Toxicity and efficacy of four carmustine-substituted conditioning regimens followed by autologous stem cell transplantation in lymphoma: a real-world comparative study.

Introduction

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains the standard treatment for relapsed/refractory (R/R) and high-risk lymphomas [ 1 – 3 ]. The efficacy of ASCT is highly dependent on the intensity and anti-lymphoma activity of the conditioning regimen [ 4 ]. For decades, the BEAM regimen (carmustine, etoposide, cytarabine, and melphalan) has been regarded as the standard myeloablative conditioning, supported by extensive clinical experience [ 5 – 8 ]. Other high-dose chemotherapy regimens, such as CBV (cyclophosphamide, carmustine, and etoposide) and BEAC (carmustine, etoposide, cytarabine, cyclophosphamide), followed by ASCT also remain standards of care [ 9 ]. However, the clinical utility of carmustine (BCNU) is limited by its well-documented toxicities, particularly pulmonary and hepatic complications, as well as drug supply shortages and high cost. As a result, alternative regimens that replace carmustine with either semustine (Me-CCNU) or bendamustine within the BEAM framework have been developed and adopted in clinical practice. These alternative effective regimens include BeEAM (bendamustine replacing carmustine in the BEAM backbone), CEAC (oral semustine, etoposide, cytarabine, cyclophosphamide) [ 4 , 10 – 16 ]and SEAM (semustine, etoposide, cytarabine, melphalan) [ 13 , 15 , 16 ]. Such adaptations aim to maintain treatment efficacy while circumventing the limitations of drug availability.

Previous studies have compared the safety and efficacy of the BeEAM, SEAM, and CEAC regimens against the BEAM protocol. The BeEAM regimen has demonstrated comparable efficacy and safety to BEAM, with a slightly improved progression-free survival (PFS) and acceptable toxicity profile [ 17 – 20 ]. The CEAC regimen exhibited similar efficacy to BEAM in Chinese patients with diffuse large B-cell lymphoma (DLBCL), along with a more favorable gastrointestinal safety profile [ 16 ]. The SEAM regimen has also been proposed as a feasible and potentially ideal alternative for lymphoma ASCT [ 13 , 14 ]. Meanwhile, CBV, although associated with a non-significantly lower 5-year PFS, resulted in reduced mucositis, diarrhea, and fewer platelet transfusions compared to BEAM [ 21 ].

Currently, as BEAM-like alternative regimens, there is a lack of direct head-to-head comparative studies evaluating the efficacy and safety of BeEAM, CBV (with semustine replacing carmustine), CEAC, and SEAM, particularly in the Chinese population. Therefore, this retrospective study performed a head-to-head comparison of the toxicity and efficacy of these four conditioning regimens in 80 patients undergoing ASCT, aiming to provide real-world evidence to support clinical decision-making.

Methods

Study design and patient population

This single-center, retrospective cohort study included consecutive patients who underwent ASCT for lymphoma at Shanghai Ninth People’s Hospital between January 2018 and December 2023. During this period, approximately 135 patients received ASCT. After excluding patients who received allogeneic HSCT ( n = 19) and patients with multiple myeloma ( n = 36), we enrolled all remaining lymphoma patients who met the eligibility criteria. A total of 80 patients meeting the following criteria were enrolled. No sample size was calculated before the study. The cohort size was determined by the actual patient flow within the study period. Eligible patients were adults with histologically confirmed lymphoma who received one of the four carmustine-substituted conditioning regimens (BeEAM, CBV, CEAC, or SEAM) and had complete clinical and follow-up data available. Exclusion criteria included prior ASCT, history of other malignancies, pregnancy or lactation, and severe dysfunction of the heart, liver, or kidneys.

Cardiac evaluation before ASCT

Before transplantation, all patients underwent comprehensive cardiac assessment, including transthoracic echocardiography (LVEF and GLS when available), 12-lead electrocardiography, and 24-hour Holter monitoring. Patients with significant cardiac dysfunction (LVEF < 50%, uncontrolled arrhythmia, or other major abnormalities) were not eligible for transplantation until their condition was optimized.

