J. Hematol. and P.M.; Supervision, J.M.A. 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. PubMed Central 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). 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). In our case, 15 AML prognostic genes including FLT3/ITD gene were all negative. Quizartinib is also being evaluated in combination with CPX-351 (NCT04209725) and with CLIA (NCT04047641) in treatment naive and R/R FLT3mut AML. 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. Blood 93, 30743080 (1999). Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. FLT3 mutation and all but one patient died shortly after FLT3 mutation was acquired. Strati, P. et al. Dhner, H. et al. Pratcorona, M. et al. 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. 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 . Haematologica 106, 1034 (2020). or reset password. Only four out of 106 patients had ITD IS in the TKD1 domain. 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). 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. Such sequential approaches need to be formally evaluated in the context of prospective clinical trials. 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. 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. Blood 136, 810 (2020). Upregulation of Bcl-2 confers resistance to FLT3 inhibition in FLT3-ITD AML with secondary acquired mutations. 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. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. 4). 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. F.R. PubMed Google Scholar. Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. The randomized phase III ADMIRAL trial evaluated gilteritinib vs investigator choice salvage chemotherapy in patients with R/R FLT3mut AML. (C) OS according to the FLT3-ITD length and allelic ratio. Zhang, W. et al. Pulmonary infiltration and acute pneumonitis-like picture are rare (<1%) but noted side effects of midostaurin that treating physicians should be aware of. 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 To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. 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. AbuDuhier, F. et al. In patients with relapsed or refractory FLT3mut AML (Fig. CAS Quizartinib, a second-generation, type I FLT3i is active against FLT3, KIT, CSF1R, PDGFR, and RET kinase34. The Programa Espaol de Tratamientos en Hematologa (PETHEMA) AML epidemiologic registry (NCT02607059) includes patients diagnosed with AML, regardless of the treatment administered. 13, 132 (2020). Higher daunorubicin exposure benefits FLT3 mutated acute myeloid leukemia. Regardless of the regimen intensity, all clinical trial participants were grouped in a separate treatment category (n=15). The main patient and disease characteristics were collected retrospectively, including demographic characteristics (age, sex), cytomorphologic assessments confirming the AML diagnosis (according to routine site practice), cytogenetics, molecular studies, first-line treatment approach, disease response assessment and disease follow-up. However, whether these findings are specific to Ven + HMA therapy remains to be . 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. Article 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. 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. Moreover, ASCT in CR1 only benefitted patients with isolated FLT3-ITDmut (without NPM1mut) irrespective of AR (P<0.05)21. 381, 17281740 (2019). Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. 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. Further evaluation and optimization of triplets is a major area of clinical research focus in FLT3mut AML. 61, 72337239 (2001). 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. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. (C) OS according to the FLT3-ITD length and allelic ratio. The prognostic value of a FLT3 mutation in the tyrosine kinase domain (FLT3-TKD), which has a lower incidence in AML (approximately 7-10% of all cases), is uncertain. Favorable relapse risk and OS were seen in NPM1mut with FLT3 wild-type; intermediate prognosis in FLT3-ITDmut with concurrent NPM1mut, and adverse prognosis in FLT3-ITDmut with NPM1 wild-type patients16. Hematology. Kayser, S. et al. and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. Acute myeloid leukemia, Version 3.2019, NCCN clinical practice guidelines in oncology. Studies have reported that a higher mutant allelic burden is associated with a worse prognosis. No statistically significant differences were found (P=0.8) (Fig. 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. *C1 D14: Perform bone marrow biopsy; if bone marrow shows <5% blasts and/or <5% cellularity/insufficient sampleStop venetoclax and FLT3i on D14. QTc prolongation >500ms emerged as a significant adverse event36. Clinical outcome stratified according to the FLT3-ITD length (cutoff 39bp) for all patients treated with intensive chemotherapy. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. 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). 373 1136 1152, N Daver RF Schlenk NH Russell MJ Levis 2019 Targeting FLT3 mutations in AML: Review of current knowledge and evidence Leukemia 33 299 312, Article Rydapt Prescribing Information. Oran, B. et al. 15, 17 In our cohort, the prevalence of FLT3-ITD mutation of de novo AML patients was 21.5%. Blood Marrow Transplant 22, 12181226 (2016). fms3flt3-itdaml molm13baf3-flt3-itd p-erkp-akt . Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. Midostaurin is a type I FLT3i active against PDGFR, KIT, SRC, and other RTKs22,23. Article The median OS was 1.3years (CI 0.71.9) and 1.4years (CI 1.01.8), respectively (P=0.8). CR+CRi rates between groups were compared with a chi-square test. Stone, R. M. et al. Blood 136, 2223 (2020). Perl, A. E. et al. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). Castao-Bonilla, T., Alonso-Dominguez, J.M., Barragn, E. et al. Flow diagram showing all AML patients with FLT3-ITD mutations in the study period between 2003 and 2019 on the basis of genetic data and treatment administered. 11, 104 (2021). is a PhD candidate at Universidad Autnoma de Madrid (UAM). Informed consent was a requisite for patients alive at the time of data lock (January 2019). and JM.A. 3). Astellas Reports XOSPATA (gilteritinib) in combination with azacitidine did not meet endpoint of overall survival in newly diagnosed flt3 mutation-positive acute myeloid leukemia patients ineligible for intensive induction chemotherapy (2020). 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. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. 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. Taken together, utilizing baseline FLT3-ITDmut AR to guide the post-remission therapy remains controversial. PubMed 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. Staurosporine, a potent inhibitor of phospholipid Ca++ dependent protein kinase. Biao Wang, X. Hua, Jihong Zhang, Weiying Gu . AR,allelic ratio. 2012;91(1):9-18. 21, 12011212 (2020). 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 ). Fms-like tyrosine kinase 3 (FLT3) is a recurrent genetic abnormality in AML (~30%)1,2,3. 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. J. Hematol. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. 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This result is similar to the RATIFY study, in which 44% of patients lost FLT3 ITD under treatment with midostaurin 36. Blood 124, 34413449 (2014). Type I FLT3is are active against both the FLT3-ITD or TKD, type II inhibitors are only active against FLT3-ITD, not TKD. We observed a low frequency of NPM1 mutation (10.1%), which correlated with the good prognosis of this 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). 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 Additionally, different subdomains have been highlighted, such as those conferring an adverse outcome9,10. DNA was extracted using automated or manual DNA extraction kits following the manufacturers recommendations. 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. Brinton, L. T. et al. https://doi.org/10.1038/s41598-021-00050-x, DOI: https://doi.org/10.1038/s41598-021-00050-x. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Therefore, these patients were not included in the analysis stratified by 2010 ELN genetic risk21. (3) Findings regarding the relationship between ITD length/site and mutational profile might be interpreted as exploratory given the high number of correlations performed. Kiyoi, H. et al. 377, 454464 (2017). Mali, R. S. et al. Yilmaz, M. et al. 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. CAS Heart J. Suppl. 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. 113, 983988 (2001). The median RFS was 1.2years (CI 0.22.2) and 0.77years (CI 0.51.1), respectively (P=0.06). 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. 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 Blood 124, 273276 (2014). 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 ]. Swaminathan, M. et al. 31, 3681 (2013). Gilteritinib was generally well tolerated but was associated with increased incidence of gastrointestinal side effects, most frequently diarrhea although nausea has been occasionally observed.
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