A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. DiNardo, C. D. et al. If material is not included in the articles Creative Commons license 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 identified 1572 adult (age 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or . 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. 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 . DNA quantification was performed with a Nanodrop (Thermo Fisher Scientific, Waltham,MA) or Qubitfluorometer (Thermo Fisher Scientific, Waltham, MA). (A) Overall survival. 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). 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. 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. CNS Relapse in Acute Promyeloctyic Leukemia - academia.edu 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 Sorafenib is a first generation, type II multi-kinase FLT3i26 that demonstrated safety and efficacy (14/15 CR) in combination with the standard anthracycline/cytarabine induction therapy in newly diagnosed FLT3mut AML27. FLT 3-ITD mutations typically were determined using polymerase chain reaction and fragment analyses. MRD detection in AML leverages cutoff points garnered from various detection methods include flow cytometry or real-time quantitative polymerase chain reaction (pCR). 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. 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. or. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3internal tandem duplication mutation (SORMAIN). FLT3 -ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. 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. Blood 97, 24342439 (2001). While the seven patients treated with the doublet had a CRc rate of 57% (n=4/7) and a median OS of 5.7 months, the fifteen R/R FLT3mut AML patients treated with the triplet had a CRc rate of 81% (n=11) with a projected 1-year OS of 60%. Cancer Res. Fms-like tyrosine kinase 3 (FLT3) is a recurrent genetic abnormality in AML (~30%)1,2,3. Pratcorona, M. et al. FLT3-ITD length was compared between mutation and wild-type groups for each of the 39 genes using a MannWhitney test. Hematol. 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. No significant difference was found between acute myeloid leukemia patients with these and P.M. Blood 130, 566 (2017). Am. The on-target mechanism of resistance includes emergence of secondary TKD mutations in patients treated with type II inhibitors like quizartinib or sorafenib69,70. 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). 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. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Prognostic relevance of FLT3-TKD mutations in AML: the combination ITD amplicons with a size greater than that of the wild type (3281 bases) were interpreted as positive for the FLT3-ITD mutation. Cancer Discov. 2, 125 (2020). Maiti et al. In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene ( FLT3- ITD) are associated with poor prognosis. 7+37 days of cytarabine and 3 days of daunorubicin. FLT3 is a receptor tyrosine kinase that is involved in regulating proliferation of hematopoietic progenitor cells. 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. Targeting FLT3 mutations in AML: review of current knowledge and Swaminathan et al. 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’ outcomes when receiving an allogeneic hematopoietic stem cell transplantation (HSCT). (A) Overall survival. Moreover, ASCT in CR1 only benefitted patients with isolated FLT3-ITDmut (without NPM1mut) irrespective of AR (P<0.05)21. Oncol. However, these studies did not apply previously validated ITD length cutoffs obtained in other smaller series11,15,16,17. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. CAS 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. PubMed Google Scholar. 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. We studied theFLT3-ITD length of 362 adult AML patients included in the PETHEMA AML registry. Ann Hematol. In the QuANTUM-R and ADMIRAL trials, only 4% and 12% of patients had received prior FLT3i therapy with induction, making it difficult to draw conclusions regarding the outcomes of contemporary patients, most of whom will have received a FLT3i (commonly midostaurin) with induction36,40. The first-generation FLT3is lack specificity for FLT3 and inhibit multiple downstream RTKs that may result in more off-target toxicities. Strati, P. et al. First, 161 AML patients with FLT3-ITD mutations treated with IC were analyzed using 39bp as the cutoff (<39bp; n=48,39bp; n=113). 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 ). 