Abstract
Background: Imatinib (STI571, Gleevec) is a protein kinase inhibitor that has become the standard treatment for chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). The recommended daily oral dose of imatinib in CML is 400mg. Imatinib is mainly metabolized in the liver with a half-life of 18 hours. The safety and efficacy of imatinib in patients with CML with abnormal liver and/or renal function at start of therapy has not been reported, frequently prompting the use of lower starting doses in these patients.
Aim: To determine the safety and efficacy of imatinib among patients with pre-existing liver and/or renal dysfunction.
Results: We analyzed the outcome of 259 patients with CML enrolled in three imatinib frontline studies at MD Anderson Cancer Center. The starting dose was 400mg in 50 patients and 800mg in 209. Renal dysfunction mild (creatinine clearance (CrCl) 40–59mg/ml) to moderate (CrCl 20–39mg/ml) was seen in 11 (4%) patients (n=4 in 400mg; n=7 in 800 mg) before start of imatinib therapy, and liver dysfunction mild (total bilirubin <1.5mg/dl, AST >upper limit of normal (ULN)) to moderate (total bilirubin between 1.5–3.0mg/dl, AST any) was seen in 38 (15%) patients (n=7 in 400 mg; n=31 in 800 mg). Dose reductions were necessary in 8/11 patients (73%, p=0.065) with renal dysfunction, 19/38 patients (50%, p=0.271) with liver dysfunction, compared with 91/211 pts (43%) with normal renal and liver functions. All 11 pts with renal dysfunction experienced further worsening of the renal function during treatment, and 2 of them (both with moderate renal dysfunction treated with imatinib 800mg) developed severe renal dysfunction (CrCl<20mg/ml), requiring dose reduction. Dose reduction resulted in normalization of renal function. Only 3/38 (8%; 1 in 400mg, 2 in 800mg) patients with liver dysfunction developed grade 3–4 liver toxicity while on imatinib, and required dose reduction. Toxicities of all grades seemed to be comparable among three groups of patients regardless of the starting dose of Imatinib. Grade 3–4 hematological toxicities including anemia (29%, 10% and 7% of patients with renal dysfunction, liver dysfunction and normal functions, respectively), neutropenia (57%, 30% and 30%) and thrombocytopenia (43%, 30% and 26%) were more frequent in patients with renal dysfunction treated with 800 mg imatinib. Grade 3–4 non-hematological toxicities were observed at similar frequencies in all groups. Complete cytogenetic response (CCyR) rates were similar among patients with renal dysfunction, liver dysfunction or normal functions regardless of the imatinib starting dose. Among those treated with a starting dose of 400 mg CCyR rates were 75% for those with renal dysfunction, 71% for patients with liver dysfunction, and 82% for patients with normal liver and renal function. Among those treated 800 mg CCyR rates were 86%, 97%, and 88%, respectively.
Conclusion: Although patients with organ dysfunction treated with imatinib may have a higher rate of hematologic toxicity and require more frequent dose reductions, particularly when treated at higher doses. With proper monitoring and dose management, most patients can be adequately treated resulting in response rates similar to those without organ dysfunction.
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