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)

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).

2.797 younger pts (<= 60 years) with aggressive lymphoma were treated on trials of the DSHNHL and the Mabthera International Trial. Pts with B-cell lymphoma (n=2.196) received 6 or 8 courses of CHO(Etoposid)P ± Rituximab (R) or were treated on the MegaCHOEP + R protocols featuring high doses of C, H, E, and P necessitating repetitive transplantation of autologous stem cells (Schmitz et al., BLOOD 2009, 404 a). Pts with lymphoma in testes, bone marrow, upper cervical nodes, sinuses, or other sites in the cranial region were to receive four i. th. injections of 15 mg MTX for prophylaxis of meningeosis during treatment courses 1 and 2 except for pts on the NHL-A and -B1 trials. In the latter studies, CNS prophylaxis was recommended for pts with lymphoblastic lymphoma only.

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.

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.

Schmitz:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Glass:Roche: Honoraria, Research Funding. Pfreundschuh:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.