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.