A Prospective Analysis of Outcomes Following Successive Lines of Treatment in Mantle Cell Lymphoma in an Unselected Previously Untreated Population: The UK MCL Biobank
Authors: Mant Sarah , Naylor Georgina , Crosbie Nicola , Aroori Sree , Bishton Mark J , Bowles Kristian , Dawi Safia , Eyre Toby A. , Ingram Wendy , Martin Abigail , McNamara Christopher , Oates Melanie , Pettitt Andrew , Scully Claire , Wainman Brian , Warner Mark , Rule Simon , Lewis David John 
Published: December 2024

Background
Novel treatments for Mantle Cell Lymphoma (MCL) have led to improvements in overall survival (OS). Despite this MCL remains incurable; almost all patients will relapse and require multiple lines of treatment. There is a paucity of prospective, real-world data characterising the outcome of relapsed MCL patients following subsequent treatment lines.
Methods
The MCL Biobank Observational study is a prospective study with all patients over the age of 16 years with newly diagnosed MCL being eligible. Recruitment was open across 73 UK sites between October 2014-19. Patients were enrolled prior to receiving systemic therapy with no specific exclusion criteria. Baseline characteristics were collected. The primary outcome measure was time to treatment (TTT). Data was collected on treatment choice and date of treatment lines. OS and TTT/death were assessed using the Kaplan Meier method. Prespecified subgroup analysis was performed on patients by age group: &lt; 65, 65-80 and &gt; 80 years. Event free survival (EFS) was defined as TTNT/death following the initiation of each line of therapy. POD24 was defined as POD within 24 months of commencement of 1L therapy. The log-rank test was used to compare survival between subgroups.
Results
A total of 588 patients were recruited. Median follow up is 5.7 years. The median age was 70 years (range 30-93), 72% were male. 497 (84.1%) had stage III/IV disease and simplified MIPI was low, intermediate and high in 112 (20%), 227 (41%) and 220 (39%) respectively. 507 (86.2%) patients were treated at a median TTT of 1.4 months (range:0-80). 507 received first line (1L) treatment, 149 (29.4%) received second line (2L), 33 (6.5%) received third line, 9 (1.8%) received fourth line, 2 (0.4%) received over 4 lines of treatment. 120 (23.8%) patients received a line of treatment within clinical trial. 6 (1.0%) underwent allogeneic stem cell transplantation.
The median OS and EFS after 1L treatment was 69.5 and 46.0 months (mo) respectively. POD 24 (n=102) was associated with shorter OS (P=&lt;0.001, med. OS 25.3 vs 70.1 mo) and shorter EFS following 2L treatment (P=0.02, 9.8 vs 24.3 mo). 127 (25.0%) patients died after 1L treatment with no 2L treatment; 54 (42.5%) died of lymphoma and 67 (52.8%) died of other causes (cause unknown n=6).
Following 2L treatment median OS and EFS was 20.3 and 15.0 mo respectively. 75 (50.3%) patients died with no 3L treatment; 54 (72%) died of lymphoma and 13 (17.3%) died of other causes (unknown n=8). Following 3L treatment median OS and EFS was 6.7 and 6.7 mo respectively and 4.5 and 2.6 mo following 4L treatment. Age &lt;65 years was associated with a longer OS and EFS after 1L treatment but not after subsequent lines.
Choice of 1L treatment had a significant effect on OS (P=&lt;0.01). The most frequent 1L treatments were NORDIC (24.9%), Bendamustine containing regimes (23.9%) (R-Bendamustine n=95.0%), R-CHOP (20.0%) and BTKi containing regimens (16.4%). Median OS was 69.1 mo in patients receiving BTKi containing regimes, 48.0 mo in Bendamustine containing regimens (R-Bendamustine=95.0%), 52.1 mo with R-CHOP. Median OS was not reached in patients receiving NORDIC or high dose cytarabine containing regimens. Of patients receiving NORDIC 1L 78 (61.9%) underwent autologous stem cell transplant.
The most frequent 2L treatment was a BTKi alone or in combination with rituximab (n=119, 79.9%). Amongst patients receiving 2L treatment following 1L BTKi (n=15), EFS was 10.5 mo (46.7%=RBAC, 26.7%=RCHOP, 3.3%=R-Bendamustine, 6.7%=Bendamustine and 6.7%=RDHAP).
In January 2021 CART for MCL was approved as 3L treatment in the UK following chemotherapy and Ibrutinib. Of 11 patients that relapsed following two prior lines of treatment from this time, four (36.4%) had CART as 3 or 4L treatment.
Conclusion
This prospective analysis confirms a progressive reduction in survival and response with successive treatment lines for relapsed MCL. This patient-level longitudinal follow up highlights the need to optimise 1L treatment. Advancing age impacts OS and TTNT/death following 1L treatment. Time to POD from 1L treatment was associated with OS. RBAC was the most common 2L treatment following 1L BTKi.