Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML. Although the triplet approaches are still in development, emerging data with the triplets as discussed previously, suggest rapid and high potency, deep molecular remissions, and encouraging survival. Blood Cancer J. Acute myeloid leukemia, Version 3.2019, NCCN clinical practice guidelines in oncology. 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. AR is defined as the ratio of ITD-mutated alleles to wild-type allele (FLT3ITD/FLT3 wild-type)13. B MD Anderson Cancer Center Approach. Article Eur. Am. 5 96 102, C Sargas 2020 Networking for advanced molecular diagnosis in acute myeloid leukemia patients is possible: The PETHEMA NGS-AML project Haematologica https://doi.org/10.3324/haematol.2020.263806, Article FLT3 testing was historically viewed as being purely prognostic; however, with the advent of FLT3 inhibitors, it will likely be seen as both prognostic and predictive. Sorafenib with azacitidine combination reported an overall response rate (ORR) of 78% (n=27) in the frontline patients not eligible for intensive induction31 and an ORR of 46% with an acceptable safety profile in R/R FLT3-ITDmut 32 which led to the inclusion of sorafenib with azacitidine combination as a 2B guideline in National Comprehensive Cancer Network (NCCN) for R/R FLT3-ITDmut AML33. Article First, 161 AML patients with FLT3-ITD mutations treated with IC were analyzed using 39bp as the cutoff (<39bp; n=48,39bp; n=113). Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. 1,2 Real-time pCR, which has . The AR was determined by fragment length analysis and calculated as previously described32. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. 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. Email. Gilteritinib was generally well tolerated but was associated with increased incidence of gastrointestinal side effects, most frequently diarrhea although nausea has been occasionally observed. 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. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. 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. CAS Canc. NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 Chinese patients with de novo acute myeloid leukemia. Naval Daver, M. D. et al. 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). Welch John, S. et al. FLT3 is a receptor tyrosine kinase that is involved in regulating proliferation of hematopoietic progenitor cells. Prognostic significance of baseline FLT3-ITD mutant allele level in acute myeloid leukemia treated with intensive chemotherapy with/without sorafenib. Patients with NPM1-/FLT3- showed complex karyotype (24%) and t(8;21) (8%). Lancet Oncol. Article Although the toxicity-related discontinuation rate was low (22%), sorafenib-treated patients did experience higher rates of graft-versus-host disease (GVHD) and skin toxicity42. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Am. A Conventional approach. 3). Among 161 intensively treated patients, 123 had the cytogenetic and molecular information required to calculate the 2010 ELN classification21. 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. These results led to the approval of gilteritinib monotherapy in the US and Europe in patients with R/R FLT3mut AML40. Blood 135, 791803 (2020). In those patients with more than one ITD mutation, only the longest mutation was selected for statistical analysis (10 patients had>1 ITD mutation). DNA quantification was performed with a Nanodrop (Thermo Fisher Scientific, Waltham,MA) or Qubitfluorometer (Thermo Fisher Scientific, Waltham, MA). 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. 17, 721749 (2019). 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). S1. Encouragingly, the response rate was maintained among patients previously exposed to other FLT3 TKIs. FLT3 -ITD is located within exon 14, corresponding to JMD,. Prognostic impact analyses of FLT3-ITD length were performed among patients treated with upfront IC regimens. Haematologica 106, 1034 (2020). Pratcorona, M. et al. Lancet Haematol. Blood 132, 598607 (2018). 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). Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. 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. J. Med. In the frontline setting, there was a sequential decrease in CRc rates (77%31%25%) and OS (16.76.01.4 months). 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. and P.M. PubMed 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). 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. Google Scholar. ; Writingreview and editing, J.M.A., E.B., R.R.V., C.S., C.G., M.C.C., M.B.V., R.G., J.M.L., R.M.A., M.J.L., E.A., R.C., A.C., E.C., E.S.S., J.L., I.R., L.A., C.R.M., C.B.S., J.A.L.L., J.S., E.C., M.J.S., M.T.O., J.S.G., M.M., C.B., J.L.L.L., D.L., J.S., D.M.C., M.A.S. Therefore, only 3.8% of the patients showed an FLT3-ITD insertion in the TKD1 domain. Blood 100, 43724380 (2002). 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. PubMed evaluated the outcomes of sequential FLT3i-based therapies in FLT3mut AML. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. 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. Hematol. (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. The FLT3-ITD allelic ratio has clear prognostic value. 15, 17 In our cohort, the prevalence of FLT3-ITD mutation of de novo AML patients was 21.5%. 7+37 days of cytarabine and 3 days of daunorubicin. PubMed Recurrent somatic internal tandem duplications (ITD) in the FMS-like tyrosine kinase 3 (FLT3) gene characterise approximately one third of patients with acute myeloid leukaemia (AML), and FLT3-ITD mutation status guides risk-adapted treatment strategies.The aim of this work was to characterise FLT3-ITD variant distribution in relation to molecular and clinical features, and overall survival in . The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in a credit line to the material. Taken together, utilizing baseline FLT3-ITDmut AR to guide the post-remission therapy remains controversial. 