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.
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; 19(1):1-18. DOI:10.1517/14728222.2014.960843 · 4.90 Impact Factor
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ABSTRACT: The objective was to evaluate the prognostic and predictive impact of allelic ratio and insertion site (IS) of internal tandem duplications (ITD), as well as concurrent gene mutations with regard to postremission therapy in 323 patients with FLT3-ITD positive acute myeloid leukemia (AML). Increasing FLT3-ITD allelic ratio (p=0.004) and IS in the tyrosine kinase domain 1 (TKD1, p=0.06) were associated with low complete remission (CR) rates. After postremission therapy including intensive chemotherapy (CTX, n=121) or autologous hematopoietic stem cell transplantation (HSCT, n=17), an allelic ratio ≥0.51 was associated with an unfavorable relapse-free (RFS, p=0.0008) and overall survival (OS, p=0.004); after allogeneic HSCT (n=93), outcome was significantly improved in patients with a high allelic ratio (RFS, p=0.02; OS, p=0.03), whereas no benefit was seen in patients with low allelic ratio (RFS, p=0.38; OS, p=0.64). Multivariable analyses revealed a high allelic ratio as a predictive factor for the beneficial effect of allogeneic HSCT; ITD IS in TKD1 remained an unfavorable factor, whereas no prognostic impact of concurrent gene mutations was observed. The clinical trials described herein were previously published or are registered as follows: AML HD93, reference 29; AML HD98A, reference 30; AMLSG 07-04, ClinicalTrials.gov identifier: NCT00151242.Blood 09/2014; 124(23). DOI:10.1182/blood-2014-05-578070 · 9.78 Impact Factor
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ABSTRACT: The detection of fetal liver tyrosine kinase 3 (FLT3) internal tandem duplications (ITDs) has been used as a powerful adverse prognostic indicator for acute myeloid leukemia (AML) in any age group. Evidence is mixed regarding the effects of allogeneic transplantation (allo-HSCT) in first complete remission (CR) for patients with FLT3/ITD AML. To fill this gap, this study provides a systematic review and meta-analysis of FLT3/ITD AML patients receiving HCT. A search of PubMed, Embase, Pubmed, OVID yielded 1706 abstracts, two researchers screening the trials based on inclusion and exclusion criteria, and assessed the methodology quality independently. Meta-analysis showed that compared with chemotherapy, both allo-HSCT and autologous hematopoietic cell transplantation (auto-HSCT) can reduce the relapse rate(P<0. 01), and improve both the OS(P<0.01)and DFS (P<0.01). But when compared allo-HSCT with auto-HSCT, the OS(P=0.27)and DFS(P=0.19)have no statistical significance, only the relapse indicator has statistical significance,P<0.01. Based on the results we can conclude that Allo-HSCT is an efficient therapy approach for AML patients with FLT3/ITD. Chemotherapy can not Change the poor prognosis. Auto-HSCT can improve OS and DFS, but it can not reduce the relapse rate.This article is protected by copyright. All rights reserved.Clinical Transplantation 11/2014; 29(2). DOI:10.1111/ctr.12495 · 1.49 Impact Factor