Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma.

Abstract

There is an unmet need for effective biological therapies for relapsed central nervous system (CNS) lymphoma. Lenalidomide is active in activated B-cell type diffuse large B-cell lymphoma and rituximab is effective in CNS lymphoma. These observations are the basis for this first trial of an immunomodulatory drug as monotherapy in CNS lymphoma, and, in patients with inadequate responses to lenalidomide, with rituximab. In an independent cohort, we evaluated lenalidomide maintenance after salvage with high-dose methotrexate or focal irradiation in relapsed primary CNS lymphoma (PCNSL). We determined safety, efficacy, and cerebrospinal fluid (CSF) penetration of lenalidomide at 10-, 15-, and 20-mg dose levels in 14 patients with refractory CD20+ CNS lymphoma. Nine subjects with relapsed, refractory CNS lymphoma achieved better than partial response with lenalidomide monotherapy, 6 maintained response ≥9 months, and 4 maintained response ≥18 months. Median progression-free survival for lenalidomide/rituximab was 6 months. In the independent cohort, response duration with lenalidomide maintenance after complete responses 2 through 5 were significantly longer than response durations after standard therapy. The CSF/plasma partition coefficient of lenalidomide was ≥20% at 15- and 20-mg dose levels. Change in CSF interleukin-10 at 1 month correlated with clinical response and response duration to lenalidomide. Metabolomic profiling of CSF identified novel biomarkers, including lactate, and implicated indoleamine-2,3 dioxygenase activity with CNS lymphoma progression on lenalidomide. We conclude that lenalidomide penetrates ventricular CSF and is active as monotherapy in relapsed CNS lymphomas. We provide evidence that maintenance lenalidomide potentiates response duration after salvage in relapsed PCNSL and delays whole brain radiotherapy (WBRT). This trial was registered at www.clinicaltrials.gov as #NCT01542918.

• Authors: James L Rubenstein, Huimin Geng, Eleanor J Fraser, Paul Formaker, Lingjing Chen, Jigyasa Sharma, Phoebe Killea, Kaylee Choi, Jenny Ventura, John Kurhanewicz, Clifford Lowell, Jimmy Hwang, Patrick Treseler, Penny K Sneed, Jing Li, Xiaomin Wang, Nianhang Chen, Jon Gangoiti, Pamela N Munster, Bertil Damato
• Journal: Blood advances (Blood Adv) Vol. 2 Issue 13 Pg. 1595-1607 (07 10 2018) ISSN: 2473-9537 [Electronic] United States
• PMID: 29986852 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society of Hematology.

Chemical References

• Rituximab
• Lenalidomide

Topics

• Aged
• Central Nervous System Neoplasms (drug therapy, mortality)
• Disease-Free Survival
• Female
• Humans
• Lenalidomide (administration & dosage)
• Lymphoma (drug therapy, mortality)
• Maintenance Chemotherapy
• Male
• Middle Aged
• Recurrence
• Rituximab (administration & dosage)
• Survival Rate