Outcomes of autologous stem cell transplantation using busulfan-melphalan conditioning with pharmacokinetic monitoring for relapsed diffuse large B-cell lymphoma
Bibliographic record
Abstract
Abstract Background: Autologous stem cell transplantation (ASCT) remains an important option for patients with late relapses of diffuse large B-cell lymphoma (DLBCL) and in regions where CAR T-cell therapy is inaccessible. Although carmustine, etoposide, cytarabine, and melphalan (BEAM) is widely used for ASCT conditioning, the rising costs, limited availability, and pneumonitis risks of carmustine have reduced its feasibility in some settings. Busulfan-melphalan (BuMel) represents a promising alternative conditioning regimen, though published data are limited. Here, we report our institutional experience with BuMel conditioning, incorporating pharmacokinetic (PK)-guided busulfan dosing to optimize dosing and mitigate toxicity. Methods: This retrospective single-centre study included consecutive patients ≥18 years old who received rituximab (R)-BuMel conditioned ASCT for relapsed/refractory DLBCL between 2012 and 2024. Conditioning consisted of rituximab 375 mg/m2 IV on day -5, busulfan 3.2 mg/kg/day IV on days -4 to -2, and melphalan 140 mg/m2 IV on day -1. PK sampling was performed after the first busulfan dose (at 5 mins, 1, 3, 5, and 7 hrs) and used to adjust the third dose to target a total busulfan AUC <13,500 μM·min. Primary outcomes were progression-free survival (PFS) and overall survival (OS) from ASCT. Results: This study included 30 patients with a median age of 59 years (range 19-70) who received R-BuMel conditioned ASCT for relapsed/refractory DLBCL NOS (n=19), high-grade B-cell lymphoma NOS (n=1) or with MYC and BCL2 rearrangements (n=4), transformed indolent B-cell lymphoma (n=3), primary mediastinal B-cell lymphoma (n=2), and T-cell/histiocyte-rich large B-cell lymphoma (n=1). International prognostic index (IPI) score was 3-5 in 19 (63%) patients at diagnosis and 14 (47%) patients at relapse. Primary refractory disease occurred in 12 (40%), early relapse within 12 months of first-line therapy in 5 (17%), and late relapse >12 months in 13 (43%) patients. With a median follow up time of 2.8 years (range 0.2-8.6), the median PFS was 2.6 years and median OS was 3.8 years. Estimated PFS rate was 46% (95% CI 24-65%) and OS rate was 57% (95% CI 34-75%) at 3 years. Inferior PFS was associated with primary refractory disease (HR 4.04, 95% CI 1.34-12.2, p=0.013) and IPI 3-5 at relapse (HR 3.36, 95% CI 1.11-10.12, p=0.031). The median CD34+ cell dose was 7.2×106/kg (range 2.8-40.0). Median time to neutrophil and platelet engraftment was 11 days (range 10-14) and 16 days (range 10-79), respectively. Median ASCT hospital stay was 19 days (range 16-81). Busulfan PK monitoring led to dose reductions in 13 (43%) patients and no increases. Infection-related toxicities during ASCT hospitalization included febrile neutropenia in 24 (80%), bacteremia in 3 (10%), C. difficile colitis in 3 (10%), pneumonia in 2 (7%), and UTI in 1 (3%) patient. Other grade 3-4 organ toxicities included mucositis in 14 (47%), colitis in 7 (23%), atrial fibrillation in 2 (7%), pulmonary edema in 3 (10%), and seizure in 1 (3%) patient. One (3%) patient required ICU admission; none required dialysis. No pneumonitis or veno-occlusive disease was observed. Non-relapse mortality was 3% (95% CI 0-15%) at 3 months and 7% (95% CI 1-20%) at 6 months, due to cardiac arrest (n=1) and aspiration pneumonia (n=1). One (3%) patient developed therapy-related myeloid neoplasm following CAR T-cell therapy for post-ASCT relapse. Estimated 2025 drug acquisition costs per patient were approximately $1,000 CAD for BuMel versus $20,000 CAD for BEAM. Busulfan PK monitoring added approximately $1,500 CAD per patient. Conclusion: These results demonstrate the efficacy and tolerability of PK-guided BuMel conditioning for patients undergoing ASCT for relapsed/refractory DLBCL, with PFS and OS comparable to those historically reported with BEAM. Drug acquisition costs are considerably lower with BuMel compared to BEAM. BuMel may represent a reasonable alternative to BEAM, particularly in settings where carmustine is unavailable or cost-prohibitive or where avoidance of pulmonary toxicity is a priority.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".