Off-target resistance includes clonal evolution during FLT3i therapy even when FLT3-ITDmut clone is lost70. Midostaurin is a type I FLT3i active against PDGFR, KIT, SRC, and other RTKs22,23. In the meantime, to ensure continued support, we are displaying the site without styles 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. CAS Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. 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. Blood 121, 46554662 (2013). 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). We used the 0.5 cutoff of the AR as recommended by the 2017 ELN guidelines8.These patients were divided on the basis of the FLT3-ITD AR into an FLT3-ITDLOWgroup (41%; n=58) and an FLT3-ITDHIGHgroup (59%; n=82). 93, 213221 (2018). Alotaibi, A. S. 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. This value highlights the scarce prognostic value of the measure. Mutations of SF3B1, EZH2 and WT1 seem to be a more ancestral event than FLT3 mutations, as expected, given the VAF of the genes. The median OS was 1.3years (CI: 0.71.9) and 1.4years (CI: 0.91.9), respectively (P=0.9). Among 161 intensively treated patients, 123 had the cytogenetic and molecular information required to calculate the 2010 ELN classification21. (B) Relapse-free survival. 377, 454464 (2017). FLT3 -ITD is located within exon 14, corresponding to JMD,. 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 . Burchert, A. et al. The landscape of mutations identified by NGS in AML patients. and P.M.; Visualization, T.C., J.M.A., D.L., J.S. Gale, R. E. et al. Zhang, W. et al. Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. 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). 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. Among 729 AML patients with FLT3-ITD mutations included in the PETHEMA AML epidemiologic registry between 2003 and 2019, FLT3-ITD length was available in 362: 188 males and 174 females; median age of 60.8years (range 17.191.4years). 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 . The FLT3-ITD patient had trisomy 8. 5, 6 The FLT3 gene is a member of the class III receptor tyrosine kinase family, including c-kit, c-fms, and the platelet-derived growth factor receptors. Statistically significant results were not observed for any other gene in this analysis. S1. contracts here. Prognostic impact analyses of FLT3-ITD length were performed among patients treated with upfront IC regimens. 381, 17281740 (2019). Blood 127, 360362 (2016). Slider with three articles shown per slide. J. Hematol. Soc. Linch, D. C., Hills, R. K., Burnett, A. K., Khwaja, A. 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. FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML. 5).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). Interestingly, all patients with an FLT3-ITD inserted in the TKD1 domain showed DNMT3A mutations. 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 . We continue the venetoclax and FLT3i until Day 21 if the Day 14 bone marrow shows >5% blasts with >/=5% cellularity. A total of 164 patients diagnosed with AML-NPM1 included in 2 consecutive CETLAM protocols and with DNMT3A and FLT3 status available were studied. Mali, R. S. et al. 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). Secondary mutations as mediators of resistance to targeted therapy in leukemia. Juan M. Alonso-Dominguez. However, whether these findings are specific to Ven + HMA therapy remains to be . The two leading types of FLT3 mutations found in AML include internal tandem duplications in the juxtamembrane domain (ITD, 17-34%) and mutations in the tyrosine kinase domain (TKD) activation loop (~7%) ( 1 ). J. Clin. Complete response (CR) or complete responses with incomplete hematologic recovery (CRi) were defined according to current 2017 ELN guidelines8. 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. Such sequential approaches need to be formally evaluated in the context of prospective clinical trials. Blood 130, 721 (2017). 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. It's the most common genetic change in acute myeloid leukemia (AML), a type of leukemia that starts in the bone marrow and. N. Engl. In the absence of clinical trial options: among patients eligible for intensive chemotherapy who had a prior remission >1012 months, we would prefer a regimen incorporating intensive therapy (FLAG-Ida, CLAG-M, CLIA, MEC) in combination with a FLT3 inhibitor with an intent to achieve a rapid and hopefully deep remission and transition patients to ASCT followed by post-ASCT maintenance. Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). Compr. Finally, a different report showed worse clinical outcomes in terms of OS and DFS in the TKD1 group. Blood 135, 791803 (2020). 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. or. In 40 patients (87%), the prognosis based on the ELN 2017 risk stratification algorithm did not change due to AR, whereas, in 6 patients (13%), the FLT3-ITD mutation burden was <0.5 in DNA and 0.5 in cDNA, which changed their risk stratification. Blood 124, 273276 (2014). Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. DiNardo, C. D. 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. 