Molecular Screening for T315I and F317L Resistance Mutations in Iraqi Chronic Myeloid Leukemia Non-Responders Patients to Imatinib

Abstract

The development of Imatinib Mesylate (IM), the first generation specific tyrosine kinase inhibitor (TKI) of BCR-ABL, has had a major impact in patients with Chronic Myeloid Leukemia (CML), establishing IM as the standard therapy for CML. Despite the clinical success obtained with the use of IM, primary resistance to IM and molecular evidence of persistent disease has been observed in 20-25% of IM treated patients. The existence of second generation TKIs (SGTKIs), which are effective in patients with IM resistance, makes identification of predictors of resistance to IM an important goal in CML. The aim of this prospective study was to determine prevalence of T315I, which confers full resistance to all available tyrosine-kinase inhibitors, and F317l mutations, which classified as resistant mutation to IM and dasatinib but sensitive to nilotinb, in IM non-responder CML patients from Iraq with highly sensitive Allele-Specific Oligonucleotide-PCR assay (ASO-PCR). Forty four CML patients were recruited from Baghdad Teaching Hospitalet-Hematology Unite from Feb. 2009 to Feb. 2013. Those patients were followed up (hematological, cytogenetically, and molecularly). At the time of sampling, thirty four CML patients in advance phase(accelerated phase(AP) or blast crisis(BC)) or loss their cytogenetic response were IM non-responders while ten CML patients in CP were IM responder, considered as T315I and F317 L mutations negative control group. Ten IM non-responders patients out of those 34 patients were recruited to SGTKIs (Dasatinib and/or Nilotinib). The results shown that only T315I mutation was detected in one IM non-responder CML patient (3%). Although relation between response to SGTKIs and mutation status was non-significance (P= 0.100), mutation is limited to only one patient who did not respond to either treatment forms. In conclusion, the uses of bcr-abl mutation screening test for T315I and F317L mutations in CML patients may influences the choice of specific SGTKIs after treatment with IM has failed.

Prevalence of BCR-ABL T315I Mutation in Malaysian Patients with Imatinib-Resistant Chronic Myeloid Leukemia

“…Elnahass et al, (2013) reported that 3.57% (1/28) T315I mutation was detected in IM resistant patients. The findings from Dhahi et al, (2013) showed the frequency of T315I mutation was detected in 1 of 34, 3.03% CML patients in accelerated phase after IM failure. Both studies were performed using allele-specific oliogonucleotide-PCR for mutation screening (Elnahass et al, 2013).…”

Epigenetic Modulation of DDIT3 and MGMT Expression Acts Synergistically with Resistance to Imatinib towards CML Disease Progression: A Hospital based Study

“…Synergistically with Resistance to Imatinib towards CML Disease Progression: A Hospital based Study al., 2007;Dhahi et al, 2013). BCR-ABL mutations were revealed in 40-60% of Imatinib mesylate-resistant patients (Hochhaus et al, 2013).…”