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 75 mg/m2 for two days as part of R-B(O)AD administered intravenously every 4 weeks for up to 4 cycles. 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 2669 ng/mL and 0.397 ng/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.

Keywords: Bendamustine; CSF; Pharmacokinetics; Primary CNS lymphoma; Salvage therapy.

Conflict of interest statement

Ethics approval and consent to participate

Study protocol was approved by the institutional ethics committee at Chonnam National University Hwasun Hospital (CNUHH-2016-145) and conducted in accordance to the Declaration of Helsinki principles. All patients provided written informed consent.

Consent for publication

Written informed consent for publication of clinical details, outcomes, and images was obtained from all patients. A copy of the consent form is available for review by the Editor of this journal.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Resolution of multi-focal (left frontal and right temporal lobe) disease in a 65 year old patient (ID No. 6) a) before and b) after two cycles of R-BOAD at interim analysis

Fig. 2

Relationship between interim response status and a) plasma Cmax and b) CSF Cmax bendamustine concentrations, and tumor location. Deep structures include periventricular regions, basal ganglia, brainstem, and cerebellum regions. Closed circles (•) represent responders and open circles (°) non-responders. Patient identification numbers are notated and the dashed line depicts mean Cmax values for plasma and CSF. Bendamustine exposure was not significantly higher for the patient resulting in treatement related death (ID No. 8)

Fig. 3

Schematics of structural model used for bendamustine. Abbreviations: V, volume of distribution; Q, inter-compartmental clearance; CL, clearance of central plasma compartment; CLcsf, clearance of CSF compartment

Fig. 4

Bendamustine concentration-time profiles. Circles represent observed values for plasma (•) and CSF (°) drug levels. Best-fit curves from the final population PK model are shown for plasma () and CSF (−---)