Outcome after 3^rd Line Treatment for Diffuse Large B-Cell Lymphoma: A Danish Population-Based Study

Background: Outcomes of patients with relapsed/refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) are generally poor. There are no generally accepted standard treatment for patients with disease recurrence after first salvage therapy. Several novel therapies are being evaluated for patients in the 3^rd line setting in single arm trials, but the efficacies of these therapies must be contextualized with efficacy data on existing treatments.

Aim To report the outcomes for R/R DLBCL following 3^rd line therapy in a population-based setting.

Methods This study was based on the Danish population-based lymphoma registry (LYFO). Adult patients (≥18 years) diagnosed with DLBCL between January 2012 - December 2019 were identified using LYFO and had their medical records reviewed by local investigators. All patients who were treated with rituximab and anthracycline based therapy (R-CHOP/CHOEP) in first or second line, and that received 3^rd line treatment after January 2015 were included. Patients with primary CNS lymphoma and post-transplant lymphoproliferative disease were excluded. The endpoints were overall survival (OS) and progression-free survival (PFS) measured from the initiation of 3^rd line therapy. Refractory disease was defined as initiation of 3^rd line therapy within 12 months after beginning of 2^nd line irrespective of response after 1^st line therapy. Outcomes were described for all patients and stratified by clinicopathologic features associated with high-risk disease.

Results A total of 3,752 patients diagnosed with DLBCL in the period were screened and 196 patients were included. At time of 3^rd line therapy, median age was 72 years (range 20-95), median time since last treatment was 6 months (range 0.5-64.8) and 145 patients were classified as refractory. Most patients had advanced stage disease (63%), extranodal involvement (63%) and/or elevated LDH (62%). 32% had ECOG score ≥2 and 23% had an IPI score ≥4. 18 (6%) patients had CNS involvement.

3^rd line treatment regimens were best supportive care BSC) (20%), ICE/DHAP/GDP (14%), other types of chemotherapy (i.e GemOX, CCVP, PREBEN, Bendamustine etc.) (46%), radiotherapy alone (9%), or treatment in clinical trials (11%). Only 42% received rituximab as part of 3^rd line treatment. 5% received allogenic and 4% received autologous bone marrow transplant (BMT). CAR-T was not available to any of the patients in the cohort.

For the entire cohort the 2-year OS and PFS were 22% (95% CI 16-28) and 12% (95% CI 7-17) respectively, and the median OS was 6 months (95% CI 4.8-7.8). Patients with high IPI (4-5) had worse outcomes than low IPI (0-1) with 2-year OS of 13% (95% CI 6-28) versus 40% (95% CI 40-95). Young patients (< 70 years) had 2-year OS and PFS of 27% (95% CI 18-41) and 16% (95% CI 9-28), which was significantly better than the OS of 19% (95% CI 13-28) and PFS of 9% (95% CI 5-17) observed in patients older than ≥ 70 (p = 0.03) (Figure 1).

27 Patients were treated with ICE/DHAP/ GDP with a median age of 66 (range 20-81) and most had a ECOG score <2 (63%). Only 7 patients achieved complete remission, and two achieved partial remission but OS was significantly better than patients treated with "other” treatments (p=0.04) or BSC (P<0.001) (Figure 2). Only 7 (26%) of patients treated with ICE/DHAP/GDP were consolidated with autologous BMT and none with allogenous BMT.

Patients classified as refractory, had poor 2-year OS of 19% (95% CI 13-27). Of the 14 that were in remission for more than 24 months after 3^rd line therapy, 4 had received consolidation with allogenic BMT.

Conclusion We report granular real-world data on 3^rd line therapy for DLBCL in a Danish population-based cohort. Outcomes were dismal as half of all patients were dead within 6 months of 3^rd line therapy and only 22% survived more than 2 years. This study highlights the major unmet need for novel therapeutics in regions where CAR-T is not yet readily available.

Updated results will be available at the time of ASH.

Ludvigsen Al-Mashhadi:Genentech: Research Funding. Jakobsen:Roche: Honoraria. Brown:Novartis: Consultancy; Roche: Consultancy; Gilead: Consultancy. Jørgensen:Gilead: Consultancy; BMS: Consultancy; Novartis: Consultancy; Orion: Consultancy; Roche: Consultancy; Incyte: Consultancy. El-Galaly:Roche: Ended employment in the past 24 months; Abbvie: Other: Teaching in 2021. Larsen:Bristol Myers Squibb: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy; Roche: Consultancy; Genentech: Research Funding.