Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (1). DLBCL is responsive to chemotherapy and patients with relapsed or refractory disease may be treated with salvage chemotherapy followed by autologous stem cell transplantation (ASCT). In a previous study, the 3-year overall survival rate was 49% for relapsed lymphoma without central nervous system (CNS) involvement (2). Patients with disease progression into the CNS exhibit poor survival, despite aggressive interventions, with a median survival of 2–5 months (3–5). The reported incidence of CNS involvement varies from 2.8 to 25%, depending on the population under investigation and the diagnostic tests used (5–7). The CNS lymphoma may involve the brain parenchyma and/or the leptomeninges. CNS may be the only disease site or may be associated with other sites of disease at relapse. There is currently no consensus regarding the optimal strategy to prevent CNS dissemination. Traditionally, the prophylactic measures include intrathecal (IT) injection of methotrexate, cytarabine and steroid, mainly in high-risk patients, i.e., those with marrow, testicular, orbital and nasal sinus involvement.
The addition of rituximab to cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) chemotherapy has improved the remission rate and the overall survival in DLBCL patients. Considering the effective eradication of systemic disease in responsive patients, we were prompted to investigate whether rituximab was also able to reduce CNS events. This is a major practical question, since CNS prophylactic measures may require improvement if CHOP with the addition of rituximab (R-CHOP) is found to be inadequate. The aim of this study was to perform a historical analysis of the patients treated with CHOP and R-CHOP to evaluate whether the CNS disease rate was reduced with the addition of rituximab and to identify the risk factors associated with CNS involvement.
Discussion
The addition of rituximab to CHOP has been shown to improve the remission rate and the overall and event-free survival of patients with DLBCL (8–11). Based on the eradication of systemic disease achieved by rituximab, we investigated whether it was able to reduce the incidence of CNS involvement since its introduction into our practice. The overall CNS event rate for DLBCL was 10.9% in our study. The majority of CNS events developed within 1 year of the diagnosis of lymphoma. The CNS disease rate was 15.5% (7/45) in the CHOP group vs. 7.6% (5/65) in the R-CHOP group. The projected 3-year CNS disease rate was 18% in the CHOP group vs. 9% in the R-CHOP group (P=0.15). Therefore, the addition of rituximab to chemotherapy did not significantly reduce the risk of CNS events in our study.
The risk of CNS events was higher in our cohort compared with that in previous studies. The CNS disease rate was previously reported to be 2.2–10.4% (3,5,12–15). This difference may be attributed to our inclusion of more patients with advanced-stage (III or IV) disease (~70%). Moreover, lumbar puncture with CSF analysis was not routinely performed at diagnosis to allow for the detection and exclusion of patients with occult CNS disease. The early CNS relapse and higher proportion of isolated CNS relapses observed in our study may also reflect the presence of subclinical CNS disease at diagnosis.
Stage IV lymphoma was identified as a significant predictor of CNS disease in our cohort. Elevated LDH levels, extranodal site involvement and advanced stage of lymphoma are the most commonly reported risk factors. Our findings are consistent with those of previous studies (12–17).
Rituximab penetrates poorly across the blood-brain barrier. A pharmacokinetic study demonstrated that, following an intravenous (i.v.) dose of rituximab, its levels in the CSF were only 0.1% of their corresponding levels in the serum (18). Therefore, it is unlikely that rituximab is able to directly access the lymphoma cells in the CNS. We observed a relatively higher proportion of parenchymal disease in the R-CHOP group compared with that in the CHOP group (80 vs. 29%, respectively). The pharmacokinetic constraints of rituximab may limit its ability to prevent lymphoma progression in the parenchymal compartment. We also observed that isolated CNS disease was more common in the R-CHOP group in our cohort. This may be due to the fact that R-CHOP is more effective in preventing systemic relapse of lymphoma.
The optimal treatment for patients with disease progression into the CNS has not yet been standardized (19,20). The majority of our patients were treated with high-dose methotrexate, with or without whole-brain RT. It was previously demonstrated that treatment with high-dose methotrexate was effective and improved survival (19). Whole-brain RT is effective for initial control of CNS lymphoma; however, it is associated with increased risk of delayed treatment-related neurotoxicity, particularly in elderly patients (21). There is also a potential role for high-dose chemotherapy followed by ASCT. Bromberg et al reported an overall survival benefit in patients undergoing ASCT and long-term survival is more likely in these patients (22).
