Pharmacogenetic Study in Hodgkin's Lymphomas, Impact of UGT1A1 on Prognosis.

Abstract

Hodgkin lymphoma is a highly curable malignancy, but treatment outcome might be influenced by some patient's germline polymorphisms that determine anticancer agent metabolism. We prospectively collected peripheral blood lymphocytes from 313 patients with Hodgkin lymphomas in order to analyze GSTP1, GSTM1, GSTT1, UGT1A1 and CYP 450-3A4 genes polymorphisms. Median age was 32 year (range 15 – 93), 60% of the patients were treated for a stage I/II (localized) Hodgkin's lymphomas. Median follow-up was 4.1 years (0.9 – 6.5 years). All patients were then treated with an anthracyclin-based chemotherapy (ABVD, EBVP and BEACOPP), associated with radiotherapy when they had localized disease. The outcome endpoints consisted in freedom from progression (FFP), freedom from treatment failure (FFTF) and overall survival (OS). The study was designed to have a 90% power to detect an absolute difference of 20% in the proportion of events between two groups: one corresponding to the most frequent polymorphism and the second group to the remaining patients, assuming that the overall proportion of events was of 20%. The patients sample size necessary was then estimated for proportions of patients carrying the most frequent polymorphism ranging from 50 to 90%. Situations with 90% of patients carrying the most frequent polymorphism group were those requiring the highest number of patients. The size of the study was then determined to be 345 patients. This corresponded to a situation where the most frequent polymorphism is found in 90% of the patients and is associated with an event rate of 18%, whereas the event rates in other patients is 38%. There was no difference for GSTP1, GSTM1, GSTT1 as well as for UGT1A1 and CYP3A4 polymorphisms distributions between Hodgkin lymphoma patient and healthy control cohorts (184 subjects). The allele frequencies were compatible with Hardy-Weinberg equilibrium for polymorphisms in the GSTP1, UGT1A1 and CYP3-A4 genes. Patients with UGT1A1 6/6 had significantly (P<0.05) poorer FFP and FFTF compared to those with one or 2 UGT1A1*28 alleles. There was also a significant relation between overall survival and GSTT1 polymorphism (P=0.04). Multivariate prognostic analyses included all gene polymorphisms and the relevant clinical parameters. UGT1A1 polymorphism was selected as an independent prognostic parameter for all the studied end-points; the wild-type homozygous phenotype being associated with a significantly worse prognosis than phenotypes with at least one UGT1A1*28 allele (OS, RR=2.87; 95% confidence interval 1,19 – 6.94; P=0.02; FFP, RR=2.70; 95% confidence interval 1,37 – 5.31; P=0.004 and FFTF RR: 2.37; 95% confidence interval 1.28 – 4.40; P=0.006). Conclusion: UGT1A1 polymorphisms influence patient's outcome in Hodgkin's lymphoma.On Behalf from the GELA group and Laboratoire de Génétique et de recherche translationnelle, Institut Gustave Roussy