Am. 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. We observed a low frequency of NPM1 mutation (10.1%), which correlated with the good prognosis of this mutation. Biophys. Additionally, different subdomains have been highlighted, such as those conferring an adverse outcome9,10. Welch John, S. et al. Identification of novel FLT3 Asp835 mutations in adult acute myeloid leukaemia. Sasaki, K. et al. Type I FLT3is are active against both the FLT3-ITD or TKD, type II inhibitors are only active against FLT3-ITD, not TKD. 13, 132 (2020). Leukemia 26, 23532359 (2012). Lancet Oncol. Weisberg, E. et al. PubMedGoogle Scholar. 31, 3681 (2013). volume11, Articlenumber:104 (2021) (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. Collectively, NPM1mut even with FLT3-ITDmut AR <0.5 are likely higher risk than truly favorable risk AML and we continue to consider them for ASCT in CR1. We prefer a second-generation FLT3i (ideally gilteritinib) in the newly diagnosed setting, and administer the FLT3i D1-D14 during induction, and continuously starting Cycle 2 Day 1 through consolidation. evaluated midostaurin with azacitidine in patients with both newly diagnosed and R/R AML regardless of FLT3 mutational status. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Blood 127, 360362 (2016). The favorable prognostic molecular mutations, such as NPM-1 and CEBPA, are uncommon in elderly AML . DiNardo, C. D. et al. 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. Of note, we tested 3 different ITD length thresholds, and to be considered significant, the P value should be<0.025. Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. In patients 55 years, this regimen appeared to overcome the negative impact of FLT3-ITDmut in NPM1 co-mutated patients, regardless of the FLT3 AR, with comparable 3-year OS rates of 64% and 68% in FLT3-ITDmut NPM1mut and FLT3-ITDWT NPM1mut patients, respectively (P>0.05). Google Scholar. Mutations of the fms-tyrosine kinase ( FLT3) were first described in 1997 4 and account for the most frequent molecular mutations in AML. 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). 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 100, 23932398 (2002). CAS 109 3981 3992, DL Stirewalt 2006 Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia Blood 107 3724 3726, S Meshinchi 2008 Structural and numerical variation of FLT3/ITD in pediatric AML Blood 111 4930 4933, R Kusec 2006 More on prognostic significance of FLT3/ITD size in acute myeloid leukemia (AML) Blood 108 405 406, RE Gale 2008 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 Blood 111 2776 2784, Y Kim 2015 Quantitative fragment analysis of FLT3-ITD efficiently identifying poor prognostic group with high mutant allele burden or long ITD length Blood Cancer J. Blood 128, 449452 (2016). Despite the encouraging development of FLT3i, resistance to FLT3i is not uncommon and it can be either primary or secondary. DiNardo, C. D. et al. DiNardo, C. D. et al. ; 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. Hematol. Precision Medicine in Myeloid Malignancies: Hype or Hope? 93, 213221 (2018). Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. or. 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. 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. Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML. In older patients not eligible for intensive therapy, patients with primary refractory disease or early relapse with a persistent FLT3 mutation we would suggest gilteritinib based therapy. Haematologica 106, 1034 (2020). fms3flt3-itdaml molm13baf3-flt3-itd p-erkp-akt . 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. ISSN 2045-2322 (online). The NPM1/FLT3-ITD patients had normal karyotypes. Hypomethylating agent and venetoclax with FLT3 inhibitor triplet therapy in older/unfit patients with FLT3 mutated AML, Mechanisms of resistance to cancer therapy, Cancel 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. Blood 121, 27342738 (2013). We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. Cancer Res. Our median ITD length was 48bp (range=3bp to 231bp), similar to previous studies12,14,17. FLT3 plays a role in cell survival, proliferation and differentiation of hematopoietic progenitor cells. J. Hematol. Yilmaz, M. et al. Complete response (CR) or complete responses with incomplete hematologic recovery (CRi) were defined according to current 2017 ELN guidelines8. Oncol. Password. Yamatani, K. et al. 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. 