OCT1 genetic variants are associated with long term outcomes in imatinib treated chronic myeloid leukemia patients.
OBJECTIVE
One third of CML patients treated with first line imatinib have suboptimal responses or treatment failures with increased risk for disease progression. Imatinib is actively transported into cells by the SLC22A1 transporter (hOCT1) and its genetic variants may affect intracellular drug import. We studied the effect of SLC22A1 genetic variants on long-term outcomes of imatinib treated patients.


METHODS
A total of 167 patients, 94% in chronic phase, were analyzed for rs41267797, rs683369, rs12208357, and rs628031 variants using the Sequenom MassARRAY platform.


RESULTS
Rates of CHR, MCyR, CCyR, and MMolR were not significantly different according to allelic variants. However, patients with AA or GA rs628031 genotypes had a higher incidence of poor response to imatinib compared to the GG genotype (47% compared to 29%, P = 0.06), and a higher rate of KD mutation discovery (8/16 vs. 5/27, P = 0.04), suggesting that secondary resistance was more common in these genotypes. Median EFS was shorter for rs628031 genotype AA/AG compared with the GG genotype (61 months and not reached, respectively, P = 0.05), and 5 yr OS rates were lower for patients with the rs628031 genotypes AA/AG compared with the GG genotype (88% and 97%, respectively, P = 0.03). Patients with AA/GA rs628031 and additional rare genotypes had worse EFS and OS compared to patients with only AA/GA rs628031 (P = 0.02 for EFS and 0.01 for OS). There was no difference in pretreatment SLC22A1 mRNA expression levels in patients with rs628031 genotypes GG/AA or GA.


CONCLUSIONS
Studying SLC22A1 genetic variants prior to TKI initiation could influence treatment decisions.
Division of Hematology, Chaim Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Maya
M
Koren-Michowitz
Zehavit
Z
Buzaglo
Elena
E
Ribakovsky
Michaela
M
Schwarz
Ilias
I
Pessach
Avichai
A
Shimoni
Katia
K
Beider
Ninette
N
Amariglio
Philipp
P
le Coutre
Arnon
A
Nagler
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D015870:Gene Expression; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
D000970:Antineoplastic Agents; D001549:Benzamides; D027702:Organic Cation Transporter 1; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate
CML; hOCT1; kinase domain mutations; resistance; tyrosine kinase inhibitor