Genetic polymorphisms in the genes coding for imatinib transporters & metabolizing enzymes might be responsible for marked inter-individual pharmacokinetic variability seen with imatinib. Whether these polymorphisms influence the risk of cytogenetic relapse in patients with CML on imatinib therapy is unknown.
Patients with chronic phase CML on imatinib therapy & have completed 5 years of follow-up were enrolled. The following single nucleotide polymorphisms were genotyped- C1236T, C3435T, G2677T & G2677A in MDR1 gene and A6986G in CYP3A5 gene. Genotyping was done using PCR-RFLP method & validated by direct gene sequencing. Plasma trough levels of imatinib were measured using LC-MS/MS. Cytogenetic relapse was defined as the presence of Philadelphia chromosome positive metaphases in conventional bone marrow cytogenetic study in patients who had already achieved complete cytogenetic response.
A total of 104 chronic phase CML patients (52 cases with cytogenetic relapse & 52 controls without cytogenetic relapse) were included. Mean age at diagnosis was 36 years. Among the SNPs genotyped, statistically significant difference in the frequency of various genotypes was seen for MDR1-C1236T & C3435T polymorphisms, between the patients with & without relapse (table 1). Patients with CC genotype for MDR1-C1236T polymorphism were at a significantly higher risk of relapse [OR = 4.382, 95%CI (1.145, 16.774), p = 0.022], while those with TT genotype for MDR1-C3435T polymorphism had a significantly lower risk of relapse [OR = 0.309, 95%CI (0.134, 0.708), p = 0.005]. Patients with cytogenetic relapse had lower trough levels of imatinib compared to those without relapse (table).
Frequency of genotypes and trough levels of imatinib in patients with and without cytogenetic relapse
|SNP||Genotype||Patients with cytogenetic relapse (n = 52)||Patients without cytogenetic relapse (n = 52)||P value|
|CYP3A5- A6986G||AA||8 (57%)||6 (43%)||0.492|
|AG||23 (55%)||19 (45%)|
|GG||21 (44%)||27 (56%)|
|MDR1-C1236T||CC||11 (79%)||3 (21%)||0.024|
|CT||34 (50%)||34 (50%)|
|TT||7 (32%)||15 (68%)|
|MDR1- C3435T||CC||11 (73%)||4 (27%)||0.010|
|CT||28 (57%)||21 (43%)|
|TT||13 (32%)||27 (68%)|
|MDR1-G2677T/A||GG||7 (70%)||3 (30%)||0.453|
|GT||23 (52%)||21 (48%)|
|TT||16 (40%)||24 (60%)|
|TA||4 (57%)||3 (43%)|
|GA||2 (67%)||1 (33%)|
|Trough levels of Imatinib (ng/mL)||1551.4 ± 1324.1||2154.2 ± 1358.3||0.041|
C1236T & C3435T genetic polymorphisms in MDR1 gene significantly influence the risk of cytogenetic relapse in patients with CML. Genotyping of MDR1 gene may be considered in patients with CML to individualize the therapy & optimize the outcomes.
Clinical trial identification
Legal entity responsible for the study
All India Institute of Medical Sciences, New Delhi
All India Institute of Medical Sciences, New Delhi (Institute funding)
All authors have declared no conflicts of interest.