Central nervous system (CNS) relapse in diffuse large B cell lymphoma (DLBCL): pre- and post-rituximab

Abstract

Central nervous system (CNS)-directed prophylactic intrathecal (IT) therapy is indicated in patients with Burkitt and acute lymphoblastic lymphoma. Its role in diffuse large B cell lymphoma (DLBCL), a heterogeneous subtype, is less well defined. While addition of rituximab to standard cyclophosphamide-hydroxydaunorubicin-oncovin-prednisone (CHOP) chemotherapy (R-CHOP) has improved the outcomes of DLBCL patients, its role in reducing CNS relapse is unclear. We aim to (1) evaluate the clinical risk factors predictive of CNS relapse, (2) the role of rituximab in influencing CNS relapse, and (3) role of intrathecal prophylaxis. Four hundred ninety-nine patients with DLBCL from 2000 to 2008 were included (CHOP 179 vs. R-CHOP 320). IT prophylaxis was administered to 82 patients based on our institution's guidelines. Baseline characteristics between CHOP- and R-CHOP-treated patients were similar. Although R-CHOP significantly increased the complete remission rate from 71% to 81% (P < 0.01), CNS relapse rates remained unchanged (R-CHOP 6% vs. CHOP 5.1%). On multivariate analysis, poor performance status (Eastern Cooperative Oncology Group >1; hazard ratio (HR) = 2.01, 95% confidence interval (CI) 1.29-3.14), failure to attain remission (non-complete response (CR) vs. CR: HR = 2.39, 95% CI = 1.03 to 5.51), testicular (HR = 6.67, 95% CI = 1.62 to 27.53), kidney (HR = 20.14, 95% CI = 5.23 to 77.46), and breast involvement (HR = 6.14, 95% CI = 1.61 to 23.37) were each independently predictive of CNS relapse. Use of IT prophylaxis did not appear to decrease CNS relapse. Median survival after CNS relapse was 3.2 months. CNS relapse, a fatal event, remains a challenge in R-CHOP-treated patients. IT prophylaxis may not be sufficient to reduce CNS relapse, and strategies including systemic agents with high CNS penetration should be evaluated in high-risk patients identified in this study.

Central nervous system prophylaxis with intrathecal liposomal cytarabine in diffuse large B‑cell lymphomas

“…11,12 In this paper, we report the experience of 2 centers in CNS prophylaxis with liposomal cytarabine in patients with DLBCL and PMBCL treated with R-CHOP. Liposomal cytarabine (Depocyte®, Mundipharma International Limited) is a sustained-release formulation of cytarabine developed for intrathecal administration, ensuring prolonged cytotoxic drug concentrations of cytarabine in the cerebrospinal fluid (CSF).…”

Successful Treatment of Elderly Diffuse Large B-Cell Lymphoma with Central Nervous System Recurrence by Rituximab, Ranimusutine, Ifosfamide, Procarbazine, Dexamethasone, and Etoposide Therapy

“…However, CNS recurrence occurs in 1.1% to 10.4% of patients, and the prognosis remains poor [2]. Whether the addition of rituximab decreases the risk of CNS recurrence for systemic DLBCL has not yet been proven [9][10][11][12].…”

“…Some reports have suggested that a high-dose intravenous rituximab infusion or intrathecal rituximab infusion may be an effective treatment option [13], although the clinical safety of such treatments has not been yet been confirmed. In order to prevent CNS recurrence of DLBCL, intrathecal chemotherapy such as MTX and cytarabine is currently performed in many institutions, although its efficacy has been controversial [2,[14][15][16][17][18]. Kim et al described the treatment of 73 DLBCL patients with secondary CNS involvement in 11 institutions in Korea [14].…”

“…However, the prognosis of CD20+ DLBCL with central nervous system (CNS) recurrence is still poor [2]. Whole brain irradiation or high dose chemotherapy including methotrexate (MTX) and cytarabine is useful for younger patients; however, these therapies are not appropriate for elderly CD20+ DLBCL patients with CNS recurrence because of treatment-related toxicities including leukoencephalopathy.…”

How I treat patients with aggressive lymphoma at high risk of CNS relapse

“…[8][9][10][11][12][13][14][15][16] To address some of these limitations, Schmitz et al developed a 6-point score from 2164 patients treated on prospective German studies and validated in 1597 patients with DLBCL treated with R-CHOP in the British Columbia Cancer Agency (BCCA) Lymphoid Malignancies Database. 6 The components of the score were the International Prognostic Index (IPI) factors: age .…”