الفهرس 
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Abstract
Diffuse large B-cell lymphoma treatment protocol is a combination chemotherapy regimen R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The treatment cycle is repeated every 21 days. Patients have complete remission (CR) received two additional cycles, while those having partial remission (PR) underwent another response assessment after 6 more cycles of treatment, and those with a further response underwent an additional 8 cycles. Patients with stable disease (SD) or progressive disease (PD) were switched to second-line therapy after 4-cycle R-CHOP according to guidelines set by the National Comprehensive Cancer Network for NHL.
During cancer treatment, the drug efficacy and toxicity may differ from one individual to another. These variations may be due to genetic factors (polymorphisms among drug-metabolizing genes) or non-genetic factors such as ethnicity, food type, co-medication, physiological status that are affected by age, sex, co-morbidities and environmental factors, such as smoking. Also, liver and kidney conditions play a role. Pharmacogenetic screening and drug-specific phenotyping studies before the start of anticancer treatment help to expect the treatment outcomes.
Toxicity of treatment may be developed from accumulation of the drug itself or its metabolites. For example the cyclophosphamide has two metabolic pathways; the major pathway is 4-hydroxylation catalyzed by the enzymes CYP2B6, CYP3A5, CYP2C19, CYP2C9, CYP2C8 and CYP2A6 to finally produce acrolein and phosphamide mustard, which has therapeutic and toxic effects including hematological toxicity such as neutropenia, anemia, thrombocytopenia and cardiac toxicity.
The current study focused on the polymorphism of two genes CYP2C19 and CYP3A4 through evaluating two single nucleotide polymorphisms (SNP) for each gene and their correlation to the risk of hematological toxicities resulting from the used therapeutic protocol. The studied SNPs for CYP2C19 are rs4986893, rs4244285 and the SNPs of CYP3A4 are rs2242480 and rs2740574. The polymorphisms detected by real-time PCR.
Total of 98 patients were divided into two groups (group A: No hematological toxicity (70 patients), group B: Hematological toxicity (28 patients)), with no significant deviation of genotype frequencies from HWE.
The logistic-regression models for the studied SNPs regarding CYP2C19 showed no significant correlation with the incidence of hematological toxicity, while rs2242480 for CYP3A4 gave a significant relationship with the homozygous codominance model (OR=22.173, CI= 95 %, p= 0.008), also the dominant model with p value 0.007 (95 % CI, OR= 4.206) and the allelic model (OR=4.148, 95 % CI, p = 0.001). For rs2740574 of the same gene, two models showed a significance, the homozygous codominance model (OR = 12.497, 95 % CI, P = 0.007) and the recessive model (OR= 7.968, 95 % CI, P= 0.005).
Haplotype of both SNPs for CYP3A4 gene polymorphism were analyzed to characterize gene-gene interaction with the incidence of hematological toxicity. In concordance with the results of multivariate logistic regression models, haplotype T/T and T/C of rs2242480 and rs2740574 (C/T haplotype is the reference haplotype) were contributed to an increased risk for development of hematological toxicity by 5.481 (1.659 -18.113) folds and 7.103 (2.11 – 23.916) folds, respectively, while C/C haplotype showed no significance (p = 0.015).
The results of linkage disequilibrium showed that there was a strong LD between rs4244285 and rs2242480 loci and an intermediated LD between rs4244285 and rs4986893.
The survival data showed significance only with homozygous codominant model of rs2740574. The model showed significance with disease free survival (DFS) rate (p = 0.012). Patients carry CC genotype relapsed after a mean period of 32 months; while the patients carry TT genotype showed longer disease free period of a mean of 54 months.
So, we concluded that the T allele of rs2242480 and C allele of rs2740574 in CYP3A4 gene increase the risk of the hematological toxicity. Also, higher risk of hematological toxicity is linked to the T/C haplotype of rs2242480 and rs274057. Also, the current study indicated that the TT genotype of rs2740574 has a longer disease free survival period than CC genotype. The promising findings of the study suggest that the investigation of these variants might evaluate the incidence of hematological toxicity in DLBCL patients. Consequently, this study recommends analyzing these SNPs prior to the beginning of the treatment strategy. Based on our findings, more studies with higher number of participants and other types of cytochrome P450 system genetic variants are recommended to validate the effect of other SNPs on the treatment outcomes.