Phase 1 Trial of Intraventricular Rituximab and Methotrexate in Heavily Pretreated Patients with Recurrent CNS Lymphoma

Abstract & Commentary

By Bindu Kanapuru, MD, Hematology/Oncology Division, IASIA-Falls Church, Falls Church, VA. Dr. Kanapuru reports no financial relationships relevant to this field of study.

Synopsis: This Phase 1 clinical trial evaluated the safety and pharmacokinetics of intraventricular immune-chemotherapy with twice weekly rituximab (10 mg and 25 mg) and methotrexate in 14 patients with recurrent central nervous system lymphoma (primary or secondary). Three patients were treated at the 10 mg dose level and 11 patients received treatment with 25 mg of rituximab. No dose-limiting toxicity was seen with this combination at the 10 mg or 25 mg dose level. Coadministration with methotrexate was associated with slower elimination of rituxan from cerebrospinal fluid. The complete response in the leptomeningeal compartment in this heavily pretreated population was 75%, and the overall complete response rate was 43%.

Source: Rubenstein JL, et al. Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma. Blood 2013;121:745-751.

Primary central nervous system (CNS) lymphoma is a rare but aggressive lymphoma, accounting for 4-6% of extranodal lymphomas. High-dose methotrexate (MTX) and cytosine arabinoside (Ara-c) is the standard of care for initial treatment of this aggressive lymphoma. However, failure rates are more than 50% and relapse is associated with a very poor prognosis. CNS relapse in patients with primary systemic lymphoma is also associated with a very poor outcome. Although prophylactic intrathecal (IT) therapy is administered to patients identified to be at high risk for CNS relapse, a clear benefit (except in Burkitt’s and acute lymphoblastic leukemia) has yet to be established.1 Addition of rituxan to standard CHOP chemotherapy has been associated with improved survival in systemic nonHodgkin’s lymphoma, but its benefit on decreasing CNS relapse or in the treatment of primary CNS lymphoma is less clear.

The reason for this discrepancy between systemic and CNS responses was thought to be due to the poor CNS penetration of the rituxan, and cerebrospinal fluid (CSF) levels of rituxan after intravenous administration were only 0.1% of the serum concentrations. In non-human primates, intrathecal administration of rituxan was shown to produce therapeutic levels in CSF and was well tolerated. In a prior Phase 1 trial with single-agent, intraventricular rituximab, the authors established that intraventricular injection at 10-50 mg reproducibly results in concentrations within the ventricles that are similar to peak levels in the serum achieved after standard intravenous injection of rituximab.2

In the current study, the authors conducted a multicenter, Phase 1 trial with intraventicular rituximab and methotrexate, with the rationale that rituximab may enhance the apoptotic effect of chemotherapeutic agents by sensitizing autoimmune B cells.3

This trial included 14 heavily pretreated patients (median of five prior regimens) with relapsed or refractory CD20+ CNS lymphoma arising from systemic NHL (8) or primary CNS lymphoma (6) without prior exposure to intrathecal rituximab. Eligible patients were older than age 17 years with Karnofsky performance status more than 50%, were HIV-seronegative, with granulocyte concentration of at least 1000/mcL, and platelet concentration of at least 50 000/mcL and had an Omaya reservoir. Patients had baseline laboratory evaluation as well as staging with slit lamp, MRI, and spinal fluid analysis. Participants were enrolled at two doses: three patients were treated with 10 mg of rituximab alone for the first dose and with 12 mg of methotrexate 3 days later (D4). The treatment was repeated every week with planned treatment for 4 weeks.

CSF studies including cytology were evaluated during the second injection every week. Serum laboratory studies were repeated at the time of the second injection every week. Lymphoma restaging and neuroimaging were done at week 5 and intraocular examination was performed if positive at baseline. PK analysis was done by matched CSF and venous blood samples.

No dose-limiting toxicity (infusional hypertension) was seen at the 10 mg or 25 mg dose levels. Adverse events were self limited and included grade I paraesthesias, chills, and rigors. No events of arachnoiditis were seen. Addition of methotrexate delayed the egress of rituxan from CSF, and the elimination rates (first-order) were 0.88/h and 0.84/h for the 10 mg and 25 mg dose levels, respectively, when rituximab was given alone and 0.47/h and 0.36/h, respectively, when administered in combination with MTX. Two patients were unable to complete treatment (4 weeks) due to disease progression. The overall complete response (CR) was 75% in 12 patients with leptomeningeal involvement at a median of three doses. However, four patients who had CR in the leptomeninges had evidence of parenchymal progression and the overall response rate was only 43% (6/14).

Commentary

The prognosis for relapsed CNS lymphoma is dismal, with median survival of 6 months.4 No standard therapies exist and the current therapies are often associated with toxicity. This is the first trial to explore the safety of intraventricular immune chemotherapy in patients with CNS lymphoma. The reported response rate of 43% is encouraging in the heavily pretreated population. Patients had received a median of five treatments prior to enrolling in this study including intravenous rituximab treatment. In addition, a synergistic effect of rituximab and methotrexate was seen, as evidenced by a rate of decline in CSF malignant lymphoma cells the day after combination therapy. Contrary to previous belief that the intra-parenchymal structures are poorly accessible via the intraventricular compartment, complete or partial responses also were seen in patients with primary parenchymal relapse. The study clearly met its primary objective and established prospectively that intraventricular immunochemotherapy is feasible and safe. However, a Phase 2 trial at the established dose level will be needed to confirm the efficacy of this regimen. In addition, despite excellent response rates, the majority of patients relapsed within 3 months suggesting development of resistance to rituximab.

References

1. Bernstein SH, et al. Natural history of CNS relapse in patients with aggressive non-Hodgkin’s lymphoma: A 20-year follow-up analysis of SWOG 8516 — the Southwest Oncology Group. J Clin Oncol 2009;27:114-119.

2. Rubenstein JL, et al. Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol 2007;25:1350-1356.

3. Edwards JC, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-2581.

4. Patrij K, et al; International Primary CNS Lymphoma Collaborative Group (IPCG). Isolated central nervous system relapse of systemic lymphoma (SCNSL): Clinical features and outcome of a retrospective analysis. Ger Med Sci 2011;9:Doc11. doi: 10.3205/000134. Epub 2011 May 2.