S2) in PETHEMA centralized diagnostic laboratories as previously described33. Our real-life cohort was composed of 362 patients, most of whom were not included in clinical trials. We observed a low frequency of NPM1 mutation (10.1%), which correlated with the good prognosis of this mutation. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. (4) Only five patients in our cohort received treatment with midostaurin (2 in induction and 3 in consolidation treatment); therefore, we were not able to draw conclusions regarding the prognostic impact of the length of the ITD as described in previous studies29,30. If C1 D28 marrow confirms remission and ANC<0.5 and/or platelet<50K consider interrupting FLT3i and using neupogen to enhance count recovery. Weisberg, E. et al. As consolidation therapy, one hundred patients received high-intensity treatment (3+7, n=68; 3+7+gemtuzumab ozogamicin (GO), n=4; 2+5=2; IDA-FLAG, n=1; high-dose cytarabine (HDARAC), n=23; low-dose cytarabine (LDARAC), n=1; and Ara-C 100mg/m25, n=1). (B) Relapse-free survival. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. 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. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Conceptualization, T.C., J.M.A., E.B. Upon achieving CR, the decision for ASCT is based on the risk-benefit assessment for ASCT. You are using a browser version with limited support for CSS. 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. Although common methylation . 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 . 2018 Oct 23;2 (20):2744-2754. doi: 10.1182/bloodadvances.2018020305. Zhang, W. et al. 113, 983988 (2001). 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. Regrettably, patients with information on the IS of ITD available had received different treatments: intensive chemotherapy, n=37; non-intensive therapy, n=14; clinical trials, n=6; and best supportive care, n=2. (5) No data regarding minimal residual disease (MRD) were available in our cohort, and MRD data could be interesting to analyze in future studies. FLT3-ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene ( FLT3- ITD) are associated with poor prognosis. 1A). 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. Interestingly, all patients with an FLT3-ITD inserted in the TKD1 domain showed DNMT3A mutations. 18, 10611075 (2017). has received research funding from Astellas, and Novartis and has served as a member of advisory board in Astellas and Novartis. 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. "For patients with AML, the 5-year survival rate is only about 29%," said Dr. Erba. Lancet Oncol. Blood 93, 30743080 (1999). Therefore, only 3.8% of the patients showed an FLT3-ITD insertion in the TKD1 domain. The PubMed database, the Cochrane Library, conference proceedings, the EMBASE databases, and references of published trials and review articles were searched. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Elderly patients with AML have a distinct genetic landscape compared with the younger population. Information regarding the ITD insertion site and mutational status of another 38 genes recurrently mutated in myeloid neoplasms was available in 106 and 118 patients, respectively. J. Med. 4). Samples from 118 of the 362 AML patients with FLT3-ITDmutations were analyzed with an NGS panel of 39 genes (see Supplementary Fig. Lancet Oncol. is a PhD candidate at Universidad Autnoma de Madrid (UAM). However, previous studies have shown that FLT3/ITD mutation was not an independent adverse prognostic factor in DEK/CAN-positive AML patients. All eligible intermediate or high-risk patients (defined as patients with FLT3-ITDmut AR>0.50 irrespective of NPM1mut status, or FLT3-ITDmut AR<0.50 without NPM1mut) are equivocally recommended to proceed to ASCT in CR1 followed by post-ASCT FLT3i maintenance for at least 2 years (although we often continue indefinite FLT3i maintenance until long-term maintenance data becomes available). 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. Stone, R. M. et al. We aimed to assess the prognostic impact of these variables on the complete remission (CR) rates, overall survival (OS) and relapse-free survival (RFS) of AML patients withFLT3-ITDmutations. Yalniz, F. et al. In patients with relapsed or refractory FLT3mut AML (Fig. We thank the PETHEMA group for its participation in this study. 21, 12011212 (2020). FLT3-ITD is located within exon 14, corresponding to JMD, in 70% of AML patients, while 30% of ITDs span exon 15, corresponding to the TKD1 domain. Sra. Article Frhling, S. et al. PubMed 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. The primary and key secondary trial end points were OS and RFS, respectively, both measured from the time of randomization. Am. To test the prognostic significance of the ITD length and its clinical applicability, we used recurrent previously published cutoffs, which were analyzed in series ranging from 28 to 100 intensively treated patients. Oncol. 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. (2) Larger studies analyzing ITD length also found no significant results14,23,28. 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. Therefore, in patients not eligible for intensive chemotherapy at MDACC, we prefer a combination of HMA with venetoclax and FLT3i (gilteritinib) over an HMA with venetoclax doublet (Fig. (A) Overall survival. Due to the preliminary nature of the . Cladribine combined with idarubicin and Ara-C (CLIA) as a frontline and salvage treatment for young patients (65 yrs) with acute myeloid leukemia. Blood 121, 27342738 (2013). Lancet Oncol. Yilmaz et al. Azacitidine and venetoclax in previously untreated 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. The addition of sorafenib to standard AML treatment results in a substantial reduction in relapse risk and improved survival. Second-generation FLT3is potently and specifically target FLT3 with fewer off-target effects. 