Clinical response and pharmacokinetics of bendamustine as a component of salvage R-B(O)AD therapy for the treatment of primary central nervous system lymphoma (PCNSL)

Abstract

Background A relatively high proportion of patients diagnosed with primary CNS lymphoma will experience recurrent disease, yet therapy options are limited in salvage therapy. This is the first study to evaluate a bendamustine-based combination regimen for the treatment of relapsed/refractory PCNSL and to characterize bendamustine pharmacokinetics in the human CSF.

Methods Patients received bendamustine 75mg/m2 for two days as part of R-B(O)AD administered intravenously every 4weeks for up to 4cycles. Response and adverse events of the regimen were assessed. A sparse sampling strategy and population based modeling approach was utilized for evaluation of plasma and CSF levels of bendamustine.

Results Ten patients were enrolled into study of whom 70% were of refractory disease and with high IELSG prognostic risk scores. The ORR of R-BOAD was 50% (95% CI, 0.24 to 0.76) with one patient achieving CR and four PR. Primary toxicity of the regimen was reversible myelosuppression, mostly grade 3 or 4 neutropenia. The Cmax mean for plasma and CSF were 2669ng/mL and 0.397ng/mL, respectively, and patients with response at deep tumor sites displayed higher trends in peak exposure. Pharmacokinetic data was best described by a four-compartment model with first-order elimination of drug from central plasma and CSF compartments.

Conclusions R-BOAD is an effective salvage option for PCNSL, but with significant hematologic toxicity. Bendamustine CSF levels are minimal; however correspond to plasma exposure and response.

Trial registration ClinicalTrials.gov NCT03392714

; retrospectively registered January 8, 2018.