We introduce venetoclax with a ramp-up when the WBC is <10,000/L to decrease the risk of tumor lysis syndrome. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. The presence of FLT3-ITD mutation correlates with a high leukemic burden with increased risk of relapse and is recognized to be a driver mutation in patients with AML ( 5 ). Close Log In. The primary and key secondary trial end points were OS and RFS, respectively, both measured from the time of randomization. The data described in the literature alongside the results that we have obtained regarding ITD mutation lead us to believe that future studies should focus on the functional characterization of the protein products of the mutated genes. We studied theFLT3-ITD length of 362 adult AML patients included in the PETHEMA AML registry. More studies will be necessary to confirm these results and to shed light on the possible physiopathologic relationship. 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. Altman, J. K. et al. 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 . 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. FLT3-ITD mutations are detected in approximately 25% of newly diagnosed adult acute myeloid leukemia (AML) patients and confer an adverse prognosis. FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. is a PhD candidate at Universidad Autnoma de Madrid (UAM). Clinical outcome stratified according to the FLT3-ITD length (cutoff 70bp) for all patients treated with intensive chemotherapy. "For patients with AML, the 5-year survival rate is only about 29%," said Dr. Erba. (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. 93, E202E205 (2018). Due to this, the development of tyrosine kinase inhibitors (TKI) blocking FLT3-ITD became a rational therapeutic concept. Oncogene 21, 25552563 (2002). Besides FLT3-ITD MRD, only a high white blood cell count and late CR appeared to be independently associated with relapse and OS. F.R. 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.. Samples from 118 of the 362 AML patients with FLT3-ITDmutations were analyzed with an NGS panel of 39 genes (see Supplementary Fig. A Conventional approach. Among 161 intensively treated patients, 123 had the cytogenetic and molecular information required to calculate the 2010 ELN classification21. ; 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. The median age of this group was 55.1years (range 17.185.3years); 76 males and 85 females. mutations (1-year survival < 1% vs 42% in their presence vs absence) which should be incorporated in patient counseling. 383, 617629 (2020). 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. Google Scholar. J. Med. Venetoclax, FLT3 Inhibitor and Decitabine in FLT3mut Acute Myeloid Leukemia: Subgroup Analysis of a Phase II Trial (ASH, 2020). Blood 114, 29842992 (2009). Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability. Timothy, J. Rydapt Prescribing Information. Both mutations lead to the activation of downstream proliferation cascades [ 19, 20 ]. We have no explanation regarding the reduced number of patients with an FLT3-ITD inserted in TKD1 found in our cohort. PubMed In subsequent cycles: FLT3i is continued for the entire duration of the cycle and the venetoclax duration is reduced to 14 days or lower to mitigate cumulative prolonged cytopenias. J. Clin. Alotaibi, A. S. et al. 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. and P.M.; Methodology, 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.L., J.S., D.M.C., M.A.S. 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. Yamatani, K. et al. CAS To obtain Approximately one third of AML patients harbor constitutive activating internal tandem duplication in FLT3 (FLT3-ITD), which is associated with very poor prognosis. Presented in part at the 42nd Annual Meeting of the American Society of Hematology, December 15, 2000, San Francisco, CA (abstract 2334). 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. 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. The on-target mechanism of resistance includes emergence of secondary TKD mutations in patients treated with type II inhibitors like quizartinib or sorafenib69,70. and P.M.; Project administration, J.M.A. Kayser, S. et al. Conclusion: The frequency of NPM1/FLT3 mutations in the study cohort showed less rate than in other studies with a distinct pattern. The AR was determined by fragment length analysis and calculated as previously described32. Pratz, K. W. et al. . Weisberg, E. et al. 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. MRD detection in AML leverages cutoff points garnered from various detection methods include flow cytometry or real-time quantitative polymerase chain reaction (pCR). Souki Cancer Research Fund and generous philanthropic contributions to the MD Anderson Moon Shots Program. Juan M. Alonso-Dominguez. Hypomethylating agent and venetoclax with FLT3 inhibitor triplet therapy in older/unfit patients with FLT3 mutated AML, Mechanisms of resistance to cancer therapy, Cancel Variant allele frequency (VAF) is the ratio of ITD-mutated alleles to ITD-mutated+wild-type alleles (FLT3ITD/FLT3ITD+FLT3 wild-type)14. has nothing to disclose. 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. Stratified KaplanMeier analysis was also employed with the AR and genetic risk, following 2010 ELN guidelines21, as classifiers of the patients. Therefore, these patients were not included in the analysis stratified by 2010 ELN genetic risk21. Biol. 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). Schneider F, Hoster E, Schneider S, Dufour A, Benthaus T, Kakadia PM, et al. FLT3-ITD length was compared between mutation and wild-type groups for each of the 39 genes using a MannWhitney test. Lancet Oncol. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. 381, 17281740 (2019). Additionally, the area under the ROC curve, which serves as an indicator of the diagnostic capacity of the ITD length as a whole, was 0.504. 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. 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. PubMed evaluated the outcomes of sequential FLT3i-based therapies in FLT3mut AML. Midostaurin is a type I FLT3i active against PDGFR, KIT, SRC, and other RTKs22,23. 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.
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