The impact of prognostic factors may change as the AML treatment landscape evolves. Authors Which FLT3 Inhibitor for Treatment of AML? We continue the venetoclax and FLT3i until Day 21 if the Day 14 bone marrow shows >5% blasts with >/=5% cellularity. J. Haematol. Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Clin. Methods: We determined the status of ITD and TKD mutations using fragment analysis and the polymerase chain reaction-restriction fragment polymorphism method, respectively. Google Scholar. Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens. Changes in FLT3 mutation status can occur during the course of disease, but the clinical impact of a change is unclear. Gilteritinib decreased the risk of death by 36% compared with salvage chemotherapy, with a median OS of 9.3 months vs 5.6 months (P<0.001), and a superior CR+CRh rate (34% vs 15.3%). 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 PubMed database, the Cochrane Library, conference proceedings, the EMBASE databases, and references of published trials and review articles were searched. 15, 17 In our cohort, the prevalence of FLT3-ITD mutation of de novo AML patients was 21.5%. 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. The AR was determined by fragment length analysis and calculated as previously described32. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood 135, 791803 (2020). Taking into account the great number of comparisons performed, we cannot assume a real relationship between these mutations. 7, e724e736 (2020). Google Scholar. Commun. Cancer 125, 37553766 (2019). 381, 17281740 (2019). Minetto and colleagues retrospectively evaluated the efficacy of fludarabine, high-dose cytarabine, and idarubicin (FAI) in 149 newly diagnosed FLT3-ITDmut and/or NPM1mut AML (only FLT3-ITDmut=29; FLT3-ITDmut NPM1mut=59, only NPM1mut=61). Brinton, L. T. et al. Although common methylation . 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. The Spanish group evaluated intermediate-risk AML patients treated with intensive chemotherapy. McMahon, C. M. et al. Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. 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. FLT3-ITDs show great variation in size (ranging from 3 to more than 400 base pairs (bp)), insertion sites (ISs), allelic ratios (ARs) and the number of clones5. We observed a low frequency of NPM1 mutation (10.1%), which correlated with the good prognosis of this mutation. FLT3-ITD has been strongly associated with a bad prognosis, leukocytosis, high blast counts, increased risk of relapse and shorter overall survival. Kiyoi, H., Ohno, R., Ueda, R., Saito, H. & Naoe, T. Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oran et al. Any variant allele frequency data were reported rarely. Cortes, J. E. et al. This work was supported in part by the MD Anderson Cancer Centre Support Grant (CCSG) CA016672, the MD Anderson Cancer Center Leukemia SPORE CA100632, the Charif. J. Hematol. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Tallman, M. S. et al. AR,allelic ratio. Heart J. Suppl. Adult patients with FLT3- ITD mutated AML treated at our institution were identified. Swaminathan et al. You are using a browser version with limited support for CSS. Oncol. Absence of FLT3-ITD mutation 0.07 . Libura, M. 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. Article As in previous works, we analyzed the clinical significance of FLT3-ITD length among fit patients treated with intensive regimens15,16. Ravandi, F. et al. 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 testing was historically viewed as being purely prognostic; however, with the advent of FLT3 inhibitors, it will likely be seen as both prognostic and predictive. The insertion site was analyzed in 106 AML patients with the FLT3-ITD mutation. Blood Marrow Transplant 22, 12181226 (2016). has received research funding from Astellas, and Novartis and has served as a member of advisory board in Astellas and Novartis. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. 109 3981 3992, DL Stirewalt 2006 Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia Blood 107 3724 3726, S Meshinchi 2008 Structural and numerical variation of FLT3/ITD in pediatric AML Blood 111 4930 4933, R Kusec 2006 More on prognostic significance of FLT3/ITD size in acute myeloid leukemia (AML) Blood 108 405 406, RE Gale 2008 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 Blood 111 2776 2784, Y Kim 2015 Quantitative fragment analysis of FLT3-ITD efficiently identifying poor prognostic group with high mutant allele burden or long ITD length Blood Cancer J. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. Clinical outcomes in patients with relapsed/refractory acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib. Stratified KaplanMeier analysis was also employed with the AR and genetic risk, following 2010 ELN guidelines21, as classifiers of the patients. 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. 