FLT3: A TARGET FOR MOLECULAR THERAPY IN EGYPTIAN ACUTE MYELOGENOUS LEUKEMIA

Constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplication (ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (TKD), has been described in patients with acute myelogenous leukemia (AML). Multiple small molecule in-hibitors are under development to target aberrant FLT3 activity that confers a poor prognosis in pa-tients. The aim of this study is to evaluate the frequency of FLT3 mutations in Egyptian acute myeloid leukemia (AML), in an attempt to identify a subset of patients, who might be candidates for targeted therapy. We have analyzed 87de novo AML patients for the presence of FLT3/ITD using genomic DNA polymerase chain reaction (PCR). Fifty-four cases were also tested for the presence of FLT3-TKD point mutation using PCR and restriction fragment length polymorphism (RFLP). The results were correlated with the clinical picture and the disease outcome. FLT3/ITDs were detected in 19/87 (22%) of the cases, including 13/67(19%) adults and 6/20 (30%) pediatric patients. The presence of mutation was significantly associated with a high peripheral blood WBC counts (P= 0.006) and a high percentage of bone marrow blast cells (p=0.039). Patients with FLT3/ITD had a lower complete remission (CR) rate (21.1%), and a lower overall survival (OS) (48%), as compared to 42.6% and 57% for those without the mutation respectively; however the difference did not reach the level of sig- nificance. Four patients showed more than one mutant allele, and in three other cases, the wild type allele was lost. All seven patients (100%) failed to attain complete remission. FLT3-TKD point mutation was detected in 1 of 54 (2%) cases. None of the cases tested had both mutations. FLT3/ITD is frequent in Egyptian AML. Routine testing of AML cases is warranted to identify the subset of patients, who might be candidates for FLT3 inhibitors, either as a primary, or as an adjunct to current standard induction and post-remission regimens.