Therapies and Outcomes for Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Contemporary, Nationwide, Population-Based Study in the Netherlands

Background Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a dismal prognosis. Encouragingly, the treatment landscape of R/R DLBCL is rapidly evolving with treatments such as CAR T-cell therapy and bispecific antibodies that significantly improve the prognosis for particular patient subsets. The SCHOLAR-1 study, the first to provide a benchmark for future clinical trials in R/R DLBCL, described outcomes in R/R DLBCL patients based on data from 2 large randomized trials and 2 academic databases. Since SCHOLAR-1 is not population-based, any extrapolation of the study results to a daily practice population requires caution. Currently, population-based studies confirming findings from SCHOLAR-1 are lacking. Therefore, our nationwide, population-based study aimed to validate the results of SCHOLAR-1 in patients with DLBCL in contemporary clinical practice.

Methods We selected all adult DLBCL patients, including transformed follicular lymphoma (tFL) and primary mediastinal B-cell lymphoma (PMBCL), diagnosed between 2014-2016 in the Netherlands from the nationwide Netherlands Cancer Registry (NCR). Data on treatment and survival were available in the NCR with follow-up until December 31, 2021. Inclusion criteria similar to SCHOLAR-1 were used: (i) diagnosis of DLBCL, tFL, or PMBCL, (ii) treatment with an anti-CD20 monoclonal antibody and an anthracycline in first-line, (iii) refractory disease defined as stable disease or progressive disease as the best response to therapy or relapse ≤12 months after autologous stem cell transplantation (ASCT), (iv) and initiation of subsequent treatment at the first instance of refractory disease. Patients were divided into 3 subgroups (i.e., primary refractory, refractory to ≥ second-line treatment, and relapsed ≤12 months post-ASCT) based on the first instance of refractory disease. Descriptive statistics and the Kaplan-Meier method were used to analyze baseline characteristics and overall survival (OS), respectively, after the start of treatment for the first instance of refractory disease. OS was measured until death or the end of follow-up (December 31, 2021).

Results Between 2014-2016, 4,085 adult DLBCL patients were diagnosed in the Netherlands, of whom 275 (7%) met the above described criteria (i, ii and iii) for R/R DLBCL. Of these 275 patients, 122 (44%) received subsequent treatment for the first instance of refractory disease. These 122 patients were included in our analytical cohort (61% male, median age: 63 years (IQR: 51-69), 70% Ann Arbor stage III-IV) and mainly comprised DLBCL (87%), followed by tFL (9%) and PMBCL (4%). Forty-six percent had primary refractory disease, 36% was refractory to ≥ second-line treatment and 18% relapsed ≤12 months post-ASCT. The best response to subsequent treatment was assessed for 86 patients, with an overall response rate and complete remission rate of 23% (N=20) and 14% (N=12), respectively. The median OS from the start of subsequent treatment was 3.5 months (95% confidence interval [CI], 2.5-4.3 months), with a 2-year OS rate of 11% (95% CI, 6-17%) (Figure 1A). More specifically, the median OS across the 3 refractory disease subgroups was 3.2 (95% CI, 1.8-4.2 months), 2.5 (95% CI, 1.7-4.3 months), and 9.2 months (95% CI, 3.0-13.9 months), respectively. The corresponding 2-year OS rates were 13% (95% CI, 5-23%), 2% (95% CI, 0.2-10%), and 23% (95% CI, 8-41%), respectively (Figure 1B).

Conclusions To contextualize results for R/R DLBCL patients in daily practice, population-based studies are vital to validate results derived from clinical trials or academic databases. Remarkably, more than 50% of the 275 patients meeting refractory disease criteria in our cohort had to be excluded, as they did not receive subsequent treatment at the first instance of refractory disease. Also, compared to SCHOLAR-1, patients with refractory disease in our study had an even lower median OS of 3.5 months (95% CI, 2.5-4.3 months) vs. 6.3 months (95% CI, 5.9-7.0 months) and a lower 2-year OS rate of 11% (95% CI, 6-17%) vs. 20% (95% CI, 16-23%). Our results emphasize the need to improve the dismal prognosis of patients with R/R DLBCL. The real-world data in this study support future research (e.g., benchmarking) and facilitate comparison of (cost-)effectiveness of novel treatments with usual care for patients with DLBCL in clinical practice.

Chamuleau:Gilead: Research Funding; BMS/Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Roche: Honoraria; Genmab: Research Funding; Novartis: Honoraria. Lugtenburg:Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kersten:Roche: Honoraria, Research Funding; Mundipharma: Research Funding; BMS/Celgene: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Kite, a Gilead Company: Honoraria, Research Funding; Miltenyi Biotec: Honoraria; Adicet Bio: Honoraria.