Clofarabine-associated acute kidney injury in patients undergoing hematopoietic stem cell transplant

Abstract

We examined clofarabine pharmacokinetics and association with renal toxicity in 62 patients participating in a phase I–II study of clofarabine–melphalan–alemtuzumab conditioning for hematopoietic stem cell transplant (HSCT). Pharmacokinetic parameters, including clofarabine area under the concentration–time curve (AUC), maximum concentration and clearance, were measured, and patients were monitored for renal injury. All patients had normal pretreatment creatinine values, but over half (55%) experienced acute kidney injury (AKI) after clofarabine administration. Age was the strongest predictor of AKI, with older patients at greater risk (p = 0.002). Clofarabine AUC was higher in patients who developed AKI, and patients with the highest dose-normalized AUCs experienced the most severe grades of AKI (p = 0.01). Lower baseline renal function, even when normal, was associated with lower clofarabine clearance (p = 0.008). These data suggest that renal-adjustment of clofarabine dosing should be considered for older and at-risk patients even when renal function is ostensibly normal.

Phase I/II multisite trial of optimally dosed clofarabine and low‐dose TBI for hematopoietic cell transplantation in acute myeloid leukemia

“…Two of 36 patients treated at the 250 mg/m 2 clofarabine dose suffered probable conditioning‐related mortality. Early hepatic and renal toxicity attributed to clofarabine‐based conditioning has been observed by others, but real‐time PK‐guided dose adjustment is not currently standard‐of‐care. Our trial included only patients with normal creatinine clearance, and nonetheless, stochastic acute kidney injury did occur.…”

Dosing‐time contributes to chronotoxicity of clofarabine in mice via means other than pharmacokinetics

“…For example, clofarabine‐treated patients might have more severe infections due to strong inhibition on bone marrow, hematological toxicity and immunosuppression [20,22]. Kidney and liver injuries are also common because clofarabine is mainly renally excreted and decomposed by the liver [23–27]. Clofarabine in combination with cytarabine caused high toxicity and unacceptable mortality in elderly AML patients in a phase II trial [28].…”

New drug toxicities in the onco-nephrology world

“…Various grades of nephrotoxicity based on serum creatinine elevations were noted and ranged from 10% to as high as 36%. 31,33,40,41 Many patients were elderly and clinical risk factors for AKI were present, including hypotension, sepsis, tumor lysis syndrome, and underlying CKD. The FDA Adverse Event Reporting System also contains evidence that supports renal toxicity associated with clofarabine therapy.…”

“…Over a 12-month period (2011-2012), 29 reports of kidney injury were noted using various search terms that reflected some form of nephrotoxicity. Petri et al 41 noted that greater age, higher drug area under curve, and, marginally, lower baseline GFR were risk factors associated with clofarabinerelated kidney injury. Five out of nine patients who experienced grade 3 AKI progressed to dialysis requirement, and two remained on dialysis until death.…”

“…At the end of the follow-up period, only one of these patients was alive without relapse. 41 Two case reports describe the temporal association of AKI with clofarabine therapy. 35,42 Kintzel et al 35 noted rapid development of AKI following exposure to clofarabine in a 65-year-old man with acute myelogenous leukemia.…”