Nature 485, 260263 (2012). A stratified analysis of FLT3-ITD length on the basis of the AR was performed in 140 patients (AR<0.5 and ITD<70bp, n=43; AR<0.5 and ITD70bp, n=15; AR>0.5 and ITD<70bp, n=61; AR>0.5 and ITD70bp, n=21). 1 FLT3 gene is one of the most frequently mutated genes in acute myeloid leukemia (AML), and is reported in 25-30% of AML patients. Furthermore, a global query was sent to the different centralized laboratories of PETHEMA to verify the ITD length, insertion site and molecular profile of the patients by NGS when these data were available. Blood 130, 721 (2017). Google Scholar. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Educ. We further compared the survival of patients with FLT3-ITD and those with FLT3-D835 mutation in the Positive/Positive and Negative/Positive groups (Figure 3). The clinical behavior and genetic characteristics of the disease are heterogeneous1. Secondary mutations as mediators of resistance to targeted therapy in leukemia. 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. 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). Yalniz, F. et al. Cancer 51 910 924, AT Cohen S Goto K Schreiber C Torp-Pedersen 2015 Why do we need observational studies of everyday patients in the real-life setting? Sorafenib is a first generation, type II multi-kinase FLT3i26 that demonstrated safety and efficacy (14/15 CR) in combination with the standard anthracycline/cytarabine induction therapy in newly diagnosed FLT3mut AML27. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. 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. The number, area and length of mutant peaks on capillary electrophoresis were analyzed using GeneMapper analysis software (Applied Biosystems, Foster City, CA). Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens. S2) in PETHEMA centralized diagnostic laboratories as previously described33. J. Med. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. However, other studies did not find significantly worse clinical outcomes in patients with non-JMD ITD mutations24,25. 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. 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. The sorafenib treatment arm had increased rates of adverse events, particularly diarrhea, bleeding, cardiac events, hand-foot-skin reaction, and rash but with no significant increase in the 30- or 60-day mortality between the two treatment arms. Low relapse rate in younger patients 60 years old with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) treated with crenolanib and cytarabine/anthracycline chemotherapy. This review describes key milestones in the clinical development of different FLT3-specific TKI with a . 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. In general, quizartinib is well tolerated with minimal skin, gastrointestinal, or pulmonary side effects. Cell 150, 264278 (2012). Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. has received research funding from Astellas, and Novartis and has served as a member of advisory board in Astellas and Novartis. Enter the email address you signed up with and we'll email you a reset link. Ohanian, M. et al. Nevertheless, some thresholds have been applied in more than one study [i.e., 39bp and 70bp]11,15,16,17. In our experienced cases FLT3-ITD mutation in MDS showed shorter duration to AML transformation and very poor prognosis. 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. 113, 983988 (2001). Biophys. 2, 125 (2020). 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. *C1 D14: Perform bone marrow biopsy; if bone marrow shows <5% blasts and/or <5% cellularity/insufficient sampleStop venetoclax and FLT3i on D14. Google Scholar, MR ODonnell 2017 Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology J. Natl. PubMed DiNardo, C. D. et al. 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 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. Blood 124, 34413449 (2014). More recently, the emergence of BCR-ABL1-positive clone was shown as a resistance mechanism to multiple FLT3is72. Midostaurin is a type I FLT3i active against PDGFR, KIT, SRC, and other RTKs22,23. fms3flt3-itdaml molm13baf3-flt3-itd p-erkp-akt . Weisberg, E. et al. Haematologica 106, 1034 (2020). 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. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Blood 100, 43724380 (2002). Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Blood 121, 27342738 (2013). Quizartinib is also being evaluated in combination with CPX-351 (NCT04209725) and with CLIA (NCT04047641) in treatment naive and R/R FLT3mut AML. (2) Larger studies analyzing ITD length also found no significant results14,23,28. Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). Oran et al. (C) OS according to the FLT3-ITD length and allelic ratio. Leukemia 10, 19111918 (1996). A Conventional approach. Cladribine added to daunorubicin-cytarabine induction prolongs survival of FLT3-ITD+ normal karyotype AML patients. 