Google Scholar. "For patients with AML, the 5-year survival rate is only about 29%," said Dr. Erba. Taking into account the great number of comparisons performed, we cannot assume a real relationship between these mutations. 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. Conclusion: The frequency of NPM1/FLT3 mutations in the study cohort showed less rate than in other studies with a distinct pattern. An alternate option would be to consider sequencing with alternate cycles of HMA with venetoclax and HMA with FLT3i. 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). Biao Wang, X. Hua, Jihong Zhang, Weiying Gu . Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Among 362 patients, NGS was performed in 118 patients using a panel of 39 genes. FLT3-ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. 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. Minetto, P. et al. volume11, Articlenumber:104 (2021) Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. 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). 7+37 days of cytarabine and 3 days of daunorubicin. 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. We also analyzed the mutational profile of 118 FLT3-ITD AML patients with an NGS panel of 39 genes and correlated mutational status with the length and IS of ITD. Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. FLT3ITD mutations in acute myeloid leukaemia - molecular Yamamoto, Y. et al. We have no explanation regarding the reduced number of patients with an FLT3-ITD inserted in TKD1 found in our cohort. This review describes key milestones in the clinical development of different FLT3-specific TKI with a . Statistical analyses were performed with SPSS 19.0 (IBM, Armonk, NY). 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. Abstract 44: CG806, a first-in-class FLT3/BTK inhibitor, exhibits Cite this article. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. No significant difference was found between acute myeloid leukemia patients with these Juan M. Alonso-Dominguez. Cancer Res. @Repeat a C1 D28 bone marrow on all patients to confirm remission. In those patients with more than one ITD mutation, only the longest mutation was selected for statistical analysis (10 patients had>1 ITD mutation). 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. Additionally, the area under the ROC curve, which serves as an indicator of the diagnostic capacity of the ITD length as a whole, was 0.504. Canc. Final results of the chrysalis trial: a first-in-human phase 1/2 dose-escalation, dose-expansion study of gilteritinib (ASP2215) in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Dipsit Digital de la Universitat de Barcelona: Prognostic impact of Schneider F, Hoster E, Schneider S, Dufour A, Benthaus T, Kakadia PM, et al. has nothing to disclose. (PDF) Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in Staurosporine, a potent inhibitor of phospholipid Ca++ dependent protein kinase. Patients with NPM1-/FLT3- showed complex karyotype (24%) and t(8;21) (8%). 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. A stratified analysis of FLT3-ITD length by 2010 ELN genetic risk was performed in 123 patients (intermediate-I group, ITD<70bp, n=75 and ITD70bp, n=24; intermediate-II group, ITD<70bp, n=14 and ITD70bp, n=1; and adverse group, ITD<70bp, n=6 and ITD70bp, n=3). Prognostic significance of baseline FLT3ITD mutant allele level in Linch, D. C., Hills, R. K., Burnett, A. K., Khwaja, A. 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). which included NPM1 mut /FLT3-ITD high AR cases. 135, 397402 (1986). Ravandi, F. et al. 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). 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. 16, 16911699 (2015). The favorable prognostic molecular mutations, such as NPM-1 and CEBPA, are uncommon in elderly AML . 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. 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. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. 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). Maiti et al. Posterior reversible encephalopathy and pancreatitis are rare (<12%) but important side effects to be aware of. Hypomethylating agent and venetoclax with FLT3 inhibitor triplet therapy in older/unfit patients with FLT3 mutated AML, Mechanisms of resistance to cancer therapy, Cancel Therefore, the value obtained is not significant, although it shows a slight trend toward being significant. PubMed 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. However, the true CR/CRi rate was only 34%. Nakao, M. et al. The addition of sorafenib to standard AML treatment results in a substantial reduction in relapse risk and improved survival. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Intriguingly, this was the first large study to show that the FLT3i may also benefit FLT3 wild-type patients, perhaps through multi-kinase blockade or prevention of emergent FLT3 clones at relapse28. Full article: Advances in the drug therapies of acute myeloid leukemia Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. Cladribine combined with idarubicin and Ara-C (CLIA) as a frontline and salvage treatment for young patients (65 yrs) with acute myeloid leukemia. Nevertheless, there are numerous and contradictory manuscripts regarding the prognostic importance of the length and insertion site of the ITD fragment. Blood 125, 32363245 (2015). (A) Overall survival. S.V. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain Quizartinib with Decitabine+/Venetoclax is Highly Active in Patients (Pts) with FLT3-ITD Mutated (mut) Acute Myeloid Leukemia (AML): Clinical Report and Signaling Cytof Profiling from a Phase IB/II Trial (ASH, 2020). Upon achieving CR, the decision for ASCT is based on the risk-benefit assessment for ASCT. Patterns of resistance differ in patients with acute myeloid leukemia treated with type I versus type II FLT3-inhibitors. CAS Biophys. Oncol. Google Scholar. 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 . We obtained a P value of 0.055 in the analysis of RFS applying the 70bp cutoff. Venetoclax Added to Cladribine, Idarubicin, and Cytarabine with or without a FLT3 Inhibitor in Newly Diagnosed Acute Myeloid Leukemia (EHA, 2020). Naval Daver. and P.M.; Methodology, T.C., 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. Blood 97, 24342439 (2001). Alotaibi, A. S. et al. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Mali, R. S. 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. and P.M. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Perl, A. E. et al. J. Hematol. As consolidation therapy, one hundred patients received high-intensity treatment (3+7, n=68; 3+7+gemtuzumab ozogamicin (GO), n=4; 2+5=2; IDA-FLAG, n=1; high-dose cytarabine (HDARAC), n=23; low-dose cytarabine (LDARAC), n=1; and Ara-C 100mg/m25, n=1). Rosnet, O. 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). Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Haematologica (2021). 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Scientific Reports (Sci Rep) However, other studies did not find significantly worse clinical outcomes in patients with non-JMD ITD mutations24,25. FLT3 mutations in acute myeloid leukemia: a review focusing on PubMed 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. 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. 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. Blood 136, 810 (2020). *C1 D14: Perform bone marrow biopsy; if bone marrow shows <5% blasts and/or <5% cellularity/insufficient sampleStop venetoclax and FLT3i on D14. More recently, the emergence of BCR-ABL1-positive clone was shown as a resistance mechanism to multiple FLT3is72. 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. Swaminathan, M. et al. 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. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain Analysis of FLT3-ITD insertion sites from 106 FLT3-ITD-positive AML patients. Informed consent was a requisite for patients alive at the time of data lock (January 2019). Both mutations lead to the activation of downstream proliferation cascades [ 19, 20 ]. 2B). Whitman, S. P. et al. Kiyoi, H., Ohno, R., Ueda, R., Saito, H. & Naoe, T. Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Yilmaz, M. et al. Patients diagnosed with acute promyelocytic leukemia (APL) were excluded. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. In the meantime, to ensure continued support, we are displaying the site without styles 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). 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. Blood 130, 566 (2017). A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. Emergence of BCR-ABL1 fusion in AML post-FLT3 inhibitor-based therapy: a potentially targetable mechanism of resistancea case series. J. Natl Cancer Inst. CAS Higher daunorubicin exposure benefits FLT3 mutated acute myeloid leukemia. 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. [PDF] Combination of ATO with FLT3 TKIs eliminates FLT3/ITD+ leukemia 2-Aminopyrimidine derivatives as selective dual inhibitors of JAK2 and 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. 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. Prognostic impact analyses of FLT3-ITD length were performed among patients treated with upfront IC regimens. 2, 3 There are two types of FLT3 mutation, internal tandem duplication of FLT3 ( FLT3-ITD) and tyrosine kinase Soc. Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 gene ( FLT3) confer a poor prognosis in adult AML. Nevertheless, we also performed an analysis with the median ITD length of our cohort (48bp). Article Welch John, S. et al. 13, 139 (2020). Rollig, C. et al. Oncol. Interestingly, all patients with an FLT3-ITD inserted in the TKD1 domain showed DNMT3A mutations. Lancet Oncol. Further evaluation and optimization of triplets is a major area of clinical research focus in FLT3mut AML. Google Scholar, MM Patnaik 2018 The importance of FLT3 mutational analysis in acute myeloid leukemia Leuk. Internet Explorer). Oncol. Article Additionally, different subdomains of TKD1 (HR or beta1-sheet) have been highlighted as those conferring an adverse outcome10. Google Scholar. 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). However, these studies did not apply previously validated ITD length cutoffs obtained in other smaller series11,15,16,17. McMahon, C. M. 