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. Sorafenib plus intensive chemotherapy improves survival in patients with newly diagnosed, FLT3-internal tandem duplication mutation-positive acute myeloid leukemia. Enter the email address you signed up with and we'll email you a reset link. Clinical outcome stratified according to the FLT3-ITD length (cutoff 39bp) for all patients treated with intensive chemotherapy. NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 Chinese patients with de novo acute myeloid leukemia. NGS, next-generation sequencing. 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. 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. 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). Perl and colleagues investigated whether prior FLT3i therapy influenced outcomes in patients treated with gilteritinib. Libura, M. et al. Acute myeloid leukemia, Version 3.2019, NCCN clinical practice guidelines in oncology. Google Scholar. We studied theFLT3-ITD length of 362 adult AML patients included in the PETHEMA AML registry. Intensive fludarabine, high dose cytarabine and idarubicin-based induction for younger NPM1-mutated AML patient: overcoming the negative prognosis of FLT3-ITD mutation. Conceptualization, T.C., J.M.A., E.B. Password. . Blood 121, 27342738 (2013). If C1 D28 marrow confirms remission and ANC<0.5 and/or platelet<50K consider interrupting FLT3i and using neupogen to enhance count recovery. Besides FLT3-ITD MRD, only a high white blood cell count and late CR appeared to be independently associated with relapse and OS. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). and JavaScript. Moreover, ASCT in CR1 only benefitted patients with isolated FLT3-ITDmut (without NPM1mut) irrespective of AR (P<0.05)21. 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 . Leukemia 26, 23532359 (2012). Nevertheless, there are numerous and contradictory manuscripts regarding the prognostic importance of the length and insertion site of the ITD fragment. 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%. 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. 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+ . 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. Res. Clinical outcome stratified according to the FLT3-ITD length (cutoff 70bp) for all patients treated with intensive chemotherapy. Clin. Hematol. First, 161 AML patients with FLT3-ITD mutations treated with IC were analyzed using 39bp as the cutoff (<39bp; n=48,39bp; n=113). Our median ITD length was 48bp (range=3bp to 231bp), similar to previous studies12,14,17. Intensive chemotherapy regimens were administered to 161 patients (idarubicin+cytarabine; 3+7, n=151 and 2+5, n=8; IDA-FLAG (fludarabine+Ara-C+idarubicin), n=1 and FLAG, n=1). The origin and evolution of mutations in acute myeloid leukemia. Changes in FLT3 mutation status can occur during the course of disease, but the clinical impact of a change is unclear. An alternate option would be to consider sequencing with alternate cycles of HMA with venetoclax and HMA with FLT3i. Nevertheless, we also performed an analysis with the median ITD length of our cohort (48bp). Slider with three articles shown per slide. Despite the encouraging development of FLT3i, resistance to FLT3i is not uncommon and it can be either primary or secondary. The insertion site was analyzed in 106 AML patients with the FLT3-ITD mutation. 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. 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. evaluated the impact of AR in 323 patients with newly diagnosed FLT3-ITDmut 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. Given the increasing importance that massive sequencing techniques are acquiring in the prognosis determination and therapeutic management of AML patients, we decided to study the possible correlation between the length or site of the insertion of the mutated ITD fragment and the mutational profile of these patients. Google Scholar. 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). J. Med. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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. AR,allelic ratio. Molecular clearance of FLT3 was noted in 50% of all evaluable patients. Sci Rep 11, 20745 (2021). The combination continues to enroll. Adult patients with FLT3- ITD mutated AML treated at our institution were identified. Hematology. 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). Nakao, M. et al. Swaminathan, M. et al. Yilmaz et al. PubMed 3 A Survival curves stratified by the presence or absence of FLT3 -ITD and NPM1 mutation for patients younger than 65 years. In sensitivity analysis, no significant . Mechanistically, FLT3-ITDs and FLT3-TKDs induce activation of transduction intermediates, including STAT5, AKT, and ERK1/2 ( 2 ). 2, 3 There are two types of FLT3 mutation, internal tandem duplication of FLT3 ( FLT3-ITD) and tyrosine kinase 61, 72337239 (2001). Cortes, J. E. et al. Unlike midostaurin, quizartinib monotherapy, even at lower doses demonstrated significant marrow remissions in R/R FLT3mut AML35,36,37. 