Blood 127, 360362 (2016). Stratified KaplanMeier analysis was also employed with the AR and genetic risk, following 2010 ELN guidelines21, as classifiers of the patients. Type I FLT3is like gilteritinib are less prone to develop secondary mutations in the TKD, although the gatekeeper F691M can confer resistance to gilteritinib71. has received research funding from Astellas, and Novartis and has served as a member of advisory board in Astellas and Novartis. A stratified analysis of FLT3-ITD length on the basis of the AR was performed in 140 patients (AR<0.5 and ITD<70bp, n=43; AR<0.5 and ITD70bp, n=15; AR>0.5 and ITD<70bp, n=61; AR>0.5 and ITD70bp, n=21). Both mutations lead to the activation of downstream proliferation cascades [ 19, 20 ]. **If the C1 D14 bone marrow show >5% blastscontinue venetoclax, FLT3i till D21. Pratz, K. W. et al. Castao-Bonilla, T., Alonso-Dominguez, J.M., Barragn, E. et al. Some studies showed a reduced CR rate, while others analyzing the IS in the same region found differences in OS. This result is similar to the RATIFY study, in which 44% of patients lost FLT3 ITD under treatment with midostaurin 36. Informed consent was a requisite for patients alive at the time of data lock (January 2019). Article mutations (1-year survival < 1% vs 42% in their presence vs absence) which should be incorporated in patient counseling. G Nagel 2017 Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO) Ann. Enter the email address you signed up with and we'll email you a reset link. 120.000 new AML cases and over . Samples from 118 of the 362 AML patients with FLT3-ITDmutations were analyzed with an NGS panel of 39 genes (see Supplementary Fig. 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. N. Engl. 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. Previously published cutoffs of ITD length, reported in more than one publication(i.e., 39bp and 70bp), were tested to check their applicability in our cohort. Ohanian, M. et al. Biao Wang, X. Hua, Jihong Zhang, Weiying Gu . 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. A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. 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. 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. PubMed which included NPM1 mut /FLT3-ITD high AR cases. PubMed Among patients treated with azacitidine and quizartinib in the frontline setting, the CRc rate was 78% (n=7/9) with a median OS of 21.1 months. Therefore, only 3.8% of the patients showed an FLT3-ITD insertion in the TKD1 domain. Lancet Oncol. Go to: Introduction QuANTUM-R, a phase 3 randomized controlled trial, evaluated quizartinib monotherapy vs investigator choice salvage chemotherapy in R/R FLT3-ITDmut AML. Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in Acute Myeloid Leukemia Patients in Eastern Algeria . Leukemia 10, 19111918 (1996). Additionally, different subdomains of TKD1 (HR or beta1-sheet) have been highlighted as those conferring an adverse outcome10. Mechanistically, FLT3-ITDs and FLT3-TKDs induce activation of transduction intermediates, including STAT5, AKT, and ERK1/2 ( 2 ). Lancet Oncol. 15 926 957, H Dhner DJ Weisdorf CD Bloomfield 2015 Acute myeloid leukemia N. Engl. 16, 16911699 (2015). and P.M.; Supervision, J.M.A. AR is defined as the ratio of ITD-mutated alleles to wild-type allele (FLT3ITD/FLT3 wild-type)13. PubMed Central Clinical outcome stratified according to the FLT3-ITD length (cutoff 39bp) for all patients treated with intensive chemotherapy. 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). Although activity was seen, the response rates were overall modest with this combination and the combination of HMA with midostaurin is not one that we routinely use or recommend for frontline FLT3-mutated AML47. 5, 6 The FLT3 gene is a member of the class III receptor tyrosine kinase family, including c-kit, c-fms, and the platelet-derived growth factor receptors. 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). CAS These observations have made FLT3 an attractive drug target. J. Hematol. In the FLT3-ITDLOW group of patients, the median OS was 2.3years (CI: 1.13.6), and in the FLT3-ITDHIGH group of patients, the median OS was 1.1years (CI: 0.71.5). PubMed Blood Marrow Transplant 22, 12181226 (2016). In the QuANTUM-R and ADMIRAL trials, only 4% and 12% of patients had received prior FLT3i therapy with induction, making it difficult to draw conclusions regarding the outcomes of contemporary patients, most of whom will have received a FLT3i (commonly midostaurin) with induction36,40. J. Clin. It is mutated in about 1/3 of acute myeloid leukemia (AML) patients, either by internal tandem duplications (ITD) of the juxtamembrane domain or by point mutations usually involving the kinase domain (KD). 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. In order to improve the clinical condition of FLT3-ITD-positive patients, several FLT3 inhibitors have been developed showing variable results. Posterior reversible encephalopathy and pancreatitis are rare (<12%) but important side effects to be aware of. The first-generation FLT3is lack specificity for FLT3 and inhibit multiple downstream RTKs that may result in more off-target toxicities. In the frontline setting (n=4), the CRc rate with the triplet was 100% with FLT3-PCR negativity in all four patients56. 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. Expression and signal transduction of the FLT3 tyrosine kinase receptor. 2B). Blood 110, 12621270 (2007). Heart J. Suppl. Which FLT3 Inhibitor for Treatment of AML? Although common methylation . and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. 3.3 TET2 in NPM1 mut /FLT3-ITD (), and CD34 and ID-Ara-C in NPM1 mut /FLT3 . Schlenk et al. 