Thiede, C. et al. Additionally, the area under the ROC curve, which serves as an indicator of the diagnostic capacity of the ITD length as a whole, was 0.504. Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in acute myeloid leukemia Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in acute myeloid leukemia Blood Adv. 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? FLT 3-ITD mutations typically were determined using polymerase chain reaction and fragment analyses. B MD Anderson Cancer Center Approach. The median RFS was 1.2years (CI: 02.4) and 0.9years (CI: 0.617.1), respectively (P=0.3). Pulmonary infiltration and acute pneumonitis-like picture are rare (<1%) but noted side effects of midostaurin that treating physicians should be aware of. Lancet Oncol. (A) Overall survival. However, other studies did not find significantly worse clinical outcomes in patients with non-JMD ITD mutations24,25. Lymphoma 54 145 152, S Schnittger 2012 Diversity of the juxtamembrane and TKD1 mutations (Exons 1315) in the FLT3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data Genes Chromosom. Despite the encouraging development of FLT3i, resistance to FLT3i is not uncommon and it can be either primary or secondary. FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) is one of the most frequent mutations found in AML patients. Venetoclax Added to Cladribine, Idarubicin, and Cytarabine with or without a FLT3 Inhibitor in Newly Diagnosed Acute Myeloid Leukemia (EHA, 2020). Naval Daver, Richard F. Schlenk, Mark J. Levis, Alexander E. Perl, Naoko Hosono, Jessica K. Altman, Pierre-Yves Dumas, Emmanuel Raffoux, Christian Rcher, Richard A. Larson, Sumithra J. Mandrekar, Richard M. Stone, Iman Abou Dalle, Ahmad Ghorab, Gautam Borthakur, Ahmad I. Antar, Zaher K. Otrock, Ali Bazarbachi, Roni Shouval, Myriam Labopin, Arnon Nagler, Blood Cancer Journal FLT3 Mutations: Biology and Treatment | Hematology, ASH Education PubMed SORAML, a randomized placebo-controlled trial evaluated the efficacy and tolerability of 3+7 induction-consolidation with or without sorafenib in patients 60 years with newly diagnosed AML, irrespective of a FLT3mut (only 34% had FLT3mut). Juan M. Alonso-Dominguez. Identification of novel FLT3 Asp835 mutations in adult acute myeloid leukaemia. Characteristics and outcome of patients with core binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study. 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. (A) Overall survival. 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. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3internal tandem duplication mutation (SORMAIN). Adult patients with FLT3- ITD mutated AML treated at our institution were identified. and P.M.; Validation, T.C., J.M.A., E.B. Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. 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. Wang, E. S. et al. PubMed Central 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. Emergence of BCR-ABL1 fusion in AML post-FLT3 inhibitor-based therapy: a potentially targetable mechanism of resistancea case series. Only four out of 106 patients had ITD IS in the TKD1 domain. We introduce venetoclax with a ramp-up when the WBC is <10,000/L to decrease the risk of tumor lysis syndrome. 93, E202E205 (2018). Results of venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with acute myeloid leukemia with FLT3 mutations. The median OS was 1.3years (CI: 0.71.9) and 1.4years (CI: 0.91.9), respectively (P=0.9). Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. FLT3-ITD mutations are detected in approximately 25% of newly diagnosed adult acute myeloid leukemia (AML) patients and confer an adverse prognosis. (5) No data regarding minimal residual disease (MRD) were available in our cohort, and MRD data could be interesting to analyze in future studies. 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. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. Therefore, these patients were not included in the analysis stratified by 2010 ELN genetic risk21. Slider with three articles shown per slide. Correspondence to Regardless of the regimen intensity, all clinical trial participants were grouped in a separate treatment category (n=15). & Ley, C., Network CGAR. 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. Stratified KaplanMeier analysis was also employed with the AR and genetic risk, following 2010 ELN guidelines21, as classifiers of the patients. volume11, Articlenumber:20745 (2021) 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. Leukemia 26, 23532359 (2012). Among 14 R/R FLT3mut AML patients, the CRc rate was 64% with FLT3-PCR negativity in 88% of responders. 16, 16911699 (2015). Blood 134, 2564 (2019). We obtained a P value of 0.055 in the analysis of RFS applying the 70bp cutoff. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Cladribine added to daunorubicin-cytarabine induction prolongs survival of FLT3-ITD+ normal karyotype AML patients. 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. FLT3-ITD fragment length analysis was performed in seven centralized PETHEMA laboratories. and P.M.; Supervision, J.M.A. The Impact of FLT3 Mutations on the Development of Acute - Hindawi Google Scholar, MM Patnaik 2018 The importance of FLT3 mutational analysis in acute myeloid leukemia Leuk. (C) OS according to the FLT3-ITD length and allelic ratio. Burchert, A. et al. More studies will be necessary to confirm these results and to shed light on the possible physiopathologic relationship. Am. A total of 164 patients diagnosed with AML-NPM1 included in 2 consecutive CETLAM protocols and with DNMT3A and FLT3 status available were studied. Molecular Diagnostics | FLT3 (ITD and TKD) Mutation Detection Precision Medicine in Myeloid Malignancies: Hype or Hope? FLT3 plays a role in cell survival, proliferation and differentiation of hematopoietic progenitor cells. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. Linch, D. C., Hills, R. K., Burnett, A. K., Khwaja, A. Internet Explorer). Late relapse after hematopoietic stem cell transplantation for acute Abhishek Maiti, M. D. et al. N. Engl. Nevertheless, there are numerous and contradictory manuscripts regarding the prognostic importance of the length and insertion site of the ITD fragment. Due to this, the development of tyrosine kinase inhibitors (TKI) blocking FLT3-ITD became a rational therapeutic concept. Chyla, B. et al. PubMed Diagn. Prognostic impact of low allelic ratio FLT3- ITD and NPM1 mutation in Blood 132, 3944 (2018). Clinical trial enrollment (if available) is always the first option, in both frontline and R/R FLT3mut AML. FLT3 mutation and all but one patient died shortly after FLT3 mutation was acquired. 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). Cell 150, 264278 (2012). Taking into account the great number of comparisons performed, we cannot assume a real relationship between these mutations. A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid Multivariate analysis showed that age < 65 years, FLT3-ITD and CEBPA bZIP in-frame mutation were independent prognostic factors. Zarrinkar, P. P. et al. S.V. We suggest that any investigator who wants to demonstrate the prognostic value of the ITD length applies some of the recurrent published thresholds used in this study or divides his cohort into training and validation subcohorts. Frhling, S. et al. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Among 38 patients with FLT3mut AML who received gilteritinib 120mg daily, the CRc rate was 81.6% (n=31) including 39.5% CR and median OS was not reached at a median follow-up of 35.8 months. 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. Interestingly, FLT3-ITD mutation, which has an adverse prognosis is found in up to one-third of younger patients but only 15-18% in >65 years. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood 128, 449452 (2016). J. Hematol. Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens. 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). Additionally, different subdomains have been highlighted, such as those conferring an adverse outcome9,10. and JavaScript. 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. Whitman, S. P. et al. J. Hematol. (2) Larger studies analyzing ITD length also found no significant results14,23,28. 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%. Cortes, J. et al. 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. Clinical impact of change of FLT3 mutation status in acute myeloid 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. We aimed to study the FLT3 gene mutation profile and prognosis in 139 adult Iranian patients with newly diagnosed AML. Type I FLT3is like gilteritinib are less prone to develop secondary mutations in the TKD, although the gatekeeper F691M can confer resistance to gilteritinib71. However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. It's the most common genetic change in acute myeloid leukemia (AML), a type of leukemia that starts in the bone marrow and. 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 ). We identified 1572 adult (age 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or . (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. Nevertheless, some thresholds have been applied in more than one study [i.e., 39bp and 70bp]11,15,16,17. 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. CAS As Dr. Erba explained, patients with FLT3 -ITD-positive AML represent a particularly poor prognostic group. This value highlights the scarce prognostic value of the measure. In summary, in our population of 161 intensively treated FLT3-ITD AML patients, we did not validate any of the previously published recurrent thresholds of ITD length obtained from smaller series. These data suggests that although responses may still be achieved with gilteritinib in patients refractory to prior first-generation FLT3i-based therapies, optimization with doublet or triplet combinations with second-generation FLT3i is likely needed to significantly improve OS with prior TKI exposure. Variant allele frequency (VAF) is the ratio of ITD-mutated alleles to ITD-mutated+wild-type alleles (FLT3ITD/FLT3ITD+FLT3 wild-type)14. 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. In patients with relapsed or refractory FLT3mut AML (Fig. Analysis of NPM1 and FLT3 Mutations in Patients with Acute Myeloid Am. Kiyoi, H. et al. Daver, N., Venugopal, S. & Ravandi, F. FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm. 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 presence of FLT3-ITD mutation correlates with a high leukemic burden with increased risk of relapse and is recognized to be a driver mutation in patients with AML ( 5 ). Staurosporine, a potent inhibitor of phospholipid Ca++ dependent protein kinase. The impact of prognostic factors may change as the AML treatment landscape evolves. 13, 132 (2020). FLT3 -ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. evaluated the outcomes of sequential FLT3i-based therapies in FLT3mut AML. 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. Ravandi, F. et al. Cite this article. Intensive fludarabine, high dose cytarabine and idarubicin-based induction for younger NPM1-mutated AML patient: overcoming the negative prognosis of FLT3-ITD mutation. However, previous studies have shown that FLT3/ITD mutation was not an independent adverse prognostic factor in DEK/CAN-positive AML patients. CR+CRi rates between groups were compared with a chi-square test. Google Scholar. (3) Findings regarding the relationship between ITD length/site and mutational profile might be interpreted as exploratory given the high number of correlations performed. Lancet Oncol. 