Conditioning regimens

Drug doses for each conditioning regimen were determined according to institutional protocols. BeEAM regimen ( n = 16): bendamustine 200 mg/m²/day on days -8 to -7, etoposide 800 mg/m²/day and cytarabine 1600 mg/m²/day on days - 6 to -3, melphalan 140 mg/m² on day -2 [ 18 ]. CBV regimen ( n = 12): cyclophosphamide 1.8 g/m², days - 3 to -2, oral semustine (Me-CCNU) 250 mg/m², day - 7, and etoposide 900 -1600 mg/m², days - 6 to -4 [ 21 ]. CEAC regimen ( n = 16): oral Me-CCNU 300 mg/m², day - 7, etoposide 800 mg/m², days - 5 to -2, cytarabine 1600 mg/m², days - 5 to -2, and cyclophosphamide 1.8 g/m², days - 6 and - 5 [ 21 ]. SEAM regimen ( n = 36): oral Me-CCNU 300 mg/m², day -8, etoposide 800 mg/m², days - 7 to -4, cytarabine 1600 mg/m², days -7 to -4, and melphalan 140 mg/m², day - 3 [ 13 ].

Treatment-related toxicities

Treatment-related toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Grade III- IV toxicities of interest included oral mucositis, nausea, vomiting, diarrhea, renal toxicity, liver and cardiac dysfunction. Febrile neutropenia (FN) was defined as an axillary temperature ≥ 38 °C for at least 1 h plus an ANC < 0.5 × 10 9 /L. Other infectious complications were defined as any documented or suspected infection caused by viruses, bacteria, or fungi within the first 100 days after transplant. NRM (non-relapse mortality) was defined as death following transplantation that was not attributable to relapse or progression of the underlying disease.

Mobilization and apheresis

The standard mobilization regimen consisted of cyclophosphamide (CTX) at 1.5-2 g/m²/day for two days, followed by G-CSF at 10 µg/kg/day starting five days after CTX completion. For patients who failed CTX-based mobilization (peripheral blood CD34 + cell count < 10/µL on the expected apheresis day), a salvage regimen with plerixafor (0.24 mg/kg, subcutaneous) was used. Apheresis was initiated when peripheral blood CD34 + count reached ≥ 10/µL. The target CD34 + cell dose was ≥ 2 × 10⁶ cells/kg.

Hematopoietic recovery

Hematopoietic recovery was assessed by the time to neutrophil engraftment (NE) and platelet engraftment (PE). NE was defined as an absolute neutrophil count (ANC) of ≥ 0.5 × 10⁹/L maintained for three consecutive days, whereas PE referred to a platelet count of ≥ 20 × 10⁹/L sustained for seven days without platelet transfusion support.

Efficacy assessment

Complete response rate (CRR) was assessed 100 days post-ASCT using the Lugano classification. PFS was calculated as the time from diagnosis to disease relapse, disease progression, or death from any cause, with surviving patients without disease progression censored at the last follow-up. Overall survival (OS) was defined as time from diagnosis to death from any cause.

Supportive care

During the conditioning period, patients were closely monitored for fluid intake and output as well as vital signs. Supportive care included antiemetic and gastroprotective agents, hepatoprotective therapy, and adequate hydration with alkalization. Post-transplant management included the initiation of granulocyte colony-stimulating factor (G-CSF) (5 µg/kg/day) from day 3 until neutrophil engraftment. Irradiated blood products were transfused to maintain hemoglobin levels above 60 g/L and platelet count above 20 × 10⁹/L. Prophylactic antimicrobial therapy against bacterial, fungal, viral, and Pneumocystis jirovecii infections was administered throughout the high-risk period. FN was managed according to institutional guidelines and microbiological test results.

Statistical analysis

Statistical analyses were performed using SPSS version 26.0 and R version 4.2.0. Quantitative variables were described as median and interquartile range (IQR), while categorical variables were presented as counts and percentages. Categorical variables were compared using the χ² test or Fisher’s exact test, and continuous variables were compared using the Kruskal-Wallis test. The follow-up time was calculated from the date of transplantation to the date of the last follow-up or death. Survival curves were generated using the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was performed using a Cox proportional hazards model to identify independent prognostic factors. A two-sided p -value < 0.05 was considered statistically significant.

Ethical considerations

This retrospective study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (Approval No. SH9H-2023-T479-2). The requirement for written informed consent was waived by the ethics committee due to the retrospective nature of the study.

Results

Patient demographics, disease profiles, and transplant characteristics

A total of 80 patients who underwent ASCT were included in this study and divided into four groups according to their conditioning regimen: BeEAM ( n = 16), CBV ( n = 12), CEAC ( n = 16), and SEAM ( n = 36). The baseline demographic and clinical characteristics of the overall cohort and each treatment group were summarized in Table 1 . Most patients were male (58.8%) and gender distribution was balanced across groups ( p = 0.456). The median age of the entire cohort was 50.5 years. Patients in the SEAM group were notably younger (median 43.0 years) compared to those in the BeEAM (57.5 years), CBV (54.0 years), and CEAC (54.5 years) groups ( p = 0.006). DLBCL was the most common histologic subtype (52.6%), followed by NK/T-cell lymphoma (NKTCL, 20.0%) and Hodgkin lymphoma (HL, 7.5%). Subtype distribution varied considerably across regimens. The SEAM group had a higher proportion of NKTCL patients (41.7%), whereas DLBCL was more frequent in the BeEAM (75.0%) and CBV (83.3%) groups ( p < 0.001). Advanced disease (Ann Arbor Stage III–IV) was common (93.8%), with comparable distribution among the groups ( p = 0.475). The SEAM group had the highest proportion of R/R disease (44.4%), while the BeEAM and CEAC groups had the lowest ( p = 0.031). At the time of transplantation, 93.7% of patients were in complete remission (CR), with no statistically significant difference between groups ( p = 0.256). The overall median follow-up for patients was 42.5 months (range, 3.8-58.5 months). The median follow‑up for the CEAC group was 20.9 months (range, 13.4-54.2 months), which was shorter than that of the other three groups ( p = 0.002).

Table 1 Patient characteristics Variable Overall N = 80 BeEAM N = 16 CBV N = 12 CEAC N = 16 SEAM N = 36 p -value Gender 0.456 Female 33 (41.3%) 4 (25.0%) 6 (50.0%) 8 (50.0%) 15 (41.7%) Male 47 (58.8%) 12 (75.0%) 6 (50.0%) 8 (50.0%) 21 (58.3%) Age (years) 0.006 Median (IQR) 50.5 (39.5, 58.5) 57.5 (47.5, 64.5) 54.0 (49.0, 61.0) 54.5 (45.0, 60.5) 43.0 (32.5, 51.5) Subtype < 0.001 DLBCL 42(52.6%) 12 (75.0%) 10 (83.3%) 9 (56.3%) 11 (30.6%) Other B-NHL 6 (7.50%) 0 (0.0%) 1 (8.33%) 2(12.5%) 3 (8.33%) NKTCL 16 (20.0%) 1 (6.25%) 0 (0.0%) 0 (0.0%) 15 (41.7%) Other T-NHL 9 (11.3%) 3 (18.8%) 1 (8.33%) 3 (18.8%) 2 (5.56%) HL 6 (7.5%) 0 (0.0%) 0 (0.0%) 1 (6.3%) 5 (13.9%) Ann Arbor Stage 0.475 I-II 5 (6.25%) 0 (0.0%) 0 (0.0%) 2 (12.5%) 3 (8.33%) III-IV 75 (93.8%) 16 (100.0%) 12 (100.0%) 14 (87.5%) 33 (91.7%) R/R 25 (31.3%) 2 (12.5%) 5 (41.7%) 2 (12.5%) 16 (44.4%) 0.031 Disease status at ASCT 0.256 PR 5 (6.30%) 1 (6.25%) 2 (16.7%) 1 (6.25%) 1 (2.78%) CR 75 (93.7%) 15 (93.8%) 10 (83.3%) 15 (93.8%) 35 (97.2%) Follow-up(months) 0.002 Median (range) 42.5(3.8–58.5) 35.1(22.6–44.6) 51.6(3.8–58.5) 20.9(13.4–54.2) 36.9(13.3–48.4) Abbreviations: IQR interquartile range, DLBCL diffuse large B-cell lymphoma, NHL non-Hodgkin lymphoma, NKTCL NK/T-cell lymphoma, HL Hodgkin lymphoma, R/R refractory or relapsed, ASCT autologous stem cell transplantation, PR partial remission, CR complete remission

Regimen-associated toxicities

The spectrum and incidence of complications following ASCT were detailed in Table 2 . The incidence of grade III-IV oral mucositis (OM), diarrhea, vomiting, abdominal pain, as well as grade I-II gastrointestinal bleeding did not differ significantly among the four groups. Hypoproteinemia was significantly less frequent in the CBV group (50.0%) than in the CEAC (100.0%), BeEAM (81.3%), and SEAM (86.1%) groups ( p = 0.006). Elevation of brain natriuretic peptide (BNP) was more commonly observed in the SEAM group (61.1%) than in the other three groups ( p = 0.040). FN occurred most frequently in the BeEAM group (100%) ( p = 0.004). A trend toward a higher incidence of bloodstream infection (BSI) was noted in the BeEAM group (25.0%), though this did not reach statistical significance ( p = 0.054). In the CEAC group, 81.3% of patients developed intestinal infections. Overall, 25% of patients had infections involving more than one site, including the oral cavity, respiratory tract, digestive tract, and bloodstream, with no significant difference between groups ( p = 0.495). Cardiovascular adverse events including paroxysmal atrial fibrillation, hypotension, chest pain, and cardiogenic shock were more frequent in the CBV group (25%) compared to the other three groups, although the difference was not statistically significant ( p = 0.081).

Table 2 Frequency of post-transplant complications Variable Overall N = 80 BeEAM N = 16 CBV N = 12 CEAC N = 16 SEAM N = 36 p -value OM(Grade III-IV) 16 (20.0%) 5 (31.3%) 4 (33.3%) 2 (12.5%) 5 (13.9%) Diarrhea(Grade III-IV) 55 (68.8%) 10 (62.5%) 8 (66.7%) 12 (75.0%) 25 (69.4%) 0.893 Vomiting(Grade III-IV) 19 (23.8%) 6 (37.5%) 1 (8.3%) 3 (18.8%) 9 (25.0%) 0.354 Abdominal Pain(Grade III-IV) 17 (21.3%) 6 (37.5%) 2 (16.7%) 2 (12.5%) 7 (19.4%) 0.405 GI Bleeding(Grade I-II) 11 (13.8%) 4 (25.0%) 0 (0.0%) 1 (6.3%) 6 (16.7%) 0.262 Hypoproteinemia 66 (82.5%) 13 (81.3%) 6 (50.0%) 16 (100.0%) 31 (86.1%) 0.006 BNP Elevation 36 (45.0%) 7 (43.8%) 3 (25.0%) 4 (25.0%) 22 (61.1%) 0.040 Cardiovascular AE(Grade III-IV) 6 (7.5%) 1 (6.3%) 3 (25.0%) 1 (6.3%) 1 (2.8%) 0.081 FN 58 (72.5%) 16 (100.0%) 9 (75.0%) 13 (81.3%) 20 (55.6%) 0.004 Intestinal Infection 44 (55.0%) 9 (56.3%) 7 (58.3%) 13 (81.3%) 15 (41.7%) 0.069 RTI 22 (27.5%) 4 (25.0%) 2 (16.7%) 6 (37.5%) 10 (27.8%) 0.698 BSI 6 (7.5%) 4 (25.0%) 0 (0.0%) 0 (0.0%) 2 (5.6%) 0.054 Multifocal Infection 20 (25.0%) 5 (31.3%) 1 (8.3%) 5 (31.3%) 9 (25.0%) 0.495 Abbreviations: OM oral mucositis, GI gastrointestinal, BNP Brain Natriuretic Peptide, AE adverse event, FN febrile neutropenia, RTI respiratory tract infection, BSI bloodstream infection

