are approved for clinical use including sorafenib, Quizartinib . A total of 164 patients diagnosed with AML-NPM1 included in 2 consecutive CETLAM protocols and with DNMT3A and FLT3 status available were studied. Compr. 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. Cladribine combined with idarubicin and Ara-C (CLIA) as a frontline and salvage treatment for young patients (65 yrs) with acute myeloid leukemia. Biochem. FLT3-ITD length was compared between mutation and wild-type groups for each of the 39 genes using a MannWhitney test. 113, 983988 (2001). Google Scholar, MR ODonnell 2017 Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology J. Natl. 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. For CEBPA, 86.7% of the patients with biallelic mutation and 9.1% of patients with the single allele mutation had in-frame mutations in the bZIP domain, which were strongly associated with a favorable prognosis. Both mutations lead to the activation of downstream proliferation cascades [ 19, 20 ]. Despite the current availability of the FLT3 inhibitor midostaurin, there is an unmet need for improved treatment options. Zarrinkar, P. P. et al. 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. Blood 135, 791803 (2020). Second-generation FLT3is potently and specifically target FLT3 with fewer off-target effects. 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. FLT3 mutations are the most common mutations in AML 2 Of patients newly diagnosed with AML and tested for FLT3 mutations: 30 were positive for FLT3-ITD 7 were positive for FLT3-TKD FLT3-ITD mutations negatively impact survival in relapsed or refractory AML 1 Haematologica 106, 1034 (2020). Although common methylation . J. Hematol. Google Scholar. Furthermore, a global query was sent to the different centralized laboratories of PETHEMA to verify the ITD length, insertion site and molecular profile of the patients by NGS when these data were available. The number, area and length of mutant peaks on capillary electrophoresis were analyzed using GeneMapper analysis software (Applied Biosystems, Foster City, CA). We aimed to shed light on the prognostic importance of theFLT3-ITD length and site of insertion by validating previously suggested sites of insertion and thresholds of ITD length. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). Blood 129, 424447 (2017). Pratcorona, M. et al. Rydapt Prescribing Information. Netw. Therefore, these patients were not included in the analysis stratified by 2010 ELN genetic risk21. N.D. has received research funding from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE, Amgen, Novimmune, Glycomimetics, and ImmunoGen and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Novartis, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, and Agios. Log in with Facebook Log in with Google. Posterior reversible encephalopathy and pancreatitis are rare (<12%) but important side effects to be aware of. 2018 Oct 23;2 (20):2744-2754. doi: 10.1182/bloodadvances.2018020305. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. 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). Google Scholar. 21, 12011212 (2020). (A) Overall survival. 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. However, whether these findings are specific to Ven + HMA therapy remains to be . 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. Altman, J. K. et al. Daver, N. et al. Yamatani, K. et al. Intriguingly, this was the first large study to show that the FLT3i may also benefit FLT3 wild-type patients, perhaps through multi-kinase blockade or prevention of emergent FLT3 clones at relapse28. Blood 99, 43264335 (2002). 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. Midostaurin is a type I FLT3i active against PDGFR, KIT, SRC, and other RTKs22,23. Our median ITD length was 48bp (range=3bp to 231bp), similar to previous studies12,14,17. and JM.A. 7+37 days of cytarabine and 3 days of daunorubicin. Green indicates non-mutated genes, red indicates mutated genes and white indicates non-mutated genes. Clinical trial enrollment (if available) is always the first option, in both frontline and R/R FLT3mut AML. We have no explanation regarding the reduced number of patients with an FLT3-ITD inserted in TKD1 found in our cohort. Cancer Netw. Naval Daver, M. D. et al. QTc prolongation >500ms emerged as a significant adverse event36. A phase I study evaluating gilteritinib with 7+3 induction and high-dose cytarabine consolidation chemotherapy, followed by single-agent maintenance therapy, in patients with newly diagnosed AML showed that gilteritinib 120mg daily was well tolerated. J. Med. 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. 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.
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