Ann Hematol. 21, 12011212 (2020). 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. Blood 132, 598607 (2018). The study protocol was conducted following the guidelines of the Declaration of Helsinki and approved by the Ethics Committee for Clinical Research of the Hospital UniversitarioFundacin Jimnez Daz (PIC169-18_FJD). 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. Blood 136, 3233 (2020). A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. It's the most common genetic change in acute myeloid leukemia (AML), a type of leukemia that starts in the bone marrow and. Am. 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). Blood Cancer J. 13 95 100. Despite the current availability of the FLT3 inhibitor midostaurin, there is an unmet need for improved treatment options. CAS 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. Patients diagnosed with acute promyelocytic leukemia (APL) were excluded. Besides FLT3-ITD MRD, only a high white blood cell count and late CR appeared to be independently associated with relapse and OS. Get the most important science stories of the day, free in your inbox. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain (3) Findings regarding the relationship between ITD length/site and mutational profile might be interpreted as exploratory given the high number of correlations performed. Dipsit Digital de la Universitat de Barcelona: Prognostic impact of 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. Canc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf2017 (2017). 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. 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). is a PhD candidate at Universidad Autnoma de Madrid (UAM). Due to the preliminary nature of the . Interestingly, all patients with an FLT3-ITD inserted in the TKD1 domain showed DNMT3A mutations. In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene ( FLT3- ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive. Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 gene ( FLT3) confer a poor prognosis in adult AML. Yamatani, K. et al. B MD Anderson Cancer Center Approach. Article 3). Our real-life cohort was composed of 362 patients, most of whom were not included in clinical trials. Overall survival (OS) was calculated from the date of the diagnosis of AML until death in all included patients. 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. 10 1 10, K Dhner 2020 Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia Blood 135 371 380, C Thiede 2002 Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: Association with FAB subtypes and identification of subgroups with poor prognosis Blood 99 4326 4335, KM Murphy 2003 Detection of FLT3 Internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay J. Mol. We aimed to shed light on the prognostic importance of theFLT3-ITD length and site of insertion by validating previously suggested sites of insertion and thresholds of ITD length. 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. You are using a browser version with limited support for CSS. 109 3981 3992, DL Stirewalt 2006 Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia Blood 107 3724 3726, S Meshinchi 2008 Structural and numerical variation of FLT3/ITD in pediatric AML Blood 111 4930 4933, R Kusec 2006 More on prognostic significance of FLT3/ITD size in acute myeloid leukemia (AML) Blood 108 405 406, RE Gale 2008 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 111 2776 2784, Y Kim 2015 Quantitative fragment analysis of FLT3-ITD efficiently identifying poor prognostic group with high mutant allele burden or long ITD length Blood Cancer J. We tried to validate the thresholds of ITD length previously published (i.e., 39bp and 70bp) in intensivelytreated AML patients (n=161). Prognostic impact analyses of FLT3-ITD length were performed among patients treated with upfront IC regimens. 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 is a receptor tyrosine kinase that is involved in regulating proliferation of hematopoietic progenitor cells. Complete response (CR) or complete responses with incomplete hematologic recovery (CRi) were defined according to current 2017 ELN guidelines8. volume11, Articlenumber:20745 (2021) Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in 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. The FMS-like tyrosine (FLT3) gene encodes a class III receptor tyrosine kinase, sharing structural and sequence homologies with family members, including c-kit, c-FMS, FLT1, and PDGF- R. FLT3 plays a key role in the control of hematopoiesis. No statistically significant differences were found (P=0.4) (Fig. We observed a low frequency of NPM1 mutation (10.1%), which correlated with the good prognosis of this mutation. Cancer 125, 37553766 (2019). Lancet Oncol. 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. 