flt3 itd mutation prognosis

The on-target mechanism of resistance includes emergence of secondary TKD mutations in patients treated with type II inhibitors like quizartinib or sorafenib69,70. Cancer Netw. Oran et al. Among 362 patients, NGS was performed in 118 patients using a panel of 39 genes. (C) OS according to the FLT3-ITD length and allelic ratio. Conceptualization, T.C., J.M.A., E.B. CAS 93, E202E205 (2018). Complete response (CR) or complete responses with incomplete hematologic recovery (CRi) were defined according to current 2017 ELN guidelines8. Mutations of FLT3 are found in approximately 30% of newly diagnosed AML patients and appear either as ITDs ( 25%) or point mutations in the tyrosine kinase domain (TKD) (710%)4. 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? Blood 132, 598607 (2018). Swaminathan, M. et al. contracts here. 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. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. mutations (1-year survival < 1% vs 42% in their presence vs absence) which should be incorporated in patient counseling. Acta Haematol. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. Progr. Hematol. 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). While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Konopleva, M. et al. 13, 132 (2020). PCR with fluorescently labeled primers followed by capillary electrophoresis for FLT3-ITD was performed as described elsewhere31. The analysis of OS and RFS applying this value did not show significant results (data not shown). Among 161 intensively treated patients, 123 had the cytogenetic and molecular information required to calculate the 2010 ELN classification21. 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. 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. Prognostic significance of FLT3-ITD length in AML patients treated with intensive regimens. @Repeat a C1 D28 bone marrow on all patients to confirm remission. Administration of the triplet is associated with prolonged cytopenias, requiring close monitoring and experience with venetoclax based combinations. Article Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia. https://doi.org/10.1038/s41598-021-00050-x, DOI: https://doi.org/10.1038/s41598-021-00050-x. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. Strati, P. et al. J. Clin. As Dr. Erba explained, patients with FLT3 -ITD-positive AML represent a particularly poor prognostic group. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. A Conventional approach. To obtain 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. J. Hematol. 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. This model of initiatory and progression mutation as FLT3 is well described 37, 38. FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia and is associated with worse clinical outcome. 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 licence, and indicate if changes were made. (D) OS according to the FLT3-ITD length and 2010 ELN genetic risk. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). 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. 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. Blood 130, 721 (2017). The clinical behavior and genetic characteristics of the disease are heterogeneous1. The origin and evolution of mutations in acute myeloid leukemia. Am. These data highlight the potent anti-leukemic activity of the triplet approach in FLT3mut AML. 3). The AUC of the ROC curve of the ITD length for OS prediction was 0.504, and no differences were found when applying any of the thresholds for OS, RFS or CR rate. 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. PubMed In our experienced cases FLT3-ITD mutation in MDS showed shorter duration to AML transformation and very poor prognosis. FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) is one of the most frequent mutations found in AML patients. 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. More recently, the emergence of BCR-ABL1-positive clone was shown as a resistance mechanism to multiple FLT3is72. and JM.A. J. Clin. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. Google Scholar. 13, 139 (2020). 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. 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. Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML. Regarding ITD length, some authors have found that patients with shorter ITD lengths have more favorable outcomes11,12 or worse prognoses13, while other researchers did not find a prognostic relationship14. The FLT3-ITD allelic ratio has clear prognostic value. The median OS was 1.3years (CI: 0.71.9) and 1.4years (CI: 0.91.9), respectively (P=0.9). Furthermore, a global query was sent to the different centralized laboratories of PETHEMA to verify the ITD length, insertion site and molecular profile of the patients by NGS when these data were available. 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&rsquo; outcomes when receiving an allogeneic hematopoietic stem cell transplantation (HSCT). J. Med. Article 61, 72337239 (2001). Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Yilmaz, M. et al. Our real-life cohort was composed of 362 patients, most of whom were not included in clinical trials. Heart J. Suppl. J. Natl Cancer Inst. 