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). Slider with three articles shown per slide. We studied theFLT3-ITD length of 362 adult AML patients included in the PETHEMA AML registry. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Am. Expression and signal transduction of the FLT3 tyrosine kinase receptor. Get the most important science stories of the day, free in your inbox. Andrew, H. et al. If material is not included in the article's Creative Commons licence 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. 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. In our case, 15 AML prognostic genes including FLT3/ITD gene were all negative. 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. Patients diagnosed with acute promyelocytic leukemia (APL) were excluded. Article 11, 104 (2021). In particular, high (>0.5) mutant-to-wild-type (WT) allelic ratios (AR) in the FLT3-ITD gene are associated with inferior prognosis ( 6, 7 ). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf2017 (2017). The landscape of mutations identified by NGS in AML patients. 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. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). 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. 2, 3 There are two types of FLT3 mutation, internal tandem duplication of FLT3 ( FLT3-ITD) and tyrosine kinase The choice of treatment backbone depends on the patients ability to successfully tolerate intensive chemotherapy. and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. MRD detection in AML leverages cutoff points garnered from various detection methods include flow cytometry or real-time quantitative polymerase chain reaction (pCR). Citation 56 The new FLT3 inhibitors, G-749 and ASP2215, have been proved to cause strong inhibition of FLT3 phosphorylation and increase the ability to overcome drug resistance in preclinical trials, but further studies are needed to evaluate their . (2) Larger studies analyzing ITD length also found no significant results14,23,28. Despite the encouraging development of FLT3i, resistance to FLT3i is not uncommon and it can be either primary or secondary. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . J. Hematol. Blood 97, 24342439 (2001). Blood 128, 449452 (2016). Blood 125, 32363245 (2015). A total of 164 patients diagnosed with AML-NPM1 included in 2 consecutive CETLAM protocols and with DNMT3A and FLT3 status available were studied. Quizartinib is also being evaluated in combination with CPX-351 (NCT04209725) and with CLIA (NCT04047641) in treatment naive and R/R FLT3mut AML. The combination continues to enroll. Nevertheless, we also performed an analysis with the median ITD length of our cohort (48bp). The size of our cohort was larger than those of the studies published using these cutoffs. 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. DNA was extracted using automated or manual DNA extraction kits following the manufacturers recommendations. However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. 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. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. and P.M.; Data curation, J.M.A. Mutations of SF3B1, EZH2 and WT1 seem to be a more ancestral event than FLT3 mutations, as expected, given the VAF of the genes. https://doi.org/10.1038/s41598-021-00050-x. Article Given the heterogeneity of treatments received and the scarce number of ISs in TKD1, we did not perform statistical analysis. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Weisberg, E. et al. Thank you for visiting nature.com. No significant difference was found between acute myeloid leukemia patients with these 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. Blood 93, 30743080 (1999). Jain, P. et al. On the other hand, we obtained a value (0.52) that was close to significant in the analysis of the prognostic impact of the FLT3-ITD AR according to the 2017 ELN cutoff8. 19, 889903 (2018). 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. In the meantime, to ensure continued support, we are displaying the site without styles These results led to the approval of gilteritinib monotherapy in the US and Europe in patients with R/R FLT3mut AML40. 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. 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. Cite this article. 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. PubMed 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. 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. Venetoclax Added to Cladribine, Idarubicin, and Cytarabine with or without a FLT3 Inhibitor in Newly Diagnosed Acute Myeloid Leukemia (EHA, 2020). For . Close Log In. Alotaibi, A. S. et al. The data described in the literature alongside the results that we have obtained regarding ITD mutation lead us to believe that future studies should focus on the functional characterization of the protein products of the mutated genes. Blood 124, 34413449 (2014). (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. 1A). N. Engl. Upregulation of Bcl-2 confers resistance to FLT3 inhibition in FLT3-ITD AML with secondary acquired mutations. Cancer Cell 1, 433443 (2002). Article However, these studies did not apply previously validated ITD length cutoffs obtained in other smaller series11,15,16,17. To mitigate prolonged myelosuppression with the triplet and avoid over-treatment, we perform an early bone marrow assessment on Cycle 1 Day 14 (Fig. Google Scholar. 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. 1,2 Real-time pCR, which has . . Blood 110, 12621270 (2007). Oncogene 21, 25552563 (2002). 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. mutations (1-year survival < 1% vs 42% in their presence vs absence) which should be incorporated in patient counseling. NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 Chinese patients with de novo acute myeloid leukemia. AbuDuhier, F. et al. 368, 20592074 (2013). Two randomized trials are evaluating the addition of gilteritinib vs midostaurin to induction and consolidation therapy in patients with newly diagnosed FLT3mut AML44 (NCT04027309, NCT03836209). 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). 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. QuANTUM-R, a phase 3 randomized controlled trial, evaluated quizartinib monotherapy vs investigator choice salvage chemotherapy in R/R FLT3-ITDmut AML. PubMed Therefore, only 3.8% of the patients showed an FLT3-ITD insertion in the TKD1 domain. The BSC group included 7 patients receiving transfusions and other supportive measures. The randomized phase III ADMIRAL trial evaluated gilteritinib vs investigator choice salvage chemotherapy in patients with R/R FLT3mut AML. J. Clin. The on-target mechanism of resistance includes emergence of secondary TKD mutations in patients treated with type II inhibitors like quizartinib or sorafenib69,70. Oran, B. et al. 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. Increase in bilirubin and transaminase can be seen with giltertiinib but are usually self-resolving and transient. and P.M.; Validation, T.C., J.M.A., E.B. All samples investigated in this study were obtained at the time of diagnosis. In our experienced cases FLT3-ITD mutation in MDS showed shorter duration to AML transformation and very poor prognosis. FLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. CAS Patterns of resistance differ in patients with acute myeloid leukemia treated with type I versus type II FLT3-inhibitors. The mutation rate of FLT3/ITD in DEK/CAN-positive AML patients is as high as 70% (8,9). Provided by the Springer Nature SharedIt content-sharing initiative. Google Scholar. FLT3-ITD mutations are detected in approximately 25% of newly diagnosed adult acute myeloid leukemia (AML) patients and confer an adverse prognosis. 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. Lancet Oncol. 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. Rllig, C. et al. Such sequential approaches need to be formally evaluated in the context of prospective clinical trials. Moreover, we performed an analysis of the correlation of FLT3-ITD length and insertion sites with the mutational landscape of AML, which has not been carried out thus far. 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 Among 362 patients, NGS was performed in 118 patients using a panel of 39 genes. Cortes, J. et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. 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). Minetto, P. et al. Wang, E. S. et al. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene ( FLT3- ITD) are associated with poor prognosis. Altman, J. K. et al. Presented in part at the 42nd Annual Meeting of the American Society of Hematology, December 15, 2000, San Francisco, CA (abstract 2334). @Repeat a C1 D28 bone marrow on all patients to confirm remission. Differential impact of allelic ratio and insertion site in FLT3-ITDpositive AML with respect to allogeneic transplantation. J. Med. Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. 16, 16911699 (2015). Biophys. Log in with Facebook Log in with Google. Gale, R. E. et al. 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. Cladribine combined with idarubicin and Ara-C (CLIA) as a frontline and salvage treatment for young patients (65 yrs) with acute myeloid leukemia. 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. Maiti et al. Staurosporine, a potent inhibitor of phospholipid Ca++ dependent protein kinase. Hematol. (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. J. Hematol. Variant allele frequency (VAF) is the ratio of ITD-mutated alleles to ITD-mutated+wild-type alleles (FLT3ITD/FLT3ITD+FLT3 wild-type)14. Leukemia 26, 23532359 (2012). The favorable prognostic molecular mutations, such as NPM-1 and CEBPA, are uncommon in elderly AML . PubMed The phase III RATIFY study (CALGB 10603), for example, looked at the addition of the tyrosine kinase inhibitor midostaurin to intensive chemotherapy in newly-diagnosed AML with FLT3 mutations (either ITD or TKD) and showed an overall survival (OS) benefit with midostaurin compared to placebo (74.7 vs. 25.6 months, respectively) . Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. 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. prospectively evaluated decitabine and quizartinib (doublet) with or without venetoclax (triplet) in patients with newly diagnosed and R/R FLT3-ITDmut AML. Eur. Our median ITD length was 48bp (range=3bp to 231bp), similar to previous studies12,14,17. CR+CRi rates between groups were compared with a chi-square test. J. Hematol. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Naval Daver, M. D. et al. Larger studies of ITD size, although they did not employ these cutoffs, did not find prognostic power of this measure, which corroborates our results. Due to the preliminary nature of the . To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. 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. 5).The study protocol was conducted following the guidelines of the Declaration of Helsinki and approved by the Ethics Committee for Clinical Research of the Hospital UniversitarioFundacin Jimnez Daz (PIC169-18_FJD). Chyla, B. et al. 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. Juan M. Alonso-Dominguez. In general, quizartinib is well tolerated with minimal skin, gastrointestinal, or pulmonary side effects. Daver, N., Venugopal, S. & Ravandi, F. FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm. Updated results from long-term follow-up of the randomized-controlled SORAML trial. Google Scholar. A phase I study evaluating gilteritinib with 7+3 induction and high-dose cytarabine consolidation chemotherapy, followed by single-agent maintenance therapy, in patients with newly diagnosed AML showed that gilteritinib 120mg daily was well tolerated. Schlenk, R. F. et al. Rollig, C. et al. Among 14 R/R FLT3mut AML patients, the CRc rate was 64% with FLT3-PCR negativity in 88% of responders. Article The addition of sorafenib significantly improved the event-free survival (EFS; 21 months vs 9 months; P=0.013) and RFS (56% vs 38%), but not OS28, although a recent update suggested an emerging trend toward improved OS29. In patients with FLT3mut AML who relapsed after first ASCT, sorafenib was found to be tolerable with long-lasting remissions in 7 of 29 patients treated, suggesting a potential synergy with post-ASCT alloimmune effects41. PubMed 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). 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. PubMed Sasaki, K. et al. 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? Blood 111, 27762784 (2008). 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. It is important to note that none of these patients received a FLT3 inhibitor (FLT3i) during induction, consolidation, or post-ASCT. Hematology. The median OS was 1.3years (CI 0.71.9) and 1.4years (CI 1.01.8), respectively (P=0.8). 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 Protein alteration seems to be much more complex than the length of the mutation or the site of insertion; therefore, our efforts to simplify FLT3-ITD characteristicsby stratifying the risk of the patients may be fruitless. The first-generation FLT3is lack specificity for FLT3 and inhibit multiple downstream RTKs that may result in more off-target toxicities. CAS Among 729 AML patients with FLT3-ITD mutations included in the PETHEMA AML epidemiologic registry between 2003 and 2019, FLT3-ITD length was available in 362: 188 males and 174 females; median age of 60.8years (range 17.191.4years). Metzelder, S. et al. 113, 983988 (2001). Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. In the last 25years, advances in molecular techniques have allowed a greater understanding of the pathogenesis of AML and the subsequent development of targeted therapies and a more refined prognostic classification based on the genetic features of the disease2,3. Clinical outcome stratified according to the FLT3-ITD length (cutoff 39bp) for all patients treated with intensive chemotherapy. volume11, Articlenumber:20745 (2021) Schlenk et al. In fact, every quartile increase in FLT3-ITD AR (from 0.01 to 0.20, 0.20 to 0.53, 0.53 to 0.80, 0.80 to 1.19) was associated with worsening complete remission (CR) rates, RFS, and OS, highlighting the prognostic value of AR. ABSTRACT. FLT3-ITD and NPM1 mutations were correlated, and the favorable prognostic impact of being FLT3-ITD negative and NPM1 mutation positive was evident only in patients aged 65 years or more. Kiyoi, H. et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. 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 older patients not eligible for intensive therapy, patients with primary refractory disease or early relapse with a persistent FLT3 mutation we would suggest gilteritinib based therapy.
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