Central Nervous System (CNS) Relapse in Agressive Non-Hodgkin’s Lymphoma; Does CNS Prophylaxis Work?.
Authors: Bernstein Steven H. , Unger Joseph , LeBlanc Micheal , Fisher Richard I. 
Published: October 2019

Abstract
Central Nervous System (CNS) relapse of aggressive non-Hodgkin’s lymphoma is a devastating clinic event. Significant controversy exists however, as to whether CNS prophylaxis affects the risk of CNS relapse and if so, which patients should be offered CNS prophylaxis. To address these questions we analyzed the twenty year follow up data of SWOG 8516, a prospective randomized trial comparing CHOP (n=225 patients), MACOP-B (n= 218), ProMACE-cytaBOM (n=233), and m-BACOD (n=233) for patients with newly diagnosed intermediate or high grade non-Hodgkin’s lymphoma. Patients that received ProMACE-cytaBOM who were bone marrow (BM) positive at baseline and BM negative after 4 cycles of treatment, received prophylactic cranial irradiation (XRT). Patients that received MACOP-B who were BM positive at baseline received intrathecal methotrexate and Ara-C (IT chemo) twice weekly for six doses. In contrast, no patient that received CHOP or m-BACOD received any CNS prophylaxis. Patient clinical characteristics were well balanced between these four arms.
Results: Of the 515 patients who relapsed with documented lymphoma, 348 (68%) relapsed only in nodal areas; 167 patients (32%) had extranodal relapse, the most common site of which was the CNS (n=34, 3.8%). Among the 34 patients with CNS relapse, 31 (91%) presented with isolated CNS relapse, 2 (6%) presented with CNS and nodal relapse and 1 (3%) presented with CNS, nodal and other extranodal relapse. 97% of all CNS relapses occurred by year 2, compared to only 73% of non-CNS relapses (p= .002). Survival after CNS relapse was significantly worse compared to that of patients with non-CNS relapse (2 year estimate 9% vs. 30%, respectively; p= .002). Using logistic regression analysis, significant differences in the incidence of CNS relapse were evident in patients with > 1 extranodal sites (5.7% vs. 2.7%, p=.03) and in patients with higher International Prognostic Index (IPI) scores (6.3% in high IPI, 4.8% in high intermediate, 3.4% in low-intermediate and 1.6% in low IPI, p=.02). There was no evidence that patients receiving any type of CNS prophylaxis (i.e., either cranial XRT or IT chemo) had different rates of CNS relapse compared to patients who did not receive any CNS prophylaxis (5.2% vs. 3.6%, p=.40). In separate analyses, there was no evidence that patients receiving cranial XRT had different rates of CNS relapse than other patients (p=.65) and no evidence that patients receiving IT chemo had different rates of CNS relapse than other patients (p=.48). Finally, if the analysis is restricted to the 238 patients that were BM positive at diagnosis, 96 patients had CNS prophylaxis and 142 did not. The rate of CNS relapse in those patients that received CNS prophylaxis was no different than that seen in the patients that did not receive CNS prophylaxis (5.2% vs. 4.2%, p=.72).
Conclusion: CNS relapse almost always occurs within 2 years of initial treatment, is usually isolated, and portends a poor prognosis. Patients with > 1 extranodal sites or those having a high IPI score have a higher incidence of CNS relapse. There is no evidence to suggest however, that CNS prophylaxis with either cranial radiation or intrathecal MTX/Ara-C decreases the risk of CNS relapse.