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.

García Herce:ABBVIE: Honoraria. Jiménez Ubieto:Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Sandoz: Speakers Bureau; Regeneron Pharmaceuticals, Inc.: Consultancy; Lilly: Consultancy; Incyte: Speakers Bureau; Kite-Gilead: Consultancy, Speakers Bureau; Genmab: Consultancy. Serna:Astrazeneca: Honoraria; Roche: Honoraria; Incyte: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Arnaldos López:Janssen: Honoraria. Bosch:Enterome: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Lava Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Advantage Allogene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony. Abrisqueta:Astrazeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy; BMS: Consultancy, Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau.