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. 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 . N. Engl. We aimed to study the FLT3 gene mutation profile and prognosis in 139 adult Iranian patients with newly diagnosed AML. Furthermore, ten patients with mutated WT1 showed a median ITD length of 77bp,and 58 patients with non-mutated WT1 showed a median ITD length of 42bp (P=0.021). The combination continues to enroll. Off-target resistance includes clonal evolution during FLT3i therapy even when FLT3-ITDmut clone is lost70. Article Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. Which FLT3 Inhibitor for Treatment of AML? PubMed However, in a recently released planned interim analysis, the study did not meet its primary endpoint of overall survival and may be terminated for futility46. Conclusion: The frequency of NPM1/FLT3 mutations in the study cohort showed less rate than in other studies with a distinct pattern. The first-generation FLT3is lack specificity for FLT3 and inhibit multiple downstream RTKs that may result in more off-target toxicities. Blood 134, 2564 (2019). Tallman, M. S. et al. FLT3i FLT3 inhibitor, HMA hypomethylating agent, VEN venetoclax, CR complete remission, ECOG PS Eastern Cooperative Oncology Group Perfromance Status, CG cytogenetics, MRD measurable residual disease, SCT stem cell transplant, CBC complete blood count. 93, 213221 (2018). Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Informed consent was a requisite for patients alive at the time of data lock (January 2019). and P.M.; Validation, T.C., J.M.A., E.B. In those patients with more than one ITD mutation, only the longest mutation was selected for statistical analysis (10 patients had>1 ITD mutation). Gilteritinib, a second-generation type I FLT3i demonstrated tolerability with CRc rates of 4555% in patients with R/R FLT3 (ITD or TKD)mut AML38,39. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Alotaibi, A. S. et al. Frontiers | First Report of Sorafenib in Patients With Acute Myeloid 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. Fms-like tyrosine kinase 3 (FLT3) is a recurrent genetic abnormality in AML (~30%)1,2,3. ISSN 2045-2322 (online). Moreover, ASCT in CR1 only benefitted patients with isolated FLT3-ITDmut (without NPM1mut) irrespective of AR (P<0.05)21. First, 161 AML patients with FLT3-ITD mutations treated with IC were analyzed using 39bp as the cutoff (<39bp; n=48,39bp; n=113). Not all FLT3-ITDmut are equal; the prognostic impact is influenced by the allele ratio (AR), insertion site, ITD length, co-mutations (NPM1), and karyotype. 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). Molecular clearance of FLT3 was noted in 50% of all evaluable patients. Secondary resistance to FLT3i could be either on-target (changes in the FLT3) or off-target (constitutive activation of non-FLT3-dependent oncogenic pathways). FLT3-TKD activating mutations also constitutively activate FLT311; however, they have not been associated with a consistent prognostic impact12. (B) Relapse-free survival. 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 & Ley, C., Network CGAR. Additionally, different subdomains of TKD1 (HR or beta1-sheet) have been highlighted as those conferring an adverse outcome10. However, emerging data does suggest that patients with FLT3-ITDmut AR<0.5 and NPM1 co-mutation without concurrent high-risk mutations such as DNMT3A, TP53, TET2, or high-risk cytogenetics may be a more favorable subset, who may be considered for induction, consolidation followed by maintenance therapy without ASCT on a case by case basis if they achieve early MRD negativity using a highly sensitive MRD assay. Kayser, S. et al. FLT3 mutation and all but one patient died shortly after FLT3 mutation was acquired. We have no explanation regarding the reduced number of patients with an FLT3-ITD inserted in TKD1 found in our cohort. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain CR or CRi was achieved in 70% of the patients in both groups (P=0.9). Two classes of activating FLT3 mutations occur in AML: (1) internal tandem duplication ( FLT3 -ITD) which occur in 20-25% of patients and (2) tyrosine kinase domain mutations ( FLT3 -TKD) which are seen in 5-10% of patients [48]. Email. Zhu, R., Li, L., Nguyen, B., Duffield, A. S. & Small, D. Gilteritinib and venetoclax synergize to eliminate FLT3/ITD+ leukemia cells through BIM. Clinical outcome stratified according to the FLT3-ITD length (cutoff 39bp) for all patients treated with intensive chemotherapy. FLT3 -ITD is located within exon 14, corresponding to JMD,. 381, 17281740 (2019). 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. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. 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. Biol. 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. Kiyoi, H. et al. Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia. Protein alteration seems to be much more complex than the length of the mutation or the site of insertion; therefore, our efforts to simplify FLT3-ITD characteristicsby stratifying the risk of the patients may be fruitless. Pratz, K. W. et al. Mutations of the fms-tyrosine kinase ( FLT3) were first described in 1997 4 and account for the most frequent molecular mutations in AML. Rosnet, O. et al. Quizartinib is also being evaluated in combination with CPX-351 (NCT04209725) and with CLIA (NCT04047641) in treatment naive and R/R FLT3mut 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. FLT3 mutations in acute myeloid leukemia: a review focusing on Google Scholar. 96 1993 2003, Article Complete response (CR) or complete responses with incomplete hematologic recovery (CRi) were defined according to current 2017 ELN guidelines8. Blood Marrow Transplant 22, 12181226 (2016). Clinical trial enrollment (if available) is always the first option, in both frontline and R/R FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3is in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3is remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML. Cancer Discov. Biao Wang, X. Hua, Jihong Zhang, Weiying Gu . Burnett, A. K., Russell, N. H. & Hills, R. K. Group obotUKNCRIAMLS. Finally, a different report showed worse clinical outcomes in terms of OS and DFS in the TKD1 group. Lancet Oncol. 120.000 new AML cases and over . 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 FLT3-ITD and its current role in acute myeloid leukaemia 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. Schneider F, Hoster E, Schneider S, Dufour A, Benthaus T, Kakadia PM, et al. Unfortunately, in our study, information on the site of insertion was not available in the whole cohort, and few patients harbored a TKD1 insertion.We did not carry out a statistical analysis of the insertion site given the heterogeneity in the treatment of patients analyzed and the small number of patients with an ITD inserted in the TKD1 domain. In patients with FLT3mut AML unsuitable for intensive chemotherapy, azacitidine with venetoclax demonstrated encouraging CR/CRi rates (5570%) and a median OS of 13.3 months64 which prompted the inclusion of this combination approach as part of NCCN AML guidelines (Fig. Canc. 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. B MD Anderson Cancer Center Approach. FLT 3-ITD mutations typically were determined using polymerase chain reaction and fragment analyses. DiNardo, C. D. et al. Interestingly, all patients with an FLT3-ITD inserted in the TKD1 domain showed DNMT3A mutations. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. More recently, the emergence of BCR-ABL1-positive clone was shown as a resistance mechanism to multiple FLT3is72. Sci Rep 11, 20745 (2021). 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). We thank the PETHEMA group for its participation in this study. Rllig, C. et al. Article Am. Among 14 R/R FLT3mut AML patients, the CRc rate was 64% with FLT3-PCR negativity in 88% of responders. Leukemia 10, 19111918 (1996). 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. Management of Newly Diagnosed Acute Myeloid Leukemia in Older Adults A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid A subsequent randomized phase IIb trial evaluated lower doses, 30 or 60mg of quizartinib daily, in patients with R/R FLT3-ITDmut AML. NGS, next-generation sequencing. Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. On the other hand, we obtained a value (0.52) that was close to significant in the analysis of the prognostic impact of the FLT3-ITD AR according to the 2017 ELN cutoff8. The clinical significance of FLT3 ITD mutation on the prognosis of Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. 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. Scientific Reports (Sci Rep) CAS 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. FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. We observed a low frequency of NPM1 mutation (10.1%), which correlated with the good prognosis of this mutation. Additionally, the area under the ROC curve, which serves as an indicator of the diagnostic capacity of the ITD length as a whole, was 0.504. 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. These authors contributed equally: Naval Daver, Sangeetha Venugopal, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Naval Daver,Sangeetha Venugopal&Farhad Ravandi, You can also search for this author in In a single-arm phase II trial of quizartinib (90 or 135mg), the CRc rates were between 46 and 56% in ~250 R/R FLT3-ITDmut patients treated across two cohorts. Precision Medicine in Myeloid Malignancies: Hype or Hope? Interestingly, their prognostic effect had a strong dependence on age: FLT3 ITD indicated poor survival in younger patients (<60 years; P = .00003), but had no effect in older patients (60-74 years; P = .5), whereas NPM1 mut indicated better survival in older patients ( P = .00002), but not in younger patients ( P = .95). Therefore, the value obtained is not significant, although it shows a slight trend toward being significant. Secondary mutations as mediators of resistance to targeted therapy in leukemia. FLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. For . 10, 588876- (2020). and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Patients diagnosed with acute promyelocytic leukemia (APL) were excluded. 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). Perl and colleagues investigated whether prior FLT3i therapy influenced outcomes in patients treated with gilteritinib. Any variant allele frequency data were reported rarely. Commun. Nature 485, 260263 (2012). 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. Blood 93, 30743080 (1999). Despite the current availability of the FLT3 inhibitor midostaurin, there is an unmet need for improved treatment options. Google Scholar, MM Patnaik 2018 The importance of FLT3 mutational analysis in acute myeloid leukemia Leuk. Perl, A. E. et al. Clinical heterogeneity under induction with different dosages of Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. Oran et al. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. 3 A Survival curves stratified by the presence or absence of FLT3 -ITD and NPM1 mutation for patients younger than 65 years. Strati, P. et al. 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%. Impact of FLT3-ITD length on prognosis of acute myeloid leukemia 2, 3 There are two types of FLT3 mutation, internal tandem duplication of FLT3 ( FLT3-ITD) and tyrosine kinase Among 161 intensively treated patients, 123 had the cytogenetic and molecular information required to calculate the 2010 ELN classification21. We stop the venetoclax and the FLT3i after Day 14 in patients who achieve marrow remission (<5% blasts) and/or marrow aplasia/hypoplasia/insufficiency (<5% cellularity). J. Hematol. Daver, N., Venugopal, S. & Ravandi, F. FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm. We tried to validate the thresholds of ITD length previously published (i.e., 39bp and 70bp) in intensivelytreated AML patients (n=161). 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. 2, 125 (2020). volume11, Articlenumber:104 (2021) 5 e336, S-B Liu 2019 Impact of FLT3-ITD length on prognosis of acute myeloid leukemia Haematologica 104 e9 e12, X Jiang 2018 Influence of FLT3-ITD mutation and length on the treatment response and prognosis in cytogenetically normal AML patients Blood 132 5245 5245, C Allen 2013 The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia Leukemia 27 1891 1901, X Quan J Deng 2020 Core binding factor acute myeloid leukemia: Advances in the heterogeneity of KIT, FLT3, and RAS mutations (Review) Mol. For post-ASCT maintenance, our agent of choice has been gilteritinib 80120mg day either as a single agent or combined with low-dose azacitidine. This model of initiatory and progression mutation as FLT3 is well described 37, 38. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. The current European Leukemia Net (ELN) guidelines categorize FLT3 -ITDmut AML as favorable (NPM1mut with FLT3 wild-type Or NPM1mut with FLT3-ITD AR<0.5), intermediate (NPM1mut with FLT3-ITD AR>0.5 Or NPM1WT with FLT3-ITD AR<0.5), or adverse (NPM1WT with FLT3-ITD AR>0.5)18. 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. DNA quantification was performed with a Nanodrop (Thermo Fisher Scientific, Waltham,MA) or Qubitfluorometer (Thermo Fisher Scientific, Waltham, MA). As we have already explained, our main goal was to validate two previous recurrently applied cutoffs: 39bp and 70bp. 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. The sorafenib treatment arm had increased rates of adverse events, particularly diarrhea, bleeding, cardiac events, hand-foot-skin reaction, and rash but with no significant increase in the 30- or 60-day mortality between the two treatment arms. 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). Of note, we tested 3 different ITD length thresholds, and to be considered significant, the P value should be<0.025. Article Kadia, T. et al. The point mutations that lead to resistance include N676, F691, and D835, together with FLT3-ITD. J. Med. Sorafenib with azacitidine combination reported an overall response rate (ORR) of 78% (n=27) in the frontline patients not eligible for intensive induction31 and an ORR of 46% with an acceptable safety profile in R/R FLT3-ITDmut 32 which led to the inclusion of sorafenib with azacitidine combination as a 2B guideline in National Comprehensive Cancer Network (NCCN) for R/R FLT3-ITDmut AML33. J. Hematol. The median OS was 1.3years (CI: 0.71.9) and 1.4years (CI: 0.91.9), respectively (P=0.9). Timothy, J. Our study has several limitations: (1) Our patients were selected from an observational registry, which can be interpreted as a limitation given the heterogeneity of treatments or as a strength because our data are thereby more similar to those observed in real-life clinical practice than those derived from a clinical trial26,27. fms3flt3-itdaml molm13baf3-flt3-itd p-erkp-akt . Google Scholar. Blood 121, 46554662 (2013). Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 gene ( FLT3) confer a poor prognosis in adult AML. Rollig, C. et al. Oncol. (C) OS according to the FLT3-ITD length and allelic ratio. Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Our real-life cohort was composed of 362 patients, most of whom were not included in clinical trials. @Repeat a C1 D28 bone marrow on all patients to confirm remission. Green indicates non-mutated genes, red indicates mutated genes and white indicates non-mutated genes. All samples investigated in this study were obtained at the time of diagnosis. We found a statistically significant correlation among SF3B1, WT1 and EZH2 mutations and ITD length. Final results of the chrysalis trial: a first-in-human phase 1/2 dose-escalation, dose-expansion study of gilteritinib (ASP2215) in patients with relapsed/refractory acute myeloid leukemia (R/R AML). 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. Molecular Diagnostics | FLT3 (ITD and TKD) Mutation Detection In the randomized phase III RATIFY trial of midostaurin combined with cytarabine and daunorubicin (3+7) induction and consolidation, midostaurin improved OS compared to placebo in patients <60years of age with newly diagnosed FLT3 (ITD and/or TKD) AML24, regardless of AR (0.7 or 0.7) or the type of mutation (ITD or TKD). Stratified KaplanMeier analysis was also employed with the AR and genetic risk, following 2010 ELN guidelines21, as classifiers of the patients. (PDF) Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in 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). 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.
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