Introduction Marginal zone lymphoma (MZL) is an indolent B-cell non-Hodgkin lymphoma with heterogeneous practice patterns. Early relapse after diagnosis in MZL has been associated with poor outcomes in one European study (Luminari et al, Blood 2019) which included only patients requiring immediate therapy for MZL and defined early relapse as lymphoma progression within 24 months (POD24) from diagnosis rather than from the initiation of systemic therapy. In contrast, many patients with MZL do not require immediate therapy, and time from diagnosis to treatment may be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse (POD24) defined as relapse/progression within 24 months from systemic therapy initiation in a large US cohort.

Methods This multicenter, retrospective cohort study of MZL patients treated at 8 US medical centers included patients who were ≥18 years old, diagnosed with MZL from 2010-2020, and had information on treatment at diagnosis. Patients who never received systemic therapy, or those who received only antibiotics, radiation, and surgery were excluded. Patients were grouped into POD24 and non-POD24 groups. The primary endpoint was overall survival (OS). Secondary endpoints were determining the predictive factors for POD24 and cumulative incidence of histologic transformation in POD24 vs non-POD24 groups. Survival analysis according to POD24 was only calculated for patients with events within 24 months (early progressors). For patients without early progression, OS was computed starting from the time of systemic therapy. Patients who were censored or expired before 24 months were excluded from analysis.

Results Among the 364 eligible patients with newly diagnosed MZL, 103 (28%) were in the POD24 group and 261 (72%) in the non-POD24 group. Patients in the POD24 group had a higher median age (66 vs 61 years), LDH >ULN (39% vs 25%), lower albumin (26% vs 16%), presence of monoclonal protein (49% vs 29%), and received rituximab monotherapy (R, 67% vs 52%) compared to non-POD24 group.

The median OS was not reached in either group, however, the 3- and 5-year OS estimates were 80% and 73% in POD24 group compared to 97% and 91% in the non-POD24 groups, respectively (p<0.001, Figure 1). In order to determine if the POD24 was independently associated with OS, we performed Cox regression analysis. After adjusting for factors associated with OS in the multivariate analysis (age, ECOG PS, MZL subtype, LDH >ULN, first-line treatment regimen), POD24 remained associated with significantly inferior OS (HR=3.69, 95%CI=1.93-7.04, p<0.0001).

Regardless of the type of first line systemic therapy (R or immunochemotherapy), POD24 group had significantly inferior OS compared to non-POD24 groups. The 3- and 5-year OS estimates for those receiving R were 80% and 75% in POD24 compared to 96% and 88% in non-POD24 (p=0.007), while the 3- and 5-year OS estimates for those receiving immunochemotherapy were 81% and 69% in the POD24 compared to 97% and 94% in the non-POD24 groups, respectively (p<0.0001, Figure 2).

To determine the factors associated with POD24, we performed multinomial logistic regression analysis and found that advanced age (continuous, OR=1.03, 95%CI=1.00-1.05, p=0.04) and elevated LDH (compared to normal LDH, OR=1.96, 95%CI=1.05-3.67, p=0.03) were associated with increased odds of POD24, while those who received immunochemotherapy had lower odds of POD24 (compared to R, OR=0.46, 95%CI=0.25-0.87, p=0.02).

The cumulative incidence of transformation was significantly higher in the POD24 group compared to non-POD24 group with 3- and 5-year rate of transformation being 18% vs 0% and 32% vs 1%, respectively (p<0.0001).

Conclusions In this study (to our knowledge, the largest dataset to date), we show the prognostic relevance of POD24 in MZL in US patient population. Patients with POD24 regardless of the type of systemic therapy received (R or immunochemotherapy) have poor outcomes. These patients represent a high-risk subset of MZL and need to be prioritized for cellular and experimental therapies. Patients with POD24 have a significantly higher risk for histologic transformation and should be considered for a repeat biopsy at relapse.

Epperla:Incyte: Speakers Bureau; Novartis: Honoraria; TG Therapeutics: Other: Ad Board; BeiGene: Other: Ad Board; Seattle Genetics: Other: Ad Board; Pharmacyclics: Other: Ad Board. Torka:ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; Lilly USA: Consultancy; Targeted Oncology, Physician Education Review: Honoraria; Epizyme: Consultancy; Genentech: Consultancy. Karmali:Morphosys/Incyte: Consultancy, Other: Advisory Board, Speakers Bureau; Pharmacyclics: Consultancy, Other: Advisory Board; Genentech/Roche: Consultancy, Other: Advisory Board; Calithera: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; BMS/Celgene: Consultancy, Research Funding; Takeda: Research Funding; AstraZeneca: Other: Advisory Board, Speakers Bureau; Karyopharm: Consultancy; Kite: Consultancy, Other: Advisory Board, Research Funding, Speakers Bureau; Eusa: Consultancy; BeiGene: Consultancy, Other: Advisory Board, Research Funding, Speakers Bureau. Greenwell:Kyowa Kirin: Consultancy; Stemline: Consultancy. Christian:Acerta: Research Funding; Celgene/Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Millennium: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shouse:Beigene Inc USA: Honoraria; Kite Pharma: Speakers Bureau. Herrera:Karyopharm: Consultancy; Gilead: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genmab: Consultancy; Pfizer: Consultancy; Regeneron: Consultancy; Tubulis: Consultancy; Takeda: Consultancy; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Caribou: Consultancy; Adicet Bio: Consultancy; KiTE Pharma: Research Funding. Bartlett:Autolus, Bristol-Meyers Squibb, Celgene, Forty Seven, Janssen, Kite Pharma, Merck, Millennium, Pharmacyclics: Research Funding; ADC Therapeutics, Roche/Genentech, Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Washington University School of Medicine: Current Employment. Grover:ADC: Other: Advisory Board; Tessa Therapeutics: Consultancy; Novartis: Consultancy; Kite: Other: Advisory Board; Genentech: Research Funding. Olszewski:TG Therapeutics: Consultancy, Research Funding; Schrodinger: Consultancy; Acrotech Biopharma: Research Funding; Celldex: Research Funding; Adaptive Biotechnologies: Research Funding; Precision Bio: Research Funding; Genmab: Consultancy, Research Funding; Genentech: Research Funding.

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