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? Castao-Bonilla, T., Alonso-Dominguez, J.M., Barragn, E. et al. This result is similar to the RATIFY study, in which 44% of patients lost FLT3 ITD under treatment with midostaurin 36. N. Engl. Remember me on this computer. FLT3 mutations occur in more than 30% of patients with acute myeloid leukemia (AML) and are associated with short relapse-free and overall survival, including internal tandem duplication (ITD) and point mutations within the tyrosine kinase domain (TKD) [1, 2].To date, multiple FLT3 kinase inhibitors have been developed and some are approved for clinical use including sorafenib, Quizartinib . 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. 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. Prognostication refinement in NPM1-mutated acute myeloid leukemia stratified by FLT3-ITD status with different induction doses of cytarabine. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Maintenance therapy for FLT3-ITD -mutated acute myeloid leukemia Characteristics and outcome of patients with core binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study. Xuan, L. 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. 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 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. Progress in Disease Detection Sets the Stage for MRD's Role in AML Clinical outcomes in patients with relapsed/refractory acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib. Wang, E. S. et al. Naval Daver, Richard F. Schlenk, Mark J. Levis, Alexander E. Perl, Naoko Hosono, Jessica K. Altman, Pierre-Yves Dumas, Emmanuel Raffoux, Christian Rcher, Richard A. Larson, Sumithra J. Mandrekar, Richard M. Stone, Iman Abou Dalle, Ahmad Ghorab, Gautam Borthakur, Ahmad I. Antar, Zaher K. Otrock, Ali Bazarbachi, Roni Shouval, Myriam Labopin, Arnon Nagler, Blood Cancer Journal 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). Blood 124, 34413449 (2014). Get the most important science stories of the day, free in your inbox. **If the C1 D14 bone marrow show >5% blastscontinue venetoclax, FLT3i till D21. Addition of venetoclax to this backbone may be associated with prolonged and potentially prohibitive myelosuppression; we have not routinely added and do not at this time recommend adding venetoclax to the backbone of CLIA/FIA with FLT3i63. 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). 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%. 95, 218223 (1996). 19, 889903 (2018). Res. In a study that identified molecular mechanisms of resistance to gilteritinib, 32% of patients had emergent mutations in the RAS/MAPK pathway (K/NRAS), and 5% had emergent BCR/ABL1 fusions71. However, the median OS was 19.2 months in FLT3-TKDmut AML (19.2 months), but only 11.5 months in FLT3-ITDmut patients65. In patients with relapsed or refractory FLT3mut AML (Fig. Slider with three articles shown per slide. 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. Pratz, K. W. et al. The point mutations that lead to resistance include N676, F691, and D835, together with FLT3-ITD. Daver, N. et al. We identified 1572 adult (age 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or . Gale, R. E. et al. Mechanistically, FLT3-ITDs and FLT3-TKDs induce activation of transduction intermediates, including STAT5, AKT, and ERK1/2 ( 2 ). 100, 184198 (2008). and P.M.; Resources, T.C., 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.M.C., M.A.S. https://doi.org/10.1038/s41598-021-00050-x. ___ This value highlights the scarce prognostic value of the measure. B MD Anderson Cancer Center Approach. Log in with Facebook Log in with Google. Article Oncogene 21, 25552563 (2002). Zhang, W. et al. We continue the venetoclax and FLT3i until Day 21 if the Day 14 bone marrow shows >5% blasts with >/=5% cellularity. This study shows that the size of FLT3-ITD mutations has no prognostic impact in terms of survival, relapse or CR rate among newly diagnosed AML patients treated with first-line intensive regimens. Thank you for visiting nature.com. 94, 984991 (2019). J. Hematol. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . 368, 20592074 (2013). 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. It should be noted that MDS-MLD and -EB-1 patients with low and intermediate risk in IPSS-R were included in FLT3-ITD mutation group, and showed poor prognosis. Chyla, B. et al. 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. Cancer 125, 37553766 (2019). J. Hematol. FLT3 -ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. or. AbuDuhier, F. et al. FLT3 Gene Mutation Profile and Prognosis in Adult Acute - PubMed 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. FLT3 -ITD has a poor prognostic impact in patients with AML at diagnosis. Prognostic significance of FLT3-ITD length in AML patients - Nature Activating FLT3 Mutants Show Distinct Gain-of-Function Phenotypes In Nature 485, 260263 (2012). Figure legend Overall survival of patients with AML following frontline venetoclax plus hypomethylating agent Therefore, there is a lack of consensus regarding the prognostic importance of the ITD IS and the subdomains that confer this adverse outcome. Yilmaz et al. Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD).Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). Am. FLT3-ITD Mutation and FLT3 Ligand Plasma Level Were Not Associated wit 2018 Oct 23;2 (20):2744-2754. doi: 10.1182/bloodadvances.2018020305. The mutation rate of FLT3/ITD in DEK/CAN-positive AML patients is as high as 70% (8,9). 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.