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P324. Value of thiopurine methyltransferase genotyping for prevention of myelotoxicity in routine clinical practice in patients with inflammatory bowel disease treated with azathioprine

M. Rivero1, M.A. Mieses1, I. Moraleja1, A. Fontalva1, B. Castro1, J. Crespo1, 1University Hospital Marques de Valdecilla, Gastroenterology unit, Santander, Spain

Background

During the course of inflammatory bowel disease (IBD), many patients will require treatment with azathioprine (AZA) to induce and mantain remission of their disease. Azathioprine is an effective drug but with a considerable rate of adverse reactions (15–40%), some of them severe, like mielotoxicity. The aim was to evaluate if Thiopurine methyltransferase (TPMT) genotyping is a valuable parameter in routine clinical practice to prevent myelotoxicity.

Methods

We performed a retrospective, cross-sectional analysis of 81 patients diagnosed with IBD who were treated with azathioprine at any time in the course of their disease. We also determined the TPMT status and the relation between the TPMT gene mutation and myelotoxicity.

Results

The median age was 43 years old (range 17–78) and male/female 44/37; 21 had ulcerative colitis and 60 Crohn's disease. Median dose of AZA was 2.14 mg per kg and the median duration of treatment was 4 years (range 1 month-18 years). Concomitant medicatos for IBD in these patients was: mesalazine (73%), biologic therapy (30%) y topical therapy (9%). Eighty-eight percent of patients were normal TPMT genotype and 12% were heterozygotes TPMT, of these, eight patients had TPMT*3A, one patient TPMT*3C and one patient TPMT*2 variant alleles. No patient was homozygote. From all the patients, 21% developed leukopenia, with only two severe cases. In the majority of cases, leukopenia developed in patients with normal TPMT gen (16 patients), whereas only one heterozygote patient developed severe leukopenia. The median time to develop leukopenia was 27 months (range 1.4–160). Other abnormal hematologic findings were: anemia (2 patients), thrombocytopenia (1 patient) and bone marrow aplasia (1 patient). Of these patients, only one was TPMT heterozygote. Other adverse reactions due to AZA were hepatotoxicity (3 patients), gastric intolerance (3 patients) and flu-like syndrome (3 patients). These symptoms led to drug discontinuation in 4 patients. None of these adverse reactions were related to heterozygous genotype.

Conclusion

Despite the limitations of our study, we observed that TPMT gene mutation was not associated with the development of mielotoxicity in our patients. Thus, it is possible that systematic genotyping is not helpful in routine clinical practice as a tool to predict mielotoxicity, and may be clinicians should continue the follow up of their patients with strict blood monitorization in order to early diagnose this adverse effect during therapy.