A Systematic Review on the Use of Intrathecal Rituximab in CNS Lymphoma

Central nervous system (CNS) involvement by non-Hodgkin lymphoma (NHL) is a rare but serious complication with a high mortality rate and few effective therapeutic options. Rituximab is an anti-CD20 monoclonal antibody that is administered systemically in combination with chemotherapy, but can also be given intrathecally. When administered intrathecally (IT), rituximab achieves more predictable and higher cerebrospinal fluid (CSF) concentrations compared to its intravenous administration, however the efficacy and safety of IT rituximab are unknown (Rubenstein et al., J Clin Oncol 2007). We recently treated a 52 year old woman for a CNS relapse of diffuse large B-cell lymphoma (DLBCL) using a combination of IT rituximab, cytarabine, methotrexate and hydrocortisone, as well as craniospinal radiation. After initial improvement, she developed subacute combined degeneration (SCD) of the spinal cord. This prompted the present systematic review of the literature in order to explore the efficacy and safety of administering rituximab directly into the CSF for the treatment of CNS involvement by NHL.

We identified all relevant citations in MEDLINE/EMBASE/CINAHL/BIOSIS Previews from their date of inception to June 20^th, 2011. Prospective studies, case reports and case series reporting on intrathecal or intraventricular (via ommaya-reservoir) use of rituximab in relapsed primary (PCNSL) or secondary CNS-lymphoma were included. All articles citing the included articles, as well as the reference lists of included articles were reviewed to ensure capture of all relevant studies. In some cases, authors were contacted to gather additional information. Two authors independently evaluated study eligibility. Disagreements were resolved by consensus and agreement was assessed using the kappa statistic. All non-human studies were excluded. Due to the nature of the studies, a meta-analysis was not performed.

The search strategy identified 148 potential reports published between 2002–2011 of which 22 were included (3 prospective trials, 2 phase-I trials, 2 case-series and 15 case reports). The kappa value for inter-author agreement was 0.881. A total of 74 patients, aged 4–84 years old (Mean age 48), with PCNSL (28%) or secondary CNS-Lymphoma (ALL 14%, DLBCL 8%, Burkitt's 4%, Mantle Cell Lymphoma 5%, Post-transplant lymphoproliferative disorder 4%, Unknown histology 37%), received 1 to 22 doses of 10–50mg of intrathecal (43%) or intraventricular (IVT) rituximab, either alone or in combination with other therapies. At a mean follow-up of 43 weeks (Range 2–178), 34% of patients were in complete remission and 28% showed a partial response. Patients having both leptomeningeal and parenchymal involvement of CNS lymphoma were the most likely to have progression of disease with IT/IVT rituximab (44%), as compared to those with isolated disease in the leptomeninges (29%) or parenchyma (33%). Fifty percent of patients with isolated disease in the leptomeningeal compartment showed complete remission with IVT/IT rituximab therapy. Fatigue, nausea/vomiting and paresthesias were the most commonly reported side effects. In one series, seven patients developed arachnoiditis. There was a single case of Hepatitis B virus reactivation in a patient with parenchymal PCNSL. In addition, our patient developed symptoms and findings consistent with SCD and in whom a relation between SCD and rituximab could not be ruled out.

In case series and reports, IT rituximab appears to be a safe and modestly effective therapy when used in conjunction with other salvage therapies for the management of refractory CNS-lymphoma. The overall proportion of complications appears to be reasonably low. To our knowledge, our patient is the first case of SCD reported in a patient who received IT rituximab. Further studies with a particular emphasis on safety are needed before widespread use can be recommended.

Off Label Use: Systematic literature review on the use of intrathecal rituximab for CNS lymphoma (off-label use). Lazo-Langner:Leo Pharma: Honoraria; Pfizer Inc.: Honoraria.