Outcomes of T-cell/histocyte-rich large B-cell lymphoma (THRLBCL): An international LEO/MER and NiHiL collaborative study

Abstract Introduction: THRLBCL is a rare disease accounting for less than 10% of all diffuse large B-cell lymphoma (DLBCL) subtypes. THRLBCL was associated with poor outcomes in the pre-rituximab era, with limited contemporaneous data. Optimal frontline treatment remains unclear with some studies advocating for intensive regimens. The goal of this international study is to analyze the survival and treatment-related outcomes in patients with newly diagnosed THRLBCL treated with rituximab-containing chemotherapy and to compare with a DLBCL, not otherwise specified (NOS) cohort. Methods: THRLBCL and DLBCL patients prospectively enrolled in the Lymphoma Epidemiology of Outcomes (LEO) (NCT02736357) (7/2015 to 5/2020), Molecular Epidemiology Resource (1/2010 to 6/2015), and Czech Lymphoma Study Group project (NiHiL) (NCT03199066) (2/2010 to 11/2023) were analyzed. Diagnosis was made in dedicated hematopathology centers in both registries. We excluded patients with prior nodular lymphocyte-predominant Hodgkin lymphoma, central nervous system involvement, and not treated with rituximab-containing therapy. Event-free survival (EFS) and overall survival (OS) were estimated by Kaplan-Meier.Univariate associations were derived via Cox model and multivariate models were constructed by forward selection of significant variables with P≤0.05. Propensity score matching (1:5, caliper 0.2) between THRLBCL and DLBCL NOS patients was performed using IPI score components and treatment as covariates. Results: We identified 158 patients (LEO: 67 and NiHiL: 91) with THRLBCL. Among them, 140 patients received rituximab-containing regimens and were included in this analysis. Median age was 58 years (range, 19-89) with 57% aged ≤60 years. Most patients were male (n= 88; 63%) and had ECOG performance status (PS) of 0-1 (n= 111; 79%), stage III-IV (n= 111; 79%), elevated LDH (n= 92; 66%), and B symptoms (n= 84; 60%). Fifty (36%) patients had ≥2 extranodal (EN) sites, mostly liver (n= 39; 28%) and lung (n= 16; 11%), bone marrow (BM) involvement was observed in 26% (n= 37). Bulky disease (≥7.5cm) was present in 50 (36%) and IPI score ≥3 in 68 (48%) patients. The median diagnosis-to-treatment interval was 23 days (IQ range, 13-38.5). Frequent regimens were R-CHOP (n= 106; 75.7%), followed by intensive regimens such as R-MegaCHOP/ESHAP, R-HyperCVAD/MA, and R-CODOX-M/IVAC (n= 15; 10.7%), and R-CHOEP/EPOCH-R (n= 10; 7.14%). With a median follow-up of 3.92 years, the 4-year EFS & OS were 71% and 80%, respectively. Lymphoma was the main cause of death (n= 15; 11%) among 30 events. No difference in 4-year EFS (70% vs. 76%; P= 0.55) & OS (80% vs 82%; P= 0.96) were observed between R-CHOP and intensive regimens. Factors associated with shorter EFS and OS in univariate analysis for THRLBCL were ECOG PS 2-4: (HR= 3.3; P<.001 & HR= 5.97, P<.001, respectively); ≥2 EN sites (HR= 1.85, P= 0.043 & HR= 2.54, P= 0.014, respectively); B symptoms (HR= 2.35, P= 0.014 & HR= 2.84, P= 0.023) and IPI score (HR= 1.5, P= 0.002 & HR= 2.16, P<.001). Stage III-IV and BM involvement were associated with shorter OS only (HR= 7.36, P= 0.05 & HR= 2.18, P= 0.036, respectively). Among them, only ECOG PS 2-4 (OS: HR= 3.6, P= 0.003) and B symptoms (EFS: HR= 2.3, P= 0.046) were independent predictors of survival in multivariate analysis. Finally, we compared baseline characteristics and survival between THRLBCL (n= 140) and DLBCL NOS (n= 6099; LEO/MER: 2069 & NiHiL: 4030) treated with rituximab-containing regimens. Patients with THRLBCL were younger (≤60 years: 57% vs. 38%; P<.001), more frequently had ECOG PS 0-1 (79% vs 76%; P= 0.012), stage III-IV (79% vs 63%; P<.001), B symptoms (60% vs 38%; P<.001), and liver involvement (28% vs 7%; P<.001), compared to DLBCL NOS. Subtype was not associated with survival (OS HR= 0.79, P= 0.262 & EFS HR= 0.93, P= 0.662) when adjusted for IPI score. With a median follow-up of 4.89 years in the DLBCL NOS cohort, we observed similar 4-year EFS (71% vs 67%; P= 0.197) & OS between histologies (80% vs 77%; P= 0.125). These results were confirmed in propensity matching for EFS (HR= 0.98, P= 0.897) and OS (HR= 1.07, P= 0.732). Conclusions: In this large international analysis of patients with newly diagnosed THRLBCL contemporaneously treated, we observed similar survival rates compared to DLBCL NOS treated with R-CHOP and intensive regimens. ECOG PS and the presence of B symptoms were independent factors associated with survival.