6-Thioguanine nucleotide (6-TGN) is the active metabolite of thiopurine drugs azathioprine and 6-mercaptopurine. 6-Methylmercaptopurine (6-MMP) is an inactive and potentially hepatotoxic metabolite. A subgroup of patients (shunters) preferentially produce 6-MMP instead of 6-TGN, therefore displaying thiopurine resistance and risk for hepatotoxicity. Outside inflammatory bowel disease literature, few data exist regarding individualized thiopurine therapy based on metabolite monitoring. This study sought to describe metabolite monitoring in patients receiving weight-based thiopurine for systemic autoimmune diseases. Patients were enrolled using a laboratory database, and data were retrospectively collected. The correlation between the highest thiopurine dose (mg/kg) and the 6-TGN concentration (pmol/8 × 10 erythrocytes) was estimated with Pearson's correlation coefficient. Seventy-one patients with various systemic autoimmune conditions were enrolled. The correlation between the thiopurine dose and the 6-TGN level was weak for the overall patient sample (r = 0.201, p = 0.092) and for the subgroup of non-shunters (r = 0.278, p = 0.053). Subjects with 6-MMP levels >5700 pmol/8 × 10 erythrocytes had more hepatic cytolysis compared to subjects with 6-MMP <5700, OR = 4.36 (CI 95% 1.18-16.13, p = 0.027). Twenty-two patients (31%) were identified as shunters. Six shunters developed hepatotoxicity, five of which had 6-MMP concentration >5700. Eleven non-shunters had hepatotoxicity, one of which had 6-MMP >5700. Thiopurine metabolite monitoring shows wide variability in 6-TGN levels among patients treated with weight-based thiopurine for systemic autoimmune diseases. Thirty-one percent of the patients in our series fulfilled the shunter definition. Thiopurine metabolite monitoring and dose adjustment to improve maintenance of remission and avoid hepatotoxicity should be studied prospectively.
INTRODUCTION Glucocorticoids (GC) are the main components of childhood acute lymphoblastic leukemia (ALL) treatment; in the past decades, there were numerous attempts at finding whether prednisone or dexamethasone is the best drug. EXPERIMENTAL PROCEDURE A retrospective study of patients (n = 119) treated according to Dana-Farber Cancer Institute (DFCI)-ALL treatment protocols 91-01 and 95-01 was done. Medical charts were reviewed and type and doses of glucocorticoids (GC) received were recorded. Bone and psychiatric symptoms, as well as all anthropomorphic data were also recorded. For each patient, a total theoretical dose was calculated according to the initial risk of relapse stratification, treatment protocol indications and assigned arms. Cumulative GC doses actually received were compared to theoretical doses in the form of a dose deviation in% ((theoretical dose - actual dose) / theoretical dose * 100). SUMMARY OF DATA Results indicate that despite an adequate correlation between planned and administered GC doses for most patients, patients treated with dexamethasone were found to have significantly more GC dose deviations than those treated with prednisone (p < 0.001). Findings also indicate that bone toxicity (p = 0.02), but not psychiatric toxicity, is associated with GC dose deviations. CONCLUSIONS Despite representing the current standard in clinical studies, using only different treatment arms or different treatment protocols may lead to significant interpretation caveats if doses actually received are not controlled for. This is of importance especially for drugs likely to induce very severe side-effects requiring dose modification, as it is the case for GC and acute bone toxicity. Citation Format: Sophie Marcoux, Aurélie Chapdelaine, Philippe Robaey, Daniel Sinnett, Maja Krajinovic, Caroline Laverdière. Prednisone versus dexamethasone acute toxicity and cumulative doses variations in childhood acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1629. doi:10.1158/1538-7445.AM2015-1629
