TPMT genotyping: Decreased hematologic adverse events in IBD
Daniel Beylik, Pharm.D. Candidate, Class of 2016
Thiopurine agents such as 6-mercaptopurine or azathioprine are used in patients with inflammatory bowel disease (IBD) as well as some pediatric cancers (i.e., acute lymphoblastic leukemia, ALL). Although these agents can be effective for maintaining remission in IBD, they are associated with risk of serious hematologic adverse reactions, including myelosuppression and leukopenia. The TPMT enzyme inactivates the cytotoxic metabolite of thiopurines, 6-thioguanine. Variability in the TPMT gene can result in higher 6-thioguanine levels and an increased risk of developing life-threatening hematologic adverse reactions.
TPMT genotyping is frequently performed in patients with ALL to guide thiopurine dosing and decrease the risk of hematologic toxicity. However, few data exist regarding the clinical benefits of TPMT genotype-guided dosing for IBD or other indications.
Coenen and colleagues conducted a multicenter, randomized, parallel, controlled trial in 30 Dutch hospitals, in which they assigned patients randomly to receive either a) standard treatment (control, n = 378 patients), or b) pretreatment screening (intervention, n = 405 patients) for the 3 common variants of TPMT, which include TPMT*2 (rs1800462), TPMT*3A (rs1800460), and TPMT*3C (rs1142345). Patients in the control group received standard treatment in accordance with the evidence-based IBD treatment guidelines. Patients in the intervention group who did not possess the TPMT variant would receive azathioprine or 6-mercaptopurine at standard dose (2–2.5 mg/kg/day azathioprine or 1–1.5 mg/kg/day 6-mercaptopurine). Intervention-group patients who were heterozygous for a TPMT variant received 50% of the standard dose and those who were homozygous for TPMT variants received 0%-10% of the standard dose. Primary outcomes included the presence of a severe hematologic adverse reaction and disease activity indices. Secondary outcomes included the presence of hepatotoxicity, pancreatitis, or anemia.
At 20 weeks, the incidence of hematologic adverse events was similar between groups (7.4% intervention vs 7.9% control; RR 0.93; 95% CI 0.57-1.52) and both groups had similar levels of disease activity (P >0.05 for all comparisons). Secondary analysis displayed a significantly smaller portion of TPMT variant carriers developed hematologic toxicity in the intervention group as compared with the control group. Specifically, in the intervention arm, only 1 of 39 patients carrying a TPMT variant (2.6%) developed a hematologic ADR compared with 8 of 35 patients (22.5%) in the control arm (RR 0.11; 95% CI 0.01-0.85).
Study authors concluded that although TPMT screening did not affect the proportion of patients between groups who experienced a hematologic adverse event, there was “a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy.”
Study results are important as few data exist on the clinical utility of TPMT screening in the treatment of IBD. In this study, preemptive identification of patients who carried a TPMT variant led to a decrease in hematologic adverse reactions.
Find more information on TPMT and treatment guidelines from the Clinical Pharmacogenetics Implementation Consortium and PharmGKB.
Coenen MJH et al. Identification of patients with variants in TPMT and dose reduction reduces hematologic events during thiopurine treatment of inflammatory bowel disease. Gastroenterology 2015 Oct; 149:907.