Kinetics of hematopoietic recovery

Hematopoietic engraftment and supportive care outcomes following ASCT were detailed in Table 3 . The overall median CD34 + cell dose infused was 4.7 × 10⁶ cells/kg, with no statistically significant difference among regimens ( p = 0.641). The median time to NE was 10 days for BeEAM, 10.5 days for CBV, 10 days for CEAC, and 10 days for SEAM, respectively ( p = 0.371). Similarly, the median time to PE was 11 days for BeEAM, 12 days for CBV, 12 days for CEAC, and 11 days for SEAM ( p = 0.717). The BeEAM group exhibited the highest incidence of PE failure (18.8%, p = 0.016), which in turn contributed to both the highest median number of platelet transfusions (6.5 units, p = 0.001) and the longest median hospitalization duration (28.5 days, p = 0.012).

Table 3 Hematopoietic engraftment and supportive care requirements after ASCT Variable Overall N = 80 BeEAM N = 16 CBV N = 12 CEAC N = 16 SEAM N = 36 p -value CD34 + infused, ×10 6 cells/kg 4.7 (2.6, 7.7) 5.4 (2.9, 7.3) 2.9 (2.1, 4.1) 6.6 (4.3, 8.5) 4.4 (2.5, 7.7) 0.641 Median time to NE (days) 10.0 (9.0, 11.0) 10.0 (9.0, 11.5) 10.5 (9.0, 11.0) 10.0 (9.0, 11.0) 10.0 (10.0, 11.5) 0.371 Median time to PE (days) 11.0 (10.0, 13.0) 11.0 (11.0, 18.0) 12.0 (10.0, 15.0) 12.0 (11.0, 13.0) 11.0 (10.0, 13.5) 0.717 Failure of PE 3 (3.8%) 3 (18.8%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0.016 Transfused PLT (units) 5.0 (3.0, 7.0) 6.5 (5.0, 12.0) 2.5 (2.0, 4.0) 6.0 (3.0, 7.0) 5.0 (4.0, 7.5) 0.001 Hospitalization duration (days) 27.0 (24.0, 29.0) 28.5 (27.0, 37.0) 27.0 (24.5, 28.5) 28.5 (25.5, 30.0) 25.0 (22.5, 28.0) 0.012 Abbreviations: NE Neutrophil Engraftment, PE Platelet Engraftment, PLT platelets

Post-transplant response and survival outcomes

Kaplan-Meier analysis comparing PFS and OS among the four regimens was shown in Fig. 1 . Although the SEAM group appeared to have an advantage in longer-term follow-up, the log-rank test did not show a statistically significant difference in PFS ( p = 0.177) or OS ( p = 0.218) across the groups. The CRR at day + 100 post-transplant was 87.5% for BeEAM, 91.7% for CBV, 93.8% for CEAC, and 100% for SEAM ( p = 0.249). The overall NRM was 2.5%, with no events in CBV or CEAC, 6.3% in the BeEAM group, and 2.8% in the SEAM group ( p = 0.648). Among the NRM cases, one patient in the BeEAM group died of COVID-19, and the other patient, in the SEAM group, died of severe pneumonia.

Fig. 1 Estimated survival outcomes according to different conditioning regimens. ( A ) Progression free survival; ( B ) Overall survival

Factors associated with post-transplant survival outcomes

Multivariate Cox regression analysis was performed to identify independent prognostic factors for PFS and OS, with results shown in Table 4 . Patients who were in PR at the time of transplantation had an independent adverse prognostic impact on PFS (HR = 4.864, 95% CI: 1.094-21.634, p = 0.038). None of the other clinical variables including age, R/R status, infused CD34 + cell dose, time to NE, time to PE and lymphoma subtype demonstrated a statistically significant association with either PFS or OS.

Table 4 Multivariate analysis of factors potentially associated with survival Variable HR PFS 95% CI p -value HR OS 95% CI p -value Age 0.989 0.938–1.043 0.686 0.932 0.859–1.011 0.092 DLBCL 4.621 0.724–29.492 0.106 1.611 0.154–16.88 0.691 R/R 3.138 0.773–12.743 0.110 0.822 0.112–6.015 0.847 PR at ASCT 4.864 1.094–21.634 0.038 1.897 0.167–21.56 0.606 SEAM conditioning regimen 0.131 0.016–1.086 0.06 0.925 0.118–7.275 0.941 CD34 + infused, ×10 6 cells/kg 1.107 0.967–1.267 0.141 1.032 0.840–1.268 0.766 Time to NE 1.068 0.794–1.437 0.662 0.886 0.577–1.359 0.579 Time to PE 1.165 0.92–1.476 0.206 1.363 0.880–2.110 0.165

Discussion

This study confirms that although the four carmustine‑substituted conditioning regimens have comparable efficacy in terms of survival and response rates, each has a distinct toxicity profile. This finding highlights the need for regimen selection based on individual patient risks. Specifically, the SEAM regimen was associated with more frequent BNP elevation, suggesting a potential risk of cardiotoxicity. The BeEAM regimen led to universal febrile neutropenia, higher platelet transfusion needs, and prolonged hospital stays. The CBV regimen was linked to more cardiovascular events, while the CEAC regimen was associated with higher rates of hypoproteinemia and intestinal infections. Taken together, these findings indicate that the choice of regimen should be guided primarily by toxicity considerations rather than efficacy alone. Such a tailored approach may help optimize outcomes for lymphoma patients who require alternative conditioning therapy during periods of carmustine shortage.

Baseline characteristics showed significant imbalances among the groups. Patients in the SEAM group were younger but had a higher rate of R/R disease. These differences, combined with the varied lymphoma subtype distributions, could have introduced confounding effects. Nevertheless, after adjusting for these potential confounders, multivariate Cox analysis showed that the SEAM regimen remained a potential independent protective factor for PFS ( p = 0.06), suggesting it may have better therapeutic efficacy. The SEAM group also achieved the highest CRR in our study, indicating that semustine-based conditioning retains strong anti-lymphoma activity. This aligns with previous studies supporting SEAM as a feasible and effective alternative to BEAM [ 13 ]. In terms of safety, the SEAM group showed a significantly higher incidence of BNP elevation, pointing to a possible cardiotoxicity risk related to semustine. This finding highlights the need for enhanced cardiac monitoring. Of note, the BNP elevation was reversible. We found that the BeEAM regimen demonstrated similar efficacy compared to the other three groups. This finding is notable because it reinforces the established role of bendamustine-based conditioning, which has previously been shown to exhibit efficacy comparable to the traditional BEAM standard in other studies [ 15 , 17 – 20 , 22 ]. In our study, however, the BeEAM regimen was associated with a considerably worse safety profile. The BeEAM group had a 100% incidence of FN, the highest rate of BSI, the greatest frequency of PE failure, the highest platelet transfusion requirements, and the longest hospital stay. These findings are consistent with previous publications indicating that bendamustine-based conditioning therapy is associated with more profound hematologic toxicity, including universal FN and increased transfusion needs [ 21 ]. Together, they highlight the critical importance of intensified supportive care measures. Given the universal occurrence of FN in the BeEAM group, patients receiving this regimen were at high risk for invasive fungal infections (IFIs). Therefore, adherence to guideline-based antifungal prophylaxis and empirical therapy was essential in this high-risk setting [ 23 , 24 ]. Although the difference did not reach statistical significance, the SEAM and BeEAM groups had a higher incidence of grade I-II gastrointestinal bleeding than the other two groups. This may be related to the mucosal toxicity of melphalan.

