Background: Central nervous system (CNS) progression/relapse of diffuse large B-cell lymphoma (DLBCL) is a rare but fatal event. As conventional chemotherapeutics used in 1st line treatment do not effectively cross the blood-brain barrier, prophylactic methotrexate (MTX) or cytarabine (AraC) can be added intravenously or directly as intrathecal injection to selected patients (pts) based on risk factors.

However, the efficacy of this practice remains controversial. Here, we evaluate the effect of primary CNS prophylaxis on a large cohort of Czech pts with DLBCL treated with R-CHOP by comparing outcomes between pts who received CNS prophylaxis and those who did not, as well as among subgroups defined by different prophylactic drugs, doses, and timing of administration.

Methods: The studied cohort consisted of consecutively diagnosed DLBCL patients enrolled in the prospective Czech National Lymphoma Project (NiHiL, NCT03199066). Individual patient records were used to complete missing data and obtain additional information on CNS prophylaxis. In total, 1196 pts with DLBCL diagnosed between 2010 and 2021 and treated initially with R-CHOP, either at the Charles University General Hospital in Prague or the University Hospital Brno, were included, of which 338 had low (0-1), 528 intermediate (2-3), and 330 high (>3) CNS-IPI, respectively.

The endpoints were cumulative incidence (CI) of CNS progression/relapse, progression-free survival (PFS) and overall survival (OS). We focused mainly on the high CNS-IPI patient subgroup.

Results: Median follow-up was 6.2 years (yrs, range 0.06-14.51). The 5-year CI of CNS progression/relapse was 3.4% in the whole cohort and 8.8% in the high CNS-IPI subgroup. In this subgroup, 158 pts (47.9%) received CNS prophylaxis according to institutional guidelines: intravenous +/- intrathecal (IV+/-IT, n=100), only intrathecal (IT, n=58); 172 pts received no prophylaxis. IV prophylaxis was typically administered as 2-3 cycles of R-HD-MTX or R-HD-AraC, and patients were grouped according to if prophylaxis was either intercalated in/alternating with R-CHOP (I/A, n=43), or administered as separate cycles at the end of treatment with R-CHOP (EoT, n=57).

High CNS-IPI pts with IV+/-IT (n=100) and IT/no prophylaxis (n=230) were compared. Baseline parameters – median age (65.5 and 67.2 yrs resp., range 25-84), clinical stage, ECOG PS, diagnosis-to-treatment interval (DTI), cell-of-origin (COO) and double expressor (DE) status – were similar between groups.

There was no difference in the CI of CNS progression/relapse between IV+/-IT group and IT/no prophylaxis group with 9.5% and 10.1% at 5 yrs resp. We have observed better PFS (median 10.99 vs 2.99 yrs; p=0.002, HR=0.592, 95% CI 0.424-0.827) and OS (median 10.86 vs 5.59 yrs; p=0.005, HR 0.609, 95% CI 0.428-0.867) in favor of the IV+/-IT cohort. Because of inherent bias (pts without R-CHOP failure were more likely to have received IV prophylaxis at the end of treatment with R-CHOP) a subgroup of pts who reached complete remission (CR) at the end of 1st line treatment (n=203) was further analyzed – here, there was no significant effect of IV prophylaxis on either CI of CNS relapse (5.6% vs 7.3% at 5 yrs, HR=1.029, 95% CI 0.34 - 3.06), PFS or OS. Furthermore, there was no significant difference in PFS, OS or CI of CNS progression/relapse between I/A and EoT IV groups.

In the whole patient cohort, diagnosis-to-prophylaxis interval and start-of-treatment-to-prophylaxis interval did not have significant impact on CNS progression. No difference in efficacy between MTX (n=131) and AraC prophylaxis (n=66) in preventing CNS progression/relapse, and no clear relationship between the dose of either IV MTX or AraC and risk of CNS progression was observed.

Conclusions: In our cohort, the addition of IV CNS prophylaxis to standard 1st line therapy of systemic DLBCL in high CNS-IPI patients did not seem to reduce the risk of secondary CNS progression. Moreover, we did not observe any impact of IV CNS prophylaxis dosage, timing, or choice of chemotherapeutic agent.

These data are consistent with a growing body of evidence suggesting that IV CNS prophylaxis may be an ineffective practice in 1st line DLBCL treatment, but prospective studies are needed to confirm this hypothesis.

Supported by grants: NU23-03-00127 and NU21-03-00411

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2025
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