Standard pentostatin dose reductions in renal insufficiency are not adequate: selected patients with steroid-refractory acute graft-versus-host disease

Abstract

Background and objective: Pentostatin is an irreversible inhibitor of adenosine deaminase and has been used to prevent graft-versus-host disease (GVHD) and to treat both acute and chronic GVHD. Dose reduction equations for patients with renal insufficiency are based on few patients with limited pharmacokinetic and clinical results. This phase II study (NCT00201786) was conducted to assess pentostatin efficacy and infectious complications seen from our previous phase I study in steroid-refractory acute GVHD (aGVHD).

Patients and methods: Hospitalized patients with steroid-refractory aGVHD were given pentostatin 1.5 mg/m(2)/day intravenously on days 1-3 of each 14-day cycle. Prior to each dose, dose modifications were based on Cockcroft-Gault estimated creatinine clearance (eCrCL) with 30-50 mL/min/1.73 m(2) leading to a 50 % dose reduction and eCrCL less than 30 mL/min/1.73 m(2) leading to study removal. Plasma pentostatin area under the concentration-time curve (AUC) and incidence of infectious complications were evaluated.

Results: Two of the eight patients treated demonstrated excessive pentostatin exposure as determined by measurement of AUC. One of these patients had renal impairment, whereas the other patient demonstrated borderline renal function. Despite dose reduction to 0.75 mg/m(2), AUCs were significantly increased compared to the other patients in this study. Seven of eight patients treated with pentostatin had cytomegalovirus (CMV) viremia after pentostatin treatment; however none developed proven CMV disease.

Conclusion: A 50 % dose reduction in patients with eCrCL 30-50 mL/min/1.73 m(2) seems reasonable. However, the eCrCL should be interpreted with extreme caution in patients who are critically ill and/or with poor performance status. Renal function assessment based on the Cockcroft-Gault method could be significantly overestimated thus risking pentostatin overdosing. These results imply a need to closely monitor pentostatin exposure in patients with renal insufficiency.

Conflict of interest statement

All authors have no conflicts of interest that are directly relevant to the content of this study.

Figures

Figure 1. Plasma pentostatin concentration versus time

Pentostatin concentrations were determined with an adenosine deaminase inhibition assay measuring the conversion of adenosine to inosine via UV absorbance. Plots are displayed for all patients and for all administered doses on the first 3 days of treatment.

Figure 2. (a) Dose-normalized plasma pentostatin AUC∞ versus estimated creatinine clearance

The outlier is from dose #2 from patient #1. (b) Pentostatin clearance versus estimated creatinine clearance. AUC∞ and clearance estimates were generated with non-compartmental analysis and normalized by dose. AUC∞ is the area under the plasma pentostatin concentration-time curve from time zero to infinity. (c) Dose-normalized plasma pentostatin maximum concentration versus estimated creatinine clearance. Creatinine clearance was estimated from serum creatinine measurements using the Cockcroft-Gault method. *Denotes dose on day 1, and ** dose on day 2 from patient #1, respectively.