Clinical Characteristics and Outcomes of Patients with Localized Stage High-Grade B-Cell Lymphoma (HGBCL) with or without MYC and BCL2 and/or BCL6 Rearrangements: A Retrospective Study from the Spanish Group Geltamo

Background: HGBCL, with or without MYC, BCL2 and/or BCL6 rearrangements, constitute approximately 10-15% of diffuse large B-cell lymphomas (DLBCL). Most cases are diagnosed at advanced stages with associated poor prognosis and tend to be treated with high-dose chemoimmunotherapy. Nevertheless, there is limited data on the optimal treatment options for localized stages of this disease. Methods: We conducted a retrospective, multicenter study in Spain, including patients diagnosed with double-hit (DH)/triple-hit (TH) HGBCL/DLBCL and HGBCL not otherwise specified (NOS), from January 2010 to May 2024. We analyzed demographic characteristics, treatment patterns (non-intensive vs. intensive treatments including dose-adjusted R-EPOCH, HyperCVAD, and BURKIMAB regimens), and survival outcomes according to clinical stage at diagnosis (localized vs. advanced stage). Kaplan-Meier and the COX model were used to analyze progression-free and overall survival (PFS and OS), as well as factors associated with these variables. Results: A total of 156 patients from 14 GELTAMO centers were included in the study. Among them, 35 (22.3%) were diagnosed at Ann Arbor stage I-II. The median age at diagnosis was 71 years (IQR 63-76) for localized stages and 63 years (IQR 55-72) for advanced stages, with no sex differences observed. Patients with localized stages had better ECOG scores (89% at ECOG 0-1 vs. 71 %, p=0.062) and fewer patients with elevated LDH levels (53% vs. 81 %, p=0.002). Among advanced-stage patients, 31 (26%) had more than one extranodal site affected and 10 (8.4%) had central nervous system (CNS) involvement and 44 (36%) had bone marrow involvement at diagnosis. Four (11.4%) localized cases and 15 (12.3%) advanced cases were transformed from follicular lymphoma. According to the Hans algorithm, the germinal center cell type was present in 23 of 26 (88.4%) localized cases vs. 89 of 108 (82.4%) advanced cases, with no differences observed. Similarly, regarding rearrangements, there were no significant differences in the prevalence of DH and TH variants: DH-BCL2 was found in 31.4% of localized vs. 44.3% of advanced cases; DH-BCL6 in 14.2% vs. 17.2%; TH in 20% vs. 20.5%; and NOS in 34.3% vs. 18%. Patterns of first-line treatment were similar between patients with localized or advanced disease: 10 (39%) patients with localized disease and 56 (48%) with advanced disease received intensive regimens, 16 (45.7%) and 50 (41%) receiving R-CHOP, while other treatments were administered to 8 (22.8%) and 16 (13.1%) of patients. The overall response rate was 60% in localized cases vs. 59% in advanced cases, while the complete response rate was 57% vs. 47.5%, respectively. Overall, 53% of localized and 48% of advanced patients received one line of treatment, 28% vs. 20% received two lines, and 19% vs. 31% received three or more lines. CAR-T therapy was administered to 3.2% of localized and 21% of advanced patients, and bispecific antibodies to 11.4% vs. 8.2%. Autologous stem cell transplantation was performed in 6.5% vs. 10%, and allogeneic stem cell transplantation in 0% vs. 1.8%. In the whole cohort, factors associated with PFS and OS included ECOG score, increased LDH, number of extranodal sites, and DH-BCL2/TH status (MYC-BCL2+/-BCL6 vs MYC-BCL6 or HGBCL-NOS). In the multivariable analysis, ECOG score and DH-BCL2/TH status retained their prognostic significance. Additionally, both univariable and multivariable analyses demonstrated that intensive treatment was associated with improved PFS. With a median follow-up of 46 months (95% CI 40-71), no significant differences were observed in OS (p = 0.6) and PFS (p = 0.3) between localized and advanced stages. The 2-year PFS was 59% (44%-78%) for localized vs. 44% (36%-55%) for advanced stages, and 2-year OS was 58% (42%-79%) vs. 55% (46%-65%). There was 1 (2.8%) CNS relapse in the localized group compared to 6 (4.9%) in the advanced group. Conclusion: In our series, patients with localized HGBCL had similar outcomes to those with advanced stages, suggesting that they should be treated with intensive regimens like those used for advanced disease.