Timing of Myelosuppression During Thiopurine Therapy for Inflammatory Bowel Disease: Implications for Monitoring Recommendations

Abstract

Background & Aims Thiopurines (azathioprine and 6-mercaptopurine) can induce life threatening myelosuppression. To help develop rational monitoring guidelines, this study determined the frequency, timing, and outcomes of mild and severe myelosuppression following initiation of thiopurine therapy. Methods This retrospective cohort study of patients with inflammatory bowel disease patients who were new users of thiopurines; those tested for thiopurine methyltransferase levels before therapy were excluded. Patients were followed from their first thiopurine prescription until the earliest of severe leucopenia [white blood count <1.0 × 109/L], severe thrombocytopenia (platelets<20 × 109/L), the end of therapy, the first gap in therapy, disenrollment, or December 31, 2006. Results Among 1997 new users, the incidence of severe leucopenia per 100 person-months was 0.16 (95% CI 0.03-0.29, n=6) in weeks 0-8, 0.00 in weeks 9-24, and 0.01 (95% CI 0-0.03, n=3) after week 26 of therapy. The incidence of severe neutropenia and severe thrombocytopenia per 100 person-months during the first 8 weeks of therapy was 0.51 (95% CI 0.31 – 0.80, n=19) and 0.08 (0.02 – 0.23, n=3), respectively. During the first 8 weeks, the median duration from a normal white blood count to severe leucopenia was 13 days (range 8-26 days) and to severe neutropenia was 14 days (range 7 to 23 days). Conclusions The high incidence of severe myelosuppression justifies frequent monitoring (weeklyx4 then biweeklyx2) during the first 8 weeks of therapy. After 8 weeks, the rate of severe myelosuppression and the proportion of patients that progress from mild to severe myelosuppression decline, justifying less-frequent monitoring.

The long-term risk of continuous immunosuppression using thioguanides in inflammatory bowel disease

“…Another study looking at timing of myelotoxicity events in these patients though showed that the majority of events will still occur within the first 8 weeks of therapy. During this period the incidence of severe neutropenia and severe thrombocytopenia per 100 person-months was 0.51 and 0.08, respectively with a median duration from a normal white blood cell count to severe leukopenia or neutropenia of 1314 days [Lewis et al 2009]. The use of allopurinol for gout augments the risk of myelosuppression with numerous cases of profound pancytopenia reported [Kennedy et al 1996;Venkat Raman et al 1990].…”

Azathioprine-associated myelodysplastic syndrome in two patients with ulcerative colitis

“…Leucopenia appeared to be the most common abnormality occurring in 3.8% and 4.6% of the patients in two large IBD cohorts 17 18. A more recent retrospective cohort study of 1997 patients reported  incidence of severe leucopenia, neutropenia and thrombocytopenia to be 0.16, 0.51 and 0.08 per 100 person-months, respectively 19. Our two cases underwent regular monitoring and did not display any preceding haematological abnormalities on blood counts.…”

A Case of Therapy-Related Myeloid Neoplasm in a Patient with Crohn’s Disease Treated with Azathioprine

“…The high incidence of severe myelosuppression justifies a frequent monitoring during the first 8 weeks of therapy. Subsequently, the rate of severe myelosuppression and the proportion of patients who progress from mild to severe myelosuppression decreases, justifying a less-frequent monitoring [42]. In the case of an abnormal white blood cell count, observation of peripheral blood smear may be useful to detect the presence of blasts, dysgranulopoiesis, dyserythropoiesis or dysmegakaryopoiesis.…”