Thiopurine methyltransferase gene polymorphisms and activity in Chinese patients with inflammatory bowel disease treated with azathioprine

Background The thiopurine drugs are well established in the treatment of inflammatory bowel disease （IBD）. However, uncertainty regarding the risk for neutropenia and hepatotoxicity deters its using. Thiopurine methyltransferase （TPMT） is the key enzyme in the metabolism of thiopurine. The aim of this study was to investigate the association of TPMT polymorphisms and activity with azathioprine （AZA）-related adverse events and clinical efficacy in Chinese Han patients with IBD. Methods Fifty-two Han IBD patients treated with AZA were assessed for TPMT＊2, ＊3A, ＊3B, and ＂3C, and for adverse events. Then, using reverse-phase high-performance liquid chromatography, TPMTactivity was measured in 13 patients to analyze its correlation with AZA-related toxicity and clinical efficacy. Results Of the 52 patients, five experienced myelotoxicity and one experienced hepatotoxicity during treatment. No TPMT＊2, ＊3A, ＊3B or ＂3C polymorphisms were detected in any of the 52 patients. In the 13 patients with TPMT activity measurement, TPMT activity ranged from 7.2 to 28.8 U/ml packed red blood cells （pRBCs）. Among the 5 patients who suffered from myelotoxicity, 3 were affected in the early stage of AZA therapy. In these 3 patients, TPMT levels were significantly lower than those in patients without myelotoxicity, which reached statistical significance （（9.3±2.1） U/ml pRBC vs. （18.0±6.2） U/ml pRBC; P=-0.046）. One patient who had higher TPMTactivity （28.8 U/ml pRBC） suffered from hepatotoxicity during AZA therapy. Patients who achieved a clinical response had lower TPMTactivity than those failed to respond （（13.7±3.5） U/ml pRBC vs. （22.0±5.5） U/ml pRBC; P=-0.009）. Conclusions TPMT variants do not completely account for the AZA-related myelotoxicity in Chinese Han IBD patients. However, measurement of TPMT activity may be helpful in reducing the risk of toxicity, and predicting the therapeutic efficacy.

Pharmacogenetics of thiopurines

Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia(ALL)always include thiopurines.Specific approaches vary in terms of drugs,dosages and combinations.Such therapeutic schemes,including risk-adapted intensity,have been extremely successful for children with ALL who have reached an outstanding 5-year survival of greater than 90%in developed countries.Innovative drugs such as the proteasome inhibitor bortezomib and the bi-specific T cell engager blinatumomab are available to further improve therapeutic outcomes.Nevertheless,daily oral thiopurines remain the backbone maintenance or continuation therapy.Pharmacogenetics allows the personalization of thiopurine therapy in pediatric ALL and clinical guidelines to tailor therapy on the basis of genetic variants in TPMT and NUDT15 genes are already available.Other genes of interest,such as ITPA and PACSIN2,have been implicated in interindividual variability in thiopurines efficacy and adverse effects and need additional research to be implemented in clinical protocols.In this review we will discuss current literature and clinical guidelines available to implement pharmacogenetics for tailoring therapy with thiopurines in pediatric ALL.

Azathioprine-induced pancytopenia:A case report

Azathioprine(AZA)is commonly used as immunosuppressive therapy for autoimmune diseases,including systemic lupus erythematosus(SLE).Myelosuppression is a common side effect of AZA.Here we report a case of severe myelosuppression following AZA therapy in a 15-year-old girl despite a normal thiopurine methyltransferase(TPMT)level.She had been receiving AZA for SLE and presented with neutropenic fever and pancytopenia.AZA was stopped.After stopping AZA,her blood counts steadily improved.When TPMT genotyping results were normal,AZA was reintroduced.Pancytopenia reappeared after starting AZA,despite normal TPMT genotype.AZA was replaced with mycophenolate mofetil which consequently resulted in improvement of blood counts.It is essential to understand the temporal relationship between AZA use and pancytopenia onset in patients with normal TPMT activity.This case illustrates that regular monitoring of blood cell counts should be routine practice after starting AZA regardless of TPMT activity.