In our case, 15 AML prognostic genes including FLT3/ITD gene were all negative. or. Cortes, J. et al. Clin. 9, 10501063 (2019). Secondary resistance to FLT3i could be either on-target (changes in the FLT3) or off-target (constitutive activation of non-FLT3-dependent oncogenic pathways). Mutations of the fms-tyrosine kinase ( FLT3) were first described in 1997 4 and account for the most frequent molecular mutations in AML. 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. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. 1,2 Real-time pCR, which has . 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). Updated results from long-term follow-up of the randomized-controlled SORAML trial. Maiti et al. The PubMed database, the Cochrane Library, conference proceedings, the EMBASE databases, and references of published trials and review articles were searched. (B) Relapse-free survival. 11, 104 (2021). 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. Second-generation FLT3is potently and specifically target FLT3 with fewer off-target effects. and JM.A. Nevertheless, some thresholds have been applied in more than one study [i.e., 39bp and 70bp]11,15,16,17. This result is similar to the RATIFY study, in which 44% of patients lost FLT3 ITD under treatment with midostaurin 36. Haematologica 106, 1034 (2020). Blood 121, 46554662 (2013). Am. 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. We analyzed 118 patients (median age at diagnosis 58.3, range 14.3&ndash . 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. 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 . The randomized phase III ADMIRAL trial evaluated gilteritinib vs investigator choice salvage chemotherapy in patients with R/R FLT3mut AML. 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]. No statistically significant differences were found (P=0.4) (Fig. Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Schlenk et al. Oran et al. Larger studies of ITD size, although they did not employ these cutoffs, did not find prognostic power of this measure, which corroborates our results. 3.3 TET2 in NPM1 mut /FLT3-ITD (), and CD34 and ID-Ara-C in NPM1 mut /FLT3 . The combination continues to enroll. We obtained a P value of 0.055 in the analysis of RFS applying the 70bp cutoff. and P.M.; Supervision, J.M.A. 21, 12011212 (2020). CR or CRi was achieved in 70% of the patients in both groups (P=0.9). Higher daunorubicin exposure benefits FLT3 mutated acute myeloid leukemia. As Dr. Erba explained, patients with FLT3 -ITD-positive AML represent a particularly poor prognostic group. 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). Slider with three articles shown per slide. 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. TM,transmembrane domain; JMD, juxtamembrane domain; JMD-B, binding motif; JMD-S, switch motif; JMD-Z, zipper motif; HR, hinge region; TKD1, tyrosine kinase domain 1; B1, beta1-sheet; NBL, nucleotide binding loop; B2, beta2-sheet; and TKD2, tyrosine kinase domain 2. Mutations of SF3B1, EZH2 and WT1 seem to be a more ancestral event than FLT3 mutations, as expected, given the VAF of the genes. Perl and colleagues investigated whether prior FLT3i therapy influenced outcomes in patients treated with gilteritinib. Leukemia 10, 19111918 (1996). Studies have reported that a higher mutant allelic burden is associated with a worse prognosis. 113, 983988 (2001). 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. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. SORAML, a randomized placebo-controlled trial evaluated the efficacy and tolerability of 3+7 induction-consolidation with or without sorafenib in patients 60 years with newly diagnosed AML, irrespective of a FLT3mut (only 34% had FLT3mut). More recently, the emergence of BCR-ABL1-positive clone was shown as a resistance mechanism to multiple FLT3is72. J. Hematol. Netw. DNA quantification was performed with a Nanodrop (Thermo Fisher Scientific, Waltham,MA) or Qubitfluorometer (Thermo Fisher Scientific, Waltham, MA). Our study has several limitations: (1) Our patients were selected from an observational registry, which can be interpreted as a limitation given the heterogeneity of treatments or as a strength because our data are thereby more similar to those observed in real-life clinical practice than those derived from a clinical trial26,27. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. DiNardo, C. D. et al. Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. and P.M.; Project administration, J.M.A. FLT3 -ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. 