| Literature DB >> 29986852 |
James L Rubenstein1,2,3, Huimin Geng2,4, Eleanor J Fraser1, Paul Formaker1, Lingjing Chen1, Jigyasa Sharma1, Phoebe Killea1, Kaylee Choi1, Jenny Ventura1, John Kurhanewicz2,5, Clifford Lowell2,4, Jimmy Hwang2,6, Patrick Treseler2,7, Penny K Sneed2,8, Jing Li9, Xiaomin Wang10, Nianhang Chen10, Jon Gangoiti11, Pamela N Munster1,2, Bertil Damato2,12.
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.Entities:
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Year: 2018 PMID： 29986852 PMCID： PMC6039666 DOI： 10.1182/bloodadvances.2017014845
Source DB: PubMed Journal: Blood Adv ISSN： 2473-9529