Outcomes of autologous stem cell transplantation using busulfan-melphalan conditioning with pharmacokinetic monitoring for relapsed diffuse large B-cell lymphoma
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».