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Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia. The on-target mechanism of resistance includes emergence of secondary TKD mutations in patients treated with type II inhibitors like quizartinib or sorafenib69,70. Naval Daver. Kiyoi, H. et al. Blood 111, 27762784 (2008). 15, 17 In our cohort, the prevalence of FLT3-ITD mutation of de novo AML patients was 21.5%. Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens. Article Nakao, M. et al. Zarrinkar, P. P. et al. The UKMRC group evaluated the presence of NPM1 co-mutations in young adult patients with AML. The BSC group included 7 patients receiving transfusions and other supportive measures. 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. 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. (A) Overall survival. In patients with ongoing cytopenias (ANC500ms emerged as a significant adverse event36. The analysis of OS and RFS applying this value did not show significant results (data not shown). (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. It is important to note that none of these patients received a FLT3 inhibitor (FLT3i) during induction, consolidation, or post-ASCT. Among 362 patients, NGS was performed in 118 patients using a panel of 39 genes. prospectively evaluated decitabine and quizartinib (doublet) with or without venetoclax (triplet) in patients with newly diagnosed and R/R FLT3-ITDmut AML. 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? Characteristics and outcome of patients with core binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study. Burnett, A. K., Russell, N. H. & Hills, R. K. Group obotUKNCRIAMLS. Regardless of the regimen intensity, all clinical trial participants were grouped in a separate treatment category (n=15). Additionally, different subdomains have been highlighted, such as those conferring an adverse outcome9,10. 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). 93, 11361141 (2018). 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. 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. Am. 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 Rollig, C. et al. 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). J. Med. CAS Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia. Zhang, W. et al. 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.) CAS The origin and evolution of mutations in acute myeloid leukemia. Yamatani, K. et al. Google Scholar. The mutation rate of FLT3/ITD in DEK/CAN-positive AML patients is as high as 70% (8,9). Rosnet, O. et al. Oran, B. et al. An FLT3/ITD mutation was present in 27% of the patients and was associated with leukocytosis and a high percentage of bone marrow blast cells (P <.001 for both). Venetoclax, FLT3 Inhibitor and Decitabine in FLT3mut Acute Myeloid Leukemia: Subgroup Analysis of a Phase II Trial (ASH, 2020). Ravandi, F. et al. Swaminathan et al. The area under the ROC curve (AUC) for OS prediction was 0.504. 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. 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. N. Engl. Educ. 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. In general, quizartinib is well tolerated with minimal skin, gastrointestinal, or pulmonary side effects. An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown). Some studies showed a reduced CR rate, while others analyzing the IS in the same region found differences in OS. It's the most common genetic change in acute myeloid leukemia (AML), a type of leukemia that starts in the bone marrow and. and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. 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. Canc. *C1 D14: Perform bone marrow biopsy; if bone marrow shows <5% blasts and/or <5% cellularity/insufficient sampleStop venetoclax and FLT3i on D14. Libura, M. et al. Sasaki, K. et al. Lymphoma 54 145 152, S Schnittger 2012 Diversity of the juxtamembrane and TKD1 mutations (Exons 1315) in the FLT3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data Genes Chromosom. Encouragingly, the response rate was maintained among patients previously exposed to other FLT3 TKIs. Similarly, the median ITD length in three patients with EZH2mutations was 26bp vs 48bp in the wild-type group (n=65) (P=0.031). Oran et al. 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. PubMed Central For . AR,allelic ratio. Oncol. We obtained a P value of 0.055 in the analysis of RFS applying the 70bp cutoff. Tamaoki, T. et al. 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. J. Med. Elderly patients with AML have a distinct genetic landscape compared with the younger population. The impact of prognostic factors may change as the AML treatment landscape evolves. FLT3 -ITD is a negative prognostic factor that remains prognostically relevant even after intensive chemotherapy and/or stem cell transplant. We observed a low frequency of NPM1 mutation (10.1%), which correlated with the good prognosis of this mutation. Among 14 R/R FLT3mut AML patients, the CRc rate was 64% with FLT3-PCR negativity in 88% of responders. Perl, A. E. et al. FLT3-ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. Background and aims: To explore the relationship between FLT3 (encoding Fms related tyrosine kinase 3) internal tandem duplication (ITD) mutations with the prognosis of acute promyelocytic leukemia. 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. Internet Explorer). 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. The CRc rate was 67% (n=10/15) in the combination arm in the safety cohort prior to commencement of randomization45. McMahon, C. M. et al. In patients with concurrent NPM1mut, the OS and relapse risk were comparable between FLT3 wild-type and FLT3-ITDmut AR <0.5, but worse when AR 0.5. Hypomethylating agent and venetoclax with FLT3 inhibitor triplet therapy in older/unfit patients with FLT3 mutated AML, Mechanisms of resistance to cancer therapy, Cancel F.R. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. 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. mutations (1-year survival < 1% vs 42% in their presence vs absence) which should be incorporated in patient counseling. 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. Fishers exact test was employed to correlate the ITD insertion site and mutational status. 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). The PubMed database, the Cochrane Library, conference proceedings, the EMBASE databases, and references of published trials and review articles were searched. Altman, J. K. et al. Zhu, R., Li, L., Nguyen, B., Duffield, A. S. & Small, D. Gilteritinib and venetoclax synergize to eliminate FLT3/ITD+ leukemia cells through BIM. It is mutated in about 1/3 of acute myeloid leukemia (AML) patients, either by internal tandem duplications (ITD) of the juxtamembrane domain or by point mutations usually involving the kinase domain (KD). The median RFS was 1.2years (CI: 02.4) and 0.9years (CI: 0.617.1), respectively (P=0.3). Precision Medicine in Myeloid Malignancies: Hype or Hope? 120.000 new AML cases and over . 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. We prefer a second-generation FLT3i (ideally gilteritinib) in the newly diagnosed setting, and administer the FLT3i D1-D14 during induction, and continuously starting Cycle 2 Day 1 through consolidation. However, in a recently released planned interim analysis, the study did not meet its primary endpoint of overall survival and may be terminated for futility46. 90, 276281 (2015). the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in 4). CAS In general, AML patients with intermediate-risk cytogenetics and with a FLT3-ITD mutation have a significantly poorer prognosis with an increased relapse risk and decreased . 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). 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. Am. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. DiNardo, C. D. et al. 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. AR is defined as the ratio of ITD-mutated alleles to wild-type allele (FLT3ITD/FLT3 wild-type)13. volume11, Articlenumber:20745 (2021) The median age of this group was 55.1years (range 17.185.3years); 76 males and 85 females. 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 . Lancet Oncol. Slider with three articles shown per slide. 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. 3 A Survival curves stratified by the presence or absence of FLT3 -ITD and NPM1 mutation for patients younger than 65 years. In sensitivity analysis, no significant . J. Hematol. Cladribine combined with idarubicin and Ara-C (CLIA) as a frontline and salvage treatment for young patients (65 yrs) with acute myeloid leukemia. 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). 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. 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). S.V.