Informed consent was a requisite for patients alive at the time of data lock (January 2019). AbuDuhier, F. et al. Biochem. 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. 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+ . Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. (A) Overall survival. CAS 3.3 TET2 in NPM1 mut /FLT3-ITD (), and CD34 and ID-Ara-C in NPM1 mut /FLT3 . Prognostic impact analyses of FLT3-ITD length were performed among patients treated with upfront IC regimens. DiNardo, C. D. et al. Overall survival (OS) was calculated from the date of the diagnosis of AML until death in all included patients. Mutations of the fms-tyrosine kinase ( FLT3) were first described in 1997 4 and account for the most frequent molecular mutations in AML. 381, 17281740 (2019). Molecular Diagnostics | FLT3 (ITD and TKD) Mutation Detection Moreover, ASCT in CR1 only benefitted patients with isolated FLT3-ITDmut (without NPM1mut) irrespective of AR (P<0.05)21. In patients with newly diagnosed AML, FLT3-ITDmut is a poor prognostic factor in terms of relapse-free (RFS) and overall survival (OS)7,8,9,10. Enter the email address you signed up with and we'll email you a reset link. Google Scholar, MR ODonnell 2017 Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology J. Natl. * Genes with a P value<0.05 in the MannWhitney test correlating mutational status with ITD length. All four patients with ITD insertions in TKD1 had mutations in DNTM3A, compared with 39 out of 96 patients (41%) with ITD insertions in the JMD domain (P=0.031). Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Tallman, M. S. et al. 368, 20592074 (2013). 6,, - 9 In normal bone marrow, FLT3 expression is Blood 121, 46554662 (2013). 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%. The PubMed database, the Cochrane Library, conference proceedings, the EMBASE databases, and references of published trials and review articles were searched. Larger studies of ITD size, although they did not employ these cutoffs, did not find prognostic power of this measure, which corroborates our results. prospectively evaluated decitabine and quizartinib (doublet) with or without venetoclax (triplet) in patients with newly diagnosed and R/R FLT3-ITDmut AML. 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. Analysis of FLT3-ITD insertion sites from 106 FLT3-ITD-positive AML patients. (A) Overall survival. Yalniz, F. et al. Lancet Oncol. Given the heterogeneity of treatments received and the scarce number of ISs in TKD1, we did not perform statistical analysis. Pulmonary infiltration and acute pneumonitis-like picture are rare (<1%) but noted side effects of midostaurin that treating physicians should be aware of. Off-target resistance includes clonal evolution during FLT3i therapy even when FLT3-ITDmut clone is lost70. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. Blood 111, 27762784 (2008). You are using a browser version with limited support for CSS. Complete response (CR) or complete responses with incomplete hematologic recovery (CRi) were defined according to current 2017 ELN guidelines8. The analysis of OS and RFS applying this value did not show significant results (data not shown). Ravandi, F. et al. Google Scholar. Canc. Due to the preliminary nature of the . (2) Larger studies analyzing ITD length also found no significant results14,23,28. Kayser, S. et al. volume11, Articlenumber:104 (2021) 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. 21, 12011212 (2020). Kadia, T. et al. Both mutations lead to the activation of downstream proliferation cascades [ 19, 20 ]. 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. Quizartinib is also being evaluated in combination with CPX-351 (NCT04209725) and with CLIA (NCT04047641) in treatment naive and R/R FLT3mut AML. Moreover, we performed an analysis of the correlation of FLT3-ITD length and insertion sites with the mutational landscape of AML, which has not been carried out thus far. Daver, N., Venugopal, S. & Ravandi, F. FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm. The AR was determined by fragment length analysis and calculated as previously described32. In patients with relapsed or refractory FLT3mut AML (Fig. Secondary mutations as mediators of resistance to targeted therapy in leukemia. 4), diligent effort must be made to refer the patient to large academic centers with clinical trial options as the outcomes remain dismal with a median OS<10 months with almost any approach. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. FLT3 testing was historically viewed as being purely prognostic; however, with the advent of FLT3 inhibitors, it will likely be seen as both prognostic and predictive. 90, 276281 (2015). Article Presented in part at the 42nd Annual Meeting of the American Society of Hematology, December 15, 2000, San Francisco, CA (abstract 2334). Among patients treated with gilteritinib, the median overall survival was similar among those with FLT3 ITD mutations alone (9.3 months) and those with FLT3 TKD mutations alone (8.0 months). CNS Relapse in Acute Promyeloctyic Leukemia - academia.edu Provided by the Springer Nature SharedIt content-sharing initiative, Current Hematologic Malignancy Reports (2022), Current Treatment Options in Oncology (2022), Blood Cancer Journal (Blood Cancer J.) A subsequent randomized phase IIb trial evaluated lower doses, 30 or 60mg of quizartinib daily, in patients with R/R FLT3-ITDmut AML. Strati, P. et al. 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. Blood 124, 273276 (2014). We currently recommend the incorporation of FLT3is and ASCT in CR1 in all ASCT eligible patients with a FLT3-ITDmut AML, irrespective of the AR and/or NPM1 co-mutation status. Prognostic Value of FLT3-Internal Tandem Duplication Residual Disease Cancer Discov. 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. CAS 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. has nothing to disclose. FLT3 -ITD has a poor prognostic impact in patients with AML at diagnosis. (B) Relapse-free survival. 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). 93, 213221 (2018). Gilteritinib with venetoclax (NCT03625505) was evaluated in 41 patients with heavily pretreated R/R FLT3mut AML (median salvage 2, 65% previously exposed to FLT3i)40,53. 135, 397402 (1986). Soc. Differential impact of allelic ratio and insertion site in FLT3-ITDpositive AML with respect to allogeneic transplantation. 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 . Email. Gilteritinib was generally well tolerated but was associated with increased incidence of gastrointestinal side effects, most frequently diarrhea although nausea has been occasionally observed. The origin and evolution of mutations in acute myeloid leukemia. Blood 132, 598607 (2018). The BSC group included 7 patients receiving transfusions and other supportive measures. Blood 136, 3233 (2020). FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) is one of the most frequent mutations found in AML patients. B MD Anderson Cancer Center Approach. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain In sensitivity analysis, no significant . Blood 110, 12621270 (2007). Article Compr. Quizartinib demonstrated an OS of 6.2 months compared with 4.7 months with salvage chemotherapy (hazard ratio 0.76 and P=0.02). A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. Ravandi, F. et al. Educ. Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 gene ( FLT3) confer a poor prognosis in adult AML. A stratified analysis of FLT3-ITD length by 2010 ELN genetic risk was performed in 123 patients (intermediate-I group, ITD<70bp, n=75 and ITD70bp, n=24; intermediate-II group, ITD<70bp, n=14 and ITD70bp, n=1; and adverse group, ITD<70bp, n=6 and ITD70bp, n=3). Decitabine combined with medium-dose cytarabine in the treatment of DEK The impact of prognostic factors may change as the AML treatment landscape evolves. 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. Thiede, C. et al. 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. FLT3 -ITD is located within exon 14, corresponding to JMD,. 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. 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). Identification of novel FLT3 Asp835 mutations in adult acute myeloid leukaemia. Article Oncol. ; 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. Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in Acute Myeloid Leukemia Patients in Eastern Algeria . and JM.A. In those patients with more than one ITD mutation, only the longest mutation was selected for statistical analysis (10 patients had>1 ITD mutation). Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. 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. 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. 10, 588876- (2020). 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. Blood Cancer Discov. Progress in Disease Detection Sets the Stage for MRD's Role in AML 2). This work is submitted in partial fulfillment of the requirement for the PhD. 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. However, other studies did not find significantly worse clinical outcomes in patients with non-JMD ITD mutations24,25. Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. The addition of sorafenib significantly improved the event-free survival (EFS; 21 months vs 9 months; P=0.013) and RFS (56% vs 38%), but not OS28, although a recent update suggested an emerging trend toward improved OS29. 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). Regarding ITD length, some authors have found that patients with shorter ITD lengths have more favorable outcomes11,12 or worse prognoses13, while other researchers did not find a prognostic relationship14. Br. Biao Wang, X. Hua, Jihong Zhang, Weiying Gu . This result is similar to the RATIFY study, in which 44% of patients lost FLT3 ITD under treatment with midostaurin 36. J. Clinl. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. No statistically significant differences were found (P=0.4) (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. The median OS was 2.4years (CI 05.5), 1.7years (CI: 04.4), 1.3years (CI 0.62.0), 1.5years (CI: 0.22.7), 0.9years (CI NC) and 2.3years (CI: 04.8), respectively. 13 95 100. 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. 31, 3681 (2013). and P.M.; Project administration, J.M.A. Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in acute myeloid leukemia Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in acute myeloid leukemia Blood Adv. 38, 29933002 (2020). 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. Burnett, A. K., Russell, N. H. & Hills, R. K. Group obotUKNCRIAMLS. Zhang, W. et al. CAS Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in QTc prolongation >500ms emerged as a significant adverse event36. Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability. Perl, A. E. et al. 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). Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain PubMed The UKMRC group evaluated the presence of NPM1 co-mutations in young adult patients with AML. 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). In the treatment-naive setting, the median time to neutrophil and platelet recovery among responders was 45 and 30 days, respectively, suggesting cumulative myelosuppression is to be expected and further optimization of triplets schedules is ongoing55. Precision Medicine in Myeloid Malignancies: Hype or Hope? Front. 1A). Although common methylation . PubMed Central Informed consent was a requisite for patients alive at the time of data lock (January 2019). Given the increasing importance that massive sequencing techniques are acquiring in the prognosis determination and therapeutic management of AML patients, we decided to study the possible correlation between the length or site of the insertion of the mutated ITD fragment and the mutational profile of these patients. S2) in PETHEMA centralized diagnostic laboratories as previously described33. Results of venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with acute myeloid leukemia with FLT3 mutations. Blood 99, 43264335 (2002). CAS Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Conceptualization, T.C., J.M.A., E.B. Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. B MD Anderson Cancer Center Approach. J. Hematol. FLT3 is a gene change, or mutation, in leukemia (blood cancer) cells. 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 161 intensively treated patients, 123 had the cytogenetic and molecular information required to calculate the 2010 ELN classification21. No significant difference was found between acute myeloid leukemia patients with these Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily.