Fludarabine Metabolite Level On Day Zero Does Not Affect Outcomes Of Hematopoietic Cell Transplantation In Patients With Normal Renal Function
Notice bibliographique
Résumé
Abstract Background Fludarabine, an immunosuppressive and cytotoxic purine analogue, is a common constituent of conditioning for hematopoietic cell transplantation (HCT). It is a prodrug that is dephosphorylated in plasma to its measurable metabolite, F-ara-A, which after intracellular rephosphorylation interferes with DNA replication, transcription and translation, and induces apoptosis. Due to variable renal clearance, F-ara-A levels on day 0 (at the time of graft infusion) may be variable. The clinical relevance of the F-ara-A persisting in plasma on day 0 is unknown. The goal of this study was to assess the relationship between F-ara-A levels on day 0 and clinical outcomes including GVHD, infections, relapse and death. Patients and Methods We included 166 consecutive patients undergoing first allogeneic transplantation of filgrastim-mobilized blood stem cells for a hematologic malignancy between December 2008 and 2012. Conditioning was myeloablative, and included fludarabine (50 mg/m2 daily from days -6 to -2), busulfan and antithymocyte globulin. Additional GVHD prophylaxis included methotrexate and cyclosporine. Creatinine level was normal in 165 of the 166 patients; it was 1.2-fold above our upper normal limit in the remaining patient. The interval between the last fludarabine infusion to graft infusion was 48-72 hours. Blood was drawn within 15 minutes before the graft infusion. F-ara-A serum levels were measured using mass spectrometry (Ng ESM et al: Journal of Chromatography B 2013; 931:103). Results As expected, there was a correlation between the day 0 F-ara-A levels and serum creatinine levels (r=0.49, p<0.01). In univariate analyses, there was no difference in median F-ara-A levels between patients who did vs did not develop acute GVHD grade 2-4, acute GVHD grade 3-4, any chronic GVHD, chronic GVHD needing systemic therapy (NST), CMV reactivation above our threshold for preemptive therapy (25,000 IU/mL), post-transplant lymphoproliferative disorder (PTLD), relapse, death or non-relapse death (Figure 1). In multivariate analyses, there was no difference in the likelihood of developing any one of the outcomes between patients whose F-ara-A level was above vs below median (14 ng/mL). Given the clustering of F-ara-A levels near the median we assessed for differences in the likelihood of developing each outcome between patients with levels in the fourth quartile (21-104 ng/mL) vs the first quartile (1-9 ng/mL). Again, in this analysis, there was no difference for any outcome. We also noted a weak correlation between F-ara-A levels on day 0 and the day of neutrophil engraftment (r=0.16, p=0.04), and a trend towards more bacterial infections in patients with F-ara-A levels in the fourth vs first quartile. Discussion The results suggest that there is no or minimal impact of day 0 F-ara-A levels on clinical outcomes. This may be due to the fact that F-ara-A levels on day 0 were relatively low (1-104 ng/mL, median 14 ng/mL) compared to levels 1-4 hours after fludarabine infusion (∼1,000 ng/mL). Conclusion Day 0 F-ara-A levels are highly variable (1-104 ng/mL), probably due to variable renal function. Given that we found no association between the day 0 levels and clinical outcomes we do not support delaying graft infusion until F-ara-A level has dropped below a certain level, as long as the last fludarabine dose is given no later than 48 hours prior to graft infusion and to patients with normal renal function. In patients with abnormal renal function, delaying graft infusion or reducing fludarabine dose may be indicated to avoid engraftment delay. Disclosures: No relevant conflicts of interest to declare.
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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 | 0,000 | 0,002 |
| 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 | 0,000 | 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 ».