This article is more than 5 years old. Information may no longer be current.
Genotyping, personalized dosing reduce hematologic events in IBD
Among patients with inflammatory bowel disease with variants in the gene encoding thiopurine S-methyltransferase, or TPMT, screening for these variants and lowering thiopurine dose based on the findings significantly reduced risk for adverse drug reactions in a recent study.
“Over 20% of [IBD] patients discontinue thiopurine therapy due to severe adverse drug reactions; leukopenia is one of the most serious,” Marieke J. H. Coenen, PhD, from the department of human genetics at Radboud Institute for Health Sciences, Radboud University Medical Center in the Netherlands, told Healio Gastroenterology. “TPMT pharmacogenetic testing can be used to optimize thiopurine safety and efficacy, but in clinical practice it is only used on a limited scale.”
Marieke J. H. Coenen
To investigate the effect of pharmacogenetic-guided TPMT dosing on the occurrence of leukopenia, Coenen and colleagues performed a randomized controlled trial from October 2007 to December 2010 involving patients with IBD who were starting thiopurine therapy at 30 Dutch hospitals.
Patients were randomly assigned standard treatment (n = 378) or pretreatment screening for three common TPMT variants (n = 405). Heterozygous TMPT variant carriers were given half the standard thiopurine dose, and homozygous carriers were given 0% to 10% of the standard dose.
Outcomes between the intervention and control groups were then compared after 20 weeks of treatment in an intention-to-treat analysis, with hematologic adverse drug reactions and disease activity as the primary outcomes.
“Overall, no difference in leukopenia occurrence was observed between the patients that received genotype-guided thiopurine dosing and the control group,” Coenen said. “However, among TPMT variant carriers, leukopenia occurrence was significantly reduced in the genotype-guided dosing group compared to the control group.”
Researchers found that 7.4% of patients in the intervention group and 7.9% of controls developed a hematologic adverse drug reaction (RR = 0.93; 95% CI, 0.57-1.52), and disease activity was also comparable between groups. However, 2.6% of TPMT variant carriers developed a hematologic adverse drug reaction compared with 22.9% of controls (RR = 0.11; 95% CI, 0.01-0.85).
Jeremy D. Sanderson
“In conclusion, prior-to-treatment TPMT screening reduces leukopenia risk in IBD patients treated with thiopurines without impeding treatment efficacy,” Coenen said.
This study “is a classic example of the difficulties of trying to put evidence behind the clinical applicability of a pharmacogenetic test,” Jeremy D. Sanderson, MD, from the department of gastroenterology at Guy’s & St. Thomas’ Hospitals NHS Foundation Trust in London, wrote in a related editorial. “The result of a well-powered study was that no difference existed between groups treated with and without application of the test. However, those with a positive test clearly fared better in the intervention arm. Hence, the conclusion is that evidence to prove benefit across all patients will not be forthcoming. In truth, I believe we all know beyond reasonable doubt that TPMT testing before starting a thiopurine is the right thing to do for our patients. The time for debate is over: just do it.” – by Adam Leitenberger
Disclosure: The researchers and Sanderson report no relevant financial disclosures.