28, 1856 (2010). Among 14 R/R FLT3mut AML patients, the CRc rate was 64% with FLT3-PCR negativity in 88% of responders. Of note, we tested 3 different ITD length thresholds, and to be considered significant, the P value should be<0.025. Clinical trial enrollment (if available) is always the first option, in both frontline and R/R FLT3mut AML. Request PDF | Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain mutation in cytogenetically normal acute myeloid leukemia: a Hokkaido Leukemia Net study | Mutation status of FLT3 . It's the most common genetic change in acute myeloid leukemia (AML), a type of leukemia that starts in the bone marrow and. S1. Schneider F, Hoster E, Schneider S, Dufour A, Benthaus T, Kakadia PM, et al. DNA was extracted using automated or manual DNA extraction kits following the manufacturers recommendations. Cite this article. None of the studies has carried out an internal ITD length cutoff validation by dividing the patients into a training cohort and a validation cohort, which, given the arbitrary selection of the cutoffs used, would be necessary. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Lancet Oncol. 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%). & Ley, C., Network CGAR. While the seven patients treated with the doublet had a CRc rate of 57% (n=4/7) and a median OS of 5.7 months, the fifteen R/R FLT3mut AML patients treated with the triplet had a CRc rate of 81% (n=11) with a projected 1-year OS of 60%. 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 ). Further evaluation and optimization of triplets is a major area of clinical research focus in FLT3mut AML. 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. Tamaoki, T. et al. 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. 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. 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. J. Clin. Thank you for visiting nature.com. and JavaScript. 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 130, 723 (2017). Tallman, M. S. et al. DiNardo, C. D. et al. Correspondence to 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. Soc. Minetto, P. et al. 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. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. Clinical outcome stratified according to the FLT3-ITD length (cutoff 70bp) for all patients treated with intensive chemotherapy. Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. Souki Cancer Research Fund and generous philanthropic contributions to the MD Anderson Moon Shots Program. Blood 114, 29842992 (2009). However, a subsequent UKMRC study of 1600 patients with cytogenetic intermediate-risk AML showed that relapse risk did not differ based on the FLT3-ITDmut AR, and that the cumulative incidence of relapse in patients with NPM1mut was increased with a concurrent FLT3-ITDmut irrespective of the AR19. Perl, A. E. et al. Daver, N., Venugopal, S. & Ravandi, F. FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm. 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). Blood 134, 2564 (2019). Among 362 patients, NGS was performed in 118 patients using a panel of 39 genes. Cell 150, 264278 (2012). Secondary mutations as mediators of resistance to targeted therapy in leukemia. PubMed 2A). Such sequential approaches need to be formally evaluated in the context of prospective clinical trials. Clinical outcome stratified according to the FLT3-ITD length (cutoff 39bp) for all patients treated with intensive chemotherapy. 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. 61, 72337239 (2001). 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. Type I FLT3is like gilteritinib are less prone to develop secondary mutations in the TKD, although the gatekeeper F691M can confer resistance to gilteritinib71. FLT3-ITD length was compared between mutation and wild-type groups for each of the 39 genes using a MannWhitney test. PubMed J. Med. FLT3-TKD activating mutations also constitutively activate FLT311; however, they have not been associated with a consistent prognostic impact12. Although the label indication for gilteritinib is as a single agent we have never used it as a single agent but always in combination with either HMA alone, venetoclax alone or as a triplet with HMA and venetoclax. FLT3-ITD has been strongly associated with a bad prognosis, leukocytosis, high blast counts, increased risk of relapse and shorter overall survival. The AR was determined by fragment length analysis and calculated as previously described32. The FLT3-ITD patient had trisomy 8. Yalniz, F. et al. In order to improve the clinical condition of FLT3-ITD-positive patients, several FLT3 inhibitors have been developed showing variable results. However, emerging data does suggest that patients with FLT3-ITDmut AR<0.5 and NPM1 co-mutation without concurrent high-risk mutations such as DNMT3A, TP53, TET2, or high-risk cytogenetics may be a more favorable subset, who may be considered for induction, consolidation followed by maintenance therapy without ASCT on a case by case basis if they achieve early MRD negativity using a highly sensitive MRD assay. 