Poster Board II-185
Hematologic and cytogenetic responses to first-line imatinib are high in patients with chronic myeloid leukemia (CML), but only a minority of patients proceeds to a complete molecular response (CMR). Persistent residual disease at the molecular level may be designated as molecular resistance and has been suggested to be accounted for by quiescent malignant stem cells. P-glycoprotein (P-gp), which is encoded by the ABCB1 multi drug resistance (MDR1) gene, has been demonstrated to mediate efflux of imatinib. As hematopoietic progenitor cells efficiently express P-gp, it was hypothesized that single nucleotide polymorphisms (SNPs) of the ABCB1 gene that account for differences in functional activity may possibly be involved in the probability of developing a molecular response to imatinib and molecular resistance. Methods: We set out to evaluate whether the 3 most prevalent MDR1 SNPs (C1236T; G2677T/A; C3435T) would be associated with molecular response in a cohort of 46 early chronic phase CML patients who received 800 mg of imatinib. Molecular response was assessed according to the International Scale. Results: Patient characteristics, including age and Sokal risk score, were distributed evenly among groups of patients, classified according to SNP-genotype. The median follow-up was 46 months (range, 32-60 months). Each of the 3 SNPs were in Hardy-Weinberg equilibrium. However, each combination of 2 SNPs was in strong linkage disequilibrium (P<.001). The overall cumulative incidences of a major molecular response (MMR) and CMR were 78% and 41%, respectively, at 2 years. Molecular responses proved to depend strongly on SNP-genotype. A cumulative incidence of MMR of 52% and 50% was observed in patients with genotype 1236CT or TT as compared to 92% in patients homozygous for 1236C (hazard ratio's (HR): 0.32 and 0.33, P=.02) in univariate analysis, which remained significant (P=.03) following multivariate analysis. Patients homozygous for allele 3435T showed a CMR rate of 10% versus a CMR of 50% at 1 year in patients homozygous for allele 3435C (HR: 0.24 (0.07-0.83, P=.04). Hazard ratio's with respect to CMR associated with C1236T and G2677T were: 0.27 (0.08-0.97, P=.01) for the 1236TT genotype versus the 1236CC genotype, and 0.23 (0.06-0.88, P=.05) for the 2677TT genotype versus the 2677GG genotype, indicating a 4-fold reduction of the probability to develop a CMR. Given the strong linkage disequilibrium, the response differences could not unequivocally be attributed to a single SNP. However, given the enhanced P-gp activity earlier associated with the 2677TT genotype, it is suggested that enhanced clearance of imatinib by the 2677TT genotype may account for the lower incidences of a MMR and CMR in those patients. Conclusions: Molecular resistance in CML patients receiving high-dose imatinib appeared strongly associated with ABCB1 genes SNPs, suggesting a role for P-gp mediated drug efflux in malignant hematopoietic progenitor cells, that may possibly account for persistent molecular residual disease in patients favourably responding to imatinib.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.