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.

Clinical outcomes of newly diagnosed primary CNS lymphoma treated with ibrutinib‐based combination therapy: A real‐world experience of off‐label ibrutinib use

“…30 Lenalidomide also has antitumor activity in PCNSL. 31,32 The pathological subtype of most PCNSL patients is non-GCB subtype, indicating the promising future of combing lenalidomide and ibrutinib as maintenance in PCNSL. For patients unfit for autologous stem transplantation, use of lenalidomide plus ibrutinib as maintenance might be promising.…”

Low‐dose lenalidomide maintenance after induction therapy in older patients with primary central nervous system lymphoma

“…In most cases, remission duration with lenalidomide maintenance was significantly longer than previous response durations. (Rubenstein et al , ).…”

Optimization of CSF biological investigations for CNS lymphoma diagnosis

“…As previously reported by Kim et al, we confirm that the IL‐10 level is not increased in low‐grade lymphoproliferations and therefore should be used only when suspecting a transformation into a more aggressive lymphoma . In addition, a recent study reports the IL‐10 concentration as a new pharmacodynamic biomarker of response to lenalidomide in CNSL …”