Patterns of imatinib resistance mutation analysis in chronic myeloid leukemia (CML) patients on imatinib at the time of loss of response to the drug in Asian Indian subjects

Abstract

7079 Background: The treatment of (CML) has undergone major changes in the past decade with the introduction of tyrosine kinase inhibitors (TKI). However the initial enthusiasm is waning with increasing recognition of drug resistance. There is an urgent need to identify the types of receptor mutations which lead to drug resistance and their significance in salvage therapy. Methods: We identified 17 males and 8 female patients with median age 40 yrs (range 9–55 years) with CML who were on imatinib at the time of loss of hematologic response (HR), cytogenetic (CyR), or molecular response (MR) and performed imatinib-resistance mutation analysis. The sequencing was done on ABI machine by direct sequencing method. Results: This group included 22 patients with chronic phase (CP) disease, 2 patients with accelerated phase (AP), and 1 patient with extramedullary blast crisis (BC). Fourteen patients received treatment with agents other than imatinib as the first-line therapy due to either nonavailability of the drug at the time of diagnosis in India, but were started on imatinib when drug became available. The other 11 patients received imatinib as first-line therapy. The best response to imatinib included major CyR in 14 patients which included 3 patients with complete CyR and minor CyR in 6 patients. Lack of HR was noted in 2 patients in whom CyR was not evaluated. Imatinib resistance mutation analysis was prompted by no HR (n = 2); loss of HR after achieving CyR (n = 9); failure to achieve CyR milestones (n = 3); loss of CyR (n = 9); development of extramedullary BC (n = 1). The analysis revealed no mutations-11 patients, M351T-4 patients, G250E-3 patients, F317L-2 patients, M244V- 1 patient, T315I-1 patient, F382L-1 patient, results awaited in 4 patients with 2 patients showing 2 mutations. Conclusions: The majority of patients 11/25 had no detectable mutations while T315I which confers resistance to all TKIs was detected only in 1/25 patients who demonstrated loss of response in our population. The correlation of the other mutations to loss of response and the response to second line TKI needs to be studied in further detail. In addition analysis of mutation patterns at baseline may help in stratifying patients for treatment. No significant financial relationships to disclose.

Mutation Analysis in Chronic Myeloid Leukemia Patient in Chronic Phase on Imatinib Having Delayed Achievement of Milestones or Loss of Response

“…Only 27 patients (27%) had mutation detected, M351T, T315I being most common in 4 patients each and F359I in 3 patients. Prakash et al [14] reported analysis of mutations in 25 patients with CML on Imatinib at the lime of loss of response to the drug in Asian-Indian patients. Twenty-two patients were in chronic phase and median age was 40 years.…”

“…Kinase domain mutations were evaluated using the fluorescent nucleotide sequencing technique followed by bioinformatics tool, multiple nucleotide sequencing alignment. Indications of mutation analysis were based on recent European LeukemiaNet guidelines [14]. Loss of hematological response (HR), cytogenetic response (CyR) or molecular response or delay in attaining defined landmarks were indications for asking imatinib resistance mutation analysis.…”

“…Loss of hematological response (HR), cytogenetic response (CyR) or molecular response or delay in attaining defined landmarks were indications for asking imatinib resistance mutation analysis. Hematological response, cytogenetic and molecular responses at different time points were defined as per ELN 2013 guidelines for chronic myeloid leukemia [14]. Poor response was defined as not achieving hematological, cytogenetic or molecular response at defined time points by ELN.…”