Temporal Trends in Relative Survival of Diffuse Large B-Cell Lymphoma in Sweden and Denmark in the Era of Targeted and Cellular Therapies: A Population-Based Binational Study

Background: The treatment landscape for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) has changed substantially in the last few years with the introduction of targeted and cellular therapies, mainly chimeric antigen receptor (CAR) T cell therapy. However, CAR T has been approved for use in routine care at different time points and clinical situations in different countries. In Sweden, CAR T was approved for use in third or later treatment lines in 2019, whereas, in Denmark, it was not approved until 2023 and for use in second line only. Here, we aimed to assess the impact of the introduction of CAR T and other new agents at the population-based level in Sweden and Denmark, taking advantage of the varying time points of introduction.

Patients and methods: We used the Swedish Lymphoma Register (SLR) and the Danish Lymphoma Register (LYFO) to identify all adult patients (aged 18 years and above) with a primary diagnosis of DLBCL during the period 2007 to 2021 (8,833 in Sweden and 6,291 in Denmark). The patients were followed from date of diagnosis to date of death or administrative censoring (December 31, 2022) whichever came first, through Population Register records with virtually no loss to follow-up. We assessed trends in patient characteristics, overall (OS) and relative survival (RS) by calendar year of diagnosis grouped in three-year periods. Univariable and multivariable excess mortality rate ratios (EMRR) were estimated using flexible parametric survival models.

Results: Median age at DLBCL diagnosis increased from 70 years in 2007-2009 to 74 years in 2019-2021 in Sweden (p<0.001), and a similar trend was observed in Denmark (from 67 years in 2007-2009 to 72 years in 2019-2021). The distribution of patients in risk groups based on age-adjusted International Prognostic Index (aaIPI) was stable over time among young and old patients (≤70 versus >70 years of age), respectively. In spite of increasing age at diagnosis, we observed a clear improvement in survival over calendar time. In Sweden, 2-year OS increased from 66% (95% confidence interval, CI: 64-68) in 2007-2009 to 71% (95% CI: 69-73) in 2019-2021 and 2-year RS from 70% (95% CI: 67-72) to 75% (95% CI: 73-78) (adjusted EMRR 0.71, 95% CI 0.62-0.82, in 2019-2021 compared to 2007-2009). In Denmark, 2-year OS increased from 67% (95% CI: 64-70) in 2007-2009 to 70% (95% CI: 68-73) in 2019-2021) and the corresponding 2-year RS increased from 70% (95% CI: 67-73) in 2007-2009 to 74% (95% CI: 71-77) in 2019-2021. Improved outcomes over time were noted in both sexes and across age groups. In Sweden, increased survival was noted in the latest time period 2019-2021 among young high-risk patients (≤70, aaIPI≥2) in particular. Here, 2-year RS increased to 82% (95% CI:77-87) compared with 75% (95% CI: 71-80) in the preceding period 2016-2018. In adjusted analysis, this represented a statistically significant 16% decrease in excess mortality in 2019-2021 compared to 2016-2018 (EMRR 0.84, 95% 0.73-0.96). A similar improvement was not observed in Denmark, where the 2-year RS among young high-risk patients was 77% (95% CI:72-82) in 2019-2021 compared to 78% (95% CI 73-83) in 2016-2018 (adjusted EMRR 1.02, 95% CI 0.87-1.21 in 2019-2021 versus 2016-2018).

Conclusion: In this large-scale evaluation of characteristics and outcome among all adult patients diagnosed with DLBCL in Sweden and Denmark 2007-2021, we note that age at diagnosis is well above 70 years of age in recent years, with implications for care management and choice of therapies. Furthermore, in this first population-based evaluation of the impact of the changing treatment landscape of DLBCL, we note a clear and encouraging benefit in particular among young high-risk patients in Sweden from 2019 and onwards, that coincide with the introduction of CAR T in routine care. However, further studies are warranted to better understand the full spectra of underlying causes of this improvement and to continue to optimize use of newly approved treatments in routine patients.