CNS Disease In Younger Patients (<=60 years) with Aggressive Lymphoma Treated In Trials of the German High Grade Non Hodgkin Lymphoma Study Group (DSHNHL) and the MabThera International Trial (MInT)

Abstract 112 Background: CNS involvement by aggressive lymphoma carries a poor prognosis. Little is known about the frequencies of CNS relapse or progression, risk factors, and the efficacy of prophylaxis in younger patients (pts) undergoing modern chemoimmunotherapy (R-CHOP). Methods: 2.797 younger pts ( Results: Overall, sixty-five of 2.797 pts (2.3%) developed meningeal and/or parenchymal CNS relapse (43.1 %) or progressed during therapy (56.9%). Relapse/ progression in the CNS was combined with systemic disease in 20 pts (32.3%) but represented the only site of disease in the majority of cases (67.7 %). Median time to relapse/ progression was 7.2 months (range: 0.2– 85.2 months); median survival after relapse or progression was 4.2 months (0 - 54.0 months). The incidence of CNS relapse/ progression was low in pts with age-adjusted International Prognostic Index (aaIPI) 0 or 1 (High-CHOEP phase III study with 385 pts: CNS events 0.3%; MInT trial with 818 pts: CNS events 1.6 %) but was significantly higher in the 463 pts on the MegaCHOEP phase II/III trials which included pts with aaIPI 2 or 3 only (CNS events: 6.4 % and 7.5 %, respectively). Focusing on 663 pts treated with state-of-the-art chemoimmunotherapy including rituximab, multivariate Cox regression analysis identified LDH>N (relative risk [RR]=4.5, p=0.046) and stage III/IV (RR=6.2, p= 0.016) as significant risk factors for CNS disease. Using this model, 32.7 % of all pts would have been considered “high-risk”; 82.4 % of those pts who developed CNS disease carried both risk factors. However, only 14/217 (6.5%) of the “high-risk” pts defined by elevated LDH and advanced stage actually experienced CNS relapse or progression. Rituximab significantly reduced the risk for CNS disease when all 1.570 pts treated with CHO(E)P- 14/21 were considered (RR= 0.3, p=0.03). In contrast, the addition of R did not reduce the RR in 309 pts treated with MegaCHOEP ± R (RR=0.8, p= 0.54). There was no indication that the addition of etoposide to CHOP (CHOEP) reduced the risk of CNS disease in any patient cohort treated with chemotherapy and R. Conclusions: Pts with aggressive lymphoma and aaIPI 0 or 1 show low frequencies of CNS relapse or progression. Omitting CNS prophylaxis in such pts seems reasonable also because – similar to our recent findings in the elderly (Boehme et al., BLOOD 2009; 113: 3896) – this analysis in younger pts failed to show benefit of prophylaxis with i.th. MTX in any of the risk groups analyzed. CNS disease remains a serious problem in younger pts with aaIPI 2 or 3. We failed to discover clinical or laboratory features to precisely define a “high-risk” group of patients all of whom might benefit from CNS-directed prophylaxis. Unfortunately, neither high-dose therapy including high-doses of etoposide (MegaCHOEP), standard dose etoposide (CHOEP), nor i. th. MTX reduced the incidence of CNS disease. Rituximab reduced the RR of CNS disease in pts with B-cell lymphoma treated with CHO(E)P- 14/21 but failed to do so in pts treated with R-MegaCHOEP. Disclosures: Schmitz: Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Glass: Roche: Honoraria, Research Funding. Pfreundschuh: Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding.