Lenalidomide Active in Relapsed CNS Lymphoma

Lenalidomide was able to penetrate ventricular cerebrospinal fluid (CSF) and was active in a small study of patients with relapsed central nervous system (CNS) diffuse large B-cell lymphoma, according to data presented by James L. Rubenstein, MD, PhD, of the University of California, San Francisco, at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago (abstract 7502).

The small study included 13 patients with refractory CNS diffuse large B-cell lymphoma. The median age of patients was 63 years. Patients were treated with lenalidomide at 10 mg- , 20 mg- , and 30-mg levels. After one cycle, patients were restaged and those with stable disease or better continued on to a second cycle of lenalidomide monotherapy.

Two dose-limiting toxicities occurred at the 20-mg dose level, consisting of a grade 4 infection and grade 3 confusion. Because each of the patients at the 20-mg dose level experienced responses, the researchers modified the protocol to develop a cohort at 15 mg, at which there were no dose-limiting toxicities.

In this heavily pretreated group, responses to lenalidomide were detected at each of the tested dose levels and occurred in 9 of the 13 patients. The drug was active in patients with intraocular, brain, and CSF disease. Six patients responded in the brain parenchymal, four in the intraocular compartment, and two in the CSF. Thus far, six responses have been durable beyond 6 months.

According to Rubenstein, a dose-dependent penetration of ventricular CSF was also confirmed in the study, with the CSF plasma partition coefficient achieving 20% or higher at the 15- and 20-mg doses.

Rubenstein and colleagues also evaluated whether or not there were prognostic biomarkers of response to lenalidomide that could be used in risk stratification. One of the most compelling for initial evaluation was CSF lactate, Rubenstein said. In the cohort of patients studied, patients with elevated CSF lactate above the cutoff point of 2.8 did very poorly, suggesting that CSF lactate could be used in risk stratification for identifying those patients who would and would not benefit from lenalidomide in this disease setting.

In addition to this biomarker, the researchers found that lenalidomide induced CD8 cell expansion in the brain microenvironment, as well as M1 macrophage responses in blood and CSF.

Based on the results of this phase I trial, the recommended starting dose of lenalidomide for CNS lymphoma is 15 mg per day on a 21-day cycle.

In a parallel study, the researchers conducted a retrospective analysis that looked at an independent cohort of 12 patients with recurrent disease who received lenalidomide monotherapy as a maintenance treatment.

“Lenalidomide maintenance at modest doses was feasible and associated with enhanced progression-free survival in relapsed, refractory CNS lymphoma patients, and in our series, it has had an impact in delaying or obviating whole-brain radiation,” Rubenstein said.