Abstract
Study of the association between single nucleotide polymorphisms (SNPs) of methotrexate (MTX) pathway genes and MTX-related toxicity in the treatment of hematological malignancies is popular. Here, we studied the association between SNPs of MTHFR and ABCB1 and MTX-related toxicity in 157 adult Chinese patients diagnosed with hematological malignancies. Patients were genotyped for MTHFR rs1801131, MTHFR rs1801133, and ABCB1 rs1045642 by fluorescence in situ hybridization. Patients with MTHFR rs1801133T allele had a significantly higher risk of hematopoietic toxicity compared with those with CC genotype (p=0.003). With respect to MTHFR rs1801131, patients with CC and AC genotypes had significantly lower frequency of hematopoietic toxicity than patients with AA genotype (p=0.044). In conclusion, we identified an important influence of the SNPs of ABCB1 and MTHFR on MTX-related hematopoietic toxicity in adults with hematological malignancies. To optimize high-dose (HD)-MTX therapy and reduce related hematopoietic toxicity, it is necessary to detect the SNPs of MTHFR and ABCB1 before initiating HD-MTX and deciding the optimal dose of MTX and duration of leucovorin rescue, according to genetic tests and disease type in adults with hematological malignancies.
Highlights
The antimetabolic drug methotrexate (MTX) has been used to treat a variety of diseases, such as tumors and autoimmune diseases (1, 2)
Our present research aimed to study the influence of single nucleotide polymorphisms (SNPs) of ABC subfamily B member 1 (ABCB1) and Methylene tetrahydrofolate reductase (MTHFR) on MTXrelated toxicity in adult Chinese patients diagnosed with hematological malignancies
The multiagent chemotherapeutic protocols used were SMILE chemotherapy for patients diagnosed with NK/T cell lymphoma and aggressive NK cell leukemia (ANKL), MA (MTX, Cytarabine/Ara-C) chemotherapy and hyper-CVAD protocol-course B for patients diagnosed with T-cell lymphoblastic lymphoma (TLBL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, and MTX monotherapy, MA (MTX, Cytarabine/Ara-C) chemotherapy and MTX plus asparaginase for patients diagnosed with acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia lymphoid blast crisis (CML-LBC)
Summary
The antimetabolic drug methotrexate (MTX) has been used to treat a variety of diseases, such as tumors and autoimmune diseases (1, 2). High-dose (HD)-MTX is a classic protocol for treating hematological malignancies (3). HD-MTX can lead to MTX-related toxicity, including mucositis (4), hepatotoxicity (5), nephrotoxicity (6) and hematopoietic toxicity (6). Gene Polymorphisms in Hematological Malignancies partly explained by the single nucleotide polymorphisms (SNPs) of MTX pathway genes, including MTHFR and ABCB1 (7–14). A genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with MTX-induced neurotoxicity, and found that polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity (15). There has been no GWAS about the relation between SNPs and other MTX-related toxicity, such as mucositis, hepatotoxicity, nephrotoxicity and myelosuppression. Our present research aimed to study the influence of SNPs of ABCB1 and MTHFR on MTXrelated toxicity in adult Chinese patients diagnosed with hematological malignancies
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