Mantle Cell Lymphoma Management and Outcome in the U.K's Population-Based Haematological Malignancy Research Network
Authors: Patmore Russell , Smith Alexandra , Appleton Simon , Howell Debra , Johnson Roderick J. , Burton Cathy H , Roman Eve 
Published: October 2019

Abstract
Introduction
Mantle cell lymphoma (MCL) is typically associated with an aggressive clinical course and poor prognosis, but few studies have evaluated its management and outcome, including the occurrence of relapsed/refractory disease, in the general patient population. We have investigated this using real-world data from the UK's specialist population-based registry, the Haematological Malignancy Research Network (www.hmrn.org), whose catchment population of 4 million is served by a 24/7 centralized diagnostic facility (Haematological Malignancy Diagnostic Service) and a unified clinical network.
Methods
All patients newly diagnosed 2004-15 with mantle cell lymphoma (n=327) were followed-up until January 2016. Demographic, prognostic, treatment and outcome data were examined using standard statistical methods; relative survival (RS) was estimated using national life tables.
Results
With a median diagnostic age of 74 years (range 39-96), 66% patients were male, 39% had B-symptoms, and 48% had a high MIPI score. 263 (80%) received first-line chemotherapy (median age 73.2); and 20 (6%) had an autologous transplantation (ASCT). Patients who had chemotherapy with ASCT were significantly younger (median age 56.3) than other patient groups (Table). As expected, first-line treatment changed over time (Figure 1a), with 50% of those treated in 2004-11 receiving fludarabine-based regimens compared to 12% by 2012-15, during which time patients were more likely to receive R-CHOP (37%) and R-Bendamustine (17%).
For all subjects combined, 5-year OS was 30% (median 2.4 years) and 5-year RS was 38%. Patients who had an ASCT had the best survival (5-year OS, 86%), followed by the 29 patients who remained on watch and wait for the duration of the follow-up period (5-year OS (59%), 5-year RS (86%)). Of the 64 patients initially managed using watch and wait, 35 were subsequently treated with chemotherapy; on average, around 56 weeks after diagnosis. Among patients treated with first-line chemotherapy, those whose regimen included rituximab had significantly better survival than those who did not (hazard ratio (HR) 0.65, 95% confidence intervals (95% CI) 0.49-0.88).
During the follow-up period, 109 patients received second-line therapy. Of these, 39 patients subsequently went on to receive third-line treatment, 16 fourth-line and 6 fifth-line. As shown in Figure 1b, during the study period the most common regimens for relapsed/refractory disease were R-CHOP (14%), Chlorambucil (10%), R-Bendamustine (10%) and FCR (10%). However, as with first-line treatments, regimens changed over time. Pre-2013, the most common regimens were fludarabine-based (20%) or R-CHOP (17%) and since 2013, 37% of patients were treated with R-Bendamustine and 25% with ibrutinib.
Overall survival is stratified by treatment line in Figure 1c. The outlook for patients who received salvage therapy was particularly poor; the median survival for those treated with second-line chemotherapy being 0.7 years decreasing to 0.4 years for those treated with a fifth-line regime. Importantly, however, as can be seen from Figure 1d, the introduction of newer agents across all therapy lines in more recent years appears to be impacting on outcome; patients initially treated 2004-2011 having a 3-year OS of 38.3% (31.2-45.4) and those treated 2012-2015 an improved 3-year OS of 54.3% (41.9-65.1). Outcomes for patients receiving second-line treatment since 2013, either for refractory or relapsed disease, also appears to have improved (HR=0.78, 95% CI = 0.41-1.48). This association will be re-examined by December 2016 including data on patients who have received salvage therapy in 2016.
Conclusions
Averaging just over 2 years, survival from MCL in the general patient population is much poorer than it is amongst patients recruited into clinical trials. Only the small proportion of younger patients receiving ASCT (5%) and those whose disease did not progress to the stage where treatment was required (7%) had a median survival in excess of 4 years. Furthermore, whilst analysis of our contemporary real-world population-based data confirms the positive benefits of first-line rituximab, it also demonstrated the extremely poor outcomes of patients treated with salvage therapy. There is evidence that newer agents may be impacting on survival and our findings highlight the importance of new therapeutic options.
Figure 1 Figure 1.

Disclosures
Patmore: Janssen Cilag: Honoraria; Roche: Honoraria. Smith:Celgene: Research Funding; Novartis: Research Funding; Jansen Cilag: Research Funding; Amgen: Research Funding.