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 median RFS was 1.2years (CI 0.22.2) and 0.77years (CI 0.51.1), respectively (P=0.06). Absence of FLT3-ITD mutation 0.07 . AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Lancet Oncol. We have no information on the treatment received by the remaining patients. 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). Alotaibi, A. S. et al. Patients with NPM1-/FLT3- showed complex karyotype (24%) and t(8;21) (8%). 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). Phase III Trial Reports Quizartinib Doubles Overall Survival in FLT3 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. Therefore, these patients were not included in the analysis stratified by 2010 ELN genetic risk21. 3). It is important to note that none of these patients received a FLT3 inhibitor (FLT3i) during induction, consolidation, or post-ASCT. No statistically significant differences were found (P=0.4) (Fig. Oncol. The BSC group included 7 patients receiving transfusions and other supportive measures. Secondary mutations as mediators of resistance to targeted therapy in leukemia. The clinical behavior and genetic characteristics of the disease are heterogeneous1. Perl and colleagues investigated whether prior FLT3i therapy influenced outcomes in patients treated with gilteritinib. Slider with three articles shown per slide. Get the most important science stories of the day, free in your inbox. Yilmaz et al. Blood 134, 2564 (2019). *C1 D14: Perform bone marrow biopsy; if bone marrow shows <5% blasts and/or <5% cellularity/insufficient sampleStop venetoclax and FLT3i on D14. Google Scholar. Minetto, P. et al. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in 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. Therefore, only 3.8% of the patients showed an FLT3-ITD insertion in the TKD1 domain. 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. The Impact of FLT3 Mutations on the Development of Acute - Hindawi 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. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. Juan M. Alonso-Dominguez. Cancer Cell 1, 433443 (2002). Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. In the FLT3-ITDLOW group of patients, the median OS was 2.3years (CI: 1.13.6), and in the FLT3-ITDHIGH group of patients, the median OS was 1.1years (CI: 0.71.5). FLT3-ITD allelic ratio and HLF expression predict FLT3 inhibitor efficacy in adult AML, Impact of numerical variation, allele burden, mutation length and co-occurring mutations on the efficacy of tyrosine kinase inhibitors in newly diagnosed FLT3- mutant acute myeloid leukemia, Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results, Distinct clinico-biological features in AML patients with low allelic ratio FLT3-ITD: role of allogeneic stem cell transplantation in first remission, Poor outcome of pediatric patients with acute myeloid leukemia harboring high FLT3/ITD allelic ratios, Mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia, Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial, Impact of FLT3-ITD allele ratio and ITD length on therapeutic outcome in cytogenetically normal AML patients without NPM1 mutation, Mutational spectrum and prognosis in NRAS-mutated acute myeloid leukemia, https://doi.org/10.3324/haematol.2020.263806, http://creativecommons.org/licenses/by/4.0/. Astellas Reports XOSPATA (gilteritinib) in combination with azacitidine did not meet endpoint of overall survival in newly diagnosed flt3 mutation-positive acute myeloid leukemia patients ineligible for intensive induction chemotherapy (2020). NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 Chinese patients with de novo acute myeloid leukemia. Higher daunorubicin exposure benefits FLT3 mutated acute myeloid leukemia. 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:20745 (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. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. 2018 Oct 23;2 (20):2744-2754. doi: 10.1182/bloodadvances.2018020305. (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. Mutations of SF3B1, EZH2 and WT1 seem to be a more ancestral event than FLT3 mutations, as expected, given the VAF of the genes. 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. NGS, next-generation sequencing. 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. CAS DiNardo, C. D. et al. Analysis of FLT3-ITD insertion sites from 106 FLT3-ITD-positive AML patients. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. Article B MD Anderson Cancer Center Approach. Ohanian, M. et al. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Timothy, J. However, previous studies have shown that FLT3/ITD mutation was not an independent adverse prognostic factor in DEK/CAN-positive AML patients. S1. Sci Rep 11, 20745 (2021). 21, 12011212 (2020). Characteristics and outcome of patients with core binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study. Lancet Oncol. & Ley, C., Network CGAR. 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. 93, E202E205 (2018). 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. Blood 132, 598607 (2018). The CRc rates with quizartinib were similar to prior studies (48.2%), and 32% patients on the quizartinib arm underwent ASCT compared with 11% with salvage chemotherapy. Internet Explorer). FLT3-ITD mutations are detected in approximately 25% of newly diagnosed adult acute myeloid leukemia (AML) patients and confer an adverse prognosis. PubMed Full article: Advances in the drug therapies of acute myeloid leukemia FLT3-TKD activating mutations also constitutively activate FLT311; however, they have not been associated with a consistent prognostic impact12. and JM.A. Measurable residual disease, FLT3ITD mutation, and disease status have Off-target resistance includes clonal evolution during FLT3i therapy even when FLT3-ITDmut clone is lost70. We thank the PETHEMA group for its participation in this study. (C) OS according to the FLT3-ITD length and allelic ratio. Acta Haematol. Interestingly, all patients with an FLT3-ITD inserted in the TKD1 domain showed DNMT3A mutations. Schlenk, R. F. et al. Zhu, R., Li, L., Nguyen, B., Duffield, A. S. & Small, D. Gilteritinib and venetoclax synergize to eliminate FLT3/ITD+ leukemia cells through BIM. 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. (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. Based on the strong preclinical synergy and synthetic lethality with venetoclax and FLT3i combination49,50,51, and the fact that BCL2 upregulation may confer resistance to FLT3 inhibition52, evaluation of several doublet and triplet combinations of venetoclax and FLT3i are ongoing. Google Scholar. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. FLT3ITD mutations in acute myeloid leukaemia - molecular No statistically significant differences were found (P=0.8) (Fig. Schneider F, Hoster E, Schneider S, Dufour A, Benthaus T, Kakadia PM, et al. 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. "For patients with AML, the 5-year survival rate is only about 29%," said Dr. Erba. PubMedGoogle Scholar. Similarly, a stratified analysis of FLT3-ITD length on the basis of 2010 ELN genetic risk was performed in 123 patients (intermediate-I group, ITD<39bp, n=31 and ITD39bp, n=68; intermediate-II group, ITD<39bp, n=5 and ITD39bp, n=10; and adverse group, ITD<39bp, n=2 and ITD39bp, n=7). AR, allelic ratio. Brinton, L. T. et al. Altman, J. K. et al. Tallman, M. S. et al. In order to improve the clinical condition of FLT3-ITD-positive patients, several FLT3 inhibitors have been developed showing variable results. 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). (4) Only five patients in our cohort received treatment with midostaurin (2 in induction and 3 in consolidation treatment); therefore, we were not able to draw conclusions regarding the prognostic impact of the length of the ITD as described in previous studies29,30. 31, 3681 (2013). Biol. These authors contributed equally: Naval Daver, Sangeetha Venugopal, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Naval Daver,Sangeetha Venugopal&Farhad Ravandi, You can also search for this author in Ravandi, F. et al. 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. However, in addition to QTcF prolongation, quizartinib is also more myelosuppressive than many other FLT3 inhibitors likely due to the inhibition of KIT. J. Clin. J. Natl Compr. Unlike midostaurin, quizartinib monotherapy, even at lower doses demonstrated significant marrow remissions in R/R FLT3mut AML35,36,37. **If the C1 D14 bone marrow show >5% blastscontinue venetoclax, FLT3i till D21. 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). evaluated the impact of AR in 323 patients with newly diagnosed FLT3-ITDmut AML. Oncol. Sra. In the frontline setting, there was a sequential decrease in CRc rates (77%31%25%) and OS (16.76.01.4 months). J. Hematol. Oncol. Blood 100, 23932398 (2002). The addition of sorafenib to standard AML treatment results in a substantial reduction in relapse risk and improved survival. mutations (1-year survival < 1% vs 42% in their presence vs absence) which should be incorporated in patient counseling. Soc. Blood 100, 43724380 (2002). Compr. 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.
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