Autologous stem cell transplantation (ASCT) is standard treatment for relapsed or refractory lymphoma [1,2]. High-dose chemotherapy followed by ASCT significantly improves both disease-free survival and overall survival (OS) in chemotherapy-sensitive patients [1,2]. The BEAM conditioning regimen is predominantly utilized for younger, medically fit patients responding to salvage chemotherapy prior to ASCT [2]. Older patients and those with poor performance status often experience significantly higher rates of non-relapse mortality (NRM) of 5–11% at 100 days post-transplant, limiting ASCT eligibility [3-6]. Patients >70 years who received BEAM conditioning had a 1.71-fold increased risk of progression or death compared to those aged 60–69 years, due to higher toxicity rates, particularly cardiovascular complications [4,7]. Furthermore, the increasing incidence of lymphoma among older adults raises pressing concerns, particularly since chronological age is frequently regarded as a negative prognostic indicator. Recent findings, however, indicate that comorbidities may exert a stronger influence on patient outcomes than age itself [3,8].
In an effort to mitigate toxicity, a reduced-dose BEAM regimen lower etoposide and cytarabine doses but remaining melphalan at 140 mg/m2 which preserves the myeloablative intensity has been proposed. This approach reduces mucositis, thrombocytopenia duration, and transfusion needs [9]. Nevertheless, skepticism remains concerning the practicality and efficacy of high-dose melphalan in frail patients, who may have varying levels of physiological reserve. Moreover, melphalan doses (100 mg/m2) has shown reduced gastrointestinal toxicity for myeloid malignancies [10,11]; however, this approach has not yet been investigated in lymphoma. Notably, there has been a gap in research focusing on dose reductions that effectively determine the minimum necessary exposure to chemotherapy that balances therapeutic efficacy with safety in these vulnerable populations. In light of these challenges, our study evaluates a reduced melphalan dose of 100 mg/m2, aiming to extend the potential eligibility for ASCT to patients who are typically deemed unsuitable for BEAM conditioning.
We retrospectively analyzed 32 consecutive adult patients with relapsed/refractory, or high-risk non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) (Central nervous system; (CNS) disease excluded.) who underwent ASCT at our institution between 1 May 2020 and 30 March 2025. All patients showed disease response after salvage chemotherapy by PET/CT criteria received either standard BEAM (Std-BEAM) [carmustine 300 mg/m2 on day −6, etoposide 200 mg/m2 and cytarabine 200 mg/m2 every 12 h on days −5 to −2 and melphalan 140 mg/m2 on day −1] [2] or Lite-BEAM [same carmustine, etoposide 100 mg/m2 and cytarabine 100 mg/m2, every 12 h on days −5 to −2 and melphalan 100 mg/m2 on day −1] based on older age (>65 years) with favorable geriatric assessment, poor performance status by Karnofsky Performance Status (KPS) less than 70%, or significant comorbidities by Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) more than 3, as determined at the discretion of the treating physician. Pre-transplant organ function screening included ejection fraction >40% and serum creatinine <2 mg/dL. Patients with B-cell NHL received rituximab 375 mg/m2 on day +1 and +8. A minimum of 2 × 106 CD34+ cells per kilogram was infused on day 0. Disease evaluation was performed on days +30, +90, +180, +365, and annually thereafter using PET/CT per Lugano classification. Lymphocyte subsets (CD3+, CD3+CD4+, CD3+CD8+, CD19+, and CD3−CD56+ cells) were assessed using multicolor flow cytometry. Adverse effects were closely monitored using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
The primary outcome was OS, while progression free survival (PFS), cumulative incidence (CI) of engraftment, relapse, and NRM were analyzed as secondary outcomes. The Kaplan–Meier method was used to estimate survival outcomes. The cumulative incidence with the competing risks method was used to estimate the endpoints of secondary outcomes. The statistical significance was established at p < 0.05. Analyzed were performed using Stata version 18.0 (StataCorp, College Station, TX, USA).
Among 32 patients participated in this study, with 26 (81%) diagnosed with NHL and 6 (19%) with HL. All patients with T-cell NHL (19%) underwent upfront ASCT due to higher risk of relapse. Sixteen patients (50%) received Lite-BEAM regimen, whereas 16 (50%) were treated with the Std-BEAM. The median age of patients in the Lite-BEAM group was 70 years (range, 49–78), significantly higher than the 56 years (range, 23–66) observed in the Std-BEAM group (p < 0.001). Additionally, patients in the Lite-BEAM group exhibited a lower median KPS [80% (range, 50–100) versus 90% (range, 70–100) in Std-BEAM group (p = 0.009)]. The median HCT-CI score was also higher in the Lite-BEAM group at 3 (range, 0–8), versus 1 (range, 0–4) (p = 0.061), respectively. A high-risk HCT-CI score had a significant impact on NRM following ASCT, particularly within the first 100 days post-transplant [12]. Other baseline and transplant characteristics were comparable between the two cohorts. (Tables 1 and 2) All patients achieved both neutrophil and platelet engraftment. The median follow-up duration was 669 days (52–1804). OS and PFS at both 100 days and 1 year were 93.8% (95% CI: 63.2–99.1) in the Lite-BEAM group and 100% in the Std-BEAM group (p = 0.317), with no cases of disease relapse reported in either group. One patient who received Lite-BEAM group succumbed to pneumonia, leading to a 100-day and 1-year NRM of 3.1% (95% CI: 0.2–13.7) compared to 0% in the Std-BEAM group (p = 0.239).
