SORMAIN, a placebo-controlled randomized phase II trial evaluated post-transplant sorafenib maintenance in patients with FLT3-ITDmut AML with RFS post-ASCT as the primary endpoint. Biao Wang, X. Hua, Jihong Zhang, Weiying Gu . The authors declare no competing interests. As in previous works, we analyzed the clinical significance of FLT3-ITD length among fit patients treated with intensive regimens15,16. PubMed Acute myeloid leukemia patient with FLT3-ITD and NPM1 double mutation Results of a Phase 2, Randomized, Double-Blind Study of Sorafenib Versus Placebo in Combination with Intensive Chemotherapy in Previously Untreated Patients with FLT3-ITD Acute Myeloid Leukemia (ALLG AMLM16) (ASH, 2020). 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. Secondary resistance to FLT3i could be either on-target (changes in the FLT3) or off-target (constitutive activation of non-FLT3-dependent oncogenic pathways). To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. FLT3-ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. Google Scholar. 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. Correspondence to AR, allelic ratio. npm1flt3-itd2017elnnpm1flt3-itd[<0.5][>0.5]flt3-itd[dna][auc]"flt3-itd"auc"flt3-" Cite this article. Sasaki, K. et al. Schneider F, Hoster E, Schneider S, Dufour A, Benthaus T, Kakadia PM, et al. Similarly, the median ITD length in three patients with EZH2mutations was 26bp vs 48bp in the wild-type group (n=65) (P=0.031). Recently, a double-blind placebo-controlled study reported a trend toward improved OS but not EFS with sorafenib combined with intensive chemotherapy in the frontline setting, especially among those with high FLT3-ITDmut AR >0.730. While the seven patients treated with the doublet had a CRc rate of 57% (n=4/7) and a median OS of 5.7 months, the fifteen R/R FLT3mut AML patients treated with the triplet had a CRc rate of 81% (n=11) with a projected 1-year OS of 60%. These combinations appear to improve the efficacy over single agent gilteritinib and could be considered if there is expertise in using such an approach, For patients relapsing while on gilteritinib or soon after gilteritinib based therapy a combination of azacitidine with sorafenib or azacitinde with venetoclax or gemtuzumab based approaches may be considered as salvage options (with clinical trials being clearly the best option if available). Clinical impact of change of FLT3 mutation status in acute myeloid The origin and evolution of mutations in acute myeloid leukemia. Clinical outcome stratified according to the FLT3-ITD length (cutoff 70bp) for all patients treated with intensive chemotherapy. You are using a browser version with limited support for CSS. 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. By submitting a comment you agree to abide by our Terms and Community Guidelines. 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]. DiNardo, C. D. et al. Type I FLT3is are active against both the FLT3-ITD or TKD, type II inhibitors are only active against FLT3-ITD, not TKD. 16, 16911699 (2015). Timothy, J. Role of Biomarkers in the Management of Acute Myeloid Leukemia 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. PubMed Patients diagnosed with acute promyelocytic leukemia (APL) were excluded. Jarno Kivioja, Disha Malani, Caroline A. Heckman, Iman Abou Dalle, Ahmad Ghorab, Gautam Borthakur, Frank G. Rcker, Ling Du, Konstanze Dhner, Feng-Ming Tien, Cheng-Hong Tsai, Hwei-Fang Tien, Kun-yin Qiu, Xiong-yu Liao, Dun-hua Zhou, Nikolaus Jahn, Ekaterina Jahn, Konstanze Dhner, Scientific Reports Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). If material is not included in the articles Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. TM,transmembrane domain; JMD, juxtamembrane domain; JMD-B, binding motif; JMD-S, switch motif; JMD-Z, zipper motif; HR, hinge region; TKD1, tyrosine kinase domain 1; B1, beta1-sheet; NBL, nucleotide binding loop; B2, beta2-sheet; and TKD2, tyrosine kinase domain 2. 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). 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. & Gale, R. E. Impact of FLT3ITD mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. 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. Google Scholar. S.V. Lancet Oncol. FLT3-ITD and its current role in acute myeloid leukaemia We found a statistically significant correlation among SF3B1, WT1 and EZH2 mutations and ITD length. Mead, A. J. et al. Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia. FLT3-ITD has been strongly associated with a bad prognosis, leukocytosis, high blast counts, increased risk of relapse and shorter overall survival. J. Hematol. Conceptualization, T.C., J.M.A., E.B. or. FLT3 mutation and all but one patient died shortly after FLT3 mutation was acquired. is a PhD candidate at Universidad Autnoma de Madrid (UAM). Secondary mutations as mediators of resistance to targeted therapy in leukemia. 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. 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 license, and indicate if changes were made. The impact of prognostic factors may change as the AML treatment landscape evolves. 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. Patients with NPM1-/FLT3- showed complex karyotype (24%) and t(8;21) (8%). Yilmaz, M. et al. Zhang, W. et al. Mutations of FLT3 are found in approximately 30% of newly diagnosed AML patients and appear either as ITDs ( 25%) or point mutations in the tyrosine kinase domain (TKD) (710%)4. Mutations of SF3B1, EZH2 and WT1 seem to be a more ancestral event than FLT3 mutations, as expected, given the VAF of the genes. Cortes, J. E. et al. (B) Relapse-free survival. FLT3 -ITD has a poor prognostic impact in patients with AML at diagnosis. We tried to validate the thresholds of ITD length previously published (i.e., 39bp and 70bp) in intensivelytreated AML patients (n=161). 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. PubMed Clinical outcome stratified according to the FLT3-ITD length (cutoff 39bp) for all patients treated with intensive chemotherapy. PubMedGoogle Scholar. Additionally, different subdomains of TKD1 (HR or beta1-sheet) have been highlighted as those conferring an adverse outcome10. Am. 2012;91(1):9-18. CAS Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. 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. Tamaoki, T. et al. 1A). 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. 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. The Programa Espaol de Tratamientos en Hematologa (PETHEMA) AML epidemiologic registry (NCT02607059) includes patients diagnosed with AML, regardless of the treatment administered. prognostic impact of FLT3-ITD and NPM1 mutation in adult AML is age Updated results from long-term follow-up of the randomized-controlled SORAML trial. FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML. Prognostic impact analyses of FLT3-ITD length were performed among patients treated with upfront IC regimens. Kiyoi, H. et al. N. Engl. Rosnet, O. et al. NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 Chinese patients with de novo acute myeloid leukemia. 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). The non-intensive chemotherapy group received FLUGA (fludarabine+Ara-C), n=22; azacytidine, n=15; and decitabine, n=5, and one patient was treated with IDA-FLAG-Lite. The FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) is one of the most frequent mutations found in acute myeloid leukemia (AML) patients, with a frequency of 20-30%. 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. and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. Jain, P. 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 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. FLT3-TKD activating mutations also constitutively activate FLT311; however, they have not been associated with a consistent prognostic impact12. ISSN 2045-2322 (online). 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. FLT3-ITD Mutation in MDS Patients Is Associated with Early While both FLT3-ITD and FLT3-TKD mutations are common in AML with a normal karyotype, these mutations are also identified in AML with various karyotypic abnormalities. In general, quizartinib is well tolerated with minimal skin, gastrointestinal, or pulmonary side effects. In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene ( FLT3- ITD) are associated with poor prognosis. 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. Ohanian, M. et al. (PDF) Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in 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). FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia and is associated with worse clinical outcome. (C) OS according to the FLT3-ITD length and allelic ratio. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Midostaurin has been approved and widely used in combination with induction and consolidation therapy in patients with newly diagnosed FLT3mut AML25. Prognostic Value of FLT3-Internal Tandem Duplication Residual Disease 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. The Spanish group evaluated intermediate-risk AML patients treated with intensive chemotherapy. Front. The PubMed database, the Cochrane Library, conference proceedings, the EMBASE databases, and references of published trials and review articles were searched. 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. Lancet Oncol. and P.M.; Visualization, T.C., J.M.A., D.L., J.S. J. Med. Outcome of patients with acute myeloid leukemia following failure of Juan M. Alonso-Dominguez. In our case, 15 AML prognostic genes including FLT3/ITD gene were all negative. 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. Swaminathan et al. Blood 114, 29842992 (2009). Upregulation of Bcl-2 confers resistance to FLT3 inhibition in FLT3-ITD AML with secondary acquired mutations. Blood 99, 43264335 (2002). There were two patients with core binding factor (CBF) translocations (one RUNX-RUNX1T1 and one CBFB-MYH11) and FLT3-ITD mutations. We used the 0.5 cutoff of the AR as recommended by the 2017 ELN guidelines8.These patients were divided on the basis of the FLT3-ITD AR into an FLT3-ITDLOWgroup (41%; n=58) and an FLT3-ITDHIGHgroup (59%; n=82). Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. McMahon, C. M. et al. CAS However, these studies did not apply previously validated ITD length cutoffs obtained in other smaller series11,15,16,17. Recurrent somatic internal tandem duplications (ITD) in the FMS-like tyrosine kinase 3 (FLT3) gene characterise approximately one third of patients with acute myeloid leukaemia (AML), and FLT3-ITD mutation status guides risk-adapted treatment strategies.The aim of this work was to characterise FLT3-ITD variant distribution in relation to molecular and clinical features, and overall survival in . Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3internal tandem duplication mutation (SORMAIN). The primary and key secondary trial end points were OS and RFS, respectively, both measured from the time of randomization. Blood 136, 1617 (2020). More recently, the emergence of BCR-ABL1-positive clone was shown as a resistance mechanism to multiple FLT3is72. Thiede, C. et al. Administration of the triplet is associated with prolonged cytopenias, requiring close monitoring and experience with venetoclax based combinations. 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 . Welch John, S. 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. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. CAS Quizartinib demonstrated an OS of 6.2 months compared with 4.7 months with salvage chemotherapy (hazard ratio 0.76 and P=0.02). To obtain Impact of FLT3-ITD length on prognosis of acute myeloid leukemia 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. H Dhner 2010 Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet Blood 115 453 474, S Kayser 2009 Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome Blood 114 2386 2392, FG Rcker 2021 Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results Leukemia 2021 1 10, O Blau R Berenstein A Sindram IW Blau 2013 Molecular analysis of different FLT3-ITD mutations in acute myeloid leukemia Leuk. Perl, A. E. et al. In our experienced cases FLT3-ITD mutation in MDS showed shorter duration to AML transformation and very poor prognosis. 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.
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