Abstract
Background: Among tyrosine kinase inhibitors (TKIs), imatinib mesylate was the first TKI successfully used for the treatment of chronic myelogenous leukemia (CML) in chronic phase (CP), and a majority of patients still remains on its long-term treatment. Although imatinib has been well tolerated in clinical practice, and the side effect profile has usually been mild to moderate, there are limited data available regarding the long-term TKIs treatment on kidney function and associated complications such as anemia. This study aimed to evaluate the effect of long-term imatinib treatment on estimated glomerular filtration rate (eGFR) and hemoglobin (Hb) level in patients with CML in CP.
Patients and methods: By using the institutional database, patients with CML in CP who had been on imatinib as the first and the only TKI for over 5 years at Keio University Hospital (Tokyo, Japan) were selected and retrospectively analyzed. Estimated GFR was calculated by the Modification of Diet in Renal Disease equation for Japanese defined by the Japanese Society of Nephrology. All statistical analyses were performed with EZR, which is a graphical user interface for R.
Results: Eighty-two patients were evaluable. The median age at initiating imatinib was 49.5 years (range, 19-76). The median duration of imatinib treatment was 105 months (range, 60-170). During this study period, imatinib was given at a dose of 400mg/day. The dose reduction was indicted in 8 patients but not because of progressing renal impairment. The mean eGFR was 77 ml/min/1.73m2 (range, 38-120), and the value was below 60 ml/min/1.73m2 in 12 patients before initiating imatinib. The mean value significantly decreased to 62 ml/min/1.73m2 (range, 34-98) over the 5 years after imatinib treatment (P<0.001), and the values reached <60 ml/min/1.73m2 in 43 of 82 patients (P<0.001). In an univariate analysis of patients excluding 12 patients with below 60 ml/min/1.73m2, older age and lower eGFR value at the initiation of imatinib were associated with later development of chronic kidney disease (<60 ml/min/1.73m2) (P<0.001 and 0.002, respectively). Mean Hb level at 5 years after starting imatinib was significantly lower as compared with that before (12.9+1.7 g/dl vs. 12.4+1.3 g/dl, P<0.01). The declining rate of eGFR was negatively correlated with those of Hb levels (correlation coefficient -0.249, P<0.05). In 20 patients with low Hb level (9.7+1.2 g/dl) and renal dysfunction, median serum erythropoietin (EPO) level was 31.9 mIU/ml (range, 9.1-119). Furthermore, 11 patients with eGFR<60 ml/min/1.73m2 achieving a durable molecular remission took part in an institutional TKI discontinuation trial. At 1 year after discontinuing imatinib, their mean eGFR values significantly improved (50.0 + 6.5 to 56.0 + 10.2 ml/min/1.73m2, P<0.05) as well as Hb level (12.0 + 1.7 to 14.0 + 1.6 g/dl, P<0.01).
Conclusion: Our findings indicated that long-term use of imatinib is frequently associated with reversible but continuous decline in eGFR level, which could lead to anemia partly due to inadequate production of EPO. Although the degree of nephrotoxicity is usually mild, close monitoring of renal function is recommended particularly in older patients with pre-existing renal dysfunction.
Disclosures
Sakurai: Celgene: Honoraria. Karigane:Celgene: Honoraria. Matsuki:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Nippon Shinyaku: Honoraria. Kikuchi:Celgene: Honoraria; Takeda Pharmaceutical Company: Honoraria; Kyowa Hakko Kirin: Honoraria. Okamoto:Nippon Shinyaku Co., Ltd.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Teijin Pharma Limited: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding.
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