Our study was limited by its retrospective nature and the small sample size. Not all patients underwent lumbar puncture and CSF analysis at the beginning of therapy; therefore, a proportion of patients with subclinical CNS disease at diagnosis may have been missed. There was also a difference in follow-up time between the two groups.
The efficacy of IT prophylaxis could not be properly assessed in our study due to the low compliance. Previous published studies on the effect of rituximab on CNS events also reported a similar low rate of IT prophylaxis, even in high-risk patients (4,13,14). It was found the effect of rituximab on the risk of CNS disease could be assessed regardless of whether IT prophylaxis had been administered (4). Although certain studies support the efficacy of IT chemotherapy, several others have questioned its ability to prevent CNS recurrence (14,23–26). Although IT chemotherapy has been effective in preventing or treating leptomeningeal disease, its efficacy in preventing parenchymal disease has been questioned due to the low penetration into the brain parenchyma and the uneven distribution within the neuroaxis. Lumbar administration of IT methotrexate also results in marked differences in peak levels throughout the subarachnoid space. Subtherapeutic levels are common due to differences in CSF movement, choroidal uptake and drug clearance (27). IT prophylaxis is associated with several rare but severe neurological complications, such as seizures, encephalopathy and spinal cord lesions manifesting as tetraplegia, paraplegia and cauda equina syndrome (28). These complications may defer patients receiving IT chemotherapy.
Patients with CNS relapse have a poor prognosis. The incidence of CNS events may be reduced by increasing the sensitivity of diagnosis of CNS disease and applying more effective prophylactic therapeutic regimens. The application of more sensitive tests may facilitate the diagnosis of occult CNS disease. Flow cytometry of CSF may prove useful for the detection of leptomeningeal involvement and it is more sensitive compared with conventional cytological analysis of CSF (29). Brain MRI or CT scan is indicated for the detection of parenchymal involvement, particularly in high-risk patients, such as those with stage IV DLBCL. More intensive upfront CNS-directed prophylaxis may be used for high-risk patients. High-dose i.v. methotrexate or cytosine arabinoside may cross the blood-brain barrier and have been used to treat established CNS disease. The incorporation of high-dose i.v. methotrexate into the rituximab combination may be a rational prophylactic approach for high-risk patients. A retrospective study with a median of 3 cycles of i.v. methotrexate 3.5 g/m2 administered to a high-risk group of DLBCL patients reported a significant reduction of CNS recurrence, with a recurrence rate of only 3% in the high-risk group at a median follow-up of 33 months (30).
Another multicenter retrospective study of patients at high-risk for CNS relapse demonstrated that the addition of high-dose i.v. methotrexate and/or cytarabine was associated with a lower incidence of CNS relapse compared with IT chemotherapy alone (31). The 3-year actuarial rates of CNS relapse in the groups receiving IT methotrexate, IT methotrexate with 2 cycles of high-dose i.v. methotrexate, and chemotherapy regimens containing high-dose i.v. methotrexate and cytarabine, were 18.4, 6.9 and 2.3%, respectively (P=0.009). The most frequent toxicity of i.v. methotrexate was renal impairment, which was grade 1 in the majority of the cases.
A prospective study of patients with DLBCL or grade III follicular lymphoma reported that 6 courses of R-CHEOP (rituximab, cyclophosphamide, doxorubicin, etoposide, vincristine and prednisolone) followed by high-dose cytarabine (3 g/m2 twice daily for 2 days) and a course of high-dose methotrexate (3 g/m2 i.v. as a 24-h infusion) achieved a CNS relapse rate of 4.5% (32). There is growing evidence that high-dose antimetabolite therapy may provide effective CNS prophylaxis in patients with DLBCL.
The optimal time of systemic high-dose chemotherapy has not yet been defined. CNS relapse is most common within the first 12 months from the completion of primary therapy (14,25–26,33). This may suggest the presence of occult CNS disease at diagnosis and early use of high-dose i.v. methotrexate is recommended.
In conclusion, although the addition of rituximab to chemotherapy may improve the remission rate and overall survival of patients with DLBCL, it did not appear to decrease the risk of CNS events in our study. There is a need for a better prophylactic strategy by increasing the sensitivity of diagnosis of CNS disease and more effective prophylactic therapeutic regimens, such as high-dose i.v. methotrexate, in order to reduce CNS events, particularly in high-risk patients.