Lenalidomide for aggressive B‐cell lymphoma involving the central nervous system?
Authors: Maria Christina Cox, Giuseppe Mannino, Luana Lionetto, Virginia Naso, Maurizio Simmaco, Maria Antonietta Aloe Spiriti
Journal: American Journal of Hematology (2011)

Lymphomas arising or relapsing in the central nervous system (CNS) have a dismal prognosis [1]. Very few active drugs passing through the blood brain barrier are available. Lenalidomide is a novel and extremely active compound in relapsed diffuse-large-B-cell-lymphoma (DLBCL) and mantle cell lymphoma (MCL) [2, 3]. The pleiotropic action of Lenalidomide needs to be further exploited in different clinical settings and in combination with other drugs [4, 5]. Thus far, patients with aggressive lymphomas and CNS involvement have been excluded from clinical trials and there are no data about Lenalidomide penetration in the CNS. Very recently, it was reported that Lenalidomide induced remission in a case of DLBCL relapsed within the CNS [6]. Here, we refer on a case of blastoid MCL [7] relapsed within the orbit and the CNS. The patient failed chemotherapy but achieved remission on Lenalidomide therapy. Furthermore, the presence of the drug was ascertained in the blood and in the cerebrospinal fluid (CSF) using an LC-MS/MS system consisting of a quadrupole mass spectrometer. In September 2010, a 74-year-old man came to our observation for the appearance of right exophthalmos and blurred vision. He had been successfully treated 2 years before for blastic MCL with upfront high-dose therapy followed by Z-Beam conditioning regimen and peripheral blood stem cell rescue [8]. Magnetic resonance imaging (MRI) of the brain and the orbits revealed pathological tissue in the right extra cone involving the lachrymal gland and the right superior rectus muscle. The lesion was contiguous to the right eyeball with a maximum anteroposterior diameter of 4 cm. Ophthalmologic assessment comprehensive of fluorine angiography showed a retinal pattern suggestive for lymphoma involvement. The biopsy of the lachrymal gland revealed relapse of blastoid MCL [9]. The complete restaging ruled out other localization but the right orbit and the CSF with 220/μL CD19+/CD5+ cells. He shortly started a 21-day cycle of high dose Ifosfamide, Dexamethasone and Rituximab and weekly intrathecal chemotherapy with Aracytin and Methotrexate. After three cycles of Ifosfamide treatment, chemotherapy was withdrawn, since MRI showed no improvement while the patient complained deterioration of the right eye vision. At this stage, no lymphoma cells were found in the CSF. In December 2010, as a compassionate treatment, he was given Lenalidomide 25 mg/day for a 21-day cycle, combined with 20 mg of weekly Dexamethasone. At the end of the first cycle, he had an impressive recover of the exophthalmos and of the visual acuity of the right eye. Lenalidomide concentration, in the blood and in the CSF was determined using an LC-MS/MS system consisting of a quadrupole mass spectrometer (See Supporting Information in the article). In May 2011, after five cycles of therapy the MRI and the orbit ultrasound revealed a greater than 50% reduction of the lesion and the CT-scan ruled out progression in other sites while the CSF flow cytometry is persistently negative. Presently, he is well in stable partial remission. Aggressive lymphomas with intraocular [10] or orbital [11] localization might be difficult to treat because of the potential damage of chemotherapy and/or radiotherapy to the functional integrity of the eye and the risk, mainly for intraocular lymphoma, of spreading within the brain and the leptomeninges. The case we describe was localized within the ocular adnexa and the CNS since the CSF was contaminated by lymphoma cells [1]. We suppose that the spreading of lymphoma cells in the CSF originated from the orbit due to the direct relation of the orbit with the CSF that flows along the optic nerve. To our knowledge, this is the first report proving that Lenalidomide is detected in the CSF and that it is effective in relapsed blastoid MCL involving the orbit. Currently, the outcome of CNS lymphoma is unsatisfactory, and the search for more effective and less toxic regimes is a big challenge [12] Although the direct or immunomediated and antiangiogenetic modality of action of Lenalidomide on tumor cells is still under debate, the detection of the drug in the CSF further support the experimentation of Lenalidomide in patients with aggressive B-cell CNS lymphomas. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Maria Christina Cox*, Giuseppe Mannino , Luana Lionetto , Virginia Naso*, Maurizio Simmaco , Maria Antonietta Aloe Spiriti*, * Department of Hematology, A.O. Sant'Andrea, University La Sapienza, Rome, Italy, Department of Ophthalmology, A.O. Sant'Andrea, University La Sapienza, Rome, Italy, Department of Molecular Biology, A.O. Sant'Andrea, University La Sapienza, Rome, Italy.