1 Introduction
Imatinib is a first generation BCR-ABL tyrosine kinase inhibitor (TKI) with anti-leukemic activity against chronic myeloid leukemia (CML). In the International Randomized Study of Interferon and STI571 (IRIS), imatinib was superior to a combination of recombinant interferon alpha (IFNα) and low-dose cytarabine with respect to the rates of cytogenetic and molecular responses1 as well as progression-free survival (PFS) and overall survival.2 Given these clinical benefits, imatinib became the first-line treatment for CML. Furthermore, randomized phase 3 trials have revealed that nilotinib and dasatinib, second-generation BCR-ABL TKIs, have superior efficacy compared with imatinib as first-line treatment for chronic myelogenous leukemia in the chronic phase.3,4 However, long-term observation of 5 years revealed higher frequency of neovascular adverse effects associated with second-generation TKIs than with imatinib.5,6 From the adverse effect profile of the three TKIs, imatinib may be selected as first-line treatment, taking into account patient background such as comorbid diseases. According to a Japanese package insert, typical adverse events of imatinib mesylate include nausea, vomiting, edema, tumor necrosis, muscle cramps, hematologic adverse effects, cardiovascular adverse effects, hepatic adverse effects, nephrotoxicity, and dermatologic adverse effects such as skin rash, pruritus, and petechiae. Initially, renal failure associated with imatinib was reported to be a rare event, occurring in less than 1.0% of the patients in the dose-escalating studies of chronic phase and blast crisis CML.7,8 Similarly, the Novartis Oncology Medical information website (www.oncologymedicalservices.com) reported renal function abnormalities in 1.6% of 1234 CML patients. However, there were no reports of renal failure among the 553 newly diagnosed CML patients treated with imatinib in the IRIS trial, with follow-up up to 6 years. It is now clear that imatinib therapy is occasionally associated with potentially irreversible acute renal injury, and long-term treatment may cause a clinically significant decrease in estimated glomerular filtration rate. In 105 patients receiving imatinib after prior interferon therapy, 7.0% developed acute kidney injury with mean decrease in glomerular filtration rate of 2.77 ml/min per 1.73 m2 per year, and 12% of patients developed chronic renal failure.9In other cases, renal failure linked to imatinib is often reversible,10,11 although hemodialysis is sometimes needed.12 Thrombotic thrombocytopenic purpura,13 acute tubular necrosis,12tubular vacuolization14 and partial Fanconi syndrome15 have been reported following imatinib therapy. At the onset of renal disorder or initiation of dialysis, treatment withdrawal or dose reduction of imatinib is required, but there are currently no guidelines for dose adjustment. This report describes a case in which the dose of re-administration of imatinib was successfully determined by therapeutic drug monitoring (TDM) in a patient with CML who initiated dialysis for acute renal dysfunction associated with the initial imatinib therapy.