P0177 Impact of genetic polymorphisms of MTHFR, SLC, and ABC on high-dose methotrexate toxicity and plasma levels in adults with haematological malignancies

Abstract

<h3>Background</h3> High-dose methotrexate has been shown to be useful in acute lymphoblastic leukaemia (ALL) or non-Hodgkin lymphoma (NHL). However, it causes toxicity in the bone marrow, liver, and gastrointestinal tract. Pharmacogenetics of methotrexate and its relationship with plasma concentrations are conflicting. We aimed to evaluate the impact of single nucleotide polymorphisms (SNPs) within the <i>MTHFR</i>, <i>SLC</i>, and <i>ABC</i> genes on methotrexate-induced toxicity and methotrexate plasma levels at 48h in Asian adults with ALL or non-Hodgkin lymphoma. <h3>Methods</h3> Seventy-one patients were genotyped for <i>MTHFR</i> C667T, <i>MTHFR</i> A1298C, <i>SLC19A1</i> G80A, <i>ABCG2</i> C421A, and <i>ABCB1</i> C3435T using the Sequenom MassARRAY platform. Plasma methotrexate concentrations at 48h were measured by fluorescence polarization immunoassay. <h3>Findings</h3> Forty-eight patients had haematopoietic toxicity, 51 had hepatic toxicity, and 36 had mucositis. Homozygous 677TT of <i>MTHFR</i> was associated with increased risk of both hematopoietic (odds ratio [OR] 9.00, 95% confidence interval [CI] 2.24–36.17, <i>p</i>=0.002) and hepatic (OR 3.94, 95% CI 1.03–15.13, <i>p</i>=0.036) toxicities. Hepatic toxicity was associated with <i>SLC19A1</i> G80A (OR 5.25, 95% CI 1.21–22.74, <i>p</i>=0.032) and <i>ABCB1</i> C3435T (OR 8.64, 95% CI 1.99–37.55, <i>p</i>=0.004). However, polymorphisms in <i>MTHFR</i> A1298C and <i>ABCG2</i> C421A were not associated with any of the toxicities, and mucositis was not associated with any polymorphisms of the methotrexate pathway genes. Patients with <i>MTHFR</i> C677T and <i>ABCB1</i> C3435T polymorphisms seemed to have significantly higher methotrexate plasma concentrations (<i>p</i><0.05). <h3>Interpretation</h3> Our findings support evidence for the pharmacogenetic contribution to the toxicity of high-dose methotrexate and plasma methotrexate concentrations at 48h in patients with ALL or NHL. These results will contribute to individualisation of high-dose methotrexate therapy.