17 D2 D8, H-S Kim S Lee JH Kim 2018 Real-world evidence versus randomized controlled trial: Clinical research based on electronic medical records J Korean Med Sci 33 e213, RF Schlenk 2014 Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation Blood 124 3441 3449, I Abou Dalle 2020 Impact of numerical variation, allele burden, mutation length and co-occurring mutations on the efficacy of tyrosine kinase inhibitors in newly diagnosed FLT3- mutant acute myeloid leukemia Blood Cancer J. and P.M.; Project administration, J.M.A. Am. In our cohort, FLT3-ITD was located in the JMD domain (JMD-B, JMD-S, JMD-Z and HR) in 98 patients and in the TKD1 domain (B1, NBL and B2) in four patients. Regarding ITD length, some authors have found that patients with shorter ITD lengths have more favorable outcomes11,12 or worse prognoses13, while other researchers did not find a prognostic relationship14. 11, 104 (2021). Cite this article. Hematology. Full article: Advances in the drug therapies of acute myeloid leukemia Administration of the triplet is associated with prolonged cytopenias, requiring close monitoring and experience with venetoclax based combinations. 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. 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. An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown). Google Scholar, MR ODonnell 2017 Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology J. Natl. FLT3 mutation and all but one patient died shortly after FLT3 mutation was acquired. We studied theFLT3-ITD length of 362 adult AML patients included in the PETHEMA AML registry. Blood 136, 810 (2020). 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. 7, e724e736 (2020). 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). Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain 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. In the frontline setting, there was a sequential decrease in CRc rates (77%31%25%) and OS (16.76.01.4 months). Biol. Yilmaz, M. et al. Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). @Repeat a C1 D28 bone marrow on all patients to confirm remission. 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). Only four out of 106 patients had ITD IS in the TKD1 domain. Wang, E. S. et al. The impact of prognostic factors may change as the AML treatment landscape evolves. Prognostic relevance of FLT3-TKD mutations in AML: the combination evaluated the impact of AR in 323 patients with newly diagnosed FLT3-ITDmut AML. Thank you for visiting nature.com. Upon achieving CR, the decision for ASCT is based on the risk-benefit assessment for ASCT. FLT3-ITD length was compared between mutation and wild-type groups for each of the 39 genes using a MannWhitney test. Heart J. Suppl. Xuan, L. et al. Progr. 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. However, other studies did not find significantly worse clinical outcomes in patients with non-JMD ITD mutations24,25. N. Engl. 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 . PubMed Blood 124, 34413449 (2014). In particular, high (>0.5) mutant-to-wild-type (WT) allelic ratios (AR) in the FLT3-ITD gene are associated with inferior prognosis ( 6, 7 ). 2013 220 226, H Dhner 2017 Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel Blood 129 424 447, F Breitenbuecher 2009 Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor Blood 113 4074 4077, S Liu 2018 Pattern and prognostic value of FLT3-ITD mutations in Chinese de novo adult acute myeloid leukemia Cancer Sci. Stratified KaplanMeier analysis was also employed with the AR and genetic risk, following 2010 ELN guidelines21, as classifiers of the patients. Cancer 51 910 924, AT Cohen S Goto K Schreiber C Torp-Pedersen 2015 Why do we need observational studies of everyday patients in the real-life setting? 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. Zhang, W. 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). Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. A phase I study evaluating gilteritinib with 7+3 induction and high-dose cytarabine consolidation chemotherapy, followed by single-agent maintenance therapy, in patients with newly diagnosed AML showed that gilteritinib 120mg daily was well tolerated. 13, 132 (2020). Res. Log in with Facebook Log in with Google. Kiyoi, H., Ohno, R., Ueda, R., Saito, H. & Naoe, T. Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. 100, 184198 (2008). Blood 97, 24342439 (2001). S2) in PETHEMA centralized diagnostic laboratories as previously described33. Tallman, M. S. et al. 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. PubMed 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). CR or CRi was achieved in 70% of the patients in both groups (P=0.9). Blood 100, 43724380 (2002). Swaminathan et al. Blood 121, 46554662 (2013). F.R. It is important to note that none of these patients received a FLT3 inhibitor (FLT3i) during induction, consolidation, or post-ASCT. However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. These observations have made FLT3 an attractive drug target. 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. FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) is one of the most frequent mutations found in AML patients. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Moreover, ASCT in CR1 only benefitted patients with isolated FLT3-ITDmut (without NPM1mut) irrespective of AR (P<0.05)21. 16, 16911699 (2015). All samples investigated in this study were obtained at the time of diagnosis. Identification of novel FLT3 Asp835 mutations in adult acute myeloid leukaemia. DNA quantification was performed with a Nanodrop (Thermo Fisher Scientific, Waltham,MA) or Qubitfluorometer (Thermo Fisher Scientific, Waltham, MA). Posterior reversible encephalopathy and pancreatitis are rare (<12%) but important side effects to be aware of. 7+37 days of cytarabine and 3 days of daunorubicin. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. FLT3 -ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. Article 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. Conceptualization, T.C., J.M.A., E.B. Schlenk, R. F. et al. Patients with NPM1-/FLT3- showed complex karyotype (24%) and t(8;21) (8%). CR or CRi was achieved in 70% of the patients in both groups (P=0.9). Intensive fludarabine, high dose cytarabine and idarubicin-based induction for younger NPM1-mutated AML patient: overcoming the negative prognosis of FLT3-ITD mutation. and JM.A. Frontiers | First Report of Sorafenib in Patients With Acute Myeloid Schlenk 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. 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. A Conventional approach. 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. 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. N. Engl. mutations (1-year survival < 1% vs 42% in their presence vs absence) which should be incorporated in patient counseling. Prevalence of FLT3, NPM1 and CEBPA Mutations and Correlation to The FLT3-ITD patient had trisomy 8. Informed consent was a requisite for patients alive at the time of data lock (January 2019). Therefore, only 3.8% of the patients showed an FLT3-ITD insertion in the TKD1 domain. Slider with three articles shown per slide. 3 A Survival curves stratified by the presence or absence of FLT3 -ITD and NPM1 mutation for patients younger than 65 years. 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. CAS Clinical trial enrollment (if available) is always the first option, in both frontline and R/R FLT3mut AML. Unlike midostaurin, quizartinib monotherapy, even at lower doses demonstrated significant marrow remissions in R/R FLT3mut AML35,36,37. Blood 100, 23932398 (2002). Prognostic significance of baseline FLT3ITD mutant allele level in Secondary resistance to FLT3i could be either on-target (changes in the FLT3) or off-target (constitutive activation of non-FLT3-dependent oncogenic pathways). Staurosporine, a potent inhibitor of phospholipid Ca++ dependent protein kinase. To test the prognostic significance of the ITD length and its clinical applicability, we used recurrent previously published cutoffs, which were analyzed in series ranging from 28 to 100 intensively treated patients. A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid FLT3-ITD mutations are detected in approximately 25% of newly diagnosed adult acute myeloid leukemia (AML) patients and confer an adverse prognosis. and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. The first-generation FLT3is lack specificity for FLT3 and inhibit multiple downstream RTKs that may result in more off-target toxicities. Oncol. Am. PCR with fluorescently labeled primers followed by capillary electrophoresis for FLT3-ITD was performed as described elsewhere31. The prognostic value of a FLT3 mutation in the tyrosine kinase domain (FLT3-TKD), which has a lower incidence in AML (approximately 7-10% of all cases), is uncertain. 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. (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. PubMed Central While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. 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. Am. Blood 114, 29842992 (2009). J. Med. Decitabine combined with medium-dose cytarabine in the treatment of DEK The median OS was 1.3years (CI 0.71.9) and 1.4years (CI 1.01.8), respectively (P=0.8). Oran, B. et al. npm1flt3-itd2017elnnpm1flt3-itd[<0.5][>0.5]flt3-itd[dna][auc]"flt3-itd"auc"flt3-" Google Scholar. Oncogene 21, 25552563 (2002). Nevertheless, some thresholds have been applied in more than one study [i.e., 39bp and 70bp]11,15,16,17. Cancers | Free Full-Text | Clinical Implications of the FLT3-ITD Therefore, there is a lack of consensus regarding the prognostic importance of the ITD IS and the subdomains that confer this adverse outcome. The on-target mechanism of resistance includes emergence of secondary TKD mutations in patients treated with type II inhibitors like quizartinib or sorafenib69,70. Castao-Bonilla, T., Alonso-Dominguez, J.M., Barragn, E. et al. Information regarding the ITD insertion site and mutational status of another 38 genes recurrently mutated in myeloid neoplasms was available in 106 and 118 patients, respectively. 