Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Pratz, K. W. et al. Blood 121, 46554662 (2013). 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). Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated In the meantime, to ensure continued support, we are displaying the site without styles Quizartinib demonstrated an OS of 6.2 months compared with 4.7 months with salvage chemotherapy (hazard ratio 0.76 and P=0.02). Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia. (A) Overall survival. Fishers exact test was employed to correlate the ITD insertion site and mutational status. Perl, A. E. et al. FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. Blood Cancer J. & Ley, C., Network CGAR. Blood 124, 273276 (2014). The FLT3-ITD allelic ratio has clear prognostic value. Wang, E. S. et al. Juan M. Alonso-Dominguez. This work is submitted in partial fulfillment of the requirement for the PhD. 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. Br. This result is similar to the RATIFY study, in which 44% of patients lost FLT3 ITD under treatment with midostaurin 36. Blood 110, 12621270 (2007). FLT3 -ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. DNA quantification was performed with a Nanodrop (Thermo Fisher Scientific, Waltham,MA) or Qubitfluorometer (Thermo Fisher Scientific, Waltham, MA). The combination continues to enroll. Oncol. FLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. Mutations of the fms-tyrosine kinase ( FLT3) were first described in 1997 4 and account for the most frequent molecular mutations in AML. Studies have reported that a higher mutant allelic burden is associated with a worse prognosis. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. 3.3 TET2 in NPM1 mut /FLT3-ITD (), and CD34 and ID-Ara-C in NPM1 mut /FLT3 . Blood 100, 23932398 (2002). Correspondence to the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Rollig, C. et al. 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. FLT3 -ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. (C) OS according to the FLT3-ITD length and allelic ratio. FLT3 -TKD mutations are point mutations in the activation loop of FLT3, mainly represented by codon D835 or deletion of codon I836, which leads to a loss of auto-inhibition [ 18 ]. PubMed prospectively evaluated decitabine and quizartinib (doublet) with or without venetoclax (triplet) in patients with newly diagnosed and R/R FLT3-ITDmut AML. Nevertheless, we also performed an analysis with the median ITD length of our cohort (48bp). FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) is one of the most frequent mutations found in AML patients. Characteristics and outcome of patients with core binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study. Am. Therefore, only 3.8% of the patients showed an FLT3-ITD insertion in the TKD1 domain. Diagn. FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. 90, 276281 (2015). Blood 125, 32363245 (2015). 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. 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). Accumulating evidence have shown improved outcomes in FLT3-ITDmut patients receiving induction with higher dose anthracyclines57, cladribine58, or fludarabine added to induction backbone21, and incorporating FLT3i with induction (either first or second generation) in FLT3mut AML24,44,59,60 (Fig. 1). CAS Intensive fludarabine, high dose cytarabine and idarubicin-based induction for younger NPM1-mutated AML patient: overcoming the negative prognosis of FLT3-ITD mutation. Maintenance therapy for FLT3-ITD -mutated acute myeloid leukemia Minetto, P. et al. 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. As in previous works, we analyzed the clinical significance of FLT3-ITD length among fit patients treated with intensive regimens15,16. FLT3 -ITD was a poor prognostic factor in both age groups, but the favorable prognostic impact of NPM1 was more evident in patients aged 65 years or more. Gale, R. E. et al. Blood 128, 1069 (2016). Altman, J. K. et al. Ravandi, F. et al. Google Scholar. Molecular landscape and prognostic impact of FLT3-ITD - Nature 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.) Type I FLT3is are active against both the FLT3-ITD or TKD, type II inhibitors are only active against FLT3-ITD, not TKD. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). Nevertheless, some thresholds have been applied in more than one study [i.e., 39bp and 70bp]11,15,16,17. A randomized, placebo-controlled phase III study of 3+7 with quizartinib (QuANTUM-First; NCT02668653) in patients with newly diagnosed FLT3-ITDmut AML eligible for induction therapy recently completed accrual. Weisberg, E. et al. 