Imatinib Resistance Mutation Analysis Pattern In Chronic Myeloid Leukemia (CML) Patients on Imatinib In Indian Population.

Imatinib has revolutionized the treatment of CML. Still there are hurdles with the drug, as, with the passage of time patients are either not responding or showing loss of response. The nonresponsiveness has been proved to be due to genetic mutations which may be primary or acquired. Still less is known about the pattern of mutations especially in asian countries. So there is a need to identify the pattern of mutations, so that second line tyrosine kinase inhibitors’ response may be studied with respect to these mutations and new drugs can be designed concentrating on the most common mutations. In an attempt to identify a pattern of mutation in asian population we carried out an analysis at our centre.

The patients who were on imatinib at Kidwai memorial institute of oncology, underwent testing for hematological response(HR) every month, cytogenetic response (CyR) every 6 month and molecular response(MR) every year. Patients who did not achieve either hematologic or cytogenetic or molecular milestones or had loss of response underwent imatinib resistance mutation analysis(IRMA). We analyzed a total of 102 patients. The IRMA was done at Oncquest Laboratories Ltd.,New Delhi, India. The method used at the laboratory is a combination of RTPCR and double pass sequencing. The sequence results were analyzed using BLAST software from NCBI and GRAPH ANALYSIS software from applied biosystems.

Between Jan. 2007 to May 2010, a total of 102 patients were analysed for imatinib resistance. Out of these 102 patients, 5(4.9 %) patients presented in blast crisis, 7(6.86%) in accelerated phase and 90(88.23%) in chronic phase. Male to female ratio was 1.7:1. 95 patients had achieved complete hematological response(CHR) at the end of 3 mths but 7 patients did not achieve CHR at 3 mths. So these were the candidates of IRMA. 2 patient had loss of HR. 42 patients did not achieve cytogenetic milestones. 28 patients had loss of cytogenetic response. 15 patients did not achieve major molecular response. and 8 had loss of molecular response. So these 102 patients were candidates for IRMA. Analysis revealed: No mutation - 74 patients. F 359 I – 3 patients, T 315 I(Thr to Ile) – 4 patients, M 351 T (Met to Thr) – 5 patients, M 244 V (Met to Val) – 2patients, H 395 R – 1 patients, Y 253 H – 2 patients, 355 G(GLU to GLY) – 1 patient, 250 E (GLY to GLU)- 1 patient, G250 E (GLY to GLY) - 1patient, F 359 C (Phe to Cys) – 1 patient, F 311 L(Phe to Leu) – 1 patient, Y 253 F(Tyr to Phe) – 1 patient, E 275 K (Glu to Lys) – 2 patients, V 253 F – 2 patients and F317L- 1 patient.

Most of the patients (74/102 patients) did not show any mutations. Most common mutation seen was M 351 T in 5 patients. T 315 I mutation was seen in 4 patients and all these patients had a loss of response. All these mutations should be studied with respect to response to second line tyrosine kinase inhibitors particularly in asian Indian population.

No relevant conflicts of interest to declare.