1. Lenalidomide Shows Promising Activity in Recurrent CNS Lymphoma
CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
CNS, central nervous system.
This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

2. Lenalidomide in Recurrent CNS Lymphoma: Background
Optimal treatment for relapsed CNS lymphoma unclear
Lenalidomide, an immunomodulatory agent, is active in DLBCL and multiple myeloma via binding to cereblon in tumor cells
Cereblon is highly expressed in primary CNS lymphoma
Pre-clinical and preliminary clinical activity of lenalidomide observed against CNS lymphoma
Phase I trial examined safety, efficacy of lenalidomide monotherapy in recurrent CNS lymphoma and combination of lenalidomide + rituximab postprogression on lenalidomide monotherapy
CNS, central nervous system; DLBCL, diffuse large b-cell lymphoma.
Rubenstein JL, et al. J Clin Oncol. 2011;29:e595-e597.
Rubenstein JL, et al. ASCO Abstract 7502.
Slide credit: clinicaloptions.com

3. Lenalidomide in Recurrent CNS Lymphoma: Phase I Study Design
Rituximab IV/IO
D1,8,15,22 PD
Pts with CD20+ recurrent/refractory CNS lymphoma involving brain, CSF, meninges, and/or eye
(N = 14)
1-mo
restaging
Lenalidomide
10, 20, or 30 mg
D1-21
Lenalidomide
D1-21
CR/PR/SD
CNS, central nervous system; CSF, cerebrospinal fluid; DoR, duration of response; PD, progressive disease; SD, stable disease.
Primary objective: safety, efficacy, establish recommended dose
Secondary objectives:
Define CSF penetration of oral lenalidomide
Response rate, DoR of lenalidomide monotherapy
Feasibility, activity of intraventricular/IV rituximab addition to lenalidomide
Identify prognostic and predictive biomarkers, mechanism of action
Slide credit: clinicaloptions.com
Rubenstein JL, et al. ASCO Abstract 7502.

4. Lenalidomide in Recurrent CNS Lymphoma: Pt Characteristics
All Pts
(N = 14)
Median age, yrs (range)
66 (47-79)
Male, % 36
Median KPS, range
65 (50-90)
Primary/secondary CNS lymphoma, n
6/8
Active systemic disease, n 3*
Compartmental involvement, n
Intraocular
+ CSF/leptomeningeal
Brain parenchymal 5 7 10
CLL, chronic lymphocytic leukemia; CNS, central nervous system; CSF, cerebrospinal fluid; KPS: Karnofsky performance status.
*2 CLL, 1 marginal zone.
Slide credit: clinicaloptions.com
Rubenstein JL, et al. ASCO Abstract 7502.

5. Lenalidomide in Recurrent CNS Lymphoma: Safety of Lenalidomide
15-mg cohort added due to 2 dose limiting toxicities at 20-mg dose
Lenalidomide Dose (mg/day)
Pts, n
Grade ≥ 3 Events* 10 3
G3: fatigue 20 6
G3: infection, confusion†, neutropenia
G4: infection† 15 4
G3: neutropenia‡, Zoster
G4: neutropenia‡, pneumonia
G5: tumor progression
CNS, central nervous system.
*All events n = 1. †Dose-limiting toxicity. ‡Grade 3 neutropenia and grade 4 pneumonia occurred in 1 pt, and grade 4 neutropenia and grade 3 Zoster occurred in 1 pt.
Slide credit: clinicaloptions.com
Rubenstein JL, et al. ASCO Abstract 7502.

6. Lenalidomide in Recurrent CNS Lymphoma: Efficacy
Heavily pretreated population, median 3 prior therapies
9 of 13 evaluable pts deemed responders
6 in brain parenchyma
4 in intraocular compartment
2 in CSF (time-dependent response by flow cytometry)
Some responses durable: 6 pts ≥ 6 mos (3 pts ≥ 9 mos)
PFS ranged from 4 wks to 112+ wks
Lenalidomide penetrates ventricular CSF in dose-dependent manner; reached 20% plasma partition coefficient with ≥ 15-mg dose
Induces reversible CD8 cell expansion in ventricular CSF
CNS, central nervous system; CSF, cerebrospinal fluid.
Slide credit: clinicaloptions.com
Rubenstein JL, et al. ASCO Abstract 7502.

7. Lenalidomide in Recurrent CNS Lymphoma: Prognostic Biomarkers
Potential prognostic biomarkers evaluated due to heterogeneity in DoR to lenalidomide monotherapy
Identified CSF lactate, which has relevance to tumor metabolism and CNS lymphoma setting
Elevated CSF lactate predicts significantly shorter PFS (P = .0093), OS (P = .0018) after lenalidomide + rituximab
Authors suggest may be useful for risk stratification
CNS, central nervous system; CSF, cerebrospinal fluid; DoR, duration of response.
Slide credit: clinicaloptions.com
Rubenstein JL, et al. ASCO Abstract 7502.

8. Lenalidomide in Recurrent CNS Lymphoma: Maintenance
Parallel retrospective analysis of lenalidomide maintenance after salvage therapy (including chemotherapy ± rituximab or focal radiation)
N = 14 (12 primary, 2 secondary CNS lymphoma)
Progressed after median 1.5 prior therapies (range 1-3)
Lenalidomide maintenance (5-10 mg/day) administered after salvage therapy significantly improved response duration (5 to 57+ mos)
Prolonged OS compared to historical OS with intensive chemotherapy followed by ASCT
CNS, central nervous system.
Rubenstein JL, et al. ASCO Abstract Soussain C, et al. J Clin Oncol. 2008;26:
Slide credit: clinicaloptions.com

9. Lenalidomide in Recurrent CNS Lymphoma: Conclusions
Lenalidomide is active in relapsed/refractory CNS lymphoma, a population with poor prognosis
Penetrates CSF and shows activity in all compartments (intraocular, brain, CSF)
Minimal toxicity
Recommended starting dose: 15 mg/day
CSF lactate may be a prognostic biomarker for identification of pts likely to benefit from lenalidomide
Investigators suggest combined intraventricular/IV rituximab + lenalidomide is feasible in heavily pretreated CNS lymphoma pts
Lenalidomide maintenance should be explored prospectively
CNS, central nervous system; CSF, cerebrospinal fluid.
Slide credit: clinicaloptions.com
Rubenstein JL, et al. ASCO Abstract 7502.

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