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. 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). 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). 93, E202E205 (2018). 3 A Survival curves stratified by the presence or absence of FLT3 -ITD and NPM1 mutation for patients younger than 65 years. Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. CR+CRi rates between groups were compared with a chi-square test. and P.M.; Project administration, J.M.A. 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. S1. Prognostic significance of baseline FLT3ITD mutant allele level in Authors Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. The median RFS was 1.2years (CI 0.22.2) and 0.77years (CI 0.51.1), respectively (P=0.06). We currently recommend the incorporation of FLT3is and ASCT in CR1 in all ASCT eligible patients with a FLT3-ITDmut AML, irrespective of the AR and/or NPM1 co-mutation status. Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. 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. Blood 135, 791803 (2020). 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. | 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. This model of initiatory and progression mutation as FLT3 is well described 37, 38. Patients treated with midostaurin had higher rates of anemia and skin rash compared to placebo and these were generally manageable with supportive care without necessitating dose reductions or interruptions in the majority of cases. 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). Its expression in acute myeloid leukemia (AML) is associated with a poor prognosis. Prognostic analyses were performed using the 70bp cutoff in 161 AML patients with FLT3-ITD mutations treated with IC (<70bp; n=119,70bp; n=42). and JavaScript. FLT3 -ITD has a poor prognostic impact in patients with AML at diagnosis. 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. PCR with fluorescently labeled primers followed by capillary electrophoresis for FLT3-ITD was performed as described elsewhere31. FLT 3-ITD mutations typically were determined using polymerase chain reaction and fragment analyses. Commun. 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. PubMed Informed consent was a requisite for patients alive at the time of data lock (January 2019). Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. PubMed Clinical outcomes in patients with relapsed/refractory acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib. A detailed analysis of all patients showed ITD integrations in the JMD-B, amino acids 572 to 578, in six patients; the JMD-S, amino acids 579 to 592, in 42 patients; the JMD-Z, amino acids 593 to 603, in 43 patients; the HR, amino acids 604 to 609, in seven patients; the B1 of TKD1, amino acids 610 to 615, in one patient; the NBL, amino acids 616 to 623, in two patients; and the B2, amino acids 624 to 630, in one patient. Leukemia 26, 23532359 (2012). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf2017 (2017). Clinical heterogeneity under induction with different dosages of Protein alteration seems to be much more complex than the length of the mutation or the site of insertion; therefore, our efforts to simplify FLT3-ITD characteristicsby stratifying the risk of the patients may be fruitless. Decitabine combined with medium-dose cytarabine in the treatment of DEK J. Med. is a PhD candidate at Universidad Autnoma de Madrid (UAM). FLT3-ITD mutations are detected in approximately 25% of newly diagnosed adult acute myeloid leukemia (AML) patients and confer an adverse prognosis. 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. 9, 10501063 (2019). Lancet Haematol. Blood 129, 424447 (2017). Blood 114, 29842992 (2009). Molecular Diagnostics | FLT3 (ITD and TKD) Mutation Detection Am. Mali, R. S. et al. You are using a browser version with limited support for CSS. Blood 136, 1617 (2020). Pulmonary infiltration and acute pneumonitis-like picture are rare (<1%) but noted side effects of midostaurin that treating physicians should be aware of. As Dr. Erba explained, patients with FLT3 -ITD-positive AML represent a particularly poor prognostic group. (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. Only four out of 106 patients had ITD IS in the TKD1 domain. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. PubMedGoogle Scholar. The size of our cohort was larger than those of the studies published using these cutoffs. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3internal tandem duplication mutation (SORMAIN). 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). 93, 213221 (2018). J. Hematol. Relapse-free survival (RFS) was calculated from the date of achieving CR/CRi until the date of relapse (death without relapse or relapse were consideredevents)8. You are using a browser version with limited support for CSS. 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). Full article: The importance of FLT3 mutational analysis in acute Posterior reversible encephalopathy and pancreatitis are rare (<12%) but important side effects to be aware of. Article Taken together, utilizing baseline FLT3-ITDmut AR to guide the post-remission therapy remains controversial. 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. More recently, the emergence of BCR-ABL1-positive clone was shown as a resistance mechanism to multiple FLT3is72. 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. The median OS was 1.3years (CI 0.71.9) and 1.4years (CI 1.01.8), respectively (P=0.8). 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. Gilteritinib, a second-generation type I FLT3i demonstrated tolerability with CRc rates of 4555% in patients with R/R FLT3 (ITD or TKD)mut AML38,39. If C1 D28 marrow confirms remission and ANC<0.5 and/or platelet<50K consider interrupting FLT3i and using neupogen to enhance count recovery. We tried to validate the thresholds of ITD length previously published (i.e., 39bp and 70bp) in intensivelytreated AML patients (n=161). 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. Sra. We continue the venetoclax and FLT3i until Day 21 if the Day 14 bone marrow shows >5% blasts with >/=5% cellularity. 2B). 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). 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. Figure legend Overall survival of patients with AML following frontline venetoclax plus hypomethylating agent Quizartinib, a second-generation, type I FLT3i is active against FLT3, KIT, CSF1R, PDGFR, and RET kinase34. In the last 25years, advances in molecular techniques have allowed a greater understanding of the pathogenesis of AML and the subsequent development of targeted therapies and a more refined prognostic classification based on the genetic features of the disease2,3. Google Scholar. Among the FLT3mut patients, response rates were numerically higher (33%) and remission duration was longer (31 versus 16 weeks, P=0.09) in those who were naive to treatment with FLT3 inhibitors compared with those who had been exposed to prior FLT3 inhibitors. Progr. The BSC group included 7 patients receiving transfusions and other supportive measures. Furthermore, a global query was sent to the different centralized laboratories of PETHEMA to verify the ITD length, insertion site and molecular profile of the patients by NGS when these data were available. Measurable residual disease, FLT3ITD mutation, and disease status have After post-remission therapy with either consolidation (high-dose cytarabine-based) or allogeneic stem cell transplant (ASCT), AR 0.51 and FLT3-ITD insertion site in TKD1 were associated with an unfavorable RFS (P=0.0008) and OS (P=0.004)15. Article However, other studies did not find significantly worse clinical outcomes in patients with non-JMD ITD mutations24,25. F fludarabine, I idarubicin, CL cladribine, A cytarabine 1.52g/m2, HMA hypomethylating agent, CR complete remission, ECOG PS Eastern Cooperative Oncology Group Performance Status, CG cytogenetics, MRD measurable residual disease, SCT stem cell transplant, HiDAC high-dose cytarabine, CBC complete blood count. 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 Central We stop the venetoclax and the FLT3i after Day 14 in patients who achieve marrow remission (<5% blasts) and/or marrow aplasia/hypoplasia/insufficiency (<5% cellularity). Yilmaz et al. 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). Tamaoki, T. et al. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain CAS 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. Strati, P. et al. FLT3 -ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. 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. "For patients with AML, the 5-year survival rate is only about 29%," said Dr. Erba. FLT3 -ITD is a negative prognostic factor that remains prognostically relevant even after intensive chemotherapy and/or stem cell transplant. Yilmaz, M. et al. The AR was determined by fragment length analysis and calculated as previously described32. J. Natl Compr. To obtain Nakao, M. et al. . Enter the email address you signed up with and we'll email you a reset link. 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. Flow diagram showing all AML patients with FLT3-ITD mutations in the study period between 2003 and 2019 on the basis of genetic data and treatment administered. FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia and is associated with worse clinical outcome. * Genes with a P value<0.05 in the MannWhitney test correlating mutational status with ITD length. Off-target resistance includes clonal evolution during FLT3i therapy even when FLT3-ITDmut clone is lost70. Blood 132, 598607 (2018). PubMed 120.000 new AML cases and over . 