In this study, the CEAC regimen was associated with the highest incidence of hypoproteinemia (100%) and a high rate of FN (81.3%), even though its gastrointestinal and mucosal toxicity profile was similar to the other regimens. This finding contrasts with previous reports emphasizing its favorable gastrointestinal safety profile compared to BEAM [ 16 ]. It suggests that the toxicity spectrum of CEAC may differ depending on the patient population or clinical setting.

The CBV regimen also had comparable anti‑tumor activity. Notably, no gastrointestinal bleeding or BSI occurred in the CBV group, and it also had the lowest incidence of multi-site infections. However, the incidence of cardiac adverse events was the highest in this group. This cardiotoxicity may be related to cyclophosphamide (CTX) and etoposide (VP‑16). Therefore, even though the CBV regimen offers better hematologic tolerance and requires fewer platelet transfusions, it may be a suitable choice for selected patients, especially those at high risk for myelosuppression. Nevertheless, close monitoring of cardiac function is recommended. As recommended by Cuomo and Schiano-Lomoriello [ 25 , 26 ], a dedicated cardio-oncology unit with strict echocardiographic monitoring (LVEF and GLS when available) and early use of cardioprotective drugs is essential for patients receiving CBV or SEAM regimens.

G-CSF-based mobilization can induce spleen enlargement [ 27 ]. Although generally reversible, we did not observe clinically significant splenomegaly in any of our 80 patients on routine ultrasound. This may be because we used longitudinal diameter rather than calculated volume, which is more sensitive [ 28 ]. Thus, subclinical volume changes cannot be excluded as a limitation.

Several limitations should be acknowledged. First, the retrospective design may have introduced selection bias, despite multivariate adjustment for key variables. Second, the sample size was limited, which reduced our statistical power to detect clinically meaningful differences. Third, imbalances in baseline characteristics, though addressed statistically, may still influence outcomes. Fourth, the high pre-transplant CR rate (93.7%) reflects our center’s policy of deferring ASCT until optimal disease control is achieved, a strategy supported by literature [ 29 ] and our own multivariate analysis (PR at transplant: HR = 7.064, p = 0.019). Therefore, our findings may not be generalizable to patients transplanted with active disease. Additionally, the single-center design and relatively short follow-up may affect generalizability and assessment of long-term outcomes. Future prospective, randomized studies with extended follow-up are needed to validate these findings.

In conclusion, this head-to-head retrospective study compared the toxicity and efficacy of four carmustine-substituted conditioning regimens and provides real‑world evidence to help address the challenges posed by carmustine shortages. Our findings suggest that regimen selection should be guided by individualized risk-benefit assessment. The SEAM regimen showed favorable efficacy but required careful cardiac monitoring. The BeEAM regimen, due to notable hematologic toxicity, might be less suitable for patients with compromised bone marrow reserve. The CBV regimen appears less ideal for those with preexisting cardiac comorbidities. The CEAC regimen offers a relatively balanced alternative in terms of both efficacy and toxicity. Taken together, these results offer a practical reference to support conditioning regimen selection for lymphoma patients undergoing ASCT. Prospective randomized studies with larger sample sizes are further warranted to validate the efficacy and safety of these carmustine-substituted regimens in this patient population.

Yuyang Pang and Xin Du are co-authors.

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Acknowledgements

Not applicable.

Author contributions

PYY and LW designed the study and collected the clinical samples. PYY and DX performed the statistical analysis and generated the figures and tables. PYY drafted the manuscript. LW and SJ revised the manuscript. All authors have read and approved the final version of the submitted manuscript.

Funding

The authors are grateful for support from the National Natural Science Foundation of China (Grant No. 81900145 and No.82270158), the Science and Technology Commission of Shanghai Municipality (Grant No.21Y31920402) and Shanghai Clinical Research Center for Cell Therapy (Grant No.23J41900100).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

The project was approved by the Ethics Committee of Shanghai Ninth People’s Hospital.

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