Analysis of flt3 in Adult AML

FLT3 gene encodes a tyrosine kinase receptor, which is involved in proliferation and differentiation of hematopoietic stem cells. FLT3 mutations are frequently encountered in all AML subgroups specially in AML with t(15;17)- Acute Promyelocytic Leukemia (APL)-, and infers poor prognostic effect. FLT3-ITD mutations represent about 80% of FLT3 mutations. In this study, we aimed to assess frequency and correlation of FLT3-ITD mutation with different AML cytogenetic subgroups, also with MPAL cases and to study the prognostic role of this mutation with focusing on APL.

Between 2011 and 2014 in NCI, Cairo University, 212 newly diagnosed acute leukemia patients [198 AML (10 M0, 47 M1, 56 M2, 30 M3, 49 M4, 4 M5, 1 M6 and 1 M7) and 14 MPAL] were included in this study. Thorough Morphological, Immunophenotypic and cytogenetic analysis were done at initial presentation and fixed follow up time points (Day 14, 28, 36) with subsequent monitoring and follow up of patients. FLT3-ITD mutation was detected using RT-PCR.

FLT3-ITD mutation was detected in 44/198 AML patients (22.2%) and in 2/14 MPAL patients (14.3%). Correlation with cytogenetic subgroups show significant higher incidence in M3 patients 13/30 (43.3%, P=0.0371) in comparison to other types (20% M0, 20.6% M1, 20.1% M2, 13.4% in Monocytic Leukemia -M4 and M5-). In non-APL patients, favorable cytogenetic changes are more common in FLT3 wild group (19.7%)[27/137 (21 patients with t(8;21) and 6 with inv 16] than in FLT3 mutant group (6.5%) [2 with t(8;21) and none with inv 16]. There were insignificant difference between FLT3 wild and mutant group regarding achieving Compete Remission (CR) by Day 36 (P= 0.261), However Overall Survival (OS) of the wild group was high significantly better than that of mutant group (P=0.002). By the end of the 1^st year only 10% of patient with mutant FLT3 were alive versus 30% of those with wild type, with 4 months median survival of mutant group versus 8 months of the wild group.

In APL patients, again there was no significance between both groups regarding achieving CR by Day 36 (P=0.06) and still OS of APL patients with wild FLT3 was significantly better than in those with mutant FLT3 (P=0.0182). By the end of 1^st year, about 90% of patients with wild group are still alive while only 46% of the mutant group are alive with 2 months median survival.

We conclude that FLT3-ITD mutations infers poor prognostic effect even in the presence of favorable cytogenetic changes like t(15;17); which indicate that patient with such mutations should be assigned to aggressive therapy.