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). Taking into account the great number of comparisons performed, we cannot assume a real relationship between these mutations. 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? AR, allelic ratio. J. Hematol. 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). Zarrinkar, P. P. et al. The impact of prognostic factors may change as the AML treatment landscape evolves. 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. H Dhner 2010 Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet Blood 115 453 474, S Kayser 2009 Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome Blood 114 2386 2392, FG Rcker 2021 Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results Leukemia 2021 1 10, O Blau R Berenstein A Sindram IW Blau 2013 Molecular analysis of different FLT3-ITD mutations in acute myeloid leukemia Leuk. However, other studies did not find significantly worse clinical outcomes in patients with non-JMD ITD mutations24,25. This work was supported in part by the MD Anderson Cancer Centre Support Grant (CCSG) CA016672, the MD Anderson Cancer Center Leukemia SPORE CA100632, the Charif. (A) Overall survival. *C1 D14: Perform bone marrow biopsy; if bone marrow shows <5% blasts and/or <5% cellularity/insufficient sampleStop venetoclax and FLT3i on D14. and JavaScript. Br. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Hematol. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. The FLT3-ITD allelic ratio has clear prognostic value. The MORPHO phase III placebo-controlled trial evaluating post-transplant maintenance with gilteritinib in FLT3mut AML recently completed accrual and results are eagerly awaited (NCT02997202). Prognostic analyses were performed using the 70bp cutoff in 161 AML patients with FLT3-ITD mutations treated with IC (<70bp; n=119,70bp; n=42). 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. 373 1136 1152, N Daver RF Schlenk NH Russell MJ Levis 2019 Targeting FLT3 mutations in AML: Review of current knowledge and evidence Leukemia 33 299 312, Article None of the studies has carried out an internal ITD length cutoff validation by dividing the patients into a training cohort and a validation cohort, which, given the arbitrary selection of the cutoffs used, would be necessary. 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. Some studies showed a reduced CR rate, while others analyzing the IS in the same region found differences in OS. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. Perl, A. E. et al. Google Scholar. Minetto, P. et al. This model of initiatory and progression mutation as FLT3 is well described 37, 38. An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown). A comparable decrease in CRc rates (45%21%10%) and OS (7.94.04.1 months) was observed with sequential FLT3i-based therapies in the R/R AML setting73. and P.M.; Supervision, J.M.A. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. You are using a browser version with limited support for CSS. Yalniz, F. et al. 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. Seventeen patients underwent autologous hematopoietic progenitor transplantation, and forty-four patients underwent allogeneic hematopoietic progenitor transplantation (Table 1). J. Natl Compr. Blood 130, 723 (2017). Juan M. Alonso-Dominguez. 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. The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients (Pts) with FLT3-ITD mutated myeloid leukemias: interim report of a phase I/II trial. Andrew, H. et al. QuANTUM-R, a phase 3 randomized controlled trial, evaluated quizartinib monotherapy vs investigator choice salvage chemotherapy in R/R FLT3-ITDmut AML. and P.M.; Validation, T.C., J.M.A., E.B. 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. In the meantime, to ensure continued support, we are displaying the site without styles In 40 patients (87%), the prognosis based on the ELN 2017 risk stratification algorithm did not change due to AR, whereas, in 6 patients (13%), the FLT3-ITD mutation burden was <0.5 in DNA and 0.5 in cDNA, which changed their risk stratification. The . Alotaibi, A. S. et al. Blood Cancer J. In the frontline setting (n=4), the CRc rate with the triplet was 100% with FLT3-PCR negativity in all four patients56. 381, 17281740 (2019). Correspondence to 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. 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. Rosnet, O. et al. Article Educ. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. We introduce venetoclax with a ramp-up when the WBC is <10,000/L to decrease the risk of tumor lysis syndrome.
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