We thank the PETHEMA group for its participation in this study. The two leading types of FLT3 mutations found in AML include internal tandem duplications in the juxtamembrane domain (ITD, 17-34%) and mutations in the tyrosine kinase domain (TKD) activation loop (~7%) ( 1 ). Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Additionally, different subdomains have been highlighted, such as those conferring an adverse outcome9,10. 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. 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. 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. Am. In order to improve the clinical condition of FLT3-ITD-positive patients, several FLT3 inhibitors have been developed showing variable results. Biophys. Correspondence to Given the heterogeneity of treatments received and the scarce number of ISs in TKD1, we did not perform statistical analysis. Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability. The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in a credit line to the material. By submitting a comment you agree to abide by our Terms and Community Guidelines. Haematologica (2021). Eur. Yilmaz et al. It is important to acknowledge the diverse mechanisms of FLT3i resistance after different FLT3is, and it is essential to proactively evaluate for these mechanisms at the time of FLT3i failure to optimize subsequent therapy. has received research funding from Astellas, and Novartis and has served as a member of advisory board in Astellas and Novartis. The median RFS was 1.2years (CI: 02.4) and 0.9years (CI: 0.617.1), respectively (P=0.3). Conclusion: The frequency of NPM1/FLT3 mutations in the study cohort showed less rate than in other studies with a distinct pattern. 7, e724e736 (2020). The randomized phase III ADMIRAL trial evaluated gilteritinib vs investigator choice salvage chemotherapy in patients with R/R FLT3mut AML. and JM.A. More recently, the emergence of BCR-ABL1-positive clone was shown as a resistance mechanism to multiple FLT3is72. We used the 0.5 cutoff of the AR as recommended by the 2017 ELN guidelines8.These patients were divided on the basis of the FLT3-ITD AR into an FLT3-ITDLOWgroup (41%; n=58) and an FLT3-ITDHIGHgroup (59%; n=82). SORMAIN, a placebo-controlled randomized phase II trial evaluated post-transplant sorafenib maintenance in patients with FLT3-ITDmut AML with RFS post-ASCT as the primary endpoint. Further evaluation and optimization of triplets is a major area of clinical research focus in FLT3mut 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? Google Scholar. Levis turned to FLT3-ITD mutations in acute myeloid leukemia (AML) to highlight the challenges with targeted therapy. As Dr. Erba explained, patients with FLT3 -ITD-positive AML represent a particularly poor prognostic group. Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. 96 1993 2003, Article FLT3i FLT3 inhibitor, HMA hypomethylating agent, VEN venetoclax, CR complete remission, ECOG PS Eastern Cooperative Oncology Group Perfromance Status, CG cytogenetics, MRD measurable residual disease, SCT stem cell transplant, CBC complete blood count. 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 . 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. Wang, E. S. et al. Despite the encouraging development of FLT3i, resistance to FLT3i is not uncommon and it can be either primary or secondary. 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. (A) Overall survival. Sasaki, K. et al. PubMed Central Characteristics and outcome of patients with core binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study. PubMed 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. Only four out of 106 patients had ITD IS in the TKD1 domain. PubMed Central Google Scholar. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . CAS Among 362 patients, NGS was performed in 118 patients using a panel of 39 genes. & Gale, R. E. Impact of FLT3ITD mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. FLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. Clinical outcome stratified according to the FLT3-ITD length (cutoff 70bp) for all patients treated with intensive chemotherapy. Blood 136, 1617 (2020). The point mutations that lead to resistance include N676, F691, and D835, together with FLT3-ITD. NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 Chinese patients with de novo acute myeloid leukemia. 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 ; Writingreview and editing, J.M.A., E.B., R.R.V., C.S., C.G., M.C.C., M.B.V., R.G., J.M.L., R.M.A., M.J.L., E.A., R.C., A.C., E.C., E.S.S., J.L., I.R., L.A., C.R.M., C.B.S., J.A.L.L., J.S., E.C., M.J.S., M.T.O., J.S.G., M.M., C.B., J.L.L.L., D.L., J.S., D.M.C., M.A.S. (B) Relapse-free survival. Off-target resistance includes clonal evolution during FLT3i therapy even when FLT3-ITDmut clone is lost70. Updated results from long-term follow-up of the randomized-controlled SORAML trial. Lancet Oncol. 2014;19(6):324-8. *C1 D14: Perform bone marrow biopsy; if bone marrow shows <5% blasts and/or <5% cellularity/insufficient sampleStop venetoclax and FLT3i on D14. Presented in part at the 42nd Annual Meeting of the American Society of Hematology, December 15, 2000, San Francisco, CA (abstract 2334). https://doi.org/10.1038/s41598-021-00050-x. Blood 136, 2223 (2020). 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). Authors Kiyoi, H. et al. Perl, A. E. et al. PubMed Pratz, K. W. et al. The CRc rate was 67% (n=10/15) in the combination arm in the safety cohort prior to commencement of randomization45. Mead, A. J. et al. Adult patients with FLT3- ITD mutated AML treated at our institution were identified. 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. 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. Venetoclax Added to Cladribine, Idarubicin, and Cytarabine with or without a FLT3 Inhibitor in Newly Diagnosed Acute Myeloid Leukemia (EHA, 2020). Staurosporine, a potent inhibitor of phospholipid Ca++ dependent protein kinase. J. Hematol. 