Reduced Intensity Continuous Infusion Busulfan for Allogeneic Hematopoietic Cell Transplant Patients with Hematologic Disorders Who Are Ineligible or Inappropriate for Treatment with a More Intensive Therapeutic Regimen: LCCC 0306
Notice bibliographique
Résumé
Abstract Background: A major advance in allogeneic stem cell transplant (SCT) has been the establishment of effective and less toxic reduced intensity regimens as alternative therapeutic approaches for patients with certain hematologic malignancies. The focus of these approaches has been to reduce treatment related mortality (TRM) while providing sufficient host immunosuppression to permit the achievement of complete donor chimerism that leads to a graft versus tumor effect, resulting in long-term disease control and cure. In this study we report overall survival (OS), relapse rate (RR), and non-relapse mortality (NRM) in patients receiving reduced intensity conditioning (RIC) with a 48 hour continuous infusion of busulfan with fludarabine followed by methotrexate (MTX) alone or with lympho-depleting anti-CD52 monoclonal antibody (mAb), alemtuzumab, or T cell depleting immunoglobulins, anti-thymocyte globulin (ATG) given as graft versus host disease (GVHD) prophylaxis. Methods: Patients with histologically confirmed hematologic malignancies, who were over the age of 55, or otherwise ineligible for more intensive busulfan-based therapy were enrolled on a Phase II protocol, LCCC 0306, at the University of North Carolina. All patients received IV fludarabine 30 mg/m2/day on days-7 through-3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days-6 through-5 and tacrolimus from day-1 plus either MTX alone, ATG or alemtuzumab alone, or a combination of these agents depending on disease risk and donor status. Results: 71 patients were enrolled. The median age was 58 (range 28 - 69). 58% were men and 42% women. 37 patients received HLA-matched related donor (MRD) stem cell grafts, and 34 patients received either matched unrelated donor (MUD) or HLA-mismatched grafts. The median HCT-Comorbidity Index (CI) score was 3 (range 0 - 8, HCT-CI score: 0 = 12 pts, 1 - 2 = 22 pts, ⪴ 3 = 36 pts). The majority of pts were intermediate risk by Disease Risk Index (DRI) score (9 low, 40 int, 19 high, 1 very high, 2 undetermined). The DRI low/int group had an estimated 18 month OS of 65% (CI 0.50 - 0.77), and DRI high/very high OS was 35% (CI 0.16 - 0.55). Estimated median survival time based on DRI for low/int was 1674 days (CI 646 - 2920) versus 375.5 days (CI 136 - 1018) (p = 0.003) for DRI high/very high pts. OS at 18 months in the MTX alone arm (n = 20) was 70% (CI 0.45 - 0.83), ATG (+/- MTX, n = 27) was 52% (CI 0.32 - 0.69), and alemtuzumab (+/- MTX, n = 24) was 46% (CI 0.26 - 0.64); (p = 0.17). The 18 month relapse rate for the MTX alone arm was 50% (CI 0.27 - 0.69), 41% in ATG (CI 0.37 - 0.76), and 41% in alemtuzumab (CI 0.36 - 0.77); (p = 0.85). The 18 month NRM in the MTX alone arm was 7% (CI 0.61 - 0.99), alemtuzumab (+/- MTX) was 32% (CI 0.42 - 0.85), and ATG (+/- MTX) was 27% (CI 0.52 - 0.86); (p = 0.05). Much of the increased NRM in the alemtuzumab and ATG arms was attributable to increased rates of fatal infectious complications: 1 in the MTX arm, 3 in the ATG arm and 8 in the alemtuzumab arm. No patients receiving MTX alone, 3 receiving alemtuzumab and 6 receiving ATG developed grade 3-4 acute GVHD. 5 of the 20 surviving patients have extensive chronic GVHD. Conclusion: Continuous infusion, reduced dose, busulfan and fludarabine can be safely administered to patients who are ineligible for myeloablative conditioning either because of age or comorbidities. The use of MTX alone with this regimen results in a median survival of over 4 years. Patients with high DRI or who received treatment with alemtuzumab or ATG had higher NRM and poorer OS irrespective of donor status. Disclosures Wood: Best Doctors: Consultancy; Inform Genomics: Consultancy.
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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 | 0,000 |
| 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 | 0,001 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».