J. Hematol. 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. 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. 13, 132 (2020). 17, 721749 (2019). Leukemia 26, 23532359 (2012). 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. 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. Lancet Haematol. Cancer Discov. Gilteritinib with venetoclax (NCT03625505) was evaluated in 41 patients with heavily pretreated R/R FLT3mut AML (median salvage 2, 65% previously exposed to FLT3i)40,53. 10, 588876- (2020). Blood 111, 27762784 (2008). Patterns of resistance differ in patients with acute myeloid leukemia treated with type I versus type II FLT3-inhibitors. Changes in FLT3 mutation status can occur during the course of disease, but the clinical impact of a change is unclear. Cancer Netw. Kayser, S. et al. PCR with fluorescently labeled primers followed by capillary electrophoresis for FLT3-ITD was performed as described elsewhere31. Am. The LACEWING phase III randomized trial evaluated gilteritinib with azacitidine vs azacitidine monotherapy (NCT02752035) in patients with newly diagnosed FLT3mut AML not eligible for intensive induction chemotherapy. 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.. 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). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The landscape of mutations identified by NGS in AML 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? CAS 3 A Survival curves stratified by the presence or absence of FLT3 -ITD and NPM1 mutation for patients younger than 65 years. Among patients treated with azacitidine and quizartinib in the frontline setting, the CRc rate was 78% (n=7/9) with a median OS of 21.1 months. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. evaluated quizartinib (60mg daily) combined with either azacitidine or low-dose cytarabine in patients with newly diagnosed or R/R FLT3mut AML not eligible for intensive chemotherapy. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. 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. A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. We analyzed 118 patients (median age at diagnosis 58.3, range 14.3&ndash . Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. Final results of the chrysalis trial: a first-in-human phase 1/2 dose-escalation, dose-expansion study of gilteritinib (ASP2215) in patients with relapsed/refractory acute myeloid leukemia (R/R AML). 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. Patients with NPM1-/FLT3- showed complex karyotype (24%) and t(8;21) (8%). Blood 134, 2564 (2019). Commun. Sorafenib plus intensive chemotherapy improves survival in patients with newly diagnosed, FLT3-internal tandem duplication mutation-positive acute myeloid leukemia. Gilteritinib decreased the risk of death by 36% compared with salvage chemotherapy, with a median OS of 9.3 months vs 5.6 months (P<0.001), and a superior CR+CRh rate (34% vs 15.3%). Green indicates non-mutated genes, red indicates mutated genes and white indicates non-mutated genes. On the other hand, we obtained a value (0.52) that was close to significant in the analysis of the prognostic impact of the FLT3-ITD AR according to the 2017 ELN cutoff8. 5 e336, S-B Liu 2019 Impact of FLT3-ITD length on prognosis of acute myeloid leukemia Haematologica 104 e9 e12, X Jiang 2018 Influence of FLT3-ITD mutation and length on the treatment response and prognosis in cytogenetically normal AML patients Blood 132 5245 5245, C Allen 2013 The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia Leukemia 27 1891 1901, X Quan J Deng 2020 Core binding factor acute myeloid leukemia: Advances in the heterogeneity of KIT, FLT3, and RAS mutations (Review) Mol. Correspondence to In the frontline setting, there was a sequential decrease in CRc rates (77%31%25%) and OS (16.76.01.4 months). Off-target resistance includes clonal evolution during FLT3i therapy even when FLT3-ITDmut clone is lost70. J. Natl Cancer Inst. 90, 276281 (2015). Methods: We determined the status of ITD and TKD mutations using fragment analysis and the polymerase chain reaction-restriction fragment polymorphism method, respectively. volume11, Articlenumber:104 (2021) Blood 93, 30743080 (1999). Increase in bilirubin and transaminase can be seen with giltertiinib but are usually self-resolving and transient. Hematol. 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. The insertion site was analyzed in 106 AML patients with the FLT3-ITD mutation. AR,allelic ratio. Background and aims: To explore the relationship between FLT3 (encoding Fms related tyrosine kinase 3) internal tandem duplication (ITD) mutations with the prognosis of acute promyelocytic leukemia. 2A). These observations have made FLT3 an attractive drug target. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. Compr. DiNardo, C. D. et al. Arsenic trioxide (ATO, As2O3) has been proven effective in treating acute promyelocytic leukemia (APL) and has shown activity in some cases of refractory and . Decitabine combined with medium-dose cytarabine in the treatment of DEK DNA was extracted using automated or manual DNA extraction kits following the manufacturers recommendations. Prognostic significance of baseline FLT3ITD mutant allele level in Tamaoki, T. et al. 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. 