Whitman, S. P. et al. Although the label indication for gilteritinib is as a single agent we have never used it as a single agent but always in combination with either HMA alone, venetoclax alone or as a triplet with HMA and venetoclax. The CRc rate was 67% (n=10/15) in the combination arm in the safety cohort prior to commencement of randomization45. Informed consent was a requisite for patients alive at the time of data lock (January 2019). Although common methylation . 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+ . 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. PubMed Central 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). 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). Blood 99, 43264335 (2002). FLT3-ITD has been strongly associated with a bad prognosis, leukocytosis, high blast counts, increased risk of relapse and shorter overall survival. However, other studies did not find significantly worse clinical outcomes in patients with non-JMD ITD mutations24,25. J. Med. An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown). Biol. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. N. Engl. CAS Scientific Reports (Sci Rep) We obtained a P value of 0.055 in the analysis of RFS applying the 70bp cutoff. Blood 121, 27342738 (2013). 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 In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene ( FLT3- ITD) are associated with poor prognosis. FLT 3-ITD mutations typically were determined using polymerase chain reaction and fragment analyses. We identified 1572 adult (age 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or . Seventeen patients underwent autologous hematopoietic progenitor transplantation, and forty-four patients underwent allogeneic hematopoietic progenitor transplantation (Table 1). Encouragingly, the response rate was maintained among patients previously exposed to other FLT3 TKIs. 94, 984991 (2019). The FMS-like tyrosine (FLT3) gene encodes a class III receptor tyrosine kinase, sharing structural and sequence homologies with family members, including c-kit, c-FMS, FLT1, and PDGF- R. FLT3 plays a key role in the control of hematopoiesis. has nothing to disclose. Brinton, L. T. et al. Google Scholar. Am. MRD detection in AML leverages cutoff points garnered from various detection methods include flow cytometry or real-time quantitative polymerase chain reaction (pCR). Kottaridis, P. D. et al. 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. Variant allele frequency (VAF) is the ratio of ITD-mutated alleles to ITD-mutated+wild-type alleles (FLT3ITD/FLT3ITD+FLT3 wild-type)14. AR,allelic ratio. The CRc rates with quizartinib were similar to prior studies (48.2%), and 32% patients on the quizartinib arm underwent ASCT compared with 11% with salvage chemotherapy. Go to: Introduction Blood Marrow Transplant 22, 12181226 (2016). These mutations arearranged in increasing order by FLT3-ITD length. Thiede, C. et al. The point mutations that lead to resistance include N676, F691, and D835, together with FLT3-ITD. Pratcorona, M. et al. Venetoclax, FLT3 Inhibitor and Decitabine in FLT3mut Acute Myeloid Leukemia: Subgroup Analysis of a Phase II Trial (ASH, 2020). We administer a second-generation FLT3i (ideally gilteritinib) continuously with HMA from cycle 1 Day 1. Jain, P. et al. FLT3 is a gene change, or mutation, in leukemia (blood cancer) cells. McMahon, C. M. et al. Perl, A. E. et al. J. Med. FLT3-ITD allelic ratio and HLF expression predict FLT3 inhibitor efficacy in adult AML, 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, Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results, Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission, Poor outcome of pediatric patients with acute myeloid leukemia harboring high FLT3/ITD allelic ratios, Mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia, Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial, Impact of FLT3-ITD allele ratio and ITD length on therapeutic outcome in cytogenetically normal AML patients without NPM1 mutation, Mutational spectrum and prognosis in NRAS-mutated acute myeloid leukemia, https://doi.org/10.3324/haematol.2020.263806, http://creativecommons.org/licenses/by/4.0/. 3.3 TET2 in NPM1 mut /FLT3-ITD (), and CD34 and ID-Ara-C in NPM1 mut /FLT3 . Hypomethylating agent and venetoclax with FLT3 inhibitor triplet therapy in older/unfit patients with FLT3 mutated AML, Mechanisms of resistance to cancer therapy, Cancel Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. 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. CAS Blood 134, 2564 (2019). Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. 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). However, the median OS was 19.2 months in FLT3-TKDmut AML (19.2 months), but only 11.5 months in FLT3-ITDmut patients65. 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. 96 1993 2003, Article J. Hematol. The survival rates in patients 60 years of age were also similar across NPM1 mut /FLT3 wt, NPM1 mut /FLT3-ITD low, and NPM1 mut . * Genes with a P value<0.05 in the MannWhitney test correlating mutational status with ITD length. Strati et al. Google Scholar. 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. Cite this article. Our treatment approach for FLT3mut AML in MD Anderson Cancer Center is as follows: in newly diagnosed patients who are eligible to receive intensive chemotherapy (Fig. The combination continues to enroll. 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. 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. 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. volume11, Articlenumber:104 (2021) Mutations of the fms-tyrosine kinase ( FLT3) were first described in 1997 4 and account for the most frequent molecular mutations in AML. or reset password. Internet Explorer). ; 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. Cladribine added to daunorubicin-cytarabine induction prolongs survival of FLT3-ITD+ normal karyotype AML patients. However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. PubMed Central Blood 128, 1639 (2016). and P.M.; Supervision, J.M.A. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Naval Daver. FLT3 -ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. 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. PubMed Blood 121, 46554662 (2013). Results of venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with acute myeloid leukemia with FLT3 mutations. J. Med. Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Article CAS 61, 72337239 (2001). Pratz, K. W. et al. Taken together, utilizing baseline FLT3-ITDmut AR to guide the post-remission therapy remains controversial. 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. 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. has received research funding from Astellas, and Novartis and has served as a member of advisory board in Astellas and Novartis. FLT3 -ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. Yilmaz et al. 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. 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. Rllig, C. et al. 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). Quizartinib, a second-generation, type I FLT3i is active against FLT3, KIT, CSF1R, PDGFR, and RET kinase34. In order to improve the clinical condition of FLT3-ITD-positive patients, several FLT3 inhibitors have been developed showing variable results. Cortes, J. E. et al. Biochem. & Gale, R. E. Impact of FLT3ITD mutant allele level on relapse risk in intermediate-risk acute myeloid 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. The addition of sorafenib to standard AML treatment results in a substantial reduction in relapse risk and improved survival. 383, 617629 (2020). Due to the preliminary nature of the . S1. Swaminathan, M. et al. In general, quizartinib is well tolerated with minimal skin, gastrointestinal, or pulmonary side effects. Lymphoma 59 2273 2286, S Schnittger 2002 Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: Correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease Blood 100 59 66, M Levis 2013 FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Musa Yilmaz, M. et al. Soc. Timothy, J. Among 362 patients, NGS was performed in 118 patients using a panel of 39 genes. 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). The two leading types of FLT3 mutations found in AML include internal tandem duplications in the juxtamembrane domain (ITD, 17-34%) and mutations in the tyrosine kinase domain (TKD) activation loop (~7%) ( 1 ). FLT3 -ITD has a poor prognostic impact in patients with AML at diagnosis. Patients diagnosed with acute promyelocytic leukemia (APL) were excluded. Any variant allele frequency data were reported rarely. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. Haematologica 106, 1034 (2020). Nevertheless, in three patients, similar VAFs (<5% difference) were detected, which might indicate that these mutations occurred at the same timepoint as the FLT3 mutation.No significant differences were found between the ITD length and the mutational status of any of the remaining genes (Fig. recently showed that ASCT in CR1 improved RFS and OS independent of the FLT3-ITDmut AR or NPM1mut status in patients with FLT3-ITDmut AML20. PubMed Central Because the comutation of DNMT3A (DNMT3A(mut)) has been suggested to negatively influence prognosis in AMLNPM1, we analyzed the impact of DNMT3A(mut) in FLT3-ITD subsets (absent, low, and high ratios). To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in Acute Myeloid Leukemia Patients in Eastern Algeria . 120.000 new AML cases and over . DiNardo, C. D. et al. Article (A) Overall survival. Rollig, C. et al. Commun. Haematologica (2021). Slider with three articles shown per slide. 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. Nakao, M. et al. Despite the encouraging development of FLT3i, resistance to FLT3i is not uncommon and it can be either primary or secondary. The analysis of OS and RFS applying this value did not show significant results (data not shown). Blood 135, 791803 (2020). which included NPM1 mut /FLT3-ITD high AR cases. 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. 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. CAS 13 95 100. Am. Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD).Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). 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. Unlike midostaurin, quizartinib monotherapy, even at lower doses demonstrated significant marrow remissions in R/R FLT3mut AML35,36,37. or. J. Natl Cancer Inst. Blood 130, 721 (2017). To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 13, 139 (2020). 2018 Oct 23;2 (20):2744-2754. doi: 10.1182/bloodadvances.2018020305. FLT3 -TKD mutations are point mutations in the activation loop of FLT3, mainly represented by codon D835 or deletion of codon I836, which leads to a loss of auto-inhibition [ 18 ]. Google Scholar. J. Hematol. 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. Smith, C. C. et al. 2012;91(1):9-18. FLT3 mutations occur in more than 30% of patients with acute myeloid leukemia (AML) and are associated with short relapse-free and overall survival, including internal tandem duplication (ITD) and point mutations within the tyrosine kinase domain (TKD) [1, 2].To date, multiple FLT3 kinase inhibitors have been developed and some are approved for clinical use including sorafenib, Quizartinib . 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. PCR with fluorescently labeled primers followed by capillary electrophoresis for FLT3-ITD was performed as described elsewhere31. 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. The . Statistical analyses were performed with SPSS 19.0 (IBM, Armonk, NY). Google Scholar. Lancet Oncol. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. NGS, next-generation sequencing. More studies will be necessary to confirm these results and to shed light on the possible physiopathologic relationship. Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. Patients treated with midostaurin had higher rates of anemia and skin rash compared to placebo and these were generally manageable with supportive care without necessitating dose reductions or interruptions in the majority of cases. Naval Daver, M. D. et al. The median OS was 1.3years (CI 0.71.9) and 1.4years (CI 1.01.8), respectively (P=0.8). Souki Cancer Research Fund and generous philanthropic contributions to the MD Anderson Moon Shots Program. 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. Password. Therefore, only 3.8% of the patients showed an FLT3-ITD insertion in the TKD1 domain. Alotaibi, A. S. et al. F fludarabine, I idarubicin, CL cladribine, A cytarabine 1.52g/m2, HMA hypomethylating agent, CR complete remission, ECOG PS Eastern Cooperative Oncology Group Performance Status, CG cytogenetics, MRD measurable residual disease, SCT stem cell transplant, HiDAC high-dose cytarabine, CBC complete blood count. We continue the venetoclax and FLT3i until Day 21 if the Day 14 bone marrow shows >5% blasts with >/=5% cellularity. Levis turned to FLT3-ITD mutations in acute myeloid leukemia (AML) to highlight the challenges with targeted therapy. 16, 16911699 (2015). The FLT3-ITD allelic ratio has clear prognostic value. Although the triplet approaches are still in development, emerging data with the triplets as discussed previously, suggest rapid and high potency, deep molecular remissions, and encouraging survival.
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