We retrospectively analyzed data from (age ≥ 15 years) 69 adult patients with BL diagnosed between November 2009 and August 2023 using the fifth edition of the World Health Organization (WHO) classification (14). Two well-experienced pathologists independently reviewed and confirmed the BL diagnosis based on morphological characteristics, CD10, CD20, Bcl-2, Bcl-6, and Ki-67 expression detected by immunohistochemistry, chromosomal translocation of t (8, 14), and c-myc overexpression detected by fluorescence in situ hybridization. We excluded patients with negative myc rearrangement and no expression of BCL-6 and CD10, or < 80% Ki-67 expression. The disease stage of all enrolled patients were assessed using computed tomography (CT) of the neck, chest, abdomen, pelvis, and fluorine-18 fluorodeoxyglucose positron emission tomography-CT (18F-FDG PETCT). Moreover, the patients routinely underwent bone marrow (BM) biopsy at the time of diagnosis and cerebrospinal fluid analysis during diagnosis and treatment. The demographic information and laboratory data of patients with BL were collected from medical records. Patients were stratified using the international prognostic index (IPI) score system with the Ann-Arbor staging. The study protocol was approved by the Institutional Review Board (IRB) and Ethics Committee of the Catholic Medical Center, Republic of Korea (approval number: KC24RASI0525). This study was conducted in accordance with the tenets of the Declaration of Helsinki and the need for informed consent was waived by the IRB as the study did not adversely affect the rights or welfare of the participants owing to the minimal risk associated with this retrospective study.

The R-hyperCVAD/MC regimen consisting of two alternating courses of R-hyperCVAD (Course A; 375 mg/m² rituximab on day 1 and 11, 300 mg/m² hyper-fractionated cyclophosphamide every 12 h for 6 doses on day 1 to 3, 50 mg/m² doxorubicin on day 4, 2 mg vincristine on day 4 and 11, and 40 mg dexamethasone daily on days 1 to 4 and day 11 to 14) and R-HDMTX/ARAC (Course B; 375 mg/m² rituximab on day 2 and 8, 1000 mg/m² methotrexate on day 1 and 3000 mg/m² cytarabine every 12 h for 4 doses on day 2 to 3) was used to treat patients with BL (12). Moreover, 300 mg of allopurinol and hydration were administered to patients in course A to prevent tumor lysis syndrome (TLS). Additionally, a single 6-mg dose of rasburicase was routinely administered 6 h before initiation of course A chemotherapy to prevent TLS after approval and reimbursement of rasburicase treatment by the National Insurance System of Korea in 2018 (15). In course B, as methotrexate is primarily excreted via the kidneys, the blood concentration of methotrexate and creatinine were routinely monitored and dose-adjusted leucovorin rescue and aggressive hydration were used as prophylactic strategies, as previously described (16). All patients received prophylactic intrathecal chemotherapy—consisting of 12 mg methotrexate, 40 mg cytarabine, and 50 mg hydrocortisone—once during each of courses A and B.

Due to BL’s aggressiveness, the interim response evaluation was performed after completion of 2–3 cycles (4 to 6 courses) of R-hyperCVAD/MC. Treatment response evaluation was conducted according to the WHO response criteria. Complete remission (CR) was defined as no evidence of residual disease, partial response (PR) was defined as at least 50% tumor mass reduction as compared to that at treatment onset, progressive disease (PD) was defined as at least a 25% increase in lesion size, and stable disease (SD) was defined as patient response not reaching PR or PD (17). If the interim response was SD or PD, we considered changing the salvage chemotherapy regimen. The standard protocol in our institute prescribes four cycles of the R-hyperCVAD/MC regimen (eight alternating courses); however, in patients achieving CR with decreased intensive chemotherapy tolerance, the treatment was halted at three cycles (six alternating courses). We employed the R-CHOP regimen (rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and vincristine 1.4 mg/m² on day 1, plus oral prednisolone 100 mg/m² on days 1–5) as an alternative in patients over 60 years of age and/or those with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 2–4, who were highly motivated to undergo treatment but were considered unfit for the R-hyperCVAD/MC regimen due to its high treatment-related mortality. All treatment-related adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.

For patients who failed to achieve at least a PR or showed evidence of PD during first-line treatment, the regimen was switched to salvage chemotherapy. The salvage regimens included DL-ICE (dexamethasone, L-asparaginase, ifosfamide, carboplatin, and etoposide), R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin), ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), or IVAM (ifosfamide, etoposide, cytarabine, and methotrexate), all of which are commonly used to treat relapsed or refractory high-grade lymphoma (18). BL recurrence is typically reported within 1 year, and salvage treatment, including allogeneic hematopoietic stem cell transplantation (allo-HSCT), is usually unsuccessful (19). However, we considered allo-HSCT in fit patients achieving PR to CR during salvage chemotherapy for curative intent. Autologous transplantation was not considered in this study as relapsed/refractory BL is mostly chemo-resistant and has challenges associated with attaining long-term remission only by chemotherapeutic agents. Patients deciding to undergo allo-HSCT were administered reduced-intensity conditioning regimens consisting of 30 mg/m²/day fludarabine for 6 days, 70 mg/kg/day melphalan for 1 day, and 800 cGy of fractionated TBI for 2 days (20). Strategies of graft-versus-host disease and infection were also established based on previous reports (20).

Clinicopathologic characteristics were compared using chi-square test or Fisher’s exact test. Overall survival (OS) and event-free survival (EFS) were calculated from the date of diagnosis to the date of the last follow-up visit or death by any cause and from the date of treatment initiation to the date of recognized disease progression, fatal events by any cause, or the last follow-up visit, respectively. OS and EFS were estimated using the Kaplan–Meier method and compared using the log-rank test. Non-relapsed mortality (NRM) was defined as death due to PD or during treatment, considering patients with relapse or disease-unrelated deaths as competing risks. The cumulative incidence of relapse (CIR) was defined as disease relapse with NRM considered as a competing risk. CIR and NRM were measured by cumulative incidence estimation, and comparisons between the groups were based on Gray’s competing risk method. Survival rates were compared for statistical differences using a log-rank test, and p values < 0.05 were considered statistically significant. Two-tailed p values were used in the analysis. The Cox proportional regression model was used for multivariate analysis to calculate survival hazard ratios (HRs), and variables were selected based on previous studies on the known prognostic factors (3, 6, 10, 12). The Fine–Gray proportional hazard regression model was used to calculate the HRs for cumulative incidences. All statistical analyses were conducted using R-software (version 4.3.3, R Foundation for Statistical Computing, 2024).

This study included 69 patients with BL treated at our hospital. Of these, 47 were males (68.1%) and 22 were females (31.9%), with a 2:1 male predominance and a median age of 55 years (range 15 – 81). ECOG-PS score of ≥ 2 at diagnosis was observed in 27 patients (39.1%) and 47 (68.1%) had elevated LDH. Moreover, 28 patients (40.6%) had B-symptoms at diagnosis. A total of 48 patients (71.0%) were classified as Ann-Arbor stage IV, and 43 patients (62.3%) had involvement of two or more extranodal sites. All patients with stage IV lymphoma had multiple intra-abdominal lymphadenopathies with 26 (37.7%) patients with BM involvement, 10 (14.5%) with Leukemic phase, and 9 (13.0%) with CNS involvement. Therefore, more than half of the patients (44/69, 63.7%) were categorized as high-intermediate to high-risk based on IPI risk classifications. Furthermore, 13 patients (18.8%) had their diagnosis changed from high-grade lymphoma to BL following detection of IGH/MYC translocations. The clinical characteristics of the enrolled patients are presented in Table 1 .

In total, 69 adult patients diagnosed with BL according to WHO criteria between 2009 and 2023 were stratified by age and ECOG-PS ( Supplementary Figure S1 ). Among these 69 patients, 60 patients (87%) who were <60 years of age or had an ECOG-PS of <2 initiated treatment with the R-hyperCVAD/MC regimen; 52 patients (75.4%) completed the full course of R-hyperCVAD/MC without switching regimens. Notably, 5 of the 52 patients were initially referred with a diagnosis of diffuse large B-cell lymphoma but were reclassified as having BL upon further evaluation at our institution. Eight patients (11.6%) who achieved CR after two cycles (four courses) of R-hyperCVAD/MC were transitioned to two additional cycles of R-CHOP owing to declining performance status. All eight patients remained in long-term remission and were alive at the last follow-up. The remaining nine patients (13%) initiated treatment with R-CHOP. This group included individuals with confirmed BL who were ineligible for R-hyperCVAD/MC owing to age ≥ 60 years or ECOG-PS ≥ 2 and those initially diagnosed with high-grade B-cell lymphoma who were later confirmed to have BL ( Supplementary Figures S1 , S2 ). Two patients, aged 31 years and 42 years, respectively, were treated with R-CHOP based on the judgment of the clinicians owing to poor performance status caused by a massive tumor burden, rendering R-hyperCVAD/MC intolerable. Among these two younger but unfit patients, one died of septic shock after the first R-CHOP cycle (Patient 6; Table 2 ). Two additional older patients were later confirmed to have BL but were not switched to R-hyperCVAD/MC owing to advanced age and poor ECOG-PS: one progressed after two cycles of R-CHOP and died without receiving salvage therapy (Patient 12; Table 2 ), while the other achieved CR. In five patients, the initial diagnosis of high-grade B-cell lymphoma was later revised to BL owing to the delayed identification of MYC rearrangement or aberrant MYC expression, complicating timely diagnosis. As treatment could not be delayed owing to rapid disease progression, R-CHOP was promptly initiated in all five cases. Following confirmation of the BL diagnosis, the regimen was switched to R-hyperCVAD/MC, resulting in long-term remission in these patients.

The interim response evaluation revealed that 49 patients achieved CR (71.0%), 5 had PR (7.2%), 8 had PD (11.6%), and the remaining 7 died (10.1%) during the 1^st chemotherapy cycle ( Supplementary Figure S3 ). All 49 patients who achieved CR maintained their remission status after completing chemotherapy; however, 3 of them relapsed, and 1 patient, who was still in CR, died from pneumonia (patient 23, Table 2 ). Among the three relapsed patients, two (patients 18 and 24, Table 2 ) died from PD without salvage treatment, while one (patient 22, Table 2 ) achieved CR after six DL-ICE salvage chemotherapy cycles, following PD after three ESHAP cycles. Among the five PR patients, one (patient 13, Table 2 ) died from fungal pneumonia in PR status, two (patients 14 and 19, Table 2 ) died from PD without salvage treatment, while two (patients 20 and 21, Table 2 ) achieved CR after salvage therapy. Patient 20 experienced systemic relapse with CNS involvement and underwent whole brain radiotherapy (WBRT), followed by four DL-ICE cycles and allo-HSCT. Patient 21 initially received three DL-ICE cycles but progressed, leading to four cycles of ESHAP and allo-HSCT. All patients developing PD (patients 8–12 and 15–17, Table 2 ) died shortly after due to disease progression.

During first-line treatment, all patients experienced at least one episode of hematologic toxicity of any grade, and most patients developed grade 3 or 4 events: neutropenia in 65 patients (94.2%), anemia in 36 (52.2%), and thrombocytopenia in 57 (82.6%). Patients treated with R-hyperCVAD/MC had a significantly higher incidence of grade 3 or 4 anemia (59.6% vs. 29.4%, p=0.030) and thrombocytopenia (88.5% vs. 64.7%, p=0.025) than those receiving mixed regimens of R-CHOP ± R-hyperCVAD/MC. No significant differences in non-hematologic adverse events were observed between groups during first-line treatment. In cycle 1 course A, 14 patients developed TLS, with 8 also experiencing concomitant acute kidney injury. Despite the implementation of all appropriate therapeutic measures, two patients succumbed to TLS, while the remaining recovered with intravenous hydration and rasburicase administration, without the need for hemodialysis. In total, 52 patients (75.4%) experienced infectious complications, and bacterial growth was confirmed in blood cultures from 43 patients (62.3%). Details of the adverse events during first-line treatment are summarized in Supplementary Table S1 .

At diagnosis, nine patients (13.0%) had CNS involvement; of these eight were administered full-dose R-hyperCVAD/MC, while one (patient 24, Table 2 ) was switched from R-CHOP to R-hyperCVAD/MC. Among them, 7 achieved long-term CR, 1 (patient 15, Table 2 ) died from PD, and 2 relapsed (patient 14 with CNS parenchymal relapse and patient 24 with multifocal bone involvement, Table 2 ), both succumbing to PD. Additionally, two patients (patients 18 and 20, Table 2 ) experienced CNS relapse despite no initial CNS involvement. Patient 18 died without salvage treatment, while patient 20 achieved long-term CR through WBRT, DL-ICE salvage therapy, and allo-HSCT. Detailed clinical characteristics and long-term outcomes of treatment failure or patients with relapsed BL are summarized in Table 2 .

The median follow-up period was 66.9 months (range 10.5–174.9) and the 5-year OS and EFS was 69.5 (95% confidence interval [CI], 57.2–78.9) and 65.1% (95% CI, 52.7-75.0), respectively ( Figures 1A, B ). The 5-year CIR and NRM was 10.2 (95% CI, 4.4–18.7) and 24.6% (95% CI, 15.2–35.2), respectively ( Figures 1C, D ). Survival outcomes stratified by initial treatment regimens—including patients treated with pure R-hyperCVAD/MC, R-CHOP, and those who switched regimens during treatment—are presented in Supplementary Figure S4 . Although differences in survival outcomes were observed among these subgroups, they did not reach statistical significance. Associations between age, sex, ECOG, stage B-symptoms, extranodal involvement of ≥ 2, BM involvement, CNS involvement, and LDH elevation were evaluated by univariate analysis in each survival outcome to identify prognostic factors, presented in Supplementary Table S2 . Multivariate analysis ( Figure 2 ) revealed that the presence of B-symptoms was significantly associated with the OS (HR 3.89, 95% CI, 1.57–9.65, p = 0.003), EFS (HR 2.40, 95% CI, 1.01–5.69, p = 0.048), and NRM (HR 3.48, 95% CI, 1.37–8.80, p = 0.009). Age ≥ 60 years was significantly correlated with OS (HR 2.54, 95% CI, 1.07–5.99, p = 0.034) and NRM (HR 3.04, 95% CI, 1.15–8.01, p = 0.025), and ECOG-PS 2–4 was significantly correlated with EFS (HR 2.72, 95% CI, 1.14–4.68, p = 0.024).