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. McMahon, C. M. et al. Regardless of the regimen intensity, all clinical trial participants were grouped in a separate treatment category (n=15). The origin and evolution of mutations in acute myeloid leukemia. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Google Scholar. Compr. ___ Conclusion: The frequency of NPM1/FLT3 mutations in the study cohort showed less rate than in other studies with a distinct pattern. As Dr. Erba explained, patients with FLT3 -ITD-positive AML represent a particularly poor prognostic group. (A) Overall survival. [PDF] Combination of ATO with FLT3 TKIs eliminates FLT3/ITD+ leukemia Article Enter the email address you signed up with and we'll email you a reset link. Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. Schneider F, Hoster E, Schneider S, Dufour A, Benthaus T, Kakadia PM, et al. Among 362 patients, NGS was performed in 118 patients using a panel of 39 genes. 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). Cladribine combined with idarubicin and Ara-C (CLIA) as a frontline and salvage treatment for young patients (65 yrs) with acute myeloid leukemia. Article 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. In general, AML patients with intermediate-risk cytogenetics and with a FLT3-ITD mutation have a significantly poorer prognosis with an increased relapse risk and decreased . The NPM1/FLT3-ITD patients had normal karyotypes. FLT3 Mutation and AML: Symptoms, Testing, and More - Healthline 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. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Jain, P. et al. Wang, E. S. et al. Secondary mutations as mediators of resistance to targeted therapy in leukemia. FLT3-ITDs show great variation in size (ranging from 3 to more than 400 base pairs (bp)), insertion sites (ISs), allelic ratios (ARs) and the number of clones5. Not all FLT3-ITDmut are equal; the prognostic impact is influenced by the allele ratio (AR), insertion site, ITD length, co-mutations (NPM1), and karyotype. Changes in FLT3 mutation status can occur during the course of disease, but the clinical impact of a change is unclear. PubMed Strati et al. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. S.V. CAS de Sonsoles de vila-Complejo Asistencial vila, vila, Spain, Hematology Department, Hospital General de Albacete, Albacete, Spain, Hematology Department, Hospital Universitario de Gran Canaria Doctor Negrn, Las Palmas de Gran Canaria, Spain, Carlos Rodrguez-Medina&Cristina Bilbao-Syeiro, Hematology Department, Hospital General Ciudad de Jan, Jan, Spain, UGC de Hematologia, Hospital U. Reina Sofia, IMIBIC, UCO, Cordoba, Crdoba, Spain, Josefina Serrano&Joaqun Snchez-Garca, Hematology Department, Hospital Comarcal del Bierzo, Len, Spain, Hematology Department, Hospital Universitario Doctor Peset, Valencia, Spain, Hematology Department, Hospital Clnico Universitario Lozano Blesa, Zaragoza, Spain, Hematology Department, Complejo Hospitalario de Navarra, Navarra, Spain, You can also search for this author in prognostic impact of FLT3-ITD and NPM1 mutation in adult AML is age These data highlight the potent anti-leukemic activity of the triplet approach in FLT3mut AML. Increase in bilirubin and transaminase can be seen with giltertiinib but are usually self-resolving and transient. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Prognostication refinement in NPM1-mutated acute myeloid leukemia stratified by FLT3-ITD status with different induction doses of cytarabine. No significant difference was found between acute myeloid leukemia patients with these Nevertheless, we also performed an analysis with the median ITD length of our cohort (48bp). Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. The PubMed database, the Cochrane Library, conference proceedings, the EMBASE databases, and references of published trials and review articles were searched. Blood 135, 791803 (2020). Lancet Oncol. In the QuANTUM-R and ADMIRAL trials, only 4% and 12% of patients had received prior FLT3i therapy with induction, making it difficult to draw conclusions regarding the outcomes of contemporary patients, most of whom will have received a FLT3i (commonly midostaurin) with induction36,40. 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. The current European Leukemia Net (ELN) guidelines categorize FLT3 -ITDmut AML as favorable (NPM1mut with FLT3 wild-type Or NPM1mut with FLT3-ITD AR<0.5), intermediate (NPM1mut with FLT3-ITD AR>0.5 Or NPM1WT with FLT3-ITD AR<0.5), or adverse (NPM1WT with FLT3-ITD AR>0.5)18. 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.