EVALUATION OF FCR THERAPY EFFICACY IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA BASED ON IMMUNOGENETIC CRITERIA

Abstract

A number of studies have shown that distinct common variants of the genes controlling immune/inflammatory response may affect efficiency of chronic lymphocytic leukemia (CLL) treatment. In a recently published paper, we reported polymorphic variants of some immune response genes in CLL patients to be associated with different rates of disease progression. Correlations between the distribution of gene modification profiles in indolent and agressive forms of CLL have been established. The present study describes results of pharmacogenetic studies aimed for identifying associations between the immune response genes polymorphism, and efficacy of FCR treatment regimen in CLL patients. 19 polymorphic loci of 14 immune response genes were studied in 33 patients with CLL who received FCR therapy. The TLR2, TLR3, TLR4, TLR6, TLR9, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17A, CD14, TNFα, FCGR2A genotypes were determined by polymerase chain reaction with allele-specific primers. CLL patients were divided into several groups depending on the terms of response to FCR treatment, i.e., achieving partial/complete remission after two, four, six courses of treatment, and those who did not respond to the therapy. Statistically significant differences in the distribution of haplotype frequencies were detected for the following genes: IL-1β (C-3953T, p = 0.02-0.009); IL-10 (C-819T, p = 0.04); IL-10 (G-1082A, p = 0.04-0.002-0.006), FCGR2A (His166Arg, p = 0.006); TLR4 (Thr399Ile, p = 0.02); TLR6 (Ser249Pro, p = 0.04); TLR9 (A2848G, p = 0.04-0.007); CD14 (C-159T, p = 0.03). When testing the significance hypothesis by multiple comparisons, the difference for the detected events was confirmed only for IL-10 gene (G-1082A, p < 0.01; χ2 = 20,082). The results show a relationship between the allelic status of the IL-10-1082 gene and the timing of response to FCR therapy, as well as predict a group of patients with primary-resistant CLL before treatment. The role of the relationship between IL-10 gene polymorphism and IL-10 production is discussed in connection with occurrence risk and clinical course of mature B-cell lymphoid malignancies. IL-10 is thought to be a growth factor for normal and transformed human B-lymphocytes, it controls a balance between cellular and humoral immune responses while exerting a pronounced immunosuppressive activity, along with ability to stimulate tumor cell proliferation. A rationale for conducting pharmacogenomic studies in CLL is provided, in order to predict efficiency of a specific drug or their combination in a distinct patient, thus representing chances to detect a factor which may influence success of the therapy since its earlier stage.

Keywords

• chronic lymphocytic leukemia
• rituximab
• gene polymorphism
• immune response
• interleukin-10
• treatment efficacy