Hydroxyurea Decreases Transfusion Utilization in Ugandan Children with Sickle Cell Anemia: Main Results from the Alternative Dosing and Prevention of Transfusions (ADAPT) Trial
Notice bibliographique
Résumé
Introduction: Over 75% of people with sickle cell anemia (SCA) live in Africa where limited access to disease-modifying treatment leads to over-reliance on scarce blood transfusions to treat acute SCA complications. Hydroxyurea may be an important individual and public health strategy to decrease transfusion use in Africa. Hydroxyurea provides the most benefits at maximum tolerated dose (MTD), which varies due to individual pharmacokinetic (PK) differences. Methods: Alternative Dosing And Prevention of Transfusions (ADAPT, NCT05662098) is a prospective, open-label trial to evaluate the impact of hydroxyurea on transfusion rates and clinical indications for children with SCA in Jinja, Uganda. A key secondary aim is to evaluate the feasibility of PK-guided hydroxyurea dosing in this setting. Children 1-10 years old with HbSS were included; those receiving hydroxyurea or monthly blood transfusions were excluded. The primary study endpoint was the transfusion incidence rate ratio (IRR) between the 3-month screening period and the 12-month treatment period. The decision to transfuse was made by local clinicians based on national guidelines. Transfusion indications, volumes, adverse reactions, and peri-transfusion vital signs, physical exam, and lab parameters were recorded. All participants underwent first-dose PK testing with sparse sample collection, local portable high performance liquid chromatography (SmartLife, HPLC), and PK-dose generation with web-based software (HdxSim). Participants for whom a PK dose was generated within 15-35 mg/kg/day started on their individualized dose; those for whom a dose was not generated or if the dose was outside of the predefined range started at a default dose (20 mg/kg/day) per national guidelines. All children had equivalent laboratory monitoring and dose adjustment criteria to reach MTD. Results: ADAPT enrolled 106 children (50% female, mean ± standard deviation (SD) age 4.3 ± 2.3 years). Most (83, 78%) had ≥1 transfusion prior to enrollment, and 37 (35%) reported ≥3 lifetime transfusions. At baseline, the average hemoglobin (Hb) =7.7 ± 1.3 g/dL and fetal Hb (HbF) = 10.3 ± 7.3%. The transfusion rate during screening was 2.40 per person-year and decreased to 1.36 on hydroxyurea (IRR 0.57, 95% CI 0.37-0.88, p=0.011). During both screening and treatment, anemia was the primary transfusion indication followed by malaria. A total of 29 (28.2%) participants started on an individualized, PK-guided dose (28.3 ± 5.3 mg/kg/day) and after 12 months of treatment were receiving 29.5 ± 2.9 mg/kg/day. Children started on the default dose (20 mg/kg/day) escalated to 26.5 ± 5.3 mg/kg/day, p=0.005 comparing PK-guided to standard dosing. After 12 months of treatment, children started on the PK dose had higher HbF responses than those started on the default dose (34.2 ± 14.7% vs 27.6 ± 11.4%, p=0.018). The rate of dose-limiting toxicities between children started on PK-guided vs default dosing was equivalent (0.2 vs 0.3 per patient year, p=0.16). The transfusion rates for those started on the default vs PK-guided dose were also similar (1.36 vs 1.39 per person-year, p=0.9). Conclusion: In ADAPT, a significant 43% reduction in transfusion use was observed in children with SCA during 12 months of hydroxyurea treatment. Prior studies have demonstrated that hydroxyurea reduces transfusion needs in children with SCA, but ADAPT is the first prospective trial to evaluate this individual and public health benefit as a primary study endpoint. ADAPT has also evaluated the feasibility and benefits of prospective PK-guided medication dosing in Africa. Although the PK process needs improvement, the PK-guided starting doses were remarkably close to MTD, achieving HbF>30% safely without stepwise escalation or increased toxicity.
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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 | 0,002 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,002 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| 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 ».