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

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

Blood Advances (Jul 2018)

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

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

Affiliations

James L. Rubenstein: Hematology/Oncology, University of California San Francisco, San Francisco, CA;; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA;; Parker Institute of Cancer Immunotherapy, University of California San Francisco, San Francisco, CA;; James L. Rubenstein, University of California, San Francisco, Division of Hematology/Oncology, M1282, Box 1270, San Francisco, CA 94143;
Huimin Geng: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA;; Laboratory Medicine, University of California San Francisco, San Francisco, CA;
Eleanor J. Fraser: Hematology/Oncology, University of California San Francisco, San Francisco, CA;
Paul Formaker: Hematology/Oncology, University of California San Francisco, San Francisco, CA;
Lingjing Chen: Hematology/Oncology, University of California San Francisco, San Francisco, CA;
Jigyasa Sharma: Hematology/Oncology, University of California San Francisco, San Francisco, CA;
Phoebe Killea: Hematology/Oncology, University of California San Francisco, San Francisco, CA;
Kaylee Choi: Hematology/Oncology, University of California San Francisco, San Francisco, CA;
Jenny Ventura: Hematology/Oncology, University of California San Francisco, San Francisco, CA;
John Kurhanewicz: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA;; Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA;
Clifford Lowell: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA;; Laboratory Medicine, University of California San Francisco, San Francisco, CA;
Jimmy Hwang: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA;; Biostatistics and Computational Biology, University of California San Francisco, San Francisco, CA;
Patrick Treseler: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA;; Pathology, University of California San Francisco, San Francisco, CA;
Penny K. Sneed: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA;; Radiation Oncology, University of California San Francisco, San Francisco, CA;
Jing Li: Medimmune, Mountain View, CA;
Xiaomin Wang: Celgene Corporation, Summit, NJ;
Nianhang Chen: Celgene Corporation, Summit, NJ;
Jon Gangoiti: Genetics and Pediatrics, University of California, San Diego, La Jolla, CA;
Pamela N. Munster: Hematology/Oncology, University of California San Francisco, San Francisco, CA;; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA;
Bertil Damato: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA;; Ocular Oncology, University of California San Francisco, San Francisco, CA

Journal volume & issue: Vol. 2, no. 13
pp. 1595 – 1607

Abstract

Read online

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.

Published in Blood Advances

ISSN: 2473-9529 (Print); 2473-9537 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine
Website: https://ashpublications.org/bloodadvances

About the journal