TKIs Have Kidney Effects in Long-Term CML Treatment

July 31, 2015

Treatment of CML with various tyrosine kinase inhibitors can induce changes in glomerular filtration rate over time and have other kidney-related effects.

Treatment of chronic myeloid leukemia (CML) with various tyrosine kinase inhibitors (TKIs) can induce changes in glomerular filtration rate (GFR) over time and have other kidney-related effects, according to a new study. Imatinib and dasatinib were associated with a decrease in GFR, while nilotinib was associated with an increase.

“Although TKIs are generally well tolerated and are associated with fewer adverse events than interferon-based therapy, these drugs demonstrate off-target effects,” wrote study authors led by Jorge E. Cortes, MD, of the MD Anderson Cancer Center in Houston, Texas. Some reports have suggested there may be some kidney effects, though data on the connection is lacking.

In the new study, researchers reviewed the records of 468 newly diagnosed CML patients who were treated with imatinib (253 patients), dasatinib (99 patients), or nilotinib (116 patients). The median duration of TKI treatment was 52 months. Results were published online ahead of print in Cancer.

Nineteen patients (4%) developed an acute kidney injury during follow-up; 16 of those received imatinib, one received dasatinib, and two nilotinib. The median time from the start of TKI therapy to the onset of this injury was nine days.

At the start of TKI treatment, 48 patients had a history of chronic kidney disease (CKD). Another 58 patients (14%) developed CKD while on therapy, most of whom were treated with imatinib (84%); this included 22% of all imatinib-treated patients, 5% of dasatinib patients, and 4% of nilotinib patients. Most (95%) of these cases were classified as stage III kidney disease, and 5% were stage IV. The median time from the start of TKI therapy to onset of TKD was 12 months.

On a multivariate analysis, treatment with imatinib was found to be the most significant factor associated with developed of CKD, with an odds ratio of 8.3 (95% CI, 3.5–19.4; P < .001).

Among patients who had no history of CKD at baseline, changes in GFR were associated with the TKI used (P < .001). In the imatinib group, the mean GFR declined from baseline to 3 months by 8 mL/min/1.73 m2, and to 6 months by 10 mL/min/1.73 m2. The authors noted that this downward trend continued for 4 years before stabilizing.

Dasatinib-treated patients also saw a decline in GFR, but it was smaller at 3 and 6 months and stabilized after 1 year. In nilotinib patients, meanwhile, the mean GFR increased from baseline to 3 months by 4 mL/min/1.73 m2, and it remained above baseline throughout treatment.

In patients who did have a history of CKD at baseline, mean GFR changes were still significantly associated with TKI type, but it increased from baseline to 3 months in all TKI groups. By 24 months, the mean GFR difference from baseline was smallest in imatinib patients, followed by dasatinib and nilotinib.

“Imatinib and, to a lesser extent, dasatinib may decrease GFR levels early during the course of treatment, but this GFR change is not clinically significant and is not associated with any significant impact on response rates or survival,” the authors concluded. “Thus, the administration of these drugs may be safe in the setting of CKD in [chronic phase] CML patients, but further studies are needed in this patient population to confirm this observation.”