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. At a median follow-up of 42 months, sorafenib demonstrated a 2-year estimated RFS of 85% and OS of 90.5% compared with 53.3% (P=0.002), and 66.2% with placebo, respectively (P=0.007). Rollig, C. et al. The UKMRC group evaluated the presence of NPM1 co-mutations in young adult patients with AML. 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). and P.M. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. We continue the venetoclax and FLT3i until Day 21 if the Day 14 bone marrow shows >5% blasts with >/=5% cellularity. 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. When comparing both subgroups using a log-rank test, there was a clear trend toward a reduced OS in FLT3-ITDHIGH patients (P=0.052). 383, 617629 (2020). The FLT3-ITD allelic ratio has clear prognostic value. Despite the encouraging development of FLT3i, resistance to FLT3i is not uncommon and it can be either primary or secondary. Blood 132, 3944 (2018). Despite the current availability of the FLT3 inhibitor midostaurin, there is an unmet need for improved treatment options. 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 CAS Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Nakao, M. et al. Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. 2014;19(6):324-8. 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. Welch John, S. et al. All samples investigated in this study were obtained at the time of diagnosis. Acute myeloid leukemia, Version 3.2019, NCCN clinical practice guidelines in oncology. 93, 11361141 (2018). Provided by the Springer Nature SharedIt content-sharing initiative, Current Hematologic Malignancy Reports (2022), Current Treatment Options in Oncology (2022), Blood Cancer Journal (Blood Cancer J.) It is important to note that none of these patients received a FLT3 inhibitor (FLT3i) during induction, consolidation, or post-ASCT. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . The Spanish group evaluated intermediate-risk AML patients treated with intensive chemotherapy. 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. 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. Multivariate analysis showed that age < 65 years, FLT3-ITD and CEBPA bZIP in-frame mutation were independent prognostic factors. 28, 1856 (2010). 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. CAS Regardless of the regimen intensity, all clinical trial participants were grouped in a separate treatment category (n=15). Type I FLT3is are active against both the FLT3-ITD or TKD, type II inhibitors are only active against FLT3-ITD, not TKD. KaplanMeier analysis and log-rank tests were employed to compare different groups.We also carried out an additional OS analysis censoring patients at the time of allo-HSCT. J. Hematol. https://doi.org/10.1038/s41408-021-00495-3, DOI: https://doi.org/10.1038/s41408-021-00495-3. Mali, R. S. et al. 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. 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. The area under the ROC curve (AUC) for OS prediction was 0.504. 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. 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). However, these studies did not apply previously validated ITD length cutoffs obtained in other smaller series11,15,16,17. Midostaurin has been approved and widely used in combination with induction and consolidation therapy in patients with newly diagnosed FLT3mut AML25. Nevertheless, we also performed an analysis with the median ITD length of our cohort (48bp). 10, 588876- (2020). J. Natl Cancer Inst. Blood Cancer J. 21, 12011212 (2020). & Gale, R. E. Impact of FLT3ITD mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Given the heterogeneity of treatments received and the scarce number of ISs in TKD1, we did not perform statistical analysis. Whitman, S. P. et al. Regarding the ITD insertion site, Kayseret al22,23 observed that adult AML patients with an ITD in the beta-1 sheet had significantly inferior OS and DFS compared to those with ITDs located in other regions. Prognostic impact analyses of FLT3-ITD length were performed among patients treated with upfront IC regimens. 1,2 Real-time pCR, which has . . Our median ITD length was 48bp (range=3bp to 231bp), similar to previous studies12,14,17. Blood 136, 2223 (2020). (A) Overall survival. The insertion site of FLT3-ITD was available in 106 of 118 patients (Fig. Lancet Oncol. An alternate option would be to consider sequencing with alternate cycles of HMA with venetoclax and HMA with FLT3i. 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. Blood 99, 43264335 (2002). Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. 13 95 100. Differential impact of allelic ratio and insertion site in FLT3-ITDpositive AML with respect to allogeneic transplantation. Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML. J. Hematol. Google Scholar. 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. Strati, P. et al. Cite this article. Abhishek Maiti, M. D. et al. The impact of prognostic factors may change as the AML treatment landscape evolves. 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