Differences in Overall Survival for Non-Western Immigrant Patients Compared to Danish-Born Patients with Diffuse Large B-Cell Lymphoma
Authors: Simonsen Mikkel Runason , Jakobsen Lasse Hjort , Severinsen Marianne Tang , Frederiksen Henrik , Niemann Carsten Utoft , Joergensen Judit Mészáros , Clausen Michael Roost , Starklint Jørn , Johnsen Søren Paaske , El-galaly Tarec Christoffer , Baech Joachim 
Published: December 2023

Background
The overall survival (OS) of patients with diffuse large B-cell lymphoma (DLBCL) have increased in the last decades, but non-Western immigrants with DLBCL may be at risk of poorer OS due to a lower socioeconomic position compared to citizens of the host population. While cancer treatment in Denmark is accessible in a tax-based healthcare system, treatment outcomes may still be affected by factors affecting the patient trajectory prior to treatment, possibly resulting in diagnostic delays, worse clinical features at diagnosis, and prolonged time from diagnosis to treatment.
Aims
The study aimed to compare OS between non-Western immigrant and Danish-born patients with DLBCL and to investigate differences in clinical and socioeconomic variables. Furthermore, mediators of possible OS differences were investigated to disentangle the causal effect of being a non-Western immigrant (immigration status) on OS.
Methods
In this Danish retrospective cohort study, patients with newly diagnosed DLBCL in 2000-2020 were identified in the Danish National Lymphoma Registry. Danish citizens born outside Denmark were defined as immigrants, while all citizens born in Denmark, and those immigrants with at least one Danish-born parent with a Danish citizenship, were considered Danish-born citizens. The study did not include second generation immigrants. Patients were followed from diagnosis of DLBCL until death or censoring (31 December 2021 or emigration from Denmark), whichever came first.
Crude OS was computed using the Kaplan-Meier estimator and differences in crude OS were tested using the log-rank test. An inverse probability weighted (IPW) Cox model considering age, sex, and calendar year as confounders were used to obtain the total causal effect of immigration status on OS.
Furthermore, a mediation analysis on the effect of immigration status on survival was performed using a natural effects Cox model considering age-adjusted International Prognostic Index (aaIPI), Income quartile, and cohabitation status as mediators, while controlling for confounders.
Results
A total of 254 non-Western immigrant and 7,901 Danish-born patients with DLBCL were included. Median age at diagnosis was 58 and 69, and the proportion of low-risk patients (aaIPI 0) was 29.8 % and 24.3%, respectively. No clinically significant differences in time-to-treatment were found, with a median of 21 days (IQR; 10 - 28) for non-Western immigrant patients and 17 days (IQR; 9 - 27) for Danish-born patients (Table 1).
Crude 5-year OS was 68% (95% CI; 63 - 74) and 57% (56 - 58) for non-Western immigrant and Danish-born patients, respectively (P &lt; 0.001, Figure 1).
The IPW Cox model yielded a hazard ratio (HR) for all-cause mortality for non-Western immigrants compared to Danish-born patients of 1.02 (0.94 - 1.11, P = 0.541), indicating an insignificant causal effect of immigration status on OS.
By considering the indirect effect on OS mediated through aaIPI, difference in aaIPI between non-Western immigrant and Danish-born patients did not significantly impact OS with a HR of 0.98 (0.88 - 1.09, P = 0.713). Similarly, the indirect effect mediated through cohabitation was insignificant with a HR of 1.00 (0.90 - 1.12, P = 0.987). Lastly, the indirect effect mediated through income quartile was significant with a HR of 1.19 (1.06 - 1.32, P = 0.002). The direct effect of immigration status, which was not mediated through any of the above mediators, was 0.88 (0.78 - 0.99, P = 0.035).
This implies that the income disparity between non-Western immigrant and Danish-born patients (indirect effect) has a significant negative effect on the survival of the non-Western immigrant patients, and that there is an unexplained (direct) positive effect of being a non-Western immigrant patient on OS compared to Danish-born patients.
Conclusion
We found that non-Western immigrant patients were younger, had similar aaIPI risk scores and time-to-treatment, and superior crude OS compared to Danish-born patients, with differences in crude OS most likely driven by age differences. The indirect effect of immigration status mediated through income was found significantly negative for the non-Western immigrants, while the unexplained (direct) effect was found significantly positive, seemingly cancelling each other out, resulting in an insignificant total causal effect.