3 A Survival curves stratified by the presence or absence of FLT3 -ITD and NPM1 mutation for patients younger than 65 years. 2B). 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. The median OS was 1.7years (CI 04.0), 1.7years (CI NC), 1.3years (CI 0.32.3), 1.5years (CI NC), 1.2years (CI: 0.52.0) and 2.4years (CI NC), respectively. (C) OS according to the FLT3-ITD length and allelic ratio. * Genes with a P value<0.05 in the MannWhitney test correlating mutational status with ITD length. 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. Relapse-free survival (RFS) was calculated from the date of achieving CR/CRi until the date of relapse (death without relapse or relapse were consideredevents)8. Additionally, different subdomains of TKD1 (HR or beta1-sheet) have been highlighted as those conferring an adverse outcome10. (3) Findings regarding the relationship between ITD length/site and mutational profile might be interpreted as exploratory given the high number of correlations performed. Nevertheless, some thresholds have been applied in more than one study [i.e., 39bp and 70bp]11,15,16,17. Juan M. Alonso-Dominguez. FLT 3-ITD mutations typically were determined using polymerase chain reaction and fragment analyses. CR or CRi was achieved in 70% of the patients in both groups (P=0.9). (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. PubMed In patients with FLT3mut AML unsuitable for intensive chemotherapy, azacitidine with venetoclax demonstrated encouraging CR/CRi rates (5570%) and a median OS of 13.3 months64 which prompted the inclusion of this combination approach as part of NCCN AML guidelines (Fig. 11, 104 (2021). 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). 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. In patients with FLT3mut AML who relapsed after first ASCT, sorafenib was found to be tolerable with long-lasting remissions in 7 of 29 patients treated, suggesting a potential synergy with post-ASCT alloimmune effects41. Interestingly, all patients with an FLT3-ITD inserted in the TKD1 domain showed DNMT3A mutations. Ohanian, M. et al. Ravandi, F. et al. 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). To mitigate prolonged myelosuppression with the triplet and avoid over-treatment, we perform an early bone marrow assessment on Cycle 1 Day 14 (Fig. Although the label indication for gilteritinib is as a single agent we have never used it as a single agent but always in combination with either HMA alone, venetoclax alone or as a triplet with HMA and venetoclax. Therefore, in patients not eligible for intensive chemotherapy at MDACC, we prefer a combination of HMA with venetoclax and FLT3i (gilteritinib) over an HMA with venetoclax doublet (Fig. 10, 588876- (2020). 4). Precision Medicine in Myeloid Malignancies: Hype or Hope? You are using a browser version with limited support for CSS. and P.M; Writingoriginal draft, T.C. and P.M.; Supervision, J.M.A. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. 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. DiNardo, C. D. et al. In those patients with more than one ITD mutation, only the longest mutation was selected for statistical analysis (10 patients had>1 ITD mutation). 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 Samples from 118 of the 362 AML patients with FLT3-ITDmutations were analyzed with an NGS panel of 39 genes (see Supplementary Fig. A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid Prognostic significance of baseline FLT3ITD mutant allele level in @Repeat a C1 D28 bone marrow on all patients to confirm remission. FLT3-TKD activating mutations also constitutively activate FLT311; however, they have not been associated with a consistent prognostic impact12. PubMed Central fms3flt3-itdaml molm13baf3-flt3-itd p-erkp-akt . 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). PubMedGoogle Scholar. Blood 97, 24342439 (2001). 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. or reset password. 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. As in previous works, we analyzed the clinical significance of FLT3-ITD length among fit patients treated with intensive regimens15,16. 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%. 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. Midostaurin has been approved and widely used in combination with induction and consolidation therapy in patients with newly diagnosed FLT3mut AML25. Statistically significant results were not observed for any other gene in this analysis. The area under the ROC curve (AUC) for OS prediction was 0.504. Mead, A. J. et al. 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. E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for KIT+ . Google Scholar. Acta Haematol. 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. Prevalence and Effect Evaluation of FLT3 and NPM1 Mutations in Acute Myeloid Leukemia Patients in Eastern Algeria . Article No statistically significant differences were found (P=0.8) (Fig. Among those with NPM1 wild-type, all FLT3-ITDmut patients had an increased risk of relapse and inferior OS, regardless of the AR17. Collectively, NPM1mut even with FLT3-ITDmut AR <0.5 are likely higher risk than truly favorable risk AML and we continue to consider them for ASCT in CR1. 