Certain genetic variants may have potential to serve as biomarkers in use of methotrexate (MTX)-based regimens for treatment of primary central nervous system lymphoma (PCNSL), according to study results reported in the journal Expert Review of Clinical Pharmacology.
PCNSL is often treated with MTX-based therapy regimens, but patients show variability in pharmacokinetics with these treatments and in clinical outcomes. Prior research had identified potential sources of genetic variation that may be linked to the MTX pathway. However, impacts of genetic variation in the MTX pathway on results with MTX in the setting of PCNSL have been unclear.
The study evaluated adult patients with newly diagnosed PCNSL who were seen at Huashan Hospital in Shanghai, China, and who received high-dose MTX-based chemotherapy. Patients’ MTX concentrations were evaluated at various time points, and patient genotypes were analyzed regarding 42 genetic polymorphisms in 12 candidate MTX-pathway genes, which were evaluated for relationships to MTX pharmacokinetics and clinical outcomes.
A total of 123 patients were included, with the average age being 57.4 years. The study had a mean follow-up duration of 23.8 months. Regarding outcomes, patients had a median progression-free survival (PFS) of 9.0 months (range, 1.0-57.0) and a median overall survival of 14.0 months (range, 4.0-60.0). There were occurrences of hepatotoxicity in 384 (73.3%) out of a total of 524 chemotherapy cycles received in this population, with 59 of these occurrences being grade 2 or higher.
MTX pharmacokinetics appeared to be associated with ABCB1 rs2032582 and GGH rs2305558 genetic variants. The peak concentration, or Cmax, of MTX was 20.5% higher in patients who had GGH rs230558 T and ABCB1 rs2303582 non-G alleles. The area under the concentration-time curve up to 48 hours after infusion, or AUC0-48h, was also 19.6% higher for these patients, and lower clearance was reduced by 19.6%.
ABCB1 rs1045642 and ABCB1 rs2032582 genetic variants showed significant relationships with PFS. The adjusted hazard ratio (HR) for PFS in patients with the GG genotype of ABCB1 rs1045642 was 1.972 (95% CI, 1.090-3.566; P =.025), in comparison with AA and AG reference genotypes. The adjusted HR for PFS in ABCB1 rs2032582 G allele carriers was 2.250 (95% CI, 1.058-4.785; P =.035), in comparison with patients lacking the G allele.
MTX-induced hepatoxicity of grade 2 or higher was linked to ATIC rs3821353, with TT and TG genotypes having an adjusted HR for this outcome of 8.157 (95% CI, 2.403-27.690; P =.001), compared with the reference GG genotype. Age also appeared to be associated with MTX-induced hepatotoxicity.
“In conclusion, this study provides new data on the association between polymorphisms and the pharmacokinetics, clinical outcomes, and toxicities of MTX, which may contribute to the development of novel biomarkers and personalized therapy for patients with PCNSL,” the researchers wrote in their report.
Wu Z, Li Z, Qiu X, Zhong M, Ding T. Germline genetic variations in methotrexate pathway are associated with pharmacokinetics, outcome, and toxicity in patients with primary central nervous system lymphoma. Expert Rev Clin Pharmacol. Published online March 27, 2023. doi:10.1080/17512433.2023.2194630