Association between the c.415C > T, c.52G > A, and 36_37insGGAGTC polymorphisms of and thiopurine-induced leukopenia, thiopurine intolerance, and severe hair loss: an updated meta-analysis.

PURPOSE

As a common immunosuppressive and anticancer drug, thiopurine has achieved remarkable clinical success. However, higher inter-individual dose variability and unpredictable toxicity still challenge its use in clinical practices. Some studies indicate that polymorphisms are associated with this variation, but specific correlation remains controversial. This meta-analysis assessed the association between three polymorphisms of and thiopurine-induced toxicities.

METHODS

Three databases were electronically searched: PubMed, Embase, and Web of Science. Only case-control studies and cohort studies were eligible. The overall pooled ORs and corresponding 95% CIs were used to represent the results.

FINDINGS

We included 16 studies that focus on c.415C > T, c.52G > A, and 36_37insGGAGTC polymorphisms in patients treated with thiopurine. Significant associations between c.415C > T polymorphism and leukopenia were found in all genetic models (TC/TT vs CC, OR: 7.64, 95% CI: (6.19, 9.44), <0.00001; TT vs CC/TC, OR: 29.66, 95% CI: (12.31, 71.46), <0.00001; TT vs CC, OR: 45.60, 95% CI: (18.84, 110.37), <0.00001; TC vs CC, OR: 6.41, 95% CI: (5.19, 7.94), <0.00001; TT vs TC, OR: 6.38, 95% CI: (2.59, 15.72), <0.00001), early/late leukopenia (in recessive and co-dominant model), leukopenia (grade 3-4), and severe hair loss in all genetic models. Besides, c.52G > A and 36_37insGGAGTC polymorphisms were also significantly associated with leukopenia. No significant association between c.415C > T polymorphism and early/late leukopenia in the Chinese population was determined in the co-dominant model (TC vs CC).

IMPLICATIONS

c.415C > T polymorphism could increase the risk of leukopenia, early/late leukopenia, leukopenia (grade 3-4), and severe hair loss. Meanwhile, c.52G > A and c.36_37insGGAGTC mutations also probably increase the risk of leukopenia. Preemptive tests for polymorphisms are highly recommended to individualize the treatment of thiopurine for a better outcome with less toxicity.