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. Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. 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. The FLT3-ITD patient had trisomy 8. FLT3-ITD Mutation in MDS Patients Is Associated with Early 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. Timothy, J. Blood 93, 30743080 (1999). and P.M.; Validation, T.C., J.M.A., E.B. Posterior reversible encephalopathy and pancreatitis are rare (<12%) but important side effects to be aware of. Nevertheless, there are numerous and contradictory manuscripts regarding the prognostic importance of the length and insertion site of the ITD fragment. Results of venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with acute myeloid leukemia with FLT3 mutations. and P.M.; Data curation, J.M.A. We continue the venetoclax and FLT3i until Day 21 if the Day 14 bone marrow shows >5% blasts with >/=5% cellularity. 28, 1856 (2010). It should be noted that MDS-MLD and -EB-1 patients with low and intermediate risk in IPSS-R were included in FLT3-ITD mutation group, and showed poor prognosis. Res. 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. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Cancer Res. PubMed FLT3 mutation and all but one patient died shortly after FLT3 mutation was acquired. Article Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. 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. We identified 1572 adult (age 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or . The FMS-like tyrosine (FLT3) gene encodes a class III receptor tyrosine kinase, sharing structural and sequence homologies with family members, including c-kit, c-FMS, FLT1, and PDGF- R. FLT3 plays a key role in the control of hematopoiesis. Alotaibi, A. S. et al. 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. Soc. Google Scholar. Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability. J. Haematol. 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. The FLT3-ITD allelic ratio has clear prognostic value. Provided by the Springer Nature SharedIt content-sharing initiative, Current Hematologic Malignancy Reports (2022), Current Treatment Options in Oncology (2022), Blood Cancer Journal (Blood Cancer J.) Biao Wang, X. Hua, Jihong Zhang, Weiying Gu . 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. Oran, B. et al. has received research funding from Astellas, and Novartis and has served as a member of advisory board in Astellas and Novartis. 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. In our cohort, FLT3-ITD was located in the JMD domain (JMD-B, JMD-S, JMD-Z and HR) in 98 patients and in the TKD1 domain (B1, NBL and B2) in four patients. Due to the preliminary nature of the . . Complete response (CR) or complete responses with incomplete hematologic recovery (CRi) were defined according to current 2017 ELN guidelines8. SORMAIN, a placebo-controlled randomized phase II trial evaluated post-transplant sorafenib maintenance in patients with FLT3-ITDmut AML with RFS post-ASCT as the primary endpoint. Absence of FLT3-ITD mutation 0.07 . 1A). Abhishek Maiti, M. D. et al. Article Stratified KaplanMeier analysis was also employed with the AR and genetic risk, following 2010 ELN guidelines21, as classifiers of the patients. 93, 11361141 (2018). Elderly patients with AML have a distinct genetic landscape compared with the younger population. Tamaoki, T. et al. The BSC group included 7 patients receiving transfusions and other supportive measures. Not all FLT3-ITDmut are equal; the prognostic impact is influenced by the allele ratio (AR), insertion site, ITD length, co-mutations (NPM1), and karyotype. 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. 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). In sensitivity analysis, no significant . Conceptualization, T.C., J.M.A., E.B. 120.000 new AML cases and over . Log in with Facebook Log in with Google. Therefore, only 3.8% of the patients showed an FLT3-ITD insertion in the TKD1 domain. J. Hematol. & Ley, C., Network CGAR. 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. However, whether these findings are specific to Ven + HMA therapy remains to be . 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. By submitting a comment you agree to abide by our Terms and Community Guidelines. NPM1 - an overview | ScienceDirect Topics 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. 2012;91(1):9-18. Naval Daver, M. D. et al. Protein alteration seems to be much more complex than the length of the mutation or the site of insertion; therefore, our efforts to simplify FLT3-ITD characteristicsby stratifying the risk of the patients may be fruitless. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. Blood 99, 43264335 (2002). You are using a browser version with limited support for CSS. The MORPHO phase III placebo-controlled trial evaluating post-transplant maintenance with gilteritinib in FLT3mut AML recently completed accrual and results are eagerly awaited (NCT02997202). 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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