Background: Thiopurines are a mainstay of therapy for autoimmune diseases. However, up to 20% to 30% of patients experience overproduction of the methylated metabolites, known as 6-MMP, to the detriment of the active metabolite, 6-thioguanine nucleotide (6-TGN). These patients, commonly referred to as “shunters”, are predisposed to thiopurine resistance and hepatotoxicity. In patients with inflammatory bowel diseases, the combination of thiopurine with a xanthine oxidase inhibitor (XOI) is used to reverse this skewed metabolism and to prevent treatment failure or hepatotoxicity. Data on the use of this strategy for patients with other diseases are limited. Objectives: To investigate and describe the use of thiopurine–XOI combination therapy in shunters with systemic autoimmune diseases. Methods: Shunters treated in the study hospital between January 1, 2005, and December 31, 2015, were identified using the hospital’s laboratory database, and clinical data were collected retrospectively. For each patient with optimization of thiopurine therapy, clinical and laboratory data were assessed over a 6-month period. Results: Thirty-four patients were identified as shunters; for 14 of these patients, thiopurine therapy was optimized with an XOI. In these 14 patients, the median dose of azathioprine was reduced from 1.95 to 0.78 mg/kg with combination therapy. In addition, median 6-TGN level increased from 135 to 385 pmol/8 × 108 erythrocytes (p = 0.001); furthermore, 6-TGN levels rose to above 235 pmol/8 ×108 erythrocytes for 11 of the 14 patients. Conversely, the median 6-MMP level decreased from 6267 to 271 pmol/8 × 108 erythrocytes (p = 0.001). Except for a 12% increase in mean corpuscular volume, no clinically significant changes in blood count were recorded. Notable infections were reported in 3 patients, and 1 patient had to discontinue treatment because of cytopenia. After 6 months, median prednisone daily dose was reduced by 74%, from 16.7 mg to 4.4 mg (p = 0.005), and 4 patients had been weaned off corticosteroids. Of the 14 patients, 11 (79%) were in full remission, and 2 (14%) were in partial remission. Conclusion: Optimizing thiopurine therapy with an XOI may be a safe and effective strategy for patients with systemic autoimmune diseases. RÉSUMÉ Contexte : Les thiopurines sont des piliers de l’intervention thérapeutique contre les maladies auto-immunes. Cependant, 20 % à 30 % des patients surproduisent des métabolites méthylés (connus sous le nom 6-MMP), au détriment du métabolite actif, le nucléotide 6-thioguanine (6-TGN). Ces patients, communément appelés « courts-circuiteurs » sont prédisposés à résister à la thiopurine et à l’hépatotoxicité. Pour les patients ayant des maladies inflammatoires intestinales, on utilise la combinaison de thiopurine avec une xanthine oxydase inhibitrice (XOI) afin d’inverser ce métabolisme anormal et prévenir l’échec du traitement ou l’hépatotoxicité. Les données concernant l’adoption de cette stratégie pour les patients atteints d’autres maladies sont limitées. Objectifs : Étudier et décrire l’utilisation de la thérapie combinée de thiopurine et de XOI pour les « courts-circuiteurs » ayant des maladies auto-immunes systémiques. Méthodes : Les « courts-circuiteurs » traités dans l’hôpital où s’est déroulée l’étude entre le 1er janvier 2005 et le 31 décembre 2015 ont été identifiés à l’aide de la base de données du laboratoire de l’hôpital et les données cliniques ont été recueillies de manière rétrospective. L’évaluation des données cliniques et de laboratoire de chaque patient bénéficiant d’une optimisation de la thérapie par la thiopurine a porté sur six mois de traitement. Résultats : Trente-quatre patients ont été identifiés comme « courts-circuiteurs » et 14 d’entre eux ont bénéficié d’une optimisation de la thérapie par la thiopurine à l’aide d’une XOI. Ces derniers ont subi une thérapie de combinaison qui a fait passer la dose moyenne d’azathioprine de 1,95 à 0,78 mg/kg. De plus, le niveau moyen de 6-TGN est passé de 135 à 385 pmol/8 × 108 érythrocytes (p = 0,001). En outre, 11 des 14 patients ont vu le niveau de 6-TGN passer à plus de 235 pmol/8 ×108 érythrocytes. Inversement, le niveau moyen de 6-MMP est passé de 6267 à 271 pmol/8 × 108 érythrocytes (p = 0,001). À l’exception d’une augmentation de 12 % du volume corpusculaire moyen, aucun changement clinique important dans la numération globulaire n’a été noté. Trois patients ont développé des infections notables et l’un d’eux a dû arrêter le traitement à cause d’une cytopénie. Après six mois, la dose moyenne quotidienne de prednisone a été réduite de 74 %, pour passer de 16,7 mg à 4,4 mg (p = 0,005), et quatre patients ont été sevrés des corticostéroïdes. Sur les 14 patients, 11 (79 %) ont été déclarés en rémission totale et 2 (14 %) en rémission partielle. Conclusion : L’optimisation de la thérapie par la thiopurine associée à une XOI pourrait être sécuritaire et constituer une stratégie efficace pour les patients ayant une maladie auto-immune systémique.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.