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 phase III RATIFY study (CALGB 10603), for example, looked at the addition of the tyrosine kinase inhibitor midostaurin to intensive chemotherapy in newly-diagnosed AML with FLT3 mutations (either ITD or TKD) and showed an overall survival (OS) benefit with midostaurin compared to placebo (74.7 vs. 25.6 months, respectively) . Oncol. PubMed (C) OS according to the FLT3-ITD length and allelic ratio. and JavaScript. Emergence of BCR-ABL1 fusion in AML post-FLT3 inhibitor-based therapy: a potentially targetable mechanism of resistancea case series. 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? Zhu, R., Li, L., Nguyen, B., Duffield, A. S. & Small, D. Gilteritinib and venetoclax synergize to eliminate FLT3/ITD+ leukemia cells through BIM. The median OS was 2.3years (CI: 1.03.6), 1.4years (CI: 1.01.8), 1.1years (CI: 0.81.3) and 1.0years (CI: 0.31.8), respectively (P=0.9). 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 136, 3233 (2020). Quizartinib demonstrated an OS of 6.2 months compared with 4.7 months with salvage chemotherapy (hazard ratio 0.76 and P=0.02). 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. Informed consent was a requisite for patients alive at the time of data lock (January 2019). Perl, A. E. et al. To obtain 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. CAS 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. Google Scholar. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Lancet Haematol. Unfortunately, in our study, information on the site of insertion was not available in the whole cohort, and few patients harbored a TKD1 insertion.We did not carry out a statistical analysis of the insertion site given the heterogeneity in the treatment of patients analyzed and the small number of patients with an ITD inserted in the TKD1 domain. 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. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. CAS Hematology Department, Hospital Universitario Fundacin Jimnez Daz, Avenida Reyes Catlicos, 2, 28040, Madrid, Spain, Tamara Castao-Bonilla,Juan M. Alonso-Dominguez,Carlos Blas&Jose L. Lpez-Lorenzo, Instituto de Investigacin Sanitaria (IIS-FJD), Hospital Universitario Fundacin Jimnez Daz, Madrid, Spain, Tamara Castao-Bonilla,Juan M. Alonso-Dominguez,Carlos Blas,Jose L. Lpez-Lorenzo,Daniel Lainez-Gonzalez&Juana Serrano, Hematology Department, Hospital Universitario La Fe de Valencia, Valencia, Spain, Eva Barragn,Rebeca Rodrguez-Veiga,Claudia Sargas,David Martnez-Cuadrn,Miguel A. Sanz&Pau Montesinos, Hematology Department, Hospital General de Alicante, Alicante, Spain, Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain, Hematology Department, Hospital General de Castelln, Castelln, Spain, Hematology Department, Hospital Universitario Doce de Octubre, Complutense University, CNIO, Madrid, Spain, Molecular Biology Department, Cimalab Diagnosis, Clnica Universitaria de Navarra, Navarra, Spain, Hematology Department, Hospital Universitario Clnico San Carlos, Medicine Department, UCM, Madrid, Spain, Hematology Department, Hospital Universitario de Valladolid, Valladolid, Spain, Hematology Department, Hospital Universitario Ro Hortega, Valladolid, Spain, Hematology Department, Hospital Universitario Virgen del Roco, Instituto de Biomedicina de Sevilla (IBIS/CISC/CIBERON), Sevilla, Spain, Hematology Department, Hospital Universitario de Burgos, Burgos, Spain, Hematology Department, Hospital Ntra. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. A stratified analysis of FLT3-ITD length on the basis of the AR was performed in 140 patients (AR<0.5 and ITD<70bp, n=43; AR<0.5 and ITD70bp, n=15; AR>0.5 and ITD<70bp, n=61; AR>0.5 and ITD70bp, n=21). 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. Enter the email address you signed up with and we'll email you a reset link. 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 ). The Programa Espaol de Tratamientos en Hematologa (PETHEMA) AML epidemiologic registry (NCT02607059) includes patients diagnosed with AML, regardless of the treatment administered. Res. Timothy, J. 11, 104 (2021). For . ; Writingreview and editing, 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.L., J.S., D.M.C., M.A.S. Compr. Despite the encouraging development of FLT3i, resistance to FLT3i is not uncommon and it can be either primary or secondary. Schlenk et al. Mead, A. J. et al. 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. 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. Dhner, H. et al. Minetto and colleagues retrospectively evaluated the efficacy of fludarabine, high-dose cytarabine, and idarubicin (FAI) in 149 newly diagnosed FLT3-ITDmut and/or NPM1mut AML (only FLT3-ITDmut=29; FLT3-ITDmut NPM1mut=59, only NPM1mut=61). 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.. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. We evaluate these patients on a case by case basis and may consider maintenance with 45 consolidation cycles of CLIA or FAI with FLT3i followed by FLT3i+/HMA maintenance for two years vs ASCT based on donor availability, age, performance status, MRD negativity, and patient preference. 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. However, previous studies have shown that FLT3/ITD mutation was not an independent adverse prognostic factor in DEK/CAN-positive AML patients. FLT3 mutation and all but one patient died shortly after FLT3 mutation was acquired. Stratified KaplanMeier analysis was also employed with the AR and genetic risk, following 2010 ELN guidelines21, as classifiers of the patients. 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. A subsequent randomized phase IIb trial evaluated lower doses, 30 or 60mg of quizartinib daily, in patients with R/R FLT3-ITDmut AML. 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. Variant allele frequency (VAF) is the ratio of ITD-mutated alleles to ITD-mutated+wild-type alleles (FLT3ITD/FLT3ITD+FLT3 wild-type)14. Chyla, B. et al. Blood 110, 12621270 (2007). 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). 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). evaluated the outcomes of sequential FLT3i-based therapies in FLT3mut AML. 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. Venetoclax Added to Cladribine, Idarubicin, and Cytarabine with or without a FLT3 Inhibitor in Newly Diagnosed Acute Myeloid Leukemia (EHA, 2020). Among the FLT3mut patients, response rates were numerically higher (33%) and remission duration was longer (31 versus 16 weeks, P=0.09) in those who were naive to treatment with FLT3 inhibitors compared with those who had been exposed to prior FLT3 inhibitors. Oncol. Smith, C. C. et al. 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. Hematol. 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. 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. 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. Metzelder, S. et al. J. Clinl. and P.M.; Project administration, J.M.A. Daver, N. et al. As we have already explained, our main goal was to validate two previous recurrently applied cutoffs: 39bp and 70bp. The survival rates in patients 60 years of age were also similar across NPM1 mut /FLT3 wt, NPM1 mut /FLT3-ITD low, and NPM1 mut . In our case, 15 AML prognostic genes including FLT3/ITD gene were all negative. An analysis of OS censoring at the time of allo-HSCT did not yield significant results (data not shown). Changes in FLT3 mutation status can occur during the course of disease, but the clinical impact of a change is unclear. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in NGS, next-generation sequencing. 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). Both mutations lead to the activation of downstream proliferation cascades [ 19, 20 ]. evaluated midostaurin with azacitidine in patients with both newly diagnosed and R/R AML regardless of FLT3 mutational status. 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. 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. FLT3 -ITD is a negative prognostic factor that remains prognostically relevant even after intensive chemotherapy and/or stem cell transplant. FLT3 is a receptor tyrosine kinase that is involved in regulating proliferation of hematopoietic progenitor cells. A phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed AML: final results. 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). 93, 11361141 (2018). Prognostic significance of baseline FLT3-ITD mutant allele level in acute myeloid leukemia treated with intensive chemotherapy with/without sorafenib. 6,, - 9 In normal bone marrow, FLT3 expression is Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. 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. Scientific Reports (Sci Rep) Oncol. In order to improve the clinical condition of FLT3-ITD-positive patients, several FLT3 inhibitors have been developed showing variable results. Fishers exact test was employed to correlate the ITD insertion site and mutational status. Am. The length of the 362 ITDs ranged from 3 to 201bp, with a median ITD length of 48bp.The distribution of ITD length can be observed in Supplementary Fig. Precision Medicine in Myeloid Malignancies: Hype or Hope? Venetoclax, FLT3 Inhibitor and Decitabine in FLT3mut Acute Myeloid Leukemia: Subgroup Analysis of a Phase II Trial (ASH, 2020). These combinations appear to improve the efficacy over single agent gilteritinib and could be considered if there is expertise in using such an approach, For patients relapsing while on gilteritinib or soon after gilteritinib based therapy a combination of azacitidine with sorafenib or azacitinde with venetoclax or gemtuzumab based approaches may be considered as salvage options (with clinical trials being clearly the best option if available). 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. . 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). 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. Molecular clearance of FLT3 was noted in 50% of all evaluable patients. Blood 136, 2223 (2020). 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. and P.M; Writingoriginal draft, T.C. J. Hematol. 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. Perl, A. E. et al. Google Scholar. Altman, J. K. et al. 16, 16911699 (2015). Moreover, ASCT in CR1 only benefitted patients with isolated FLT3-ITDmut (without NPM1mut) irrespective of AR (P<0.05)21. Slider with three articles shown per slide. However, other studies did not find significantly worse clinical outcomes in patients with non-JMD ITD mutations24,25. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution . 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.

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