1).
Activating FLT3 Mutants Show Distinct Gain-of-Function Phenotypes In recently showed that ASCT in CR1 improved RFS and OS independent of the FLT3-ITDmut AR or NPM1mut status in patients with FLT3-ITDmut AML20. 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. Internet Explorer). J. Hematol. 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. It is mutated in about 1/3 of acute myeloid leukemia (AML) patients, either by internal tandem duplications (ITD) of the juxtamembrane domain or by point mutations usually involving the kinase domain (KD).
Role of Biomarkers in the Management of Acute Myeloid Leukemia 1A). 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.. PubMed Central 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. 96 1993 2003, Article Patients were classified into four therapeutic groups according to the first-line approach: intensive chemotherapy (IC), n=161; non-intensive therapy, n=43; clinical trial, n=15; and best supportive care (BSC) only, n=7. J. Hematol. Expression and signal transduction of the FLT3 tyrosine kinase receptor. Blood 132, 3944 (2018). 11, 104 (2021). volume11, Articlenumber:20745 (2021) Close Log In. Xuan, L. et al. 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. N. Engl. Cancer Netw. 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). Libura, M. et al. Cortes, J. E. et al. DiNardo, C. D. et al. We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. Quizartinib demonstrated an OS of 6.2 months compared with 4.7 months with salvage chemotherapy (hazard ratio 0.76 and P=0.02). The impact of prognostic factors may change as the AML treatment landscape evolves. Prognostic significance of baseline FLT3-ITD mutant allele level in acute myeloid leukemia treated with intensive chemotherapy with/without sorafenib. N.D. has received research funding from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE, Amgen, Novimmune, Glycomimetics, and ImmunoGen and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Novartis, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, and Agios. FLT3-ITD has been strongly associated with a bad prognosis, leukocytosis, high blast counts, increased risk of relapse and shorter overall survival. 61, 72337239 (2001). 38, 29933002 (2020). 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. Kiyoi, H. et al. The landscape of mutations identified by NGS in AML patients. Lancet Oncol. Moreover, ASCT in CR1 only benefitted patients with isolated FLT3-ITDmut (without NPM1mut) irrespective of AR (P<0.05)21. The favorable prognostic molecular mutations, such as NPM-1 and CEBPA, are uncommon in elderly AML . This work is submitted in partial fulfillment of the requirement for the PhD. Daver, N. et al. Tamaoki, T. et al. Smith, C. C. et al. Nevertheless, we also performed an analysis with the median ITD length of our cohort (48bp). J. Natl Compr. We currently recommend the incorporation of FLT3is and ASCT in CR1 in all ASCT eligible patients with a FLT3-ITDmut AML, irrespective of the AR and/or NPM1 co-mutation status.
The Impact of FLT3 Mutations on the Development of Acute - Hindawi . Commun. Prognostic analyses were performed using the 70bp cutoff in 161 AML patients with FLT3-ITD mutations treated with IC (<70bp; n=119,70bp; n=42). Among patients treated with gilteritinib, the median overall survival was similar among those with FLT3 ITD mutations alone (9.3 months) and those with FLT3 TKD mutations alone (8.0 months). FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. Perl, A. E. et al.
FLT3-ITD Mutation in MDS Patients Is Associated with Early 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 ). PubMed Due to the preliminary nature of the . evaluated the impact of AR in 323 patients with newly diagnosed FLT3-ITDmut AML. Netw. Res. Enter the email address you signed up with and we'll email you a reset link. The FLT3-ITD patient had trisomy 8. Blood 136, 3233 (2020).
A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid To obtain FLT3 is a gene change, or mutation, in leukemia (blood cancer) cells. PubMed Central
FLT3 Gene Mutation Profile and Prognosis in Adult Acute - PubMed Therefore, only 3.8% of the patients showed an FLT3-ITD insertion in the TKD1 domain. We administer a second-generation FLT3i (ideally gilteritinib) continuously with HMA from cycle 1 Day 1. PubMed Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Results of a Phase 2, Randomized, Double-Blind Study of Sorafenib Versus Placebo in Combination with Intensive Chemotherapy in Previously Untreated Patients with FLT3-ITD Acute Myeloid Leukemia (ALLG AMLM16) (ASH, 2020). Jain, P. et al. Finally, a different report showed worse clinical outcomes in terms of OS and DFS in the TKD1 group. However, in a recently released planned interim analysis, the study did not meet its primary endpoint of overall survival and may be terminated for futility46. Log in with Facebook Log in with Google. 15, 17 In our cohort, the prevalence of FLT3-ITD mutation of de novo AML patients was 21.5%. Upregulation of Bcl-2 confers resistance to FLT3 inhibition in FLT3-ITD AML with secondary acquired mutations. Musa Yilmaz, M. 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). Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. 10, 588876- (2020). 2012;91(1):9-18. and P.M.; Formal analysis, J.M.A., Investigation,T.C., J.M.A. Naval Daver. 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. J. Natl Cancer Inst. 1,2 Real-time pCR, which has . Blood 128, 1069 (2016).
FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm "FLT3 is a particularly nasty version of the disease," Levis said. FLT3 -TKD mutations are point mutations in the activation loop of FLT3, mainly represented by codon D835 or deletion of codon I836, which leads to a loss of auto-inhibition [ 18 ]. In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene ( FLT3- ITD) are associated with poor prognosis. An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown). 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. S.V. Enter the email address you signed up with and we'll email you a reset link. Gale, R. E. et al. Elderly patients with AML have a distinct genetic landscape compared with the younger population. 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). Favorable relapse risk and OS were seen in NPM1mut with FLT3 wild-type; intermediate prognosis in FLT3-ITDmut with concurrent NPM1mut, and adverse prognosis in FLT3-ITDmut with NPM1 wild-type patients16. Overall survival (OS) was calculated from the date of the diagnosis of AML until death in all included patients.
