Outcomes of Novel Agents Compared to Conventional Treatment in Relapsed and Refractory Diffuse Large B Cell Lymphoma after Second Line Chemoimmunotherapy at the Christie, a Single Centre Retrospective Study
Authors: Raj Sonia , Wang Xin , Linton Kim 
Published: December 2024

The prognosis of relapsed or refractory diffuse large B cell lymphoma (DLBCL) is poor. Conventional immunochemotherapy offers limited benefit, especially when delivered in third or later lines after failure of salvage immunochemotherapy (Ardeshna et al, 2005). Novel, targeted therapies may improve prognosis in this setting. We evaluated outcomes for targeted vs standard immunochemotherapy from third line therapy onwards in a single centre retrospective series.
Methods
We extracted data from hospital records at the Christie NHS Foundation Trust for consecutive adult patients aged 18 or older with a diagnosis of DLBCL or PMBCL treated with at least 1 prior line of immunochemotherapy and at least 1 relapse/ refractory event between 1st Jan 2011 and 31st December 2023. Patients with a history of transformation from indolent lymphoma, CNS or leptomeningeal involvement were excluded.
Patients were divided into conventional immunochemotherapy (ICT) and novel investigational treatment (novel) groups and treatment in third line (3L) and fourth line (4L). Survival analyses were performed using R statistical software, version 4.3.1.
Results
We identified 200 eligible patients ( DLBCL n=115, PMBCL n=7): 122 in the ICT arm and 78 in the novel arm. 65 patients received ICT in 3L and 27 received 4L. 46 patients received novel agents in 3L and 25 in 4L.
Baseline demographics were similar between ICT and novel groups, including median age (62 and 64 years); male gender (62.3% and 57.7%); advanced stage disease (83.6% and 74.4%). ECOG 0-1 ( 85.2% and 91.0%) and primary refractory disease ( 37.7% and 43.6%).
The most common novel agents at 3L were Loncastuximab tesirine (39.1%) and lenalidomide based therapy (19.6%) and at 4L Loncastuximab tesirine (20%) and epcoritamab (12%).
The most common 3L and 4L ICT treatments were Bendamustine- Rituximab( 21.5% and 22.2%) and Bendamustine- Rituximab- Polatuzumab vedotin ( 10.8% and 18.5%).
A total of 62 patients received 3L ICT without subsequent stem cell transplant. Excluding 11 (17.4%) patients in this group who received CAR-T cell consolidation, 5/51 (9.8%) ICT treated patients achieved a complete metabolic response (CMR), 5 (9.8%) had a partial metabolic response (PMR) and 40 (78.5%) had progressive disease (PD). Three PMR patients progressed within a median of 1 month.
Responses were numerically higher for patients receiving 3L novel therapy, with 7/46 (15.2%) patients achieving CMR, 2 (4.3%) patients PMR and 3 (6.5%) patients stable disease (SD). Thirty-four (73.9%) had progressive disease.
Response rates were also numerically higher for patients receiving novel vs ICT at 4L. Excluding patients who underwent consolidation CAR-T therapy (n=1), allogeneic transplant (n=2) or with undocumented response assessment (n=1), response rates for novel vs ICT groups were CMR: 6/25 (24%) vs 1/21 (4.8%); PMR: 1/25 ( 4.0%) vs 2/21 (9.5%) and PD: 17/25 (68%) vs. 18/21 (85.7%).
When excluding CAR T cell consolidation therapy, there was a trend towards improved 12 month event free survival (EFS) for patients who received novel vs ICT in both 3L and 4L settings ( 3L: 12.5% vs 6.25% ; 4L: 25% vs 9.4%).
Two-year overall survival (OS) probability was 12.5% for novel and 10% for ICT treated patients at 3L and 12.5% and 7.5% respectively at 4L.The median overall survival was 4.55 and 3.47 months (p=0.55) at 3L and 5.82 and 2.71 months, (p=0.044) at 4L.
Conclusion
Notwithstanding the limitations of non-randomised comparisions, this study indicates better outcomes for DLBCL patients receiving novel investigational therapy compared to standard ICT in the third- and fourth-line treatment settings. Numerically higher responses and survival with novel agents at fourth compared to third line may reflect a higher proportion treated with bispecific T cell engaging therapies.
Our findings underscore the futility of conventional immunochemotherapy in later treatment lines when most patients have chemo-refractory disease and the ongoing need to develop novel treatment approaches to further improve outcomes.