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P541. Can we predict myelotoxicity development during thiopurine therapy for inflammatory bowel disease?

A. Kharitonov1, O. Shchukina1, S. Lapin2, T. Bulgakova2, A. Baranovsky1, 1North-Western state medical university named after I.I.Mechnikov, Chair of gastroenterology and dietology, Saint-Petersburg, Russian Federation, 2First Saint-Petersburg state medical university named after I.P. Pavlov, Laboratory of autoimmune diseases, Saint-Petersburg, Russian Federation

Background

Myelotoxicity occurs in 2–25% patients as side effect during treatment with azathioprine (AZA) and 6-mercaptopurine (6MP).

Aim of study was to determinate frequency of the G238C, A719G, and G460A TPMT gene polymorphisms and to measure the TPMT enzyme activity in red blood cells in Russian inflammatory bowel disease (IBD) patients with myelotoxicity during AZA/6MP treatment.

Methods

27 IBD patients with myelotoxicity during AZA/6MP treatment were included (male:female - 0.9, average age - 37.3 years). AZA/6MP dose and treatment duration before development of myelotoxicity were assessed. Average therapeutic dose of thiopurines was 2.37 mg/kg/d (range 2.0–2.5 mg/kg/d). Myelotoxicity was defined as white blood cells levels <4.0×109/L (Russian laboratory value norms) and/or platelet count <180×109/L. Measuring of TPMT activity in red blood cells was performed in all patients using TPMT ELISA Kit (Biomerica, Inc.). Based on the manufacturer's instruction very low enzyme activity was determined as <7 U, moderate as 7–17 U, normal as >17 U. Genotyping for TPMT gene polymorphisms (G238C, A719G, and G460A) were performed by polymerase chain reaction and, separately, using DNA-microchip in 21 patients.

Results

17/27 patients (63%) had isolated leukopenia, 1 (4.7%) had thrombocytopenia, in 9 cases (33.3%) a combination of leukopenia and thrombocytopenia was shown. 14/27 patients with myelosuppression (51.9%) showed a decreased TPMT enzyme activity, the mean enzyme level was 13.57±0.64 U. Other patients had normal TPMT activity (21.02±1.61 U). In patients with pancytopenia average TPMT activity level was lower compared to patients with leukopenia and thrombocytopenia alone: 14.61±0.91 vs 19.28±1.66 (p = 0.02). There was no correlation found between the enzyme activity and the degree of leuko- and thrombocytopenia. Thus, patients with reduced activity of TPMT had a mean value of white blood cells equal to 2.96±0.17×109/L, patients with normal enzyme activity had 2.75±0.1×109/L (p > 0.05). Using the world recommendations in definition of leukopenia (<3×109/L), we could not find differences in white blood cell levels depending on TPMT activity. Only one patient (4.8%) with IBD was heterozygous for TPMT*3A (G460A and A719G). No TPMT*2 (G238C), TPMT*3B (G460A) or TPMT*3C (A719G) alleles were detected. There was no association between genotypes and TPMT activity and time of development of myelotoxicity.

Conclusion

Neither TMPT genotype nor the TPMT activity not allow to predict development of myelotoxicity during AZA/6MP treatment in IBD patients. However low TMPT activity is associated with more severe myelosuppression. Patients receiving thiopurines need regular monitoring of the full blood count tests throughout the course of thiopurine therapy.