Table 1.
Demographics and clinical characteristics of patients.
| Lite-BEAM (N = 16) | BEAM (N = 16) | p value | |
|---|---|---|---|
| Age (median in year; range) | 70 (49–78) | 56 (23–66) | <0.001 |
| Sex: male, n (%) | 10 (52.6) | 7 (47.4) | 0.719 |
| Diagnosis, n (%) | 0.070 | ||
| Non-Hodgkin lymphoma | 15 (93.8) | 11 (68.8) | |
| Hodgkin lymphoma | 1 (6.3) | 5 (31.2) | |
| Subtype of NHL, n (%) | 0.453 | ||
| DLBCL | 10 (66.7) | 6 (54.5) | |
| FL | 1 (6.7) | 1 (9.1) | |
| T-cell lymphoma | 3 (20.0) | 3 (27.3) | |
| MCL | 1 (6.7) | 1 (9.1) | |
| Stage by Ann-Arbor, n (%) | 1.000 | ||
| Stage I–II | 5 (31.3) | 5 (31.3) | |
| Stage III–IV | 11 (68.7) | 11 (68.7) | |
| IPI score for NHL (n = 21), n (%) | 0.124 | ||
| 0–2 | 10 (71.4) | 4 (40.0) | |
| 3–5 | 4 (28.6) | 6 (60.0) | |
| Disease risk index (DRI), n (%) | 0.195 | ||
| Low | 1 (6.3) | 6 (37.4) | |
| Intermediate | 12 (75.0) | 8 (50.0) | |
| High | 2 (12.4) | 1 (6.3) | |
| Very high | 1 (6.3) | 1 (6.3) | |
| Disease status before transplant, n (%) | |||
| CR1 | 5 (31.3) | 6 (37.5) | 0.321 |
| CR2 | 9 (56.3) | 6 (37.5) | |
| PR | 0 (0) | 3 (18.8) | |
| PDa | 2 (12.4) | 1 (6.2) | |
| Indication for ASCT | 0.733 | ||
| Relapse | 10 (62.5) | 8 (50.0) | |
| Primary induction failure | 2 (12.5) | 2 (12.5) | |
| Consolidation/upfront | 4 (25.0) | 6 (37.5) | |
| HCT-CI (median; range) | 3 (0–8) | 1 (0–4) | 0.061 |
| KPS (median; range) % | 80 (50–100) | 90 (70–100) | 0.009 |
| Line of therapy (median; range) | 2 (1–3) | 2 (1–3) | 0.775 |
| Anthracycline based regimen for first-line treatment | 15 (93.8) | 13 (81.3) | 0.285 |
| Number of patients with NHL received rituximab, n (%) | 12 (100) | 7 (87.5) | 0.209 |
| LDH level (mean; range) (U/L) | 315.31 (130–1288) | 279.13 (108–1104) | 0.705 |
| Stem cell mobilization, n (%) | 0.076 | ||
| G-CSF alone | 3 (18.7) | 7 (43.7) | |
| G-CSF + plerixafor | 3 (18.7) | 1 (6.3) | |
| Chemotherapy + G-CSF | 6 (37.5) | 8 (50.0) | |
| Chemotherapy + G-CSF + plerixafor | 4 (25.0) | 0 (0.0) |
Abbreviations: ASCT: autologous stem cell transplantation, CR: complete remission, DLBCL: diffuse large B cell lymphoma, FL: follicular lymphoma, G-CSF: granulocyte colony-stimulating factor, HCT-CI: Hematopoietic Cell Transplantation Comorbidity Index, IPI: International Prognostic Index, KPS: Karnofsky Performance Status, LDH: lactate dehydrogenase, MCL: Mantle cell lymphoma, NHL: non-Hodgkin lymphoma, PD: progressive disease, PR: partial remission.
Progressive disease was identified by PET/CT according to the Lugano classification prior to transplantation, despite a reduction in lesion size observed on CT imaging.
Table 2.