11, 104 (2021). The AR was determined by fragment length analysis and calculated as previously described32. These mutations arearranged in increasing order by FLT3-ITD length. Castao-Bonilla, T., Alonso-Dominguez, J.M., Barragn, E. et al. Levis turned to FLT3-ITD mutations in acute myeloid leukemia (AML) to highlight the challenges with targeted therapy. Stratified KaplanMeier analysis was also employed with the AR and genetic risk, following 2010 ELN guidelines21, as classifiers of the patients. Type I FLT3is like gilteritinib are less prone to develop secondary mutations in the TKD, although the gatekeeper F691M can confer resistance to gilteritinib71. 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. Maiti et al. The primary and key secondary trial end points were OS and RFS, respectively, both measured from the time of randomization. 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. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf2017 (2017). Remember me on this computer. 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. FLT3 is a gene change, or mutation, in leukemia (blood cancer) cells. 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. 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. PubMedGoogle Scholar. Taken together, utilizing baseline FLT3-ITDmut AR to guide the post-remission therapy remains controversial. 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 Additionally, different subdomains of TKD1 (HR or beta1-sheet) have been highlighted as those conferring an adverse outcome10. Internet Explorer). Altman, J. K. et al. Google Scholar. Characteristics and outcome of patients with core binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study. FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) is one of the most frequent mutations found in AML patients. Pratcorona, M. et al. As more potent FLT3 inhibitors are developed, additional acquired point mutations have been identified, commonly at . Article Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. In older patients not eligible for intensive therapy, patients with primary refractory disease or early relapse with a persistent FLT3 mutation we would suggest gilteritinib based therapy. 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. PubMed 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. Am. 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. Cladribine added to daunorubicin-cytarabine induction prolongs survival of FLT3-ITD+ normal karyotype AML patients. 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. 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. Second-generation FLT3is potently and specifically target FLT3 with fewer off-target effects. Br. PubMed We introduce venetoclax with a ramp-up when the WBC is <10,000/L to decrease the risk of tumor lysis syndrome. 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. Therefore, only 3.8% of the patients showed an FLT3-ITD insertion in the TKD1 domain. The addition of sorafenib significantly improved the event-free survival (EFS; 21 months vs 9 months; P=0.013) and RFS (56% vs 38%), but not OS28, although a recent update suggested an emerging trend toward improved OS29. Log in with Facebook Log in with Google. J. Med. 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. Google Scholar. As we have already explained, our main goal was to validate two previous recurrently applied cutoffs: 39bp and 70bp. 17, 721749 (2019). All samples investigated in this study were obtained at the time of diagnosis. 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). Yamamoto, Y. et al. Further evaluation and optimization of triplets is a major area of clinical research focus in FLT3mut AML. We aimed to assess the prognostic impact of these variables on the complete remission (CR) rates, overall survival (OS) and relapse-free survival (RFS) of AML patients withFLT3-ITDmutations. 13, 139 (2020). 2018 Oct 23;2 (20):2744-2754. doi: 10.1182/bloodadvances.2018020305. (A) Overall survival. 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. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Hematology Department, Hospital Universitario Fundacin Jimnez Daz, Avenida Reyes Catlicos, 2, 28040, Madrid, Spain, Tamara Castao-Bonilla,Juan M. Alonso-Dominguez,Carlos Blas&Jose L. Lpez-Lorenzo, Instituto de Investigacin Sanitaria (IIS-FJD), Hospital Universitario Fundacin Jimnez Daz, Madrid, Spain, Tamara Castao-Bonilla,Juan M. Alonso-Dominguez,Carlos Blas,Jose L. Lpez-Lorenzo,Daniel Lainez-Gonzalez&Juana Serrano, Hematology Department, Hospital Universitario La Fe de Valencia, Valencia, Spain, Eva Barragn,Rebeca Rodrguez-Veiga,Claudia Sargas,David Martnez-Cuadrn,Miguel A. Sanz&Pau Montesinos, Hematology Department, Hospital General de Alicante, Alicante, Spain, Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain, Hematology Department, Hospital General de Castelln, Castelln, Spain, Hematology Department, Hospital Universitario Doce de Octubre, Complutense University, CNIO, Madrid, Spain, Molecular Biology Department, Cimalab Diagnosis, Clnica Universitaria de Navarra, Navarra, Spain, Hematology Department, Hospital Universitario Clnico San Carlos, Medicine Department, UCM, Madrid, Spain, Hematology Department, Hospital Universitario de Valladolid, Valladolid, Spain, Hematology Department, Hospital Universitario Ro Hortega, Valladolid, Spain, Hematology Department, Hospital Universitario Virgen del Roco, Instituto de Biomedicina de Sevilla (IBIS/CISC/CIBERON), Sevilla, Spain, Hematology Department, Hospital Universitario de Burgos, Burgos, Spain, Hematology Department, Hospital Ntra.