Is less more: does leukopenia predict remission in patients with inflammatory bowel disease receiving thiopurine treatment?

Abstract

The thiopurine drugs azathioprine (AZA) and mercaptopurine (MP) effectively maintain remission in patients with inflammatory bowel disease (IBD) [1]. Dosing of AZA and MP is generally weight based, with the intention of achieving the highest therapeutic efficacy and, at the same time, reducing the incidence of adverse effects. Several strategies have been proposed to optimally dose thiopurines with the intention, on the one hand, to identify patients at risk of adverse effects (mainly myelotoxicity) and, on the other hand, to detect patients with subtherapeutic doses and inadequate immunosuppression [2]. These strategies include monitoring changes in the red cell mean corpuscular volume, induction of leukopenia, quantification of 6-thioguanine nucleotides (6-TGN), and the monitoring of thiopurine methyltransferase (TPMT) activity. Mild or chronic leukopenia, generally defined as a white cell count between 3,000 and 4,000/lL, is the commonest hematologic effect of thiopurines, appearing in 5–25 % of the patients receiving these drugs [3]. The incidence rate of myelotoxicity in IBD patients receiving AZA/MP has been calculated, in a recent systematic review, to be approximately 3 %/patient-year of treatment [3]. Although leukopenia is a well-recognized effect of AZA/MP treatment, its association with therapeutic efficacy has yet to be determined, although the induction of leukopenia is probably closely related to the therapeutic mechanisms of thiopurines. In this context, the aim of the study by Park et al. [4] published in this issue of Digestive Diseases and Sciences was to evaluate the correlation between thiopurine-induced leukopenia and clinical outcomes in Korean IBD patients who achieved clinical remission with thiopurines. The authors included 196 IBD patients [45 with ulcerative colitis (UC), 68 with Crohn’s disease (CD), and 83 with intestinal Behcet’s disease] who were treated with AZA/ MP and had achieved remission. Then, the authors retrospectively analyzed the lowest white blood cell (WBC) count during AZA/MP treatment, duration of remission, and the occurrence of relapse and compared the clinical evolution between leukopenic (WBC count \4,000/lL) and non-leukopenic patients. The authors reported that the cumulative relapse-free survival rate was higher in the leukopenic group. Thus, relapse occurred in 31 % of leukopenic patients and in 54 % of non-leukopenic patients (P = 0.001). Using multivariate analysis, the presence of leukopenia was inversely associated with relapse. Therefore, the authors concluded that leukopenia occurring during thiopurine maintenance therapy is associated with prolonged remission in patients with IBD, including those with Behcet’s disease. Although undoubtedly interesting and clinically relevant, this study has several limitations that should be taken into account: