Prognostic Impact of Internal Tandem Duplications in the Juxtamembrane Domain of FMSLike Tyrosine Kinase 3 Gene (FLT3-ITDs) in Patients with De Novo Acute Myeloid Leukemia with Favorable Karyotypes
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Prognostic Impact of Internal Tandem Duplications in the Juxtamembrane Domain of FMSLike Tyrosine Kinase 3 Gene (FLT3-ITDs) in Patients with De Novo Acute Myeloid Leukemia with Favorable Karyotypes,YASSER A. SALLAM, FARIDA GADALLAH, SHEREEN I. SALEM and ESSAM H. ABDOU
Abstract
Acute myeloid leukemia (AML), refer to a group of marrow-based neoplasms that have clinical similarities but distinct morphologic, immunophenotypic and cytogenetic features. The overall annual incidence is 3.4/100,000. Affects all age groups. The incidence of AML increases with age, with a median of 68 years. in adults, AML accounts for 80% of cases of acute leukemia, At National Cancer Institute, Cairo University; 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 [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.
So we conducted a study to investigate the incidence and prognostic impact of FLT3 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; 32 were males and 28 were females they all presented to the medical oncology clinics, National Cancer Institute, Cairo University, during the time period from January 2005 to December 2007.
Analysing the association of FLT3 mutations with FAB subtypes and biological characteristics of the 60 AML patients studied, showed that 11 had the FLT3/ITD mutation (18.3%). The patients ranged in age from 18 to 60 years with a median age of 39.5 years the age of patients at presentation was similar in both groups. There was no statistically significant difference in age and sex between the patients harboring mutations in the FLT3 gene and patients with no FLT3 muta-tion. The majority of FLT3 mutations were detected in patients with M1 9 of 22 (40.9%), M2 5 of 16 (31.3%), M4 2 of 7 (22.2%). Stratifying patients using FAB classification of AML there was a statistically significant difference between the
distribution of FLT3/ITD(+) and FLT3/ITD(-) by FAB classi-fication, where FAB classification in FLT3/ITD(+) cases was [M1: 7 patients (31.8%), M2: 4 patients (25%)] and in FLT3/ ITD(-) cases was [M1 15 patient (68.2%), M2 12 patient (75%), M3, M4, M5 and M7 22 patients (100%)]. (p value 0.005).
Statistical comparison of laboratory results between FLT3/ ITD(+) and FLT3/ITD(-) revealed that the percentage of bone marrow blasts at day 15 of treatment between the two groups in patients with FLT3/ITD(+) was 28.36±32.76% denoting resistance to treatment and lack of response, while in the patients with FLT3/ITD(-) was 6.59±14.59% with a highly significant difference between the two groups (p value 0.005). However, no difference was reported between the two groups as regard the percent of blasts in the peripheral blood or bone marrow at presentation. The mean value of HB, WBCs in the peripheral blood, the platelet count between the two groups revealed no significant difference between the two groups. Likewise more patients with FLT3/ITD(-) had remission to treatment at day 15 compared to FLT3/ITD(+) patients, how-ever such difference was not statistically different. Also, time to relapse was shorter for patients with FLT3/ITD(+) compared to FLT3/ITD(-) with a statistically significant difference between the two groups (p value 0.0013).
Survival analysis showed the ITD(+) patients had a worse DFS, compared to the FLT3/WT patients (95%confidence interval 0.43-5.57) (p value 0.0013), however the median Survival did not show such effect, with median OS of 4.00 months (95%confidence interval 1.92-6.08) for the ITD+ and 3.00 months (95%confidence interval 0.72-5.28) for FLT3/WT (p-value 0.28). Our data support the previous studies that FLT3/ITD may be a strong prognostic factor in AML patients, and is associated with a high rate of relapse and lower DFS.