The publication of studies demonstrating significant uncertainty in the efficacy of central nervous system (CNS) prophylaxis in large B-cell lymphomas (LBCL) has led to a change in UK guidelines (Wilson et al, BJHaem, 2024). The East of England lymphoma group changed practice from 1st April 2022, omitting CNS prophylaxis in non-Burkitt LBCL patients except in cases of testicular LBCL. This study was conducted to compare the incidence of CNS relapse in patients with LBCL treated with standard dose anthracycline-containing chemotherapy before and after this change in practice.

This is a tertiary centre retrospective study of 268 patients in two cohorts: 150 with a diagnostic biopsy from 01/01/17 to 31/03/22; and 118 with a biopsy between 01/04/22 and 31/04/25 after CNS prophylaxis was removed. The CNS prophylaxis was either intrathecal methotrexate (IT MTX), high dose methotrexate (HD MTX) or both. Unless stated otherwise, data is presented in the order: 2017-2022 cohort followed by 2022-2025 cohort.

The two cohorts were well matched with no significant difference in age (median 64 vs 66 years, p=0.337), sex (male 52.7% vs 61.0%, p=0.171), Ann Arbor stage (3-4 in 68.7% vs 70.1%, p=0.803) and LDH (raised in 73.5% vs 65.0%, p=0.135)

Across both cohorts, diffuse LBCL (DLBCL) NOS was the most common diagnostic subtype (58.0% vs 55.1%), and double/triple hit lymphoma prevalence was 12.0% vs 8.5%. De novo LBCL and high grade transformation occurred in similar proportions (67.3% vs 73.7% and 21.3% vs 16.1%, p=0.234). There was a comparable distribution in immunophenotype: 42.0% vs 44.1% germinal centre, 34.7% vs 36.4% non-germinal centre, and 23.3% vs 19.5% unascertainable (p=0.448).

At diagnosis, the CNS-International Prognostic Index (CNS IPI) was low risk (0-1) in 24.0% vs 22.9%, intermediate risk (CNS IPI 2-3) in 51.3% vs 42.4%, high risk (CNS IPI 4-6) in 22.7% vs 33.9% (p=0.0415); with insufficient data in 2.0% vs 0.8%. The higher proportion of patients in the high-risk category is due to a trend towards ECOG performance score >1 in this cohort (21.3% vs 24.6%, p=0.395), significantly more patients with >1 extranodal sites (26.7% vs 39.3%, p=0.0282), and greater kidney/adrenal gland involvement (4.8% vs 12.8%, p=0.0186).

The first-line chemotherapy protocols were R-CHOP (84.0% vs 63.6%), R-DA-EPOCH (16.0% vs 13.6%), R-Pola-CHP (0.0% vs 22.9%) – all had a median of 6 cycles given (range 1-6). More patients in the 2017-2022 cohort received consolidative radiotherapy (33.3% vs 18.6%, p=0.0062). A similar proportion of patients had a best response of complete remission (both 73.5%), although more patients in the 2022-2025 cohort had a best response of progressive disease (6.8% vs 10.6%). The number of deaths was 48 and 21, with the leading primary cause of death in both cohorts being lymphoma (25/48 and 12/21).

In the 2017-2022 cohort, 20.7% of patients (31/150) received IT MTX (median 4 doses); 4/31 patients also received HD MTX. In the 2022-2025 cohort, 1 patient (0.8%) received 4 doses of IT MTX due to initial concern for Burkitt lymphoma but later confirmed DLBCL, and none received prophylactic HD MTX. In the 2017-2022 cohort, 5/31 patients discontinued CNS prophylaxis early, 3 of these being due to methotrexate toxicity.

In the 2017-2022 cohort, the median follow up was 66.3 months with 11 CNS relapses: median time from biopsy to CNS relapse was 7.1 months (range 1.5-23.0 months). 3 of 11 CNS relapse patients had received CNS prophylaxis. In the 2022-2025 cohort, the median follow up was 17.8 months with 2 CNS relapses and a median time from biopsy to CNS relapse of 5.3 months (range 2.2-8.4 months). In the 2017-2022 cohort, cumulative incidence of CNS relapse (adjusted for competing risk of death) at 1 year is 5.50% (CI 95: 1.78-9.22%); at 2 years 7.74% (CI 95: 3.32-12.2%). In the 2022-2025 cohort, cumulative incidence of CNS relapse at 1 year is 1.92% (CI 95: 0-4.58%); at 2 years 1.92% (CI 95: 0-4.58%). The best response to treatment for CNS relapse was progressive disease in most patients across both cohorts (54.5% and 100.0%).In conclusion, this study suggests that the removal of CNS prophylaxis using IT or HD MTX did not result in increased rates of CNS relapse in patients diagnosed with LBCL in Cambridge from April 2022 to 2025. Considering the rarity of CNS relapse the dataset is small; however, these early results are very encouraging and we are preparing to expand this study to the East of England region.

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2025
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