2, 125 (2020). Acta Haematol. Yilmaz, M. et al. Variant allele frequency (VAF) is the ratio of ITD-mutated alleles to ITD-mutated+wild-type alleles (FLT3ITD/FLT3ITD+FLT3 wild-type)14. Am. 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. This work is submitted in partial fulfillment of the requirement for the PhD. 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. An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown).A stratified analysis of FLT3-ITD length on the basis ofthe AR was performed in 140 patients (AR<0.5 and ITD<39bp, n=17; AR<0.5 and ITD39bp, n=41; AR>0.5 and ITD<39bp, n=23; AR>0.5 and ITD39bp, n=59). Among 14 R/R FLT3mut AML patients, the CRc rate was 64% with FLT3-PCR negativity in 88% of responders. A Conventional approach. Nakao, M. et al. FLT3-ITD length was compared between mutation and wild-type groups for each of the 39 genes using a MannWhitney test. 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. All samples investigated in this study were obtained at the time of diagnosis. N. Engl. Blood 132, 598607 (2018). Google Scholar, MM Patnaik 2018 The importance of FLT3 mutational analysis in acute myeloid leukemia Leuk. As Dr. Erba explained, patients with FLT3 -ITD-positive AML represent a particularly poor prognostic group. Blood 132, 3944 (2018). Blood 136, 3233 (2020). 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 tried to validate the thresholds of ITD length previously published (i.e., 39bp and 70bp) in intensivelytreated AML patients (n=161). 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. Based on the strong preclinical synergy and synthetic lethality with venetoclax and FLT3i combination49,50,51, and the fact that BCL2 upregulation may confer resistance to FLT3 inhibition52, evaluation of several doublet and triplet combinations of venetoclax and FLT3i are ongoing. Ohanian, M. et al. Correspondence to 5 96 102, C Sargas 2020 Networking for advanced molecular diagnosis in acute myeloid leukemia patients is possible: The PETHEMA NGS-AML project Haematologica https://doi.org/10.3324/haematol.2020.263806, Article Therefore, the value obtained is not significant, although it shows a slight trend toward being significant. For CEBPA, 86.7% of the patients with biallelic mutation and 9.1% of patients with the single allele mutation had in-frame mutations in the bZIP domain, which were strongly associated with a favorable prognosis. 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 ]. Canc. 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. DNA was extracted using automated or manual DNA extraction kits following the manufacturers recommendations. Finally, a different report showed worse clinical outcomes in terms of OS and DFS in the TKD1 group. evaluated the outcomes of sequential FLT3i-based therapies in FLT3mut AML. 2013 220 226, H Dhner 2017 Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel Blood 129 424 447, F Breitenbuecher 2009 Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor Blood 113 4074 4077, S Liu 2018 Pattern and prognostic value of FLT3-ITD mutations in Chinese de novo adult acute myeloid leukemia Cancer Sci. J. Hematol. The AR was determined by fragment length analysis and calculated as previously described32. FLT3 activating mutations (FLT3mut) may involve either the juxta membrane domain [internal tandem duplication mutations (FLT3-ITD)]4 or the tyrosine kinase domain (FLT3-TKD)5,6. 6,, - 9 In normal bone marrow, FLT3 expression is Google Scholar. mutations (1-year survival < 1% vs 42% in their presence vs absence) which should be incorporated in patient counseling. Rydapt Prescribing Information. Haematologica 106, 1034 (2020). 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). CBF translocations have been associated with FLT3-ITD mutations in very few patients, and there is no clear information regarding their ELN prognostication18,19,20. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in CAS 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). (A) Overall survival. Among those with NPM1 wild-type, all FLT3-ITDmut patients had an increased risk of relapse and inferior OS, regardless of the AR17. 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. 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. Addition of venetoclax to this backbone may be associated with prolonged and potentially prohibitive myelosuppression; we have not routinely added and do not at this time recommend adding venetoclax to the backbone of CLIA/FIA with FLT3i63. evaluated midostaurin with azacitidine in patients with both newly diagnosed and R/R AML regardless of FLT3 mutational status. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . 38, 29933002 (2020). Figure legend Overall survival of patients with AML following frontline venetoclax plus hypomethylating agent Biophys. Enter the email address you signed up with and we'll email you a reset link. Res. PubMed We identified 1572 adult (age 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or . The . and P.M.; Visualization, T.C., J.M.A., D.L., J.S. Internet Explorer). 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. Cancer Netw. 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. Minetto, P. 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. and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. 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. Sci Rep 11, 20745 (2021). 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 PubMed Central 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. PubMedGoogle Scholar. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Informed consent was a requisite for patients alive at the time of data lock (January 2019).

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