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). Despite the current availability of the FLT3 inhibitor midostaurin, there is an unmet need for improved treatment options. and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. Blood 93, 30743080 (1999). FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML. FLT3-ITD mutations are detected in approximately 25% of newly diagnosed adult acute myeloid leukemia (AML) patients and confer an adverse prognosis. Patients with NPM1-/FLT3- showed complex karyotype (24%) and t(8;21) (8%). 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. Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML. PubMedGoogle Scholar. recently presented the first triplet combination of venetoclax, FLT3i (mainly gilteritinib or sorafenib), and decitabine from the FLT3mut subset of the prospective decitabine 10 days with venetoclax study (NCT03404193)54. and JavaScript. Acute myeloid leukemia, Version 3.2019, NCCN clinical practice guidelines in oncology. Canc. FLT3 is a receptor tyrosine kinase that is involved in regulating proliferation of hematopoietic progenitor cells. Because the comutation of DNMT3A (DNMT3A(mut)) has been suggested to negatively influence prognosis in AMLNPM1, we analyzed the impact of DNMT3A(mut) in FLT3-ITD subsets (absent, low, and high ratios). FLT3 mutation and all but one patient died shortly after FLT3 mutation was acquired. 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. Rllig, C. et al. Article 377, 454464 (2017). The size of our cohort was larger than those of the studies published using these cutoffs. 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 Am. This is in line with the preclinical data49 and molecular profiling of pre- and post-treatment samples66 identifying FLT3-ITDmut as a putative mechanism of resistance to venetoclax based therapies67, suggesting that FLT3-ITDmut patients may need a FLT3i incorporated into the HMA with venetoclax therapy either in a triplet or sequential approach to improve OS. B MD Anderson Cancer Center Approach. First, 161 AML patients with FLT3-ITD mutations treated with IC were analyzed using 39bp as the cutoff (<39bp; n=48,39bp; n=113). 2). Therefore, these patients were not included in the analysis stratified by 2010 ELN genetic risk21. 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). Scientific Reports (Sci Rep) (3) Findings regarding the relationship between ITD length/site and mutational profile might be interpreted as exploratory given the high number of correlations performed. 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. evaluated the impact of AR in 323 patients with newly diagnosed FLT3-ITDmut AML. CAS 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. Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability. The FLT3-ITD AR was available in 140 intensively treated patients. FLT3-ITD mutational load, expressed as an AR determined by fragment length analysis, has a clear prognostic value and is, therefore, included in the genetic prognostic classification of the European Leukemia Net (ELN) published in 20178. The BSC group included 7 patients receiving transfusions and other supportive measures. S.V. Therefore, only 3.8% of the patients showed an FLT3-ITD insertion in the TKD1 domain. J. Hematol. QuANTUM-R, a phase 3 randomized controlled trial, evaluated quizartinib monotherapy vs investigator choice salvage chemotherapy in R/R FLT3-ITDmut AML. Blood 99, 43264335 (2002). In the meantime, to ensure continued support, we are displaying the site without styles 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. AML patients with FLT3-ITD mutations show an increased relapse rate, reduced disease-free survival (DFS), and decreased long-term survival, while the rate of complete remission (CR) after induction chemotherapy is not significantly affected6,7. 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. Article 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. 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). These mutations arearranged in increasing order by FLT3-ITD length. We have no explanation regarding the reduced number of patients with an FLT3-ITD inserted in TKD1 found in our cohort. Slider with three articles shown per slide. We thank the PETHEMA group for its participation in this study. The first-generation FLT3is lack specificity for FLT3 and inhibit multiple downstream RTKs that may result in more off-target toxicities. DiNardo, C. D. et al. Oncol. In a single-arm phase II trial of quizartinib (90 or 135mg), the CRc rates were between 46 and 56% in ~250 R/R FLT3-ITDmut patients treated across two cohorts. Blood Marrow Transplant 22, 12181226 (2016). E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for KIT+ . Get the most important science stories of the day, free in your inbox. PubMed Central Precision Medicine in Myeloid Malignancies: Hype or Hope? 17, 721749 (2019). Levis turned to FLT3-ITD mutations in acute myeloid leukemia (AML) to highlight the challenges with targeted therapy. has received research funding from Astellas, and Novartis and has served as a member of advisory board in Astellas and Novartis. PubMedGoogle Scholar. We identified 1572 adult (age 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or . Although the presence of FLT3-ITD, as well as levels of the FLT3-ITD allelic ratio, have been described as prognostic factors in acute myeloid leukemia (AML), little is known about how the FLT3-ITD allelic ratio impacts patients&rsquo; outcomes when receiving an allogeneic hematopoietic stem cell transplantation (HSCT). 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). Therefore, in patients not eligible for intensive chemotherapy at MDACC, we prefer a combination of HMA with venetoclax and FLT3i (gilteritinib) over an HMA with venetoclax doublet (Fig. Interestingly, FLT3-ITD mutation, which has an adverse prognosis is found in up to one-third of younger patients but only 15-18% in >65 years. Thiede, C. et al. (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. Andrew, H. et al. 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 2, 125 (2020). 6,, - 9 In normal bone marrow, FLT3 expression is Which FLT3 Inhibitor for Treatment of AML? Stone, R. M. et al. PubMed Central 96 1993 2003, Article Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia. **If the C1 D14 bone marrow show >5% blastscontinue venetoclax, FLT3i till D21. and P.M. Fishers exact test was employed to correlate the ITD insertion site and mutational status. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. 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. Figure legend Overall survival of patients with AML following frontline venetoclax plus hypomethylating agent PubMed Central Rydapt Prescribing Information. (C) OS according to the FLT3-ITD length and allelic ratio. has nothing to disclose. This work was supported in part by the MD Anderson Cancer Centre Support Grant (CCSG) CA016672, the MD Anderson Cancer Center Leukemia SPORE CA100632, the Charif. Both mutations lead to the activation of downstream proliferation cascades [ 19, 20 ]. Metzelder, S. et al. Yilmaz, M. et al. However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. 90, 276281 (2015). volume11, Articlenumber:20745 (2021) Gilteritinib was generally well tolerated but was associated with increased incidence of gastrointestinal side effects, most frequently diarrhea although nausea has been occasionally observed. 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. Blood 100, 23932398 (2002). The landscape of mutations identified by NGS in AML patients. Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens. J. Med. T.C. Blood 100, 43724380 (2002). By submitting a comment you agree to abide by our Terms and Community Guidelines. In subsequent cycles: FLT3i is continued for the entire duration of the cycle and the venetoclax duration is reduced to 14 days or lower to mitigate cumulative prolonged cytopenias. Prognostication refinement in NPM1-mutated acute myeloid leukemia stratified by FLT3-ITD status with different induction doses of cytarabine. Article We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. However, the median OS was 19.2 months in FLT3-TKDmut AML (19.2 months), but only 11.5 months in FLT3-ITDmut patients65. 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. 4). Perl, A. E. et al. 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. Am. Google Scholar. Cite this article. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 132, 598607 (2018). This review describes key milestones in the clinical development of different FLT3-specific TKI with a . Azacitidine and venetoclax in previously untreated acute myeloid leukemia. FLT3 -ITD has a poor prognostic impact in patients with AML at diagnosis. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITDmutated, relapsed or refractory AML. Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. Timothy, J. Moreover, ASCT in CR1 only benefitted patients with isolated FLT3-ITDmut (without NPM1mut) irrespective of AR (P<0.05)21. Article (A) Overall survival. 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. 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).