Transplant characteristics and outcomes.
| Lite-BEAM (N = 16) |
BEAM (N = 16) | p value | |
|---|---|---|---|
| Median CD34 count (×106/kg) (median; range) | 4.6 (2–12.2) | 5.3 (2.6–18.4) | 0.346 |
| Median time to neutrophil engraftment (range) | 13 (11–26) | 12 (10–27) | 0.993 |
| 30 day-CI | 100% | 100% | 0.993 |
| Median time to platelet engraftment (range) | 21 (10–111) | 19 (9–77) | 0.576 |
| 100 day-CI | 93.8% | 100% | 0.578 |
| Median duration time of admission | 20 (16–42) | 21 (17–40) | 0.835 |
| OS | 0.317 | ||
| 100 days | 93.8% (63.2–99.1) | 100% | |
| 1 year | 93.8% (63.2–99.1) | 100% | |
| 3 years | 93.8% (63.2–99.1) | 100% | |
| PFS | 0.317 | ||
| 100 days | 93.8% (63.2–99.1) | 100% | |
| 1 year | 93.8% (63.2–99.1) | 100% | |
| 3 years | 93.8% (63.2–99.1) | 100% | |
| Relapse | – | ||
| 100 days | 0% | 0% | |
| 1 year | 0% | 0% | |
| NRM | 0.239 | ||
| 100 days | 3.1% (0.2–13.7) | 0% | |
| 1 year | 3.1% (0.2–13.7) | 0% |
Abbreviations: CI: cumulative incidence, OS: overall survival, PFS: progression free survival, NRM: non-relapse mortality.
Adverse events post-transplant are summarized in Table 3. Neutropenic fever occurred in 59.4% of patients overall, with a slightly higher incidence in the Std-BEAM group (75.0%) versus Lite-BEAM (43.8%) (p = 0.072). Gastrointestinal toxicities were the most prevalent in both groups, mainly grade 1-2 nausea/vomiting and diarrhea. Mucositis was significantly more frequent in the Std-BEAM group (37.5%) than in Lite-BEAM group (6.3%) (p = 0.033). The incidence of grade ≥3 non-hematologic adverse events was not statistically significant differences between the groups (p = 0.365).
Table 3.
Adverse events or post-transplant complications.
| Lite-BEAM (N = 16) |
BEAM (N = 16) | p value | |
|---|---|---|---|
| Neutropenic fever | 7 (43.8) | 12 (75.0) | 0.072 |
| Documented bacterial infection (Bacteremia) | 5 (31.3) | 1 (6.3) | 0.070 |
| Viral infection | |||
| CMV | 0 (0) | 1 (6.3) | 0.518 |
| HHV-6 | 1 (6.3) | 0 (0) | 0.524 |
| GI toxicity | |||
| Nausea and vomiting | |||
| Grade I–II | 10 (62.5) | 12 (75.0) | 0.446 |
| Grade III–IV | 0 (0.0) | 0 (0.0) | 1.000 |
| Diarrhea | |||
| Grade I–II | 8 (50.0) | 10 (62.5) | 0.476 |
| Grade III–IV | 2 (12.5) | 0 (0.0) | 0.144 |
| Mucositis | 1 (6.3) | 6 (37.5) | 0.033 |
| Pulmonary complication | 2 (12.5) | 0 (0.0) | 0.171 |
| Cardiac complication | |||
| Arrhythmia | |||
| VT/AF | 5 (31.3) | 1 (6.3) | 0.070 |
| Heart failure | 2 (12.5) | 2 (12.5) | 1.000 |
| Renal complication (AKI) | 3 (18.8) | 0 (0.0) | 0.069 |
| Neurological complication | 4 (25.0) | 2 (12.5) | 0.365 |
| Delirium | 2 (12.5) | 0 (0.0) | 0.144 |
| Abnormal movement/imbalance | 2 (12.5) | 0 (0.0) | 0.144 |
| Peripheral neuropathy | 0 (0.0) | 2 (12.5) | 0.144 |
| VTE (DVT + SVT) | 4 (25.0) | 5 (31.3) | 0.694 |
| Engraftment syndrome | 1 (6.3) | 1 (6.3) | 1.000 |
| Grade 3–4 non-hematologic toxicity (exclude neutropenic fever) | 7 (43.8) | 5 (31.3) | 0.465 |
| Grade 3–4 non-hematologic toxicity (include neutropenic fever) | 12 (75.0) | 14 (87.5) | 0.365 |
| Transfusion requirement (median (bags); range) | |||
| Red cells | 3 (0–9) | 2.5 (1–8) | 0.969 |
| Platelet | 9.5 (2–35) | 8 (2–26) | 0.533 |
Abbreviations: AF: atrial fibrillation, AKI: acute kidney injury, CMV: cyto-megalovirus, DVT: deep vein thrombosis, HHV-6: human herpesvirus-6, SVT: superficial vein thrombosis, VT: ventricular tachycardia, VTE: venous thromboembolism.
Note: All variables reported as number (per cent) unless otherwise stated.
Complete immune recovery of lymphocyte subsets was observed in all patients by 1-year post-transplant (Figure 1). When comparing immune reconstitution between the Lite-BEAM and Std-BEAM, there were no significant differences in the recovery of total lymphocyte counts (ALC), CD3+, CD3+CD4+, CD3+CD8+, or CD3−CD56+ subsets. However, the reconstitution of CD19+ B-cells was notably slower in the Lite-BEAM group (p < 0.001).
Figure 1.
Lymphocyte subset recovery post-transplant.
Our study investigated the transplant outcomes of a reduced-intensity BEAM conditioning regimen (Lite-BEAM) in older or medically unfit lymphoma patients compared to those receiving std-BEAM. As anticipated, the demographic and clinical characteristics of the two groups differed significantly. Despite these unfavorable characteristics, Lite-BEAM regimen represents a feasible and well-tolerated alternative for older patients or those with comorbidities who might otherwise be excluded from receiving the std-BEAM. Notably, we found no significant differences in engraftment outcomes, lengths of hospitalization, or transfusion requirements between two groups. Compared to larger retrospective analyses reporting higher toxicity, increased 1-year NRM, and lower OS and PFS in older and frail patients receiving std-BEAM, our study showed more favorable outcomes despite a similar median follow-up (20 months). This may be partly due to the inclusion of more toxic regimens such as cyclophosphamide-carmustine-etoposide (CBV) or busulfan-cyclophosphamide (BU-CY) in prior studies, as well as improvement in supportive care. Additionally, the BEAM regimen comprises multiple chemotherapeutic agents with proven activity against lymphoid malignancies, where the synergistic effect among agents may play a more critical role than the absolute dose intensity [3,6].
Melphalan doses of 140–200 mg/m2 in std-BEAM have been associated with severe mucositis, exceeding 40% in patients undergoing ASCT for lymphoma [13]. We have seen a decrease incidence of severe mucositis for patients receiving Lite-BEAM regimen, better tolerated in older patients, potentially associated with lower likelihood of infectious complications [10,11]. However, the rates of neutropenic fever and bacterial infections were not significantly different yet a significantly older population received Lite-BEAM, although the Lite-BEAM regimen showed a trend toward fewer grade ≥3 non-hematologic adverse events (excluded neutropenic fever). There is no statistically significant difference in transfusion requirements between two groups, possibly because reduced-intensity regimen was better tolerated by older or frail patients [9].
Immune reconstitution post-ASCT showed complete lymphocyte subset recovery in all patients by 1-year post-transplant. A slower recovery of CD19+ B-cells was observed in the Lite-BEAM group, possibly due to greater cumulative exposure to rituximab. Delayed CD19+ recovery has been reported for up to 18 months post-ASCT in rituximab-treated patients [14]. It is worth noting that a higher proportion of patients in the Lite-BEAM group (12 patients) received rituximab compared to the Std-BEAM group (7 patients), which could have influenced the dis-parities in CD19+ B-cell recovery. Although the Lite-BEAM group tended to have lower creatinine clearance, this difference does not significantly affect rituximab clearance [15]. Stratified by rituximab exposure confirmed that delayed CD19+ B-cell recovery was significantly associated with rituximab use (p < 0.001).
Limitations of this study include its retrospective design, relatively small sample size, and single-center nature, all of which may limit the generalizability of our findings. Larger studies are needed to confirm these findings.
In conclusion, although constrained by the limited patient numbers, our results indicate that older patients, up to age 80, or those with lower KPS and/or higher HCT-CI scores can safely undergo ASCT with the Lite-BEAM reduced-intensity conditioning. The comparable outcomes, engraftment kinetics, and manageable toxicity profile associated with Lite-BEAM relative to Std-BEAM conditioning are encouraging. Furthermore, the remarkably low NRM and absence of relapse observed in both treatment groups underscore the utility of this approach for lymphoma patients in remission, even into advanced age.
Acknowledgments
The authors sincerely thank all patients for entrusting their care in us and for participating in this study. The authors are grateful to the Hematopoietic Stem Cell Transplantation and Cellular Therapy Program Team at University of California, Irvine for their dedication to patient care and data collection.
Funding
The authors received no specific funding for this work.
Footnotes
Ethics approval and consent to participate
All patients provided written informed consent for transplant, and consent for research data collection/report, in accordance with the Declaration of Helsinki [UCI International Review Board (IRB #20206215)]. The study adhered to STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for cohort studies.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.