FLT3 Mutations: Biology and Treatment | Hematology, ASH Education * Genes with a P value<0.05 in the MannWhitney test correlating mutational status with ITD length. Cite this article. Pratz, K. W. et al. N. Engl. Compr. Biol. which included NPM1 mut /FLT3-ITD high AR cases. The insertion site of FLT3-ITD was available in 106 of 118 patients (Fig. Blood Marrow Transplant 22, 12181226 (2016).
| 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). Analysis of FLT3-ITD insertion sites from 106 FLT3-ITD-positive AML patients. Heart J. Suppl. Presented in part at the 42nd Annual Meeting of the American Society of Hematology, December 15, 2000, San Francisco, CA (abstract 2334). Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. Posterior reversible encephalopathy and pancreatitis are rare (<12%) but important side effects to be aware of. 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. 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. 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. It's the most common genetic change in acute myeloid leukemia (AML), a type of leukemia that starts in the bone marrow and. Schlenk, R. F. et al. 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. DiNardo, C. D. et al. CAS Quizartinib is also being evaluated in combination with CPX-351 (NCT04209725) and with CLIA (NCT04047641) in treatment naive and R/R FLT3mut AML. 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). In order to improve the clinical condition of FLT3-ITD-positive patients, several FLT3 inhibitors have been developed showing variable results.
Prognostic significance of baseline FLT3ITD mutant allele level in Citation 56 The new FLT3 inhibitors, G-749 and ASP2215, have been proved to cause strong inhibition of FLT3 phosphorylation and increase the ability to overcome drug resistance in preclinical trials, but further studies are needed to evaluate their . https://doi.org/10.1038/s41598-021-00050-x, DOI: https://doi.org/10.1038/s41598-021-00050-x. We currently recommend post-transplant maintenance with a FLT3i for at least 2 years (potentially indefinitely as there is limited data on the incidence of possible late relapses) in all FLT3mut AML. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . 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. prospectively evaluated decitabine and quizartinib (doublet) with or without venetoclax (triplet) in patients with newly diagnosed and R/R FLT3-ITDmut AML. As Dr. Erba explained, patients with FLT3 -ITD-positive AML represent a particularly poor prognostic group. Scientific Reports (Sci Rep) 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 AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). J. Clin. Such sequential approaches need to be formally evaluated in the context of prospective clinical trials. Am. We continue the venetoclax and FLT3i until Day 21 if the Day 14 bone marrow shows >5% blasts with >/=5% cellularity. 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). CAS Among 14 R/R FLT3mut AML patients, the CRc rate was 64% with FLT3-PCR negativity in 88% of responders.
FLT3 mutations in acute myeloid leukemia: a review focusing on 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. Blood 100, 43724380 (2002). Kayser, S. et al. 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%. 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. In particular, high (>0.5) mutant-to-wild-type (WT) allelic ratios (AR) in the FLT3-ITD gene are associated with inferior prognosis ( 6, 7 ). 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. 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. Br. These results led to the approval of gilteritinib monotherapy in the US and Europe in patients with R/R FLT3mut AML40. The clinical behavior and genetic characteristics of the disease are heterogeneous1. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). PubMedGoogle Scholar. 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. The combination continues to enroll. More recently, the emergence of BCR-ABL1-positive clone was shown as a resistance mechanism to multiple FLT3is72. Further evaluation and optimization of triplets is a major area of clinical research focus in FLT3mut AML.
Abstract 44: CG806, a first-in-class FLT3/BTK inhibitor, exhibits 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. Mechanistically, FLT3-ITDs and FLT3-TKDs induce activation of transduction intermediates, including STAT5, AKT, and ERK1/2 ( 2 ). A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/refractory FLT3-mutated Acute Myeloid Leukemia in the Expansion Cohort of a Phase 1b Study (ASH, 2020). Two cases with an NPM1 mut missense each occurred concomitant with type-A mutation. (A) Overall survival. Some studies showed a reduced CR rate, while others analyzing the IS in the same region found differences in OS. The FLT3-ITD AR was available in 140 intensively treated patients. The addition of sorafenib to standard AML treatment results in a substantial reduction in relapse risk and improved survival. Informed consent was a requisite for patients alive at the time of data lock (January 2019). 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. 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. Article Nakao, M. et al. Biophys. Google Scholar. 17 D2 D8, H-S Kim S Lee JH Kim 2018 Real-world evidence versus randomized controlled trial: Clinical research based on electronic medical records J Korean Med Sci 33 e213, RF Schlenk 2014 Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation Blood 124 3441 3449, I Abou Dalle 2020 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 Blood Cancer J. Am. Green indicates non-mutated genes, red indicates mutated genes and white indicates non-mutated genes. Thank you for visiting nature.com. 2A). We identified 1572 adult (age 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or . In the frontline setting (n=4), the CRc rate with the triplet was 100% with FLT3-PCR negativity in all four patients56. Ohanian, M. et al. and P.M; Writingoriginal draft, T.C.
Molecular landscape and prognostic impact of FLT3-ITD - Nature Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. 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. 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. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. 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.
Progress in Disease Detection Sets the Stage for MRD's Role in AML J. Clinl. Only four out of 106 patients had ITD IS in the TKD1 domain. 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.
Activating FLT3 Mutants Show Distinct Gain-of-Function - PLOS