The Addition of Systemic High-Dose Methotrexate (HD-MTX) to Intrathecal Chemotherapy (IT) for Central Nervous System (CNS) Prophylaxis Substantilly Reduces CNS Recurrence Rates in Patients with at-Risk Aggressive Lymphoma: A Historically Controlled Prospective Study
Authors: Herbert Kirsten , Wolf Max , Carney Dennis , Westerman David Alan , Januszewicz Henry , Harrison Simon , Ritchie David , Prince H. Miles , Seymour John Francis 
Published: October 2019

Abstract
CNS relapse is a devastating and usually fatal complication of NHL, and controversy exists regarding the best methods of CNS prophylaxis. We have previously shown that IT alone is inadequate in patients (pts) with aggressive NHL at high risk of CNS relapse (Leuk Lymphoma2002;43:1783). We therefore assessed the efficacy of adding systemic HD-MTX to IT prophylaxis, based on drug penetration into the CSF and brain parenchyma.
Methods: from 1/91 to 3/08, 85 pts with newly diagnosed aggressive NHL and negative baseline CSF cytology were treated with CNS prophylaxis due to risk factors such as multiple extranodal (EN) sites and elevated LDH. Patients were classified into 3 groups:
CHOP-like therapy & IT (n=24), systemic therapy incorporating HD-MTX (≥1g/m2 eg Hyper-CVAD; n=25) and CHOP-like therapy & IT followed by 2 doses of MTX 3g/m2 24 hour CIVI q14d (n=36).
Results: Median age was 52 years (16–82). Groups 1, 2 and 3 were similar in proportions of advanced stage (III and IV), baseline LDH >1× ULN, gender, performance status and number of extranodal sites. Groups 2 & 3, who both received HD-MTX, were similar and were combined for all analyses. The CNS risk index (van Besien Blood1998;91;1178) was well matched for group 1 versus Groups 2/3 combined (P=0.3). The median number of IT treatments received was 5 (1 – 6) in group 1 and 6 (1 – 13) in groups 2/3. HD-MTX administration (total 101 admissions) was safe with a median 4(1–27) days inpatient stay and no treatment-related mortality. Complications included reversible renal impairment and mucositis grade ≥2 in 4% and 2% of cycles respectively. With a median follow-up of 29.5 months (2.6–164.4) there are 8 CNS relapses; 6 in group 1, 0 in group 2 and 2 in group 3. Sites of CNS recurrence were leptomeningeal alone in 4, isolated parenchymal in 2 and both in 2. All CNS recurrences occurred within 25.5 months (range 3.7–25.5) from diagnosis. Median survival after CNS relapse was 118 (14–264) days. Pts receiving systemic HD-MTX had a lower rate of CNS recurrence compared to group 1 pts (At 30 Mo; 4.5 ± 3% versus 27 ± 10%; P = 0.0033; figure 1). The only predictor for CNS relapse was the absence of systemic HD-MTX, with a hazard ratio of 10.07 (95%CI 2.16–46.97) for relapse in the IT-alone group (P=0.003). The relative risk of CNS relapse was 0.13 (0.03-0.6) in the groups treated with IT plus systemic HD-MTX. The 5-year actuarial CNS-relapse free survival rates were 42 ± 11% for group 1, and 82 ± 7% for groups 2/3 (P=0.0003).
Conclusion: These data demonstrate that IT alone is inadequate CNS prophylaxis in at-risk patients with aggressive NHL. The addition of systemic HD-MTX either as part of primary therapy or administered following CHOP-like therapy significantly reduces CNS recurrence and may improve overall survival.
Figure SEQ Figure \* ARABIC 1: CNS relapse in patients receiving IT chemotherapy alone compared to IT plus IV HD-MTX Figure. SEQ Figure \* ARABIC 1: CNS relapse in patients receiving IT chemotherapy alone compared to IT plus IV HD-MTX