Potent Graft-versus-Leukemia Effect after Reduced-Intensity Allogeneic SCT for Intermediate-Risk AML with FLT3-ITD or Wild-Type NPM1 and CEBPA without FLT3-ITD.
ABSTRACT To investigate the role of reduced-intensity allogeneic (RIC-allo) stem cell transplant (SCT) as postremission therapy in adult intermediate-risk patients with acute myelogenous leukemia (AML) with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD, we conducted a single-center retrospective study between January 2001 and December 2010. Sixty-six patients were included: 37 treated with RIC-alloSCT and 29 with nonallogeneic SCT therapies. Both groups were comparable concerning age, WBC count at diagnosis, gender, karyotype, genotype, and number of courses of chemotherapy to reach complete remission (CR1). Median follow-up after CR1 was 37 months (range, 11-112 months) and 48 months (range, 9-83 months) in the allo and no-allo groups, respectively. In the allo versus no-allo groups, the 3-year cumulative incidence of relapse (CIR) rates were 25% ± 8% versus 61% ± 9%; P = .005. The 3-year nonrelapse mortality (NRM), overall survival (OS), and relapse-free survival (RFS) were 22% ± 7% versus 4% ± 4% (P = .005), 52% ± 9% versus 44% ± 10% (P = .75), and 53% ± 9% versus 35% ± 9% (P = .28), respectively. Multivariate analysis indicated that CIR was reduced by allo (hazard ratio [HR], 0.32; P = .01). A landmark analysis performed at day 185 after CR1 confirmed a lower CIR after allo. RIC-allo reduces the risk of relapse, suggesting a potent graft-versus-leukemia (GVL) effect in these patients at a high risk of relapse.
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ABSTRACT: FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in AML. Thirty percent of patients with acute myeloid leukemia (AML) harbor activating mutations in FLT3, either internal tandem duplication mutations in the juxtamembrane domain (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3 TKD). Small molecule FLT3 inhibitors have emerged as an attractive therapeutic option in patients with FLT3 mutations; however, the clinical activity of early inhibitors was limited by a lack of selectivity, potency and unfavorable pharmacokinetic properties. Newer agents such as quizartinib have improved potency and selectivity associated with much higher bone marrow response rates; however, response duration is limited by the development of secondary resistance. We will review here a number of FLT3 inhibitors that have been evaluated in clinical trials and discuss challenges facing the use of these agents in AML.Current Hematologic Malignancy Reports 03/2014; 9(2).
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ABSTRACT: Patients with acute myeloid leukemia who harbor an FMS-like tyrosine kinase 3 (FLT3) mutation present several dilemmas for the clinician. The results of an FLT3 mutation test, which can be influenced by several variables, need to be interpreted according to the clinical setting and there is a need for internationally standardized FLT3 mutation assays. Because of the lack of prospective studies, the role of allogeneic transplantation as consolidation therapy is still somewhat controversial, but the preponderance of evidence suggests that transplantation in first remission, if possible, is probably the best option. Clinically useful FLT3 inhibitors are hopefully on the near horizon and are being studied in the context of current treatment paradigms.Hematology 12/2013; 2013:220-6. · 1.49 Impact Factor
Article: Targeting FLT3 to treat leukemia.[Show abstract] [Hide abstract]
ABSTRACT: Introduction: Approximately 23% of acute myeloid leukemia (AML) patients younger than 60 years of age carry a mutation in the transmembrane domain of the FMS-like tyrosine kinase-3 (FLT3) gene (FLT3/internal tandem duplications [ITD]). In normal karyotype AML, the presence of a FLT3/ITD mutation is associated with poor prognosis, as mirrored by a high risk of relapse even after allogeneic stem cell transplantation. The poor prognostic impact along with the observation that FLT3 is frequently overexpressed in the majority of AML cases has formed the platform for the development of FLT3-targeted strategies. To date, several FLT3 kinase inhibitors have been investigated in preclinical and clinical studies. However, as of yet, none of the studied FLT3 inhibitors has received FDA approval for routine clinical use in AML. This is in part due to the 'off target' effects observed with most inhibitors when administered at concentrations needed to achieve sustained levels of FLT3 inhibition, which are required to exhibit substantial cytotoxic effects against leukemic blasts. Furthermore, the development of resistance mutations has emerged as a clinical issue posing a threat to successful FLT3 inhibitor therapy. Areas covered: In this review, the authors provide a brief summary of FLT3 inhibitors investigated thus far, and discuss current treatment approaches and strategies how to best incorporate FLT3 tyrosine kinase inhibitors (TKIs) into therapy. Expert opinion: The combination of a FLT3 inhibitor with conventional chemotherapeutic regimens, epigenetic modifiers or inhibitors of FLT3 downstream and collateral effectors has emerged as a promising strategy to improve treatment outcome. The future of a tailored, molecular-based treatment approach for FLT3-mutated AML demands novel clinical trial concepts based on harmonized and aligned research goals between clinical and research centers and industry.Expert Opinion on Therapeutic Targets 09/2014; · 4.90 Impact Factor