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is a PhD candidate at Universidad Autnoma de Madrid (UAM). 7, e724e736 (2020). Regardless of the regimen intensity, all clinical trial participants were grouped in a separate treatment category (n=15). These observations have made FLT3 an attractive drug target. However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. Among patients treated with azacitidine and quizartinib in the frontline setting, the CRc rate was 78% (n=7/9) with a median OS of 21.1 months. Biochem. Midostaurin has been approved and widely used in combination with induction and consolidation therapy in patients with newly diagnosed FLT3mut AML25. The median OS was 2.3years (CI: 1.03.6), 1.4years (CI: 1.01.8), 1.1years (CI: 0.81.3) and 1.0years (CI: 0.31.8), respectively (P=0.9). Google Scholar. *C1 D14: Perform bone marrow biopsy; if bone marrow shows <5% blasts and/or <5% cellularity/insufficient sampleStop venetoclax and FLT3i on D14. (A) Overall survival. We administer a second-generation FLT3i (ideally gilteritinib) continuously with HMA from cycle 1 Day 1. 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. 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. which included NPM1 mut /FLT3-ITD high AR cases. Patients were classified into four therapeutic groups according to the first-line approach: intensive chemotherapy (IC), n=161; non-intensive therapy, n=43; clinical trial, n=15; and best supportive care (BSC) only, n=7. 10, 588876- (2020). Progress in Disease Detection Sets the Stage for MRD's Role in AML The area under the ROC curve (AUC) for OS prediction was 0.504. Blood 134, 2564 (2019). 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. 2, 125 (2020). 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 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. Souki Cancer Research Fund and generous philanthropic contributions to the MD Anderson Moon Shots Program. 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). Lancet Haematol. 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. de Sonsoles de vila-Complejo Asistencial vila, vila, Spain, Hematology Department, Hospital General de Albacete, Albacete, Spain, Hematology Department, Hospital Universitario de Gran Canaria Doctor Negrn, Las Palmas de Gran Canaria, Spain, Carlos Rodrguez-Medina&Cristina Bilbao-Syeiro, Hematology Department, Hospital General Ciudad de Jan, Jan, Spain, UGC de Hematologia, Hospital U. Reina Sofia, IMIBIC, UCO, Cordoba, Crdoba, Spain, Josefina Serrano&Joaqun Snchez-Garca, Hematology Department, Hospital Comarcal del Bierzo, Len, Spain, Hematology Department, Hospital Universitario Doctor Peset, Valencia, Spain, Hematology Department, Hospital Clnico Universitario Lozano Blesa, Zaragoza, Spain, Hematology Department, Complejo Hospitalario de Navarra, Navarra, Spain, You can also search for this author in 383, 617629 (2020). We observed a low frequency of NPM1 mutation (10.1%), which correlated with the good prognosis of this mutation. 3.3 TET2 in NPM1 mut /FLT3-ITD (), and CD34 and ID-Ara-C in NPM1 mut /FLT3 . A Conventional approach. 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). 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. FLT3 is a gene change, or mutation, in leukemia (blood cancer) cells. 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 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. Tallman, M. S. et al. NGS, next-generation sequencing. Type I FLT3is are active against both the FLT3-ITD or TKD, type II inhibitors are only active against FLT3-ITD, not TKD. Stone, R. M. et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. 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. FLT3ITD mutations in acute myeloid leukaemia - molecular In patients with ongoing cytopenias (ANCFLT3-ITD Mutation and FLT3 Ligand Plasma Level Were Not Associated wit In patients with FLT3mut AML unsuitable for intensive chemotherapy, azacitidine with venetoclax demonstrated encouraging CR/CRi rates (5570%) and a median OS of 13.3 months64 which prompted the inclusion of this combination approach as part of NCCN AML guidelines (Fig. recently showed that ASCT in CR1 improved RFS and OS independent of the FLT3-ITDmut AR or NPM1mut status in patients with FLT3-ITDmut AML20. Statistically significant results were not observed for any other gene in this analysis. J. Hematol. Any variant allele frequency data were reported rarely. In summary, in our population of 161 intensively treated FLT3-ITD AML patients, we did not validate any of the previously published recurrent thresholds of ITD length obtained from smaller series. Sasaki, K. et al. Stratified KaplanMeier analysis was also employed with the AR and genetic risk, following 2010 ELN guidelines21, as classifiers of the patients. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. The role of ASCT in patients with FLT3-ITDmut AR<0.50 with concomitant NPM1mut in the absence of concomitant high-risk features such as DNMT3A, TP53, or RUNX1 co-mutations, adverse cytogenetics, therapy-related or secondary AML, who achieve MRD negativity by high-sensitivity PCR (ideally for NPM1mut), or patients with FLT3-TKDmut is an area of ongoing debate. In patients 55 years, this regimen appeared to overcome the negative impact of FLT3-ITDmut in NPM1 co-mutated patients, regardless of the FLT3 AR, with comparable 3-year OS rates of 64% and 68% in FLT3-ITDmut NPM1mut and FLT3-ITDWT NPM1mut patients, respectively (P>0.05). FLT3 is a receptor tyrosine kinase that is involved in regulating proliferation of hematopoietic progenitor cells. We identified 1572 adult (age 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or . Progr. To obtain The CRc rates (47%) were similar between both doses, and the frequency of QTcF >500ms was significantly reduced (35%) with these lower doses of quizartinib35. 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. The point mutations that lead to resistance include N676, F691, and D835, together with FLT3-ITD. volume11, Articlenumber:104 (2021) Cancer Discov. The NPM1/FLT3-ITD patients had normal karyotypes. FLT3-ITD and its current role in acute myeloid leukaemia The CRc rate was 67% (n=10/15) in the combination arm in the safety cohort prior to commencement of randomization45. T.C. AR, allelic ratio. 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. Samples from 118 of the 362 AML patients with FLT3-ITDmutations were analyzed with an NGS panel of 39 genes (see Supplementary Fig. 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.. 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. Blood 136, 3233 (2020). S.V. Schlenk et al. The median RFS was 1.2years (CI: 02.4) and 0.9years (CI: 0.617.1), respectively (P=0.3). The impact of prognostic factors may change as the AML treatment landscape evolves. DNA quantification was performed with a Nanodrop (Thermo Fisher Scientific, Waltham,MA) or Qubitfluorometer (Thermo Fisher Scientific, Waltham, MA). Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf2017 (2017). Therefore, there is a lack of consensus regarding the prognostic importance of the ITD IS and the subdomains that confer this adverse outcome. 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. This work is submitted in partial fulfillment of the requirement for the PhD. 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. All samples investigated in this study were obtained at the time of diagnosis. Oncol. 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 PubMed 38, 29933002 (2020). Google Scholar. Schlenk, R. F. et al. evaluated the impact of AR in 323 patients with newly diagnosed FLT3-ITDmut AML. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. PubMed 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 . and P.M.; Supervision, J.M.A. Activating FLT3 Mutants Show Distinct Gain-of-Function Phenotypes In ISSN 2044-5385 (online), FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm, https://doi.org/10.1038/s41408-021-00495-3, Targeting FLT3 mutations in AML: review of current knowledge and evidence, Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib, Gilteritinib activity in refractory or relapsed FLT3-mutated acute myeloid leukemia patients previously treated by intensive chemotherapy and midostaurin: a study from the French AML Intergroup ALFA/FILO, Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial, 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, FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions, Risk stratification using FLT3 and NPM1 in acute myeloid leukemia patients autografted in first complete remission, European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia, Impact of FLT3-ITD allele ratio and ITD length on therapeutic outcome in cytogenetically normal AML patients without NPM1 mutation, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf2017, http://creativecommons.org/licenses/by/4.0/, Feasibility of autologous peripheral blood stem cell mobilization and harvest in adult patients with FLT3-mutated acute myeloid leukemia receiving chemotherapy combined with midostaurin: a single-center experience, Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy. Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability. In another randomized phase III study comparing post-ASCT sorafenib maintenance (n=100) to non-maintenance (n=102), sorafenib demonstrated an improved 1-year OS (82.1% vs 68%, P=0.012) and a decreased 1-year cumulative incidence of relapse (7% vs 24.5%, P=0.001) in FLT3-ITDmut AML patients undergoing ASCT in CR143. For post-ASCT maintenance, our agent of choice has been gilteritinib 80120mg day either as a single agent or combined with low-dose azacitidine. Perl, A. E. et al. Swaminathan, M. et al. Ohanian, M. et al. 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%). Alotaibi, A. S. et al. The Spanish group evaluated intermediate-risk AML patients treated with intensive chemotherapy. 93, E202E205 (2018). 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). Google Scholar, MR ODonnell 2017 Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology J. Natl. 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. FLT3-ITD mutations are detected in approximately 25% of newly diagnosed adult acute myeloid leukemia (AML) patients and confer an adverse prognosis. PDF FLT3-ITD Expression as a Potential Biomarker for the Assessment of Slider with three articles shown per slide. Burnett, A. K., Russell, N. H. & Hills, R. K. Group obotUKNCRIAMLS. 17, 721749 (2019). Quizartinib, a second-generation, type I FLT3i is active against FLT3, KIT, CSF1R, PDGFR, and RET kinase34. FLT3 Mutations in R/R Acute Myeloid Leukemia (AML) - XOSPATA Maiti et al. CAS https://doi.org/10.1038/s41598-021-00050-x, DOI: https://doi.org/10.1038/s41598-021-00050-x. Frhling, S. et al. Blood 99, 43264335 (2002). Gilteritinib with venetoclax (NCT03625505) was evaluated in 41 patients with heavily pretreated R/R FLT3mut AML (median salvage 2, 65% previously exposed to FLT3i)40,53. Further evaluation and optimization of triplets is a major area of clinical research focus in FLT3mut AML. The origin and evolution of mutations in acute myeloid leukemia. Among patients treated with gilteritinib, the median overall survival was similar among those with FLT3 ITD mutations alone (9.3 months) and those with FLT3 TKD mutations alone (8.0 months). Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models. Google Scholar. Resistance Mutations Present an Ongoing Challenge in Aggressive Tamaoki, T. et al. The on-target mechanism of resistance includes emergence of secondary TKD mutations in patients treated with type II inhibitors like quizartinib or sorafenib69,70. Gilteritinib was generally well tolerated but was associated with increased incidence of gastrointestinal side effects, most frequently diarrhea although nausea has been occasionally observed. Fig. The median OS was 1.7years (CI 04.0), 1.7years (CI NC), 1.3years (CI 0.32.3), 1.5years (CI NC), 1.2years (CI: 0.52.0) and 2.4years (CI NC), respectively. 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). 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. Zhu, R., Li, L., Nguyen, B., Duffield, A. S. & Small, D. Gilteritinib and venetoclax synergize to eliminate FLT3/ITD+ leukemia cells through BIM. 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 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. Zhang, W. et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. As in previous works, we analyzed the clinical significance of FLT3-ITD length among fit patients treated with intensive regimens15,16. **If the C1 D14 bone marrow show >5% blastscontinue venetoclax, FLT3i till D21. Blood 114, 29842992 (2009). However, the median OS was 19.2 months in FLT3-TKDmut AML (19.2 months), but only 11.5 months in FLT3-ITDmut patients65. Blood 130, 566 (2017). Remarkably, the NPM1 mutation status and the FLT3-ITD allelic ratio at diagnosis lost their prognostic value for relapse and survival when FLT3-ITD MRD was taken into account . Musa Yilmaz, M. et al. Am. Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in Acute Myeloid Leukemia Patients in Eastern Algeria . Yilmaz, M. et al. Article (PDF) Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in 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). Go to: Introduction Google Scholar. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. 93, 11361141 (2018). Fishers exact test was employed to correlate the ITD insertion site and mutational status.