Assessment of Targeted Systemic Exposure Based on Ex-Vivo Concentrations of Bendamustine and Chlorambucil and Related Clinical Outcomes

The alkylating agent bendamustine (100 mg/m² iv) was recently shown to be superior to chlorambucil (0.8 mg/kg po) in the treatment of patients with chronic lymphocytic leukemia, in respect to both overall response rate and progression-free survival (Knauf et al 2007). In order to better understand the greater activity exhibited by bendamustine, the ex-vivo potencies of these two drugs against primary CLL cells were compared with the peak plasma concentrations obtained in patients. Published studies indicate that ex-vivo bendamustine treatment results in a mean LD50 (dose causing 50% cell death) of 7.4 and 4.3 μg/ml in CLL cells from chemo-naive and previously-treated patients respectively (Schwanen et al 2002). This is comparable to the Cmax attained in patients: a 120 mg/m² dose of bendamustine infused over 60 min resulted in a mean Cmax of 5.6 μg/ml in a study of lymphoma patients. In contrast, the corresponding LD50 values for chlorambucil were reported to be 12.3 and 26.2 μg/ml for chemo-naive and previously-treated CLL patients (Silber et al 1994). These concentrations are considerably higher than the plasma concentrations attained with oral administration of chlorambucil: an oral dose of 60 mg (~0.8 mg/kg) resulted in a mean Cmax of 2.2 μg/ml of parent compound and 1.1 μg/ml of the active phenylacetic acid metabolite. A higher dose of 70 mg did not result in higher plasma exposure (Hartvig et al 1988). The ability to achieve adequate therapeutic concentrations of bendamustine in CLL patients may explain, in part, the greater activity observed with this novel chemotherapy as compared to chlorambucil.