Patient Selection for High-Dose Methotrexate As Central Nervous System Prophylaxis in Diffuse Large B-Cell Lymphoma in Australia: Are We Getting It Right?

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy. While central nervous system (CNS) relapse in DLBCL is uncommon, it is usually fatal. As many relapses are parenchymal, systemic high-dose methotrexate (HDMTX) has largely replaced intrathecal methotrexate as CNS prophylaxis in high risk patients (historically characterised using IPI score/number of extranodal sites) in Australia. However, the efficacy of HDMTX in this context remains undetermined, can be associated with nephrotoxicity, myelosuppression and hepatotoxicity and necessitates the use of significant hospital resources for administration and monitoring. The German high-grade non-Hodgkin lymphoma study group (DSHNHL) prognostic model separates patients with DLBCL into 3 risk groups for CNS disease based on a score derived from 6 factors. The aims of this study were to evaluate the toxicity of HDMTX, and describe outcomes in HDMTX and non-HDMTX patients according to the DSHNHL model.

Methods: 150 patients diagnosed with DLBCL between 2004 and 2014, initially treated with RCHOP-like chemotherapy and given or not given HDMTX for CNS prophylaxis were identified by pharmacy records at two teaching hospitals. Patient records were retrospectively reviewed for HDMTX toxicity, CNS disease risk factors as specified in the DSHNHL model and CNS relapse. All surviving patients had at least a year of follow-up. The toxicity parameters of 28 HDMTX patients was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4, up to 30 days from the date of the last dose of HDMTX. Statistical analysis was performed using STATA Data Analysis and Statistical Software version 13. Analysis involved Fisher's exact test for categorical variables and Mann-Whitney U test for continuous variables. A p-value was statistically significant if it was equal to or less than 0.05.

Results: 28 patients with DLBCL selected to receive HDMTX were planned for 2 doses. All initial doses were administered at a concentration of 3g/m² except for 2 patients who had a first dose of 1.5g/m². Two of 28 patients received only one dose, and 3 had their second dose reduced, all due to renal impairment. 20 of 28 patients (71%) did not experience nephrotoxicity and no patient progressed to grade 4 or 5 renal toxicity. Myelosuppression was the most common toxicity, with anaemia grade 3-4 in 1 (4%), grade 3 and 4 neutropenia in 8 and 3 (but with febrile neutropenia in only one case) and grade 3-4 thrombocytopenia in 2 (7%) patients.

24 of 28 HDMTX patients and 122 non-HDMTX had sufficient data available for the 6 components of the DSHNHL model. Comparison of the DSHNHL model score for HDMTX and non-HDMTX patients showed no significant difference in the distribution of scores (p-value 0.478). No patient had all 6 factors. Fourteen (58%) HDMTX and 66 (54%) non-HDMTX patients were categorized as low risk (score 0 to 2), 8 (33%) HDMTX and 31 (25%) non-HDMTX were intermediate risk (score 3) and 2 (8%) HDMTX and 25 (20%) non-HDMTX were high risk (score 4 to 6) according to the DSHNHL model.

The 2 (of 24) HDMTX patients who relapsed in the CNS had DSHNHL model scores of 1 and 3. Of the 122 non-HDMTX patients, 3 relapsed in the CNS, all with intermediate or high risk disease.

Conclusions: HDMTX was well-tolerated by patients, therefore can safely be administered as CNS prophylaxis under current hospital protocols. Application of the DSHNHL prognostic model identifies a different population of candidates for CNS prophylaxis compared to historical risk factors and may lead to better patient selection for this intervention.