21, 12011212 (2020). 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. These results led to the approval of gilteritinib monotherapy in the US and Europe in patients with R/R FLT3mut AML40. Sci Rep 11, 20745 (2021). 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. Blood 124, 273276 (2014). Article Gale, R. E. et al. Venetoclax, FLT3 Inhibitor and Decitabine in FLT3mut Acute Myeloid Leukemia: Subgroup Analysis of a Phase II Trial (ASH, 2020). Blood 130, 723 (2017). 381, 17281740 (2019). Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. 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. (C) OS according to the FLT3-ITD length and allelic ratio. DNA was extracted using automated or manual DNA extraction kits following the manufacturers recommendations. Close Log In. Stone, R. M. et al. For . Additionally, different subdomains of TKD1 (HR or beta1-sheet) have been highlighted as those conferring an adverse outcome10. 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. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. PubMed Central We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . 100, 184198 (2008). In subsequent cycles: FLT3i is continued for the entire duration of the cycle and the venetoclax duration is reduced to 14 days or lower to mitigate cumulative prolonged cytopenias. Front. Blood 130, 566 (2017). (PDF) Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in PDF FLT3-ITD Expression as a Potential Biomarker for the Assessment of Higher daunorubicin exposure benefits FLT3 mutated acute myeloid leukemia. Heart J. Suppl. Pratcorona, M. et al. Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 gene ( FLT3) confer a poor prognosis in adult AML. Midostaurin has been approved and widely used in combination with induction and consolidation therapy in patients with newly diagnosed FLT3mut AML25. 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. and P.M.; Resources, 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.M.C., M.A.S. Blood 130, 721 (2017). or. 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. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Prognostic significance of FLT3-ITD length in AML patients - Nature 368, 20592074 (2013). Quizartinib is also being evaluated in combination with CPX-351 (NCT04209725) and with CLIA (NCT04047641) in treatment naive and R/R FLT3mut 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). The area under the ROC curve (AUC) for OS prediction was 0.504. and JavaScript. The median RFS was 1.2years (CI 0.22.2) and 0.77years (CI 0.51.1), respectively (P=0.06). Jarno Kivioja, Disha Malani, Caroline A. Heckman, Iman Abou Dalle, Ahmad Ghorab, Gautam Borthakur, Frank G. Rcker, Ling Du, Konstanze Dhner, Feng-Ming Tien, Cheng-Hong Tsai, Hwei-Fang Tien, Kun-yin Qiu, Xiong-yu Liao, Dun-hua Zhou, Nikolaus Jahn, Ekaterina Jahn, Konstanze Dhner, Scientific Reports Yilmaz, M. et al. Google Scholar. These data highlight the potent anti-leukemic activity of the triplet approach in FLT3mut AML. Lancet Oncol. 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. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. and JM.A. 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. 3). We continue the venetoclax and FLT3i until Day 21 if the Day 14 bone marrow shows >5% blasts with >/=5% cellularity. Molecular clearance of FLT3 was noted in 50% of all evaluable patients. FLT3ITD mutations in acute myeloid leukaemia - molecular These mutations arearranged in increasing order by FLT3-ITD length. Our median ITD length was 48bp (range=3bp to 231bp), similar to previous studies12,14,17. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Article You are using a browser version with limited support for CSS. and P.M. In the frontline setting (n=4), the CRc rate with the triplet was 100% with FLT3-PCR negativity in all four patients56. The first-generation FLT3is lack specificity for FLT3 and inhibit multiple downstream RTKs that may result in more off-target toxicities. Levis turned to FLT3-ITD mutations in acute myeloid leukemia (AML) to highlight the challenges with targeted therapy. 2-Aminopyrimidine derivatives as selective dual inhibitors of JAK2 and PubMedGoogle Scholar. Therefore, there is a lack of consensus regarding the prognostic importance of the ITD IS and the subdomains that confer this adverse outcome. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 7, e724e736 (2020). 120.000 new AML cases and over . Cortes, J. E. et al. (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. Impact of FLT3-ITD length on prognosis of acute myeloid leukemia Addition of venetoclax to this backbone may be associated with prolonged and potentially prohibitive myelosuppression; we have not routinely added and do not at this time recommend adding venetoclax to the backbone of CLIA/FIA with FLT3i63. Presented in part at the 42nd Annual Meeting of the American Society of Hematology, December 15, 2000, San Francisco, CA (abstract 2334). 2, 3 There are two types of FLT3 mutation, internal tandem duplication of FLT3 ( FLT3-ITD) and tyrosine kinase Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. Andrew, H. et al. Prognostication refinement in NPM1-mutated acute myeloid leukemia stratified by FLT3-ITD status with different induction doses of cytarabine. Blood 100, 43724380 (2002). 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. Rydapt Prescribing Information. 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. We have no explanation regarding the reduced number of patients with an FLT3-ITD inserted in TKD1 found in our cohort. ITD amplicons with a size greater than that of the wild type (3281 bases) were interpreted as positive for the FLT3-ITD mutation. 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). Google Scholar. Hematol. 2, 125 (2020). These observations have made FLT3 an attractive drug target.