James L. Rubenstein, MD, PhD
Lenalidomide (Revlimid) penetrates ventricular cerebral spinal fluid (CSF) within 15 to 18 hours of the first dose allowing it to be highly active in patients with relapsed/refractory central nervous system (CNS) non-Hodgkin lymphoma (NHL), according to an interim analysis presented at the 13th International Conference on Malignant Lymphoma in Lugano, Switzerland.
In the phase I study, antitumor activity was seen with lenalidomide in combination rituximab and for lenalidomide monotherapy in patients with CNS lymphoma. Additionally, maintenance therapy with lenalidomide demonstrated a significant improvement in progression-free survival (PFS).
“For this study we asked if more effective therapies could be developed that are tolerated by the growing population of CNS lymphoma older patients and whether whole brain radiotherapy [WBRT] can be eliminated,” said lead investigator James L. Rubenstein, MD, PhD, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center. “In this series, lenalidomide maintenance was associated with enhanced PFS in relapsed/refractory CNS lymphoma patients that may delay or potentially obviate the need for WBRT.”
In the study, lenalidomide was examined at 10, 20, and 30 mg in combination with intraventricular rituximab. The study included 7 patients with recurrent/refractory CNS NHL and 10 with diffuse large B-cell lymphoma (DLBCL), with involvement in the brain, CNS, meninges, and/or intraocular compartments. The median age of patients was 63 years (range, 46-77) and 80% were female. Five patients had intraocular involvement, 4 had CSF involvement, and 7 had brain/parenchymal involvement. The study assessed the level of CSF penetration by lenalidomide.
Treatment with the combination of lenalidomide and rituximab showed partial responses (PR) in 2 of 3 patients receiving a 10 mg lenalidomide dose. At a dose of 20 mg of lenalidomide, 100% of patients showed a response, with 2 patients achieving a complete response (CR) and 4 with a PR. Four responses remain durable at ≥6 to 20 months.
An independent expansion cohort enrolled 8 patients with relapsed/refractory primary CNS lymphoma (PCNSL) and 2 patients with secondary CNSL (SCNSL) with a median age of 70 years (range, 45-81). This arm examined the feasibility of lenalidomide monotherapy at 5 mg to 10 mg as maintenance therapy. Lenalidomide was found to potentiate the effects of salvage therapy, including resection, Gamma Knife, and/or methotrexate/rituximab.
At median follow-up of 18 months, this cohort demonstrated an impressive extension in PFS with 5 patients maintaining durable responses for 2 or more years. Nine patients achieved a CR and one patient experience stable disease. Forty percent of patients remained progression-free for longer than 50 months. The 5-year overall was 100% in patients receiving monotherapy lenalidomide as maintenance therapy.
“The maintenance therapy results need to be confirmed in a prospective clinical trial,” said Rubenstein. “These are preliminary results; however the data may be immediately relevant to community practice.”
There was minimal toxicity in this elderly population with one case of non-invasive basal cell carcinoma reported. Of 3 patients receiving lenalidomide at 10 mg plus rituximab from 4 to 92 weeks, one grade 3/4 adverse event (AE) of fatigue was observed. In 6 patients receiving 20 mg lenalidomide from 4 to 92 weeks, grade 3/4 AEs of fatigue and neutropenia occurred in one patient each and 2 patients had infections. No grade 3/4 AEs were reported for 4 patients.
“The recommended starting dose of lenalidomide for CNS NHL has not yet been defined. There is evidence for activity at modest doses of 5 to 10 mg, but we are now enrolling at a 15 mg dose level,” said Rubenstein.
Lenalidomide has a broad mechanism of action, with distinct immunomodulatory properties. The agent has anti-angiogenic and anti-osteoclastogenic properties. In a previous study, activity was seen with single-agent lenalidomide in aggressive NHL, particularly in ABC-type DLBCL. This study showed that lenalidomide had activity in recurrent/refractory intraocular and CNS lymphoma (J Clin Oncol
Since receiving an initial approval for patients with myelodysplastic syndrome with a deletion 5q cytogenetic abnormality in 2005, lenalidomide has been explored across a number of indications. In 2006, it was approved for patients with pretreated multiple myeloma in combination with dexamethasone. In June 2013, the FDA approved the immunomodulatory agent for patients with mantle cell lymphoma following two prior therapies.