Activating Mutation of D835 within the Activation Loop of FLT3 in Egyptian Patients with De Novo Acute Myeloid Leukemia with Low or Intermediate Risk Karyotypes are Associated with Poor Disease-Free Survival
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- Category: Vol. 82, March 2014
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Activating Mutation of D835 within the Activation Loop of FLT3 in Egyptian Patients with De Novo Acute Myeloid Leukemia with Low or Intermediate Risk Karyotypes are Associated with Poor Disease-Free Survival, YASSER A. SALLAM, ESSAM H. ELNOSHOKATY, FARIDA H. GADALLAH and SHEREN I. SALEM
Abstract
Background: AML accounts for approximately 41.5% (349) out of the 840 newly diagnosed cases with acute leukemia registered in the time period between January 2002 and December 2003, at National Cancer Institute, Cairo University [1].
Despite improvement in AML diagnosis and therapeutics, most patients die from relapse, even those with favourable karyotypes. Hence the need for employing, other genetic parameters that can predict risk of relapse. Several studies reported the significance of FLT3 as independent marker for clinical outcome in most AML patients.
FLT3 mutations, which were originally described in 1996 by Nakao et al., [15], are present in approximately one third of AML cases, making FLT3 the most frequently mutated gene found in AML [1,2,15,16]. Two classes of FLT3 mutations have been described. The first class, consisting of internal tandem duplications (FLT3-ITDs) in exons 14 and/or 15 of the receptor, occur in approximately 25% of AML patients [1,15,16,20]. The second class, small deletions or insertions in the activation loop of the tyrosine kinase domain (FLT3- TKDs), occur in 5%-14% of AML patients [16,23-25].
Aim: The clinical relevance of D835 mutations in the second tyrosine kinase domain of FLT3 (FLT3 TKD), that occur in 5%-14% of patients (pts), remains controversial. Relative to FLT3 WT pts, FLT3 TKD remained significantly associated with adverse DFS. FLT3 TKD appears to be an independent predictor for DFS among AML adult pts without FLT3 ITD.
Methods: So we conducted a study to investigate the incidence, prognostic impact of mutations and the ratio between mutant and wild type FLT3 in patients with de novo AML expressing normal or intermediate risk karyotypes.
Our study included 60 subjects with newly diagnosed acute leukemia ranging in age from 18 to 60 years. They all presented to the medical oncology clinics, National Cancer Institute, Cairo University, over a time period of 2 years.
Results: Analyzing the association of mutations with FAB subtypes and biological characteristics of the 60 AML patients studied, showed that five patients (8.3%) showed D835 mu-tation.
Statistical comparison of laboratory data between D835(+) and D835(–) revealed a higher platelet count in patients had D835(+) was 118.2±68.99x109/l compared to patients who had D835(–) was 44.63±37.95 x109/l with a significant dif-ference between the two groups (p-value 0.02), otherwise differences in HB, WBCs in the peripheral, percentage of blasts in the peripheral blood, percentage of bone marrow blasts at presentation, percentage of bone marrow blast at day 15 of treatment were all statistically insignificant between the two groups.
Comparison of response to treatment at day 15, in patients (5) who had D835(+), 4 patients (80%) had complete remission (CR) and 1 patient (20%) had partial remission (PR). In patients (44) had FLT3 wild type 22 patients (50%) had Complete remission, 2 patients (4.5%) had partial remission, 4 patients (9.09%) had no response and 16 patients (36.36%) died.
As regard time to relapse in patients with D835(+) was 3.2±0.73 month and in patients had D835(–) was 10.45±1.49 month with a high statistical significant difference between the two groups (p-value 0.0073).
The D835(+) patients had a worse DFS, median DFS being 4.0 month (95% confidence interval 2.25-5.75) as compared with the FLT3/WT patients for whom median DSF was 10 months (95% confidence interval 6.53-13.47) (p-value 0.0073). The median OS for D835+ were not different from those for WT patients (p-value 0.34).
Conclusions: For AML patients harboring (FLT3-TKDs)/ D835(+) had a a higher platelet count, worse DFS, compared to FLT3 WT pts.