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. (3) Findings regarding the relationship between ITD length/site and mutational profile might be interpreted as exploratory given the high number of correlations performed. J. Hematol. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf2017 (2017). 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. Blood 99, 43264335 (2002). Swaminathan et al. This work is submitted in partial fulfillment of the requirement for the PhD. 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. 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. Any variant allele frequency data were reported rarely. 93, E202E205 (2018). Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/refractory FLT3-mutated Acute Myeloid Leukemia in the Expansion Cohort of a Phase 1b Study (ASH, 2020). evaluated the outcomes of sequential FLT3i-based therapies in FLT3mut AML. We analyzed 118 patients (median age at diagnosis 58.3, range 14.3&ndash . FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML. Minetto, P. et al. Front. Therefore, there is a lack of consensus regarding the prognostic importance of the ITD IS and the subdomains that confer this adverse outcome. FLT3 plays a role in cell survival, proliferation and differentiation of hematopoietic progenitor cells. Cortes, J. E. et al. Rosnet, O. et al. Elderly patients with AML have a distinct genetic landscape compared with the younger population. or. PubMed Wang, E. S. et al. Pratcorona, M. et al. Given the magnitude of OS benefit and concerns over therapeutic equipoise and potential cardiac safety signals, quizartinib was not approved in the US and Europe, but approved in Japan as a monotherapy in R/R FLT3-ITDmut AML. We observed a low frequency of NPM1 mutation (10.1%), which correlated with the good prognosis of this mutation. CR+CRi rates between groups were compared with a chi-square test. Enter the email address you signed up with and we'll email you a reset link. Administration of the triplet is associated with prolonged cytopenias, requiring close monitoring and experience with venetoclax based combinations. 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 Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. 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. (A) Overall survival. 38, 29933002 (2020). 383, 617629 (2020). Our results, alongside those of other non-significant reports, lead us to believe that FLT3-ITD length has neither prognostic value nor possible clinical application. 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. J. Hematol. 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+ . Article 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. Unlike midostaurin, quizartinib monotherapy, even at lower doses demonstrated significant marrow remissions in R/R FLT3mut AML35,36,37. The presence of FLT3-ITD mutation correlates with a high leukemic burden with increased risk of relapse and is recognized to be a driver mutation in patients with AML ( 5 ). A Conventional approach. 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. Cancer 125, 37553766 (2019). Similarly, the median ITD length in three patients with EZH2mutations was 26bp vs 48bp in the wild-type group (n=65) (P=0.031). AML patients with FLT3-ITD mutations show an increased relapse rate, reduced disease-free survival (DFS), and decreased long-term survival, while the rate of complete remission (CR) after induction chemotherapy is not significantly affected6,7. Of note, we tested 3 different ITD length thresholds, and to be considered significant, the P value should be<0.025. Blood 135, 791803 (2020). The PubMed database, the Cochrane Library, conference proceedings, the EMBASE databases, and references of published trials and review articles were searched. 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. J. Natl Compr. Fig. The authors declare no competing interests. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. When comparing both subgroups using a log-rank test, there was a clear trend toward a reduced OS in FLT3-ITDHIGH patients (P=0.052). PubMed It is important to note that none of these patients received a FLT3 inhibitor (FLT3i) during induction, consolidation, or post-ASCT. The FLT3-ITD allelic ratio has clear prognostic value. prospectively evaluated decitabine and quizartinib (doublet) with or without venetoclax (triplet) in patients with newly diagnosed and R/R FLT3-ITDmut AML. A subsequent randomized phase IIb trial evaluated lower doses, 30 or 60mg of quizartinib daily, in patients with R/R FLT3-ITDmut AML. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. 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. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Lancet Oncol. 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 FLT3-ITD AR was available in 140 intensively treated patients. Cite this article. Gilteritinib was generally well tolerated but was associated with increased incidence of gastrointestinal side effects, most frequently diarrhea although nausea has been occasionally observed. 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. 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. Eur. Blood 125, 32363245 (2015). 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. Metzelder, S. et al. FLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. Burnett, A. K., Russell, N. H. & Hills, R. K. Group obotUKNCRIAMLS. Log in with Facebook Log in with Google. FLT3 is a gene change, or mutation, in leukemia (blood cancer) cells. 17 D2 D8, H-S Kim S Lee JH Kim 2018 Real-world evidence versus randomized controlled trial: Clinical research based on electronic medical records J Korean Med Sci 33 e213, RF Schlenk 2014 Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation Blood 124 3441 3449, I Abou Dalle 2020 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 Blood Cancer J.
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