Comparison Of Treatment Results Using High-Dose MTX Plus High-Dose AraC and High-Dose MTX Plus CHOP Regimens For Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma. High-dose (HD) methotrexate (MTX) plus HD cytarabine (AraC) followed by whole-brain radiation therapy (WBRT) is currently considered the standard therapy for PCNSL. However, at present, the prognosis of patients is not always favorable, because neurotoxicity, particularly dementia, occurs in long-surviving patients at a high rate, and affects their quality of life. In recent years, therapy without WBRT has been attempted in patients, particularly the elderly. In this study, we investigated whether the prognosis of PCNSL patients was improved by the use of different therapeutic regimens.

Japanese patients with newly diagnosed PCNSL who had been admitted to our insutitute between January 2002 and March 2013 were retrospectively analyzed. Their medical records were reviewed regarding the histopathological diagnosis, performance status (PS), prognostic factors used by the International Extranodal Lymphoma Study Group (IELSG), and therapeutic regimens. Data were tabulated, stratified, and analyzed in terms of response rates and overall and progression-free survival. The response to treatment was evaluated by brain MRI. Overall and progression-free survival were estimated using the Kaplan-Meier method. The statistical analysis of observed differences was assessed using the log-rank test.

Thirty-two patients with newly diagnosed PCNSL were admitted. Their median age at the start of treatment was 71 years (range, 42-86 years), with a male-to-female ratio of 21: 11. All patients were HIV-antibody-negative. Whole-body CT or FDG-PET excluded secondary CNS lymphoma in all patients. All of them underwent biopsy, and 28, 1, 1, and 2 were histopathologically diagnosed with diffuse large B-cell lymphoma, MALT lymphoma, ALK-negative anaplastic large-cell lymphoma, and unclassified type, respectively. In 25 patients, cerebrospinal fluid examination was performed, enabling the calculation of the IELSG prognostic score. Based on the prognostic score, 8, 14, and 3 patients were classified as high-, intermediate- and low-risk groups, respectively. Twenty-two patients received 6 courses of 3-3.5 g/m² of HD-MTX (adjusted based on creatinine clearance) plus 2 courses of 4-6 g/m²of HD-AraC for 2 days with or without WBRT (30-36 Gy), while 4 underwent HD-MTX plus rituximab (R)-CHOP (6 courses) with or without WBRT. Four and 1 received WBRT and R-CHOP alone, respectively. The median follow-up period was 13 months (range, 1-123 months), and the overall response rate was 81.2% (complete and partial responses in 19 and 7 patients, respectively). To date, 14 patients have died, and 9 patients have survived. In all patients, the overall survival (OS) and progression-free survival (PFS) were 30 and 25 months, respectively. The median OS were 5 and 29 months in the high- and intermediate-risk groups, respectively, and the median OS was not reached in the low-risk group (p=0.03). On the other hand, the median PFS were 5, 20, and 77 months, respectively (p=0.07). No significant difference in the OS or PFS was observed between the HD-MTX plus HD-AraC and HD-MTX plus R-CHOP groups. However, univariate analysis showed that the OS and PFS were significantly improved in both groups treated with regimens including WBRT (p=0.005 and 0.008, respectively). Analysis by age revealed that the overall survival rate was significantly poorer in patients older than 65 years (p=0.03). Stratification based on PS and the use/non-use of rituximab showed no significant differences in the treatment results.

The treatment results were comparable in the HD-MTX plus HD-AraC and HD-MTX plus R-CHOP groups. On the other hand, the results of regimens with were better than those without WBRT. Thus, HD chemotherapy alone is insufficient for the management of PSCNL, and this study reinforced the importance of WBRT. We consider that HD chemotherapy regimens including HD-MTX and WBRT remain the standard therapy for PCNSL. The results also suggest that R-CHOP can be substituted for HD-AraC, and that it is necessary to reconsider the treatment strategy for PCNSL in the era of rituximab.

Taniwaki:celgene: Research Funding.