Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in newly diagnosed patients with chronic myeloid leukemia.
Polymorphisms in genes coding for imatinib transporters and metabolizing enzymes may affect imatinib pharmacokinetics and clinical response. Aim of this study was to assess the influence of polymorphisms in MDR1 and CYP3A5 genes on imatinib trough levels, cytogenetic and molecular response in patients with CML. Newly diagnosed patients with chronic-phase CML started on imatinib therapy were enrolled and followed up prospectively for 24 months. The following single nucleotide polymorphisms were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene. Genotyping was done using PCR-RFLP method and validated by direct gene sequencing. Trough levels of imatinib were measured using LC-MS/MS. Cytogenetic response was assessed by conventional bone-marrow cytogenetics. Molecular response was assessed by qRTPCR using international scale. A total of 173 patients were included, out of which 71 patients were imatinib responders, while 102 were non-responders. Marked inter-individual variability in trough levels of imatinib was seen. Patients with GG genotype for CYP3A5-A6986G (P=0.016) and TT genotype for MDR1-C3435T (P=0.013) polymorphisms had significantly higher trough levels of imatinib. Patients with AA genotype for CYP3A5-A6986G [RR=1.448, 95% CI (1.126, 1.860), P=0.029] and CC genotype for MDR1-C1236T [RR=1.397, 95% CI (1.066, 1.831), P=0.06] &MDR1-C3435T [RR=1.508, 95% CI (1.186, 1.917), P=0.018] polymorphisms were at high risk for failure of imatinib therapy. Patients with CGC haplotype for MDR1 polymorphisms had significantly lower imatinib trough levels and were at a higher risk of imatinib failure [RR=1.547, 95% CI (1.324, 1.808), P<0.001]. GG vs. non-GG genotype for CYP3A5-A6986G [adjusted OR: 0.246; 95% CI (0.116, 0.519); P<0.001] and TT vs. non-TT genotype for MDR1-C1236T [adjusted OR: 0.270; 95% CI (0.110, 0.659); P=0.004] &MDR1-C3435T [adjusted OR: 0.289; 95% CI (0.135, 0.615); P=0.001] polymorphisms were independent factors predicting imatinib response in multivariate analysis. To conclude, MDR1 and CYP3A5 genetic polymorphisms significantly influence plasma trough levels and therapeutic response of imatinib in patients with CML. Genotyping of these polymorphisms could be of value to individualize the therapy and optimize the clinical outcomes.
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India.
Natarajan
N
Harivenkatesh
Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India.
Lalit
L
Kumar
Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India.
Sameer
S
Bakhshi
Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India.
Atul
A
Sharma
Department of Pediatrics (Genetics Unit), All India Institute of Medical Sciences, New Delhi 110029, India.
Madhulika
M
Kabra
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India.
Thirumurthy
T
Velpandian
Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India.
Ajay
A
Gogia
Department of Pediatrics (Genetics Unit), All India Institute of Medical Sciences, New Delhi 110029, India.
Shivaram S
SS
Shastri
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India.
Nihar Ranjan
NR
Biswas
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: yk.ykgupta@gmail.com.
Yogendra Kumar
YK
Gupta
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000097:blood / Q000627:therapeutic use*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate / Q000097:blood / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D055815:Young Adult
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; D051544:Cytochrome P-450 CYP3A
Imatinib resistance; P-glycoprotein; Personalized medicine; Pharmacogenetics; Single nucleotide polymorphisms; Tyrosine kinase inhibitor