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 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). As Dr. Erba explained, patients with FLT3 -ITD-positive AML represent a particularly poor prognostic group. Internet Explorer). Emergence of BCR-ABL1 fusion in AML post-FLT3 inhibitor-based therapy: a potentially targetable mechanism of resistancea case series. Lymphoma 59 2273 2286, S Schnittger 2002 Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: Correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease Blood 100 59 66, M Levis 2013 FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Off-target resistance includes clonal evolution during FLT3i therapy even when FLT3-ITDmut clone is lost70. J. Haematol. Google Scholar. 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. A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. Diagn. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. In patients 55 years, this regimen appeared to overcome the negative impact of FLT3-ITDmut in NPM1 co-mutated patients, regardless of the FLT3 AR, with comparable 3-year OS rates of 64% and 68% in FLT3-ITDmut NPM1mut and FLT3-ITDWT NPM1mut patients, respectively (P>0.05). Moreover, ASCT in CR1 only benefitted patients with isolated FLT3-ITDmut (without NPM1mut) irrespective of AR (P<0.05)21. and P.M.; Methodology, T.C., J.M.A., E.B., R.R.V., C.S., C.G., M.C.C., M.B.V., R.G., J.M.L., R.M.A., M.J.L., E.A., R.C., A.C., E.C., E.S.S., J.L., I.R., L.A., C.R.M., C.B.S., J.A.L.L., J.S., E.C., M.J.S., M.T.O., J.S.G., M.M., C.B., J.L.L.L., D.L., J.S., D.M.C., M.A.S. 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. Pratz, K. W. 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 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. The favorable prognostic molecular mutations, such as NPM-1 and CEBPA, are uncommon in elderly AML . 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). Hematol. Enter the email address you signed up with and we'll email you a reset link. The main patient and disease characteristics were collected retrospectively, including demographic characteristics (age, sex), cytomorphologic assessments confirming the AML diagnosis (according to routine site practice), cytogenetics, molecular studies, first-line treatment approach, disease response assessment and disease follow-up. 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. In the R/R setting, the CRc rate was 64% (n=18/28) with a median OS of 12.0 months, with responses observed even in prior FLT3i exposed patients48. FLT3 -ITD has a poor prognostic impact in patients with AML at diagnosis. The Spanish group evaluated intermediate-risk AML patients treated with intensive chemotherapy. 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. 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. . We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . PubMed Central However, the median OS was 19.2 months in FLT3-TKDmut AML (19.2 months), but only 11.5 months in FLT3-ITDmut patients65. Quizartinib is also being evaluated in combination with CPX-351 (NCT04209725) and with CLIA (NCT04047641) in treatment naive and R/R FLT3mut AML. No statistically significant differences were found (P=0.8) (Fig. 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. Enter the email address you signed up with and we'll email you a reset link. The non-intensive chemotherapy group received FLUGA (fludarabine+Ara-C), n=22; azacytidine, n=15; and decitabine, n=5, and one patient was treated with IDA-FLAG-Lite. Blood 130, 723 (2017). 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. 2, 125 (2020). In our experienced cases FLT3-ITD mutation in MDS showed shorter duration to AML transformation and very poor prognosis. T.C. Google Scholar. 31, 3681 (2013). Cancer Discov. Regardless of the regimen intensity, all clinical trial participants were grouped in a separate treatment category (n=15). B MD Anderson Cancer Center Approach. Patients diagnosed with acute promyelocytic leukemia (APL) were excluded. 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. QuANTUM-R, a phase 3 randomized controlled trial, evaluated quizartinib monotherapy vs investigator choice salvage chemotherapy in R/R FLT3-ITDmut AML. Castao-Bonilla, T., Alonso-Dominguez, J.M., Barragn, E. et al. Blood 130, 566 (2017). Hematol. Mead, A. J. et al. Furthermore, ten patients with mutated WT1 showed a median ITD length of 77bp,and 58 patients with non-mutated WT1 showed a median ITD length of 42bp (P=0.021). Abhishek Maiti, M. D. et al. 4), diligent effort must be made to refer the patient to large academic centers with clinical trial options as the outcomes remain dismal with a median OS<10 months with almost any approach. volume11, Articlenumber:20745 (2021) Stratified KaplanMeier analysis was also employed with the AR and genetic risk, following 2010 ELN guidelines21, as classifiers of the patients. Google Scholar. prospectively evaluated decitabine and quizartinib (doublet) with or without venetoclax (triplet) in patients with newly diagnosed and R/R FLT3-ITDmut AML. Midostaurin is a type I FLT3i active against PDGFR, KIT, SRC, and other RTKs22,23. Informed consent was a requisite for patients alive at the time of data lock (January 2019). 135, 397402 (1986). Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models. Zhang, W. et al. Nakao, M. et al. Additionally, different subdomains have been highlighted, such as those conferring an adverse outcome9,10. Timothy, J. Strati et al. 1A). 1B) we add a second generation FLT3i to the intensive induction backbone of cladribine or fludarabine with cytarabine and idarubicin (CLIA or FIA, respectively) as published previously by our group61,62. Weisberg, E. et al. 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 . Updated results from long-term follow-up of the randomized-controlled SORAML trial. 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. Oran et al. Blood 127, 360362 (2016). 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. Oncol. To obtain Wang, E. S. et al. 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]. FLT3-ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. Blood 136, 3233 (2020). @Repeat a C1 D28 bone marrow on all patients to confirm remission. Souki Cancer Research Fund and generous philanthropic contributions to the MD Anderson Moon Shots Program.