Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia. 9, 10501063 (2019). N. Engl. Due to the preliminary nature of the . PubMed Central Alotaibi, A. S. et al. 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. Molecular clearance of FLT3 was noted in 50% of all evaluable patients. ITD amplicons with a size greater than that of the wild type (3281 bases) were interpreted as positive for the FLT3-ITD mutation. Although the presence of FLT3-ITD, as well as levels of the FLT3-ITD allelic ratio, have been described as prognostic factors in acute myeloid leukemia (AML), little is known about how the FLT3-ITD allelic ratio impacts patients’ outcomes when receiving an allogeneic hematopoietic stem cell transplantation (HSCT). Lancet Oncol. J. Med. Characteristics and outcome of patients with core binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study. Activating FLT3 Mutants Show Distinct Gain-of-Function - PLOS Patterns of resistance differ in patients with acute myeloid leukemia treated with type I versus type II FLT3-inhibitors. In the frontline setting (n=4), the CRc rate with the triplet was 100% with FLT3-PCR negativity in all four patients56. It is important to note that none of these patients received a FLT3 inhibitor (FLT3i) during induction, consolidation, or post-ASCT. Musa Yilmaz, M. et al. Additionally, different subdomains of TKD1 (HR or beta1-sheet) have been highlighted as those conferring an adverse outcome10. Acta Haematol. 38, 29933002 (2020). You are using a browser version with limited support for CSS. 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 15, 17 In our cohort, the prevalence of FLT3-ITD mutation of de novo AML patients was 21.5%. Mead, A. J. et al. and JavaScript. Am. evaluated quizartinib (60mg daily) combined with either azacitidine or low-dose cytarabine in patients with newly diagnosed or R/R FLT3mut AML not eligible for intensive chemotherapy. 2B). In subsequent cycles: FLT3i is continued for the entire duration of the cycle and the venetoclax duration is reduced to 14 days or lower to mitigate cumulative prolonged cytopenias. 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. Absence of FLT3-ITD mutation 0.07 . 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. Among those with NPM1 wild-type, all FLT3-ITDmut patients had an increased risk of relapse and inferior OS, regardless of the AR17. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with 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). The clinical behavior and genetic characteristics of the disease are heterogeneous1. FLT3-ITD Mutation in MDS Patients Is Associated with Early Among 14 R/R FLT3mut AML patients, the CRc rate was 64% with FLT3-PCR negativity in 88% of responders. 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. 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. The choice of treatment backbone depends on the patients ability to successfully tolerate intensive chemotherapy. 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Phase III Trial Reports Quizartinib Doubles Overall Survival in FLT3 This model of initiatory and progression mutation as FLT3 is well described 37, 38. Front. and P.M.; Supervision, J.M.A. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. . 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. 3.3 TET2 in NPM1 mut /FLT3-ITD (), and CD34 and ID-Ara-C in NPM1 mut /FLT3 . Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens. J. Hematol. The randomized phase III ADMIRAL trial evaluated gilteritinib vs investigator choice salvage chemotherapy in patients with R/R FLT3mut AML. Zhang, W. et al. 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. Internet Explorer). J. Hematol. FLT3-TKD activating mutations also constitutively activate FLT311; however, they have not been associated with a consistent prognostic impact12. We suggest that any investigator who wants to demonstrate the prognostic value of the ITD length applies some of the recurrent published thresholds used in this study or divides his cohort into training and validation subcohorts. Strati et al. 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 licence, and indicate if changes were made. Enter the email address you signed up with and we'll email you a reset link. FLT3-ITD mutational load, expressed as an AR determined by fragment length analysis, has a clear prognostic value and is, therefore, included in the genetic prognostic classification of the European Leukemia Net (ELN) published in 20178. Thank you for visiting nature.com. & Ley, C., Network CGAR. The prognostic value of a FLT3 mutation in the tyrosine kinase domain (FLT3-TKD), which has a lower incidence in AML (approximately 7-10% of all cases), is uncertain. Burchert, A. et al. Naval Daver, M. D. et al. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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. Rollig, C. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. 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. Article 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). Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. Blood 129, 424447 (2017). Blood 128, 449452 (2016). PubMed PubMed Provided by the Springer Nature SharedIt content-sharing initiative. FLT3 -ITD has a poor prognostic impact in patients with AML at diagnosis. 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. Blood 128, 1639 (2016). 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. Adult patients with FLT3- ITD mutated AML treated at our institution were identified. Log in with Facebook Log in with Google. Samples from 118 of the 362 AML patients with FLT3-ITDmutations were analyzed with an NGS panel of 39 genes (see Supplementary Fig. 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. AbuDuhier, F. et al. 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. These observations have made FLT3 an attractive drug target. ___ The AR was determined by fragment length analysis and calculated as previously described32. Oran et al. Close Log In. We introduce venetoclax with a ramp-up when the WBC is <10,000/L to decrease the risk of tumor lysis syndrome. However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. Blood 124, 34413449 (2014). Impact of FLT3-ITD length on prognosis of acute myeloid leukemia Clin. Am. The median RFS was 1.2years (CI: 02.4) and 0.9years (CI: 0.617.1), respectively (P=0.3). Eur. 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. (3) Findings regarding the relationship between ITD length/site and mutational profile might be interpreted as exploratory given the high number of correlations performed. Compr. Schlenk, R. F. et al. As in previous works, we analyzed the clinical significance of FLT3-ITD length among fit patients treated with intensive regimens15,16. PubMed We thank the PETHEMA group for its participation in this study. Article . PubMed Central 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. Cortes, J. et al. Blood 136, 3233 (2020). In our case, 15 AML prognostic genes including FLT3/ITD gene were all negative. The clinical significance of FLT3 ITD mutation on the prognosis of Arsenic trioxide (ATO, As2O3) has been proven effective in treating acute promyelocytic leukemia (APL) and has shown activity in some cases of refractory and . Blood 127, 360362 (2016). No statistically significant differences were found (P=0.4) (Fig. Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in Acute Myeloid Leukemia Patients in Eastern Algeria . Welch John, S. et al. Clinical outcome stratified according to the FLT3-ITD length (cutoff 70bp) for all patients treated with intensive chemotherapy. J. Med. PDF FLT3-ITD Expression as a Potential Biomarker for the Assessment of 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 FLT3-ITD allelic ratio has clear prognostic value. 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). Although the toxicity-related discontinuation rate was low (22%), sorafenib-treated patients did experience higher rates of graft-versus-host disease (GVHD) and skin toxicity42. 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. FLT3ITD mutations in acute myeloid leukaemia - molecular Blood Cancer J. Whitman, S. P. et al. 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. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. 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. Burnett, A. K., Russell, N. H. & Hills, R. K. Group obotUKNCRIAMLS. DNA was extracted using automated or manual DNA extraction kits following the manufacturers recommendations. 2018 Oct 23;2 (20):2744-2754. doi: 10.1182/bloodadvances.2018020305. 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. or. This is in line with the preclinical data49 and molecular profiling of pre- and post-treatment samples66 identifying FLT3-ITDmut as a putative mechanism of resistance to venetoclax based therapies67, suggesting that FLT3-ITDmut patients may need a FLT3i incorporated into the HMA with venetoclax therapy either in a triplet or sequential approach to improve OS. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. The median OS was 1.0years [CI not calculable (NC)], 2.3years (CI: 1.23.5), 1.6years (CI: 0.62.6) and 1.0years (CI: 0.81.2), respectively (P=0.9). Linch, D. C., Hills, R. K., Burnett, A. K., Khwaja, A. 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). 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.
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