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). Mali, R. S. et al. In our case, 15 AML prognostic genes including FLT3/ITD gene were all negative. Expression and signal transduction of the FLT3 tyrosine kinase receptor. Besides FLT3-ITD MRD, only a high white blood cell count and late CR appeared to be independently associated with relapse and OS. Cite this article. All four patients with ITD insertions in TKD1 had mutations in DNTM3A, compared with 39 out of 96 patients (41%) with ITD insertions in the JMD domain (P=0.031). Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. 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. 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 ). First, 161 AML patients with FLT3-ITD mutations treated with IC were analyzed using 39bp as the cutoff (<39bp; n=48,39bp; n=113). 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. Chyla, B. et al. NGS, next-generation sequencing. CAS Nature 485, 260263 (2012). 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. Acute myeloid leukemia, Version 3.2019, NCCN clinical practice guidelines in oncology. 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. 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). Schlenk 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. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. 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 . These data highlight the potent anti-leukemic activity of the triplet approach in FLT3mut AML. 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. The first-generation FLT3is lack specificity for FLT3 and inhibit multiple downstream RTKs that may result in more off-target toxicities. In patients with newly diagnosed AML, FLT3-ITDmut is a poor prognostic factor in terms of relapse-free (RFS) and overall survival (OS)7,8,9,10. Ninety-eight patients had ITD insertion sites in the JMD domain (JM-B, n=6; JM-S, n=42; JM-Z, n=43; and hinge region (HR), n=7), four patients had ITD insertion sites in the TKD1 domain (beta1-sheet, n=1; beta2-sheet, n=1; and nucleotide binding loop (NBL), n=2) and four patients had ITD insertion sites in the extracellular domain (ED) (Fig. Swaminathan, M. et al. 120.000 new AML cases and over . FLT3-ITD mutation is one of the most commonly identified gene mutations in AML while being an infrequent mutation in MDS and acute lymphocytic leukemia. Biol. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. J. Hematol. and P.M.; Visualization, T.C., J.M.A., D.L., J.S. Souki Cancer Research Fund and generous philanthropic contributions to the MD Anderson Moon Shots Program. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. 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. 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. Lancet Haematol. * Genes with a P value<0.05 in the MannWhitney test correlating mutational status with ITD length. The LACEWING phase III randomized trial evaluated gilteritinib with azacitidine vs azacitidine monotherapy (NCT02752035) in patients with newly diagnosed FLT3mut AML not eligible for intensive induction chemotherapy. "For patients with AML, the 5-year survival rate is only about 29%," said Dr. Erba. Oncol. An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown). PubMed Sorafenib plus intensive chemotherapy improves survival in patients with newly diagnosed, FLT3-internal tandem duplication mutation-positive acute myeloid leukemia. 93, E202E205 (2018). or reset password. 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). The insertion site was analyzed in 106 AML patients with the FLT3-ITD mutation. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. Elderly patients with AML have a distinct genetic landscape compared with the younger population. 94, 984991 (2019). Although the toxicity-related discontinuation rate was low (22%), sorafenib-treated patients did experience higher rates of graft-versus-host disease (GVHD) and skin toxicity42. We administer a second-generation FLT3i (ideally gilteritinib) continuously with HMA from cycle 1 Day 1. 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. The favorable prognostic molecular mutations, such as NPM-1 and CEBPA, are uncommon in elderly AML . Which FLT3 Inhibitor for Treatment of AML? Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML. The addition of sorafenib to standard AML treatment results in a substantial reduction in relapse risk and improved survival. Diagn. Using the same response criteria, the CRc rate was 85.4% (n=35/41) which compared favorably to 52% with gilteritinib alone in the ADMIRAL study. Two classes of activating FLT3 mutations occur in AML: (1) internal tandem duplication ( FLT3 -ITD) which occur in 20-25% of patients and (2) tyrosine kinase domain mutations ( FLT3 -TKD) which are seen in 5-10% of patients [48]. Type I FLT3is are active against both the FLT3-ITD or TKD, type II inhibitors are only active against FLT3-ITD, not TKD. Prognostication refinement in NPM1-mutated acute myeloid leukemia stratified by FLT3-ITD status with different induction doses of cytarabine. Venetoclax, FLT3 Inhibitor and Decitabine in FLT3mut Acute Myeloid Leukemia: Subgroup Analysis of a Phase II Trial (ASH, 2020). The FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) is one of the most frequent mutations found in acute myeloid leukemia (AML) patients, with a frequency of 20-30%. ITD amplicons with a size greater than that of the wild type (3281 bases) were interpreted as positive for the FLT3-ITD mutation. The insertion site of FLT3-ITD was available in 106 of 118 patients (Fig. N. Engl. Clinical outcome stratified according to the FLT3-ITD length (cutoff 39bp) for all patients treated with intensive chemotherapy. Progr. For . FLT3-ITD fragment length analysis was performed in seven centralized PETHEMA laboratories. Gale, R. E. et al. 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. 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.