AUTHORS
Juan Pablo Alderuccio, MD, Isildinha Reis, PhD2, Jean Koff, MD, MSc3, Wei Zhao4, Jennifer Chapman, MD5, Melissa Larson, MS6, Dai Chihara, MD, PhD7, Thomas M. Habermann, MD8, Matthew E. Maurer, ScD9, Peter Martin, FRCPC, MD, MS10, Eric Mou, MD11, Brad S. Kahl, MD12, Georgios N Pongas13, Jose C Villasboas, MD14, Gita Thanarajasingam, MD15, Jonathon B. Cohen, MD, MS16, Andrew L. Feldman, MD17, Jonathan W. Friedberg, MD18, James R. Cerhan, MD, PhD19, Christopher R. Flowers Jr, MD, MS20, Izidore S. S. Lossos, M.D.21
AFFILIATIONS
1 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States
2 Sylvester Comprehensive Cancer Center, Miami, Florida, United States
3 Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States
4 Sylvester Comprehensive Cancer Center, Miami, Florida, United States
5 Sylvester Comprehensive Cancer Center, Miami, Florida, United States
6 Mayo Clinic, Rochester, Minnesota, United States
7 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
8 Mayo Clinic, Rochester, Minnesota, United States
9 Mayo Clinic, Rochester, Minnesota, United States
10 Weill Cornell Medical College-New York Presbyterian Hospital, New York, New York, United States
11 University of Iowa, Iowa, Iowa, United States
12 Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States
13 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States
14 Mayo Clinic, Rochester, Minnesota, United States
15 Mayo Clinic, Rochester, Minnesota, United States
16 Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States
17 Mayo Clinic, Rochester, Minnesota, United States
18 Wilmot Cancer Institute; University of Rochester Medical Center, Rochester, New York, United States
19 Mayo Clinic, Rochester, Minnesota, United States
20 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
21 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States
ABSTRACT
Introduction: Marginal zone lymphoma (MZL) comprises extranodal (EMZL), nodal (NMZL), and splenic (SMZL) subtypes, which differ in the frequency of advanced-stage (stage III-IV) disease at diagnosis. Asymptomatic patients may undergo active surveillance, but the impact of initial management approach on survival in advanced-stage MZL remains unclear. We aimed to analyze survival and causes of death in advanced-stage MZL using prospectively collected data from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic (2002-2015) that was expanded to the multi-institutional Lymphoma Epidemiology of Outcomes (LEO) cohort (2015-2025).
Methods: We extracted baseline characteristics, initial management approaches (active surveillance, immunochemotherapy, or single-agent rituximab), survival, and causes of death for patients with newly diagnosed advanced-stage MZL. Event-free survival (EFS), defined as time from diagnosis to relapse/progression, retreatment, or death due to any cause, and overall survival (OS), defined as time from diagnosis to death irrespective of cause, were estimated by Kaplan-Meier. EFS24, defined as no progression/death or retreatment within first 24 months, was also evaluated in treated patients. Data from LEO and MER cohorts were merged to conduct this analysis. Association of clinical factors with outcomes was examined using Cox models in treated patients.
Results: Among 495 patients identified, the majority had EMZL (51.5%, n=255), followed by NMZL (26.9%, n=133) and SMZL (21.6%, n=107). Baseline characteristics included anemia (Hb <12g/dL) in 31.3% (n=155), presence of B symptoms in 19% (n=94), thrombocytopenia in 9.1% (n=45), and bulky disease in 7.1% (n=35). Active surveillance was the most common initial approach 39.5% (n=199), followed by immunochemotherapy (31.5%, n=159) and single-agent rituximab (29%, n=146). Patients selected for active surveillance were typically without B symptoms (90.8%, n=177) or bulky disease (83.1%, n=162), and most presented with EMZL (47.2%, n=92) compared to 27.2% (n=53) NMZL and 25.6% (n=50) SMZL.
With a median follow-up of 84 months (range, 2.5 to 262.9), the 5-year EFS and OS in the whole cohort were 53.6% (95%CI 49-58%) and 83.4% (95%CI 79.7-86.4%), respectively. Patients in active surveillance and those treated with single-agent rituximab had significantly lower EFS (5-year rates 50.9% and 48.8%, respectively) compared to patients treated with immunochemotherapy (61.4%; P=0.016). No difference in OS was observed by treatment approach (5-year rates: active surveillance 84.5%, single-agent rituximab: 81.9%, and immunochemotherapy 83.4%; P=0.871).
Among 300 MZL patients treated with immunochemotherapy (n=155) or single-agent rituximab (n=145), no difference by subtype was observed in either EFS or OS. In multivariable analysis, factors associated with shorter EFS were age ≥70 years (HR= 1.61, 95%CI 1.11-2.33; P=0.012), anemia (HR= 1.63, 95%CI 1.12-2.37; P=0.011) and single-agent rituximab vs immunochemotherapy (HR=1.71, 95%CI 1.17-2.50; P=0.005). Independent factors associated with shorter OS included age ≥70 years (HR=5.09, 95%CI 3.07-8.44; P<.001), ECOG performance status ≥2 (HR= 2.0, 95%CI 1.05-3.78; P=0.034), bulky disease (HR= 2.26, 95%CI 1.13-4.50; P=0.02), anemia (HR=1.86, 95%CI 1.16-2.97; P=0.01), and leukocytosis >11.0×10?/L (HR=3.95, 95%CI 2.09-7.47; P<.001).
Patients not achieving EFS24, had a much higher 5-year cumulative incidence of lymphoma-related mortality of 19.0% (95%CI 11-28.8) compared with 2.8% (95%CI 1.2-5.7) for patients achieving EFS24, as well as for 5-year cumulative incidence of non-lymphoma-related mortality: 22.3% (95%CI 13.4-32.6) compared with 6.5% (95% CI 3.7-10.4). No MZL subtype was associated with significantly higher cumulative incidence of lymphoma or non-lymphoma related death.
Conclusions: In this large prospective cohort of patients with advanced-stage MZL, immunochemotherapy was associated with longer EFS compared to active surveillance or single-agent rituximab, although no OS benefit was observed. Event-free at 24 months had a low risk of subsequent lymphoma-related death, supporting EFS24 as a clinically informative prognostic milestone for patient selection in relapsed/refractory MZL clinical trials. Furthermore, failure to achieve EFS24 was associated with substantially higher lymphoma and non-lymphoma-related mortality.
DISCLOSURES
Juan Pablo Alderuccio, MD: ADC Therapeutics, Genmab, BeOne, Genentech, Natera - Research Funding; Novartis, ADC Therapeutics, Regeneron, Eli Lilly, Abbvie, Genmab, Natera, Tanabe Pharma Corporation - Consultancy (Includes expert testimony)