Graft-Versus-Host Disease (Gvhd) Prophylaxis with Tacrolimus and Mycophenolate Mofetil (MMF) in 131 Matched Sibling Nonmyeloablative (NMA) Transplant Recipients: Long-Term Follow-up Confirms Extremely Low Incidence of Acute (a) Gvhd, High Incidence of Extensive Chronic (c) Gvhd and Favorable Disease Outcome.
Notice bibliographique
Résumé
Abstract Incidences of grade II–IV aGvhd in the range of 30–50% have been reported in sibling NMA transplant recipients despite prophylaxis with cyclosporine and methotrexate. To date, the ideal Gvhd prophylaxis regimen still remains undefined. Because tacrolimus is more potent than cyclosporine and MMF does not lead to mucositis, we hypothesized that early use of a combination of these two oral agents could offer an effective strategy to prevent Gvhd. We therefore designed an outpatient prospective phase II clinical trial with a NMA conditioning regimen consisting of daily fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 for 5 days, followed by infusion of at least 4 × 106 CD34+ cells/kg. All donors were 6/6 matched siblings. Tacrolimus 3 mg bid orally was started on day (D)-8, adjusted to achieve levels of 10–15 nmol/L until D+50, then tapered off by D+100 or +180 according to estimated risk of relapse. MMF 1000 mg bid was given between D+1 to D+50 without taper. Enrollment criteria included age >55 years, an estimated increased risk of toxicity with an ablative transplant or participation in a multiple myeloma (MM) sequential therapy. Between 07/2000 and 07/2007, 131 patients (M/F: 75/56) with a median age of 54 years (range: 20–66) have received an allogeneic transplant according to our protocol. Indication for transplant included age (26%), fear of toxicity (28%) or participation in the sequential therapy (48%). Overall, 101 (77%) patients had previously received an autologous transplant. Diagnoses included MM (N=62), non Hodgkin’s lymphoma (NHL; N=46) including low grade (N=33), diffuse large cell (N=5), mantle (N=7) and Sezary (N=1), acute leukemia (N=10), and others (N=13). After infusion of a median of 6.8 × 106 CD34+ cells/kg (range 0.30 to 22.3), engraftment occurred in 95% of patients by D+180. Overall, 15 patients developed grade I–IV conventional aGvhd by D+120, with a Kaplan-Meier (KM) probability of 11.6% (95%CI: 7.1–18.5), a median of 64 (range: 31–120) days after transplant. At presentation, aGvhd grade was I in 5, II in 7, and III in 3 patients, respectively. No grade IV was observed. Organs involved included skin (13/15) or gastro-intestinal (GI; 4/15), but not liver. Additionally, 15 patients (12%; 95%CI: 7.4–19.2) developed an overlap syndrome consisting of clinical and histological features of both acute and cGvhd simultaneously, at a median of 140 (range 92–177) days post transplant. Altogether, the incidence of conventional II–IV aGvhd and overlap syndrome was 19.7% (95%CI: 13.7–27.7). In contrast, extensive cGvhd occurred in 84 patients surviving beyond D+80 (median D+148, range 83–1042), with a cumulative KM incidence at 7 years of 83.3% (95%CI: 74.3–90.6). Involved organs at diagnosis of extensive cGvhd included mouth (100%), skin (89%), liver (65%), eyes (51%), GI (20%), joints (6%) and lungs (6%), similar to other reported series. Nine of 76 (12%) patients at risk are still taking immunosuppressors after 5 years. To date, 37 patients have died; causes of death include relapse of initial malignancy (N=24), cGvhd (N=3), viral or fungal infection (N=3), or other (N=7). With a cohort median follow-up of 33 (range 2.7–86) months, KM probability of non-relapse mortality (NRM) is 15.5% (95% CI: 9.0–26.1) at 7 years. Overall survival (OS) at 1, 3 and 7 years are 88.5% (95%CI: 81.7–92.9), 71.0% (95%CI: 61.1–78.7) and 62.7% (CI: 51.4–72.1), respectively. Following NMA transplant, disease-free survival (DFS) at 3 years is highest in recipients with low-grade NHL (81.4%; 95%CI: 60.5–91.9) and lowest in intermediate grade NHL (40.0%; 95%CI: 6.6–73.4) or leukemia (35.7%; 95%CI: 13.0–59.4). We conclude that early use of tacrolimus and MMF is an effective strategy to prevent aGvhd and leads to very low NRM. Despite a high incidence of extensive cGvhd, OS, DFS and probability of discontinuing immunosuppression are excellent. Future strategies will need to focus on decreasing the incidence of extensive cGvhd without increasing the risk of relapse.
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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) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 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) | 0,001 | 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 ».