Real World Patient Diagnostic and Treatment Patterns in Marginal Zone Lymphoma (MZL): First Results of the Prospective National MZL Registry of the German Lymphoma Alliance

Background: Despite being the third most frequent B-cell lymphoma, marginal zone lymphoma (MZL) has been largely underrepresented in prospective clinical trials and registries. Based on this we initiated a prospective publicly funded registry for MZL with the primary objective to establish a comprehensive overview about clinical characteristics, diagnostic procedures and real-world treatment patterns for MZL patients.

Method: This prospective nationwide observational registry as part of the German Lymphoma Registry (GLA-R) based on 107 sites in Germany includes patients with MZL with mandatory reference pathology. Standardized data collection includes among others biological variables such as blastic morphology and proliferation rate with an arbitrary cut-off value >20% as proliferative active disease. Risk classification is calculated for each of MZL subtype based on the MALT-IPI for extranodal EMZL, the FLIPI for NMZL, and the simplified prognostic index of the SMZL Study Group for SMZL. Progression-free survival (PFS) and overall survival (OS) is calculated using the Kaplan-Meier method and applied the log-rank test for comparisons. All risk factors with a p-value <0.20 by univariate analysis were included in the multivariate Cox regression. P-values <0.05 are considered as statistically significant.

Results: Starting in 2015 the registry is actively recruiting and has included 822 patients until July 2024 so far. For this report records of 252 patients were centrally reviewed by a hematologist to ensure highest data quality. Median follow-up of the entire patient cohort was 4.5 years (95% CI: 4.2-4.9). 58% (n=145) belonged to the EMZL, 21%, (n=54) to the NMZL and 21 % (n=53) to the SMZL subtype. Gender was balanced and the median age at diagnosis was 64.5 years. For EMZL 55% of the patients belonged to the intermediate/high risk group, 66% for NMZL and 74% of patients with SMZL. Either blastic morphology and/or proliferative variant was reported in 11%. Evidence of monoclonal gammopathy was found in 34% of MZL with nearly every second case of NMZL showing monoclonal gammopathy (of these 52% with monoclonal IgM gammopathy, 36% with monoclonal IgG gammopathy). Every fifth patient did not obtain bone marrow (BM) biopsy at diagnosis, documenting that in the real-world setting many patients are managed without any information about BM involvement. PET-CT imaging was performed in 12% of the total cohort. Prior oncologic disease at the time of initial diagnosis of MZL was recorded in 17% (n=43) and history of autoimmune disease in 11% (n=27) with no major differences between subgroups.

Median PFS for the entire MZL patient cohort was 12.7 years (95% CI:7.9-NA) with a 5-year PFS of 66% (95% CI: 58-72) and a 5-year OS of 91% (95% KI 86-95). Median PFS (p=0.40) and OS (p=0.27) was comparable between the different subtypes. Also for NMZL PFS and OS was excellent with a median PFS of 9.2 years (95% CI 3.4-NA) and a 5-years OS of 85% (95% CI 70-92). In multivariate analysis, independent factors of shorter OS (p<0.01) were age (HR=1.11, 95% CI=1.04-1.18, p=0.001) and bone marrow infiltration (HR=8.95, 95% CI=2.03-39.40, p=0.004). Overall, POD24 frequency after systemic treatment approaches was observed in only 8% of cases. The 3 most common first-line treatments included immunochemotherapy (43%), local treatment (25%) and single agent anti-CD20 antibody treatment (13%). Within the group of patients who received immunochemotherapy, the two most common regimens were rituximab/bendamustine (74%) and R-CHOP (23%). One quarter of patients received local treatment as first line treatment. 18% (n=22/122) of patients treated with immunochemotherapy or single agent rituximab were assigned to rituximab maintenance. Of the 66 who progressed after front-line treatment and initiated second-line therapy, 43% received immunochemotherapy with rituximab/bendamustine being the most used regimen. At first relapse, immunochemotherapy was dominating in NMZL and SMZL, whereas in relapsed EMZL radiation, rituximab single agent treatment as well as anti-infectives played a major role.

Conclusion:

These prospective data provide a detailed and comprehensive overview about diagnostics and treatment choice for MZL in a real-world setting. They show that in the community diagnostic and clinical management of MZL is highly heterogenous and lacks a well defined standard approach.