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

Evidence from previous preclinical tissue distribution studies and single agent intravenous drug therapy trials in CNS malignancies suggests that bendamustine penetrates brain and tumor tissue [12, 21–23], and while cerebrospinal fluid (CSF) drug concentrations are commonly used as a surrogate marker of CNS delivery, there are no clinical data available on the pharmacokinetics (PK) of bendamustine in the CSF. In light of rarity of the disease and difficulties in obtaining extensive data samples, a nonlinear mixed-effects modeling approach was considered appropriate for drug evaluation. [...]we evaluated the PK of plasma and CSF drug levels through a population based model approach in a R/R PCNSL cohort with the goals to define the currently unknown PK profile of bendamustine in the CSF and to further characterize the relationship between plasma and CSF drug levels, and the influence of exposure on response to therapy. Sex/ Age (years) ECOG PS IELSG score* Disease state Previous therapy Tumor location R-B(O)AD cycles completed Final response PFS/OS (months) 1 F/68 2 5 Ref HDMTX+ AraC D; periventricular, basal ganglia 3 PD 1.8/7.3 2 F/55 2 4 Ref HDMTX+ AraC D; periventricular, corpus callosum 2 PD 2.5/6.8 3 M/75 1 4 Rel HDMTX + WBRT; MPV-A ND; L optic nerve 4 CR 21.7/> 21.7 4 M/42 2 3 Ref HDMTX D; basal ganglia 2 PD 1.6/9.1 5 M/78 2 3 Rel HDMTX+ AraC ND; L parietal 4 PR 6.9/> 6.9 6 F/55 2 4 Ref HDMTX+ AraC ND; L frontal, R temporal 3 PD 2.8/3.3 7 F/47 1 2 Ref HDMTX+ AraC Dt; L frontal, periventricular 1 PR 2.8/2.8 8 F/73 2 5 Rel HDMTX+ AraC ND; L frontal 4 PR 4.4/4.4 9 M/75 2 4 Ref HDMTX+ AraC NDt; L frontal 2 SD 4.2/> 4.2 10 M/65 2 5 Ref HDMTX Dt; L frontal, basal ganglia 2 PR 3.9/3.9 Abbreviations: M, male; F, female; PS, performance status; Rel, relapsed; Ref, refractory; HDMTX, high dose methotrexate; AraC, cytarabine; WBRT, whole brain radiotherapy; MPV-A, methotrexate, vincristine, procarbazine, cytarabine; D, deep; ND, non-deep; L, left; R, right; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; PFS, progression free survival; OS, overall survival *IELSG risk = intermediate (IELSG score 2–3), high (IELSG score 4–5) tPatients with leptomeningeal involvement in recurrent disease Efficacy and safety The ORR of R-B(O)AD was 50% (95% CI, 0.24 to 0.76), one patient achieving CR (10%) and four PR (40%). Best-fit curves from the final population PK model are shown for plasma () and CSF (−---) Table 2 Population PK model parameter estimates and nonparametric bootstrap 90% confidence intervals Parameter Estimate RSE (%) /CV (%) Bootstrap Replicates Median CI (90%) V1 14.9 19.2 14.1 4.9 20.7 CL 32.5 10.5 31.4 23.9 39.2 V2 0.508 14.4 0.455 0.186 0.846 Q1 0.238 15.3 0.205 0.041 0.660 V3 0.323 9.8 0.322 0.186 0.442 Q2 0.569 15.8 0.569 0.344 0.836 V4 0.032 40.9 0.032 0.014 0.041 Q3 0.793 16.8 0.795 0.573 1.360 CLcsf 0.075 43.5 0.075 0.059 0.140 IIV V1 0.230 42.9 0.220 0.011 0.480 IIV CL 0.089 39.9 0.086 0.014 0.190 RV 0.420 17.4 0.390 0.210 0.620 Abbreviations: RSE (%, for structural parameter estimates), relative standard error; CV (%, for IIV), coefficient of variance; CI, confidence interval; V (L), volume of distribution; CL (L/h), elimination clearance; Q (L/h), inter-compartmental clearance; CLcsf (L/h), CSF compartment clearance; IIV, inter-individual variability; RV, residual variability Discussion This was a prospective pilot trial investigating a bendamustine-based combination regimen in patients with R/R primary CNS lymphoma.