Treatment intensity and region of diagnosis affect survival in primary CNS lymphoma in England: A national cohort study from the uncover project.

Abstract

Abstract Introduction. The IELSG32 study established MATRix as a standard remission induction regimen for patients ≤70 years with newly diagnosed primary CNS lymphoma (PCNSL), followed by consolidation with autologous stem cell transplantation (ASCT). Older patients may receive alternative high-dose methotrexate (HD-MTX)-based regimens with or without ASCT depending on performance status (PS) and physiological reserve. Comprehensive national data describing PCNSL treatment outcomes are scarce. Methods. The UNCOVER programme uses the National Cancer Registration Dataset (NCRD) which registers all cancer diagnoses in the English National Health Service with linked data on socio-demographics, Systemic Anti-Cancer Therapy (SACT), and survival. PCNSL cases were identified using ICD-O3 codes for DLBCL and CNS diagnostic biopsy sites between Jan 2014-Dec 2021 with follow up to July 2023. Prior or concurrent lymphoma at non-CNS sites or those untreated within 90 days of diagnosis were excluded as were patients who did not receive HD-MTX or CNS directed treatment. Intensive HD-MTX regimens were defined as including high dose cytarabine with or without thiotepa. HD-MTX alone or with less intensive agents such as procarbazine were considered non-intensive. ASCT was identified via ICD10 and OPCS4 (surgical procedure) codes and SACT. Overall survival (OS) was analysed using Kaplan–Meier from date of first HD-MTX and for ASCT, to reduce immortal time bias, from the day of transplant. Associations between time to treatment following biopsy and OS were estimated using a multivariable Cox regression model adjusted for age, gender, ethnicity, deprivation, region, year of diagnosis and Charlson co-morbidities index (CCI), in addition to recorded body mass index (BMI), and ECOG PS at initiation of chemotherapy where available. A restricted cubic spline model was fitted to allow modelling of non-linear relationships. Results. Of 804 eligible patients, 622 received intensive and 182 non-intensive HD-MTX regimens. Median time from biopsy to treatment was 20 days (IQR 13-29) and 21 days (IQR 13-30) respectively with no variation by age, deprivation, geographical region or year of diagnosis. Median age of the intensive group was 62 years (IQR 54-69) and 344 (53.5%) were male. 502 (80.7%) had CCI of 0 and 311/476 (65%) were recorded as PS 0-1. Median age of the non-intensive group was 71 years (IQR 66-76) and 94 (51.6%) were male. 132 (72.5%) had CCI of 0, with 63/132 (47.7%) recorded PS 0-1. For both groups, a larger proportion of patients were in the least deprived quintile (24.4% and 20.9% respectively) compared to the most deprived (14.1% and 13.7% respectively). Across the whole cohort, median follow-up from treatment initiation was 19 months (IQR 5-44), median OS 21 months (95% CI: 15-29) and 3-year OS 44% (95% CI: 40-47). For the intensive group median OS was 30 months (95% CI: 21-39) and 3-year OS 48% (95% CI: 44-52). For the non-intensive group, median OS was 9 months (95% CI: 7-13) and 3-year OS 32% (95% CI: 26-40). PS was a risk factor for death in both groups after adjustment for aforementioned variables (intensive p<0.001, non-intensive p=0.031). In the intensive group, age (p<0.001), CCI (p<0.001), and region (p<0.001; HR ranging 0.72-1.91 vs London 1) were risk factors for death in the adjusted model. Patients in the intensive group initiating treatment ≤1 week from diagnosis experienced inferior OS compared to those receiving later treatment (HR 1.61 [1.01-2.58], p=0.045), but this was not seen for the non-intensive group and, as a continuous variable, time to treatment did not affect OS (intensive, global p=0.108; non-intensive, global p=0.073). 174 (21.6%) patients underwent ASCT (165 intensive, 9 non-intensive); 3-year OS was 77% (95% CI: 70-84). Use of ASCT consolidation in intensively treated patients varied markedly by region (19-46.4%). Conclusion. Our nationwide PCNSL cohort confirmed age, CCI and PS are associated with OS in intensively treated patients. Notably, OS varied markedly over geographic regions. Only PS was associated with OS for non-intensively treated patients, potentially reflecting a more homogenous group by age with few consolidated by ASCT. Patients receiving urgent chemotherapy had worse OS. Patients who undergo ASCT experience have very good outcomes, although its application as first-line consolidation for PCNSL varies markedly between regions, potentially contributing to geographical variation in survival.