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. 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. Ravandi, F. et al. Due to this, the development of tyrosine kinase inhibitors (TKI) blocking FLT3-ITD became a rational therapeutic concept. Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia. 10, 588876- (2020). Therefore, the value obtained is not significant, although it shows a slight trend toward being significant. Clinical impact of change of FLT3 mutation status in acute myeloid Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain Yalniz, F. et al. 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. We have no explanation regarding the reduced number of patients with an FLT3-ITD inserted in TKD1 found in our cohort. Tallman, M. S. et al. 2, 3 There are two types of FLT3 mutation, internal tandem duplication of FLT3 ( FLT3-ITD) and tyrosine kinase Our median ITD length was 48bp (range=3bp to 231bp), similar to previous studies12,14,17. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. DiNardo, C. D. et al. 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. All samples investigated in this study were obtained at the time of diagnosis. 13 95 100. B MD Anderson Cancer Center Approach. Haematologica 106, 1034 (2020). and P.M. The origin and evolution of mutations in acute myeloid leukemia. 6,, - 9 In normal bone marrow, FLT3 expression is Results of a Phase 2, Randomized, Double-Blind Study of Sorafenib Versus Placebo in Combination with Intensive Chemotherapy in Previously Untreated Patients with FLT3-ITD Acute Myeloid Leukemia (ALLG AMLM16) (ASH, 2020). 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. We administer a second-generation FLT3i (ideally gilteritinib) continuously with HMA from cycle 1 Day 1. Regardless of prior FLT3i therapy, gilteritinib-treated patients had CRc rates >40%, however, the median OS with single-agent gilteritinib was 6.5 vs 9.6 months in prior FLT3i exposed (n=31) vs naive patients (n=216) with FLT3mut R/R AML74. Second-generation FLT3is potently and specifically target FLT3 with fewer off-target effects. 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. Strati et al. Analysis of NPM1 and FLT3 Mutations in Patients with Acute Myeloid 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. Although activity was seen, the response rates were overall modest with this combination and the combination of HMA with midostaurin is not one that we routinely use or recommend for frontline FLT3-mutated AML47. and P.M.; Supervision, J.M.A. and JavaScript. Article A Conventional approach. These data highlight the potent anti-leukemic activity of the triplet approach in FLT3mut AML. Close Log In. 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). Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. FLT3-ITD has been strongly associated with a bad prognosis, leukocytosis, high blast counts, increased risk of relapse and shorter overall survival. Souki Cancer Research Fund and generous philanthropic contributions to the MD Anderson Moon Shots Program. Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine Abhishek Maiti, M. D. et al. Slider with three articles shown per slide. Phase 3, Multicenter, Open-label Study of Gilteritinib, Gilteritinib plus Azacitidine, or Azacitidine Alone in Newly Diagnosed FLT3-Mutated (FLT3mut+) Acute Myeloid Leukemia (AML) Patients Ineligible for Intensive Induction Chemotherapy (ASH, 2020). Brinton, L. T. et al. J. Hematol. volume11, Articlenumber:104 (2021) No significant difference was found between acute myeloid leukemia patients with these contracts here. Article 13, 132 (2020). There were two patients with core binding factor (CBF) translocations (one RUNX-RUNX1T1 and one CBFB-MYH11) and FLT3-ITD mutations. The first-generation FLT3is lack specificity for FLT3 and inhibit multiple downstream RTKs that may result in more off-target toxicities. We have no information on the treatment received by the remaining patients. DiNardo, C. D. et al. Perl and colleagues investigated whether prior FLT3i therapy influenced outcomes in patients treated with gilteritinib. 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. 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. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Sci Rep 11, 20745 (2021). 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. Burchert, A. et al. 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.