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. Schlenk, R. F. et al. Full article: Advances in the drug therapies of acute myeloid leukemia Cortes, J. et al. Statistical analyses were performed with SPSS 19.0 (IBM, Armonk, NY). Thank you for visiting nature.com. Minetto, P. et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3internal tandem duplication status. J. Hematol. Yamamoto, Y. et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. 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 . Rydapt Prescribing Information. Prognostic significance of FLT3-ITD length in AML patients - Nature Molecular clearance of FLT3 was noted in 50% of all evaluable patients. PubMed Hematology. 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. ___ Molecular landscape and prognostic impact of FLT3-ITD - Nature (2) Larger studies analyzing ITD length also found no significant results14,23,28. Upregulation of Bcl-2 confers resistance to FLT3 inhibition in FLT3-ITD AML with secondary acquired mutations. Thiede, C. et al. 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). J. Hematol. (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain 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. However, emerging data does suggest that patients with FLT3-ITDmut AR<0.5 and NPM1 co-mutation without concurrent high-risk mutations such as DNMT3A, TP53, TET2, or high-risk cytogenetics may be a more favorable subset, who may be considered for induction, consolidation followed by maintenance therapy without ASCT on a case by case basis if they achieve early MRD negativity using a highly sensitive MRD assay. 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. FLT3 -ITD mutations occur in the form of a replicated sequence in the juxtamembrane domain (JMD) and/or TKD1 of the FLT3 gene. Biochem. Blood 100, 23932398 (2002). The clinical significance of FLT3 ITD mutation on the prognosis of Br. 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. Nevertheless, in three patients, similar VAFs (<5% difference) were detected, which might indicate that these mutations occurred at the same timepoint as the FLT3 mutation.No significant differences were found between the ITD length and the mutational status of any of the remaining genes (Fig. 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. Alotaibi, A. S. et al. Enter the email address you signed up with and we'll email you a reset link. Unlike midostaurin, quizartinib monotherapy, even at lower doses demonstrated significant marrow remissions in R/R FLT3mut AML35,36,37. Moreover, we performed an analysis of the correlation of FLT3-ITD length and insertion sites with the mutational landscape of AML, which has not been carried out thus far. Google Scholar. AML patients with FLT3-ITD mutations show an increased relapse rate, reduced disease-free survival (DFS), and decreased long-term survival, while the rate of complete remission (CR) after induction chemotherapy is not significantly affected6,7. Oran, B. et al. Yalniz, F. et al. is a PhD candidate at Universidad Autnoma de Madrid (UAM). Close Log In. Due to the preliminary nature of the . 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. and P.M.; Supervision, J.M.A. 31, 3681 (2013). Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. 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. A Conventional approach. Molecular Diagnostics | FLT3 (ITD and TKD) Mutation Detection 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. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. and P.M.; Visualization, T.C., J.M.A., D.L., J.S. J. Med. CAS Role of Biomarkers in the Management of Acute Myeloid Leukemia NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 Chinese patients with de novo acute myeloid leukemia. Nevertheless, the short duration of remission with single-agent FLT3is in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3is remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML. Which FLT3 Inhibitor for Treatment of AML? Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability. Schlenk et al. In sensitivity analysis, no significant . Given the magnitude of OS benefit and concerns over therapeutic equipoise and potential cardiac safety signals, quizartinib was not approved in the US and Europe, but approved in Japan as a monotherapy in R/R FLT3-ITDmut AML. 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 . Internet Explorer). Ninety-eight patients had ITD insertion sites in the JMD domain (JM-B, n=6; JM-S, n=42; JM-Z, n=43; and hinge region (HR), n=7), four patients had ITD insertion sites in the TKD1 domain (beta1-sheet, n=1; beta2-sheet, n=1; and nucleotide binding loop (NBL), n=2) and four patients had ITD insertion sites in the extracellular domain (ED) (Fig. Additionally, different subdomains of TKD1 (HR or beta1-sheet) have been highlighted as those conferring an adverse outcome10. To mitigate prolonged myelosuppression with the triplet and avoid over-treatment, we perform an early bone marrow assessment on Cycle 1 Day 14 (Fig. Konopleva, M. et al. https://doi.org/10.1038/s41408-021-00495-3, DOI: https://doi.org/10.1038/s41408-021-00495-3. 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. Our real-life cohort was composed of 362 patients, most of whom were not included in clinical trials. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in However, a subsequent UKMRC study of 1600 patients with cytogenetic intermediate-risk AML showed that relapse risk did not differ based on the FLT3-ITDmut AR, and that the cumulative incidence of relapse in patients with NPM1mut was increased with a concurrent FLT3-ITDmut irrespective of the AR19. Biao Wang, X. Hua, Jihong Zhang, Weiying Gu . Blood 125, 32363245 (2015). Precision Medicine in Myeloid Malignancies: Hype or Hope? 93, 213221 (2018). H Dhner 2010 Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet Blood 115 453 474, S Kayser 2009 Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome Blood 114 2386 2392, FG Rcker 2021 Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results Leukemia 2021 1 10, O Blau R Berenstein A Sindram IW Blau 2013 Molecular analysis of different FLT3-ITD mutations in acute myeloid leukemia Leuk. Daver, N., Venugopal, S. & Ravandi, F. FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm. FLT3-ITD has been strongly associated with a bad prognosis, leukocytosis, high blast counts, increased risk of relapse and shorter overall survival. Whitman, S. P. et al. FLT3 -ITD has a poor prognostic impact in patients with AML at diagnosis. Slider with three articles shown per slide. 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. It's the most common genetic change in acute myeloid leukemia (AML), a type of leukemia that starts in the bone marrow and. 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. Am. Kiyoi, H., Ohno, R., Ueda, R., Saito, H. & Naoe, T. Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. 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). Maintenance therapy for FLT3-ITD -mutated acute myeloid leukemia Rollig, C. et al. evaluated midostaurin with azacitidine in patients with both newly diagnosed and R/R AML regardless of FLT3 mutational status. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . Further evaluation and optimization of triplets is a major area of clinical research focus in FLT3mut AML. FLT3 Gene Mutation Profile and Prognosis in Adult Acute - PubMed Blood 128, 1069 (2016). No statistically significant differences were found (P=0.8) (Fig. Both mutations lead to the activation of downstream proliferation cascades [ 19, 20 ]. 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). Regrettably, patients with information on the IS of ITD available had received different treatments: intensive chemotherapy, n=37; non-intensive therapy, n=14; clinical trials, n=6; and best supportive care, n=2. Cancer 125, 37553766 (2019). FLT3 is a gene change, or mutation, in leukemia (blood cancer) cells. Lancet Oncol. Timothy, J. Wang, E. S. et al. FLT3 -ITD is located within exon 14, corresponding to JMD,. Zhu, R., Li, L., Nguyen, B., Duffield, A. S. & Small, D. Gilteritinib and venetoclax synergize to eliminate FLT3/ITD+ leukemia cells through BIM. https://doi.org/10.1038/s41598-021-00050-x, DOI: https://doi.org/10.1038/s41598-021-00050-x. Article 11, 104 (2021). Larger studies of ITD size, although they did not employ these cutoffs, did not find prognostic power of this measure, which corroborates our results. For post-ASCT maintenance, our agent of choice has been gilteritinib 80120mg day either as a single agent or combined with low-dose azacitidine. Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. Regardless of the regimen intensity, all clinical trial participants were grouped in a separate treatment category (n=15). Am. Blood 128, 1639 (2016). The median OS was 1.3years (CI 0.71.9) and 1.4years (CI 1.01.8), respectively (P=0.8). Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Blood 128, 449452 (2016). Correspondence to Enter the email address you signed up with and we'll email you a reset link. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. N. Engl. 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. Prognostication refinement in NPM1mutated acute myeloid leukemia Previously published cutoffs of ITD length, reported in more than one publication(i.e., 39bp and 70bp), were tested to check their applicability in our cohort. Cortes, J. E. et al. J. Med. 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. The impact of prognostic factors may change as the AML treatment landscape evolves. 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. 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). The FLT3-ITD patient had trisomy 8. Samples from 118 of the 362 AML patients with FLT3-ITDmutations were analyzed with an NGS panel of 39 genes (see Supplementary Fig. CAS J. Clinl. The authors declare no competing interests. Oncol. 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. 2, 125 (2020). An FLT3/ITD mutation was present in 27% of the patients and was associated with leukocytosis and a high percentage of bone marrow blast cells (P <.001 for both). The median RFS was 1.2years (CI: 02.4) and 0.9years (CI: 0.617.1), respectively (P=0.3). Article 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. Among 161 intensively treated patients, 123 had the cytogenetic and molecular information required to calculate the 2010 ELN classification21. J. Med. Blood 135, 791803 (2020). evaluated the outcomes of sequential FLT3i-based therapies in FLT3mut AML. and P.M.; Data curation, J.M.A. Blood 110, 12621270 (2007). Clinical outcome stratified according to the FLT3-ITD length (cutoff 39bp) for all patients treated with intensive chemotherapy. contracts here. The FLT3-ITD allelic ratio has clear prognostic value. Oncol. 4). Andrew, H. et al. Article Gilteritinib was generally well tolerated but was associated with increased incidence of gastrointestinal side effects, most frequently diarrhea although nausea has been occasionally observed.
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