Hepatotoxicity during 6-thioguanine treatment in inflammatory bowel disease and childhood acute lymphoblastic leukaemia:A systematic review

<div><p>Background</p><p>The recently established association between higher levels of DNA-incorporated thioguanine nucleotides and lower relapse risk in childhood acute lymphoblastic leukaemia (ALL) calls for reassessment of prolonged 6-thioguanine (6TG) treatment, while avoiding the risk of hepatotoxicity.</p><p>Objectives</p><p>To assess the incidence of hepatotoxicity in patients treated with 6TG, and to explore if a safe dose of continuous 6TG can be established.</p><p>Data sources</p><p>Databases, conference proceedings, and reference lists of included studies were systematically searched for 6TG and synonyms from 1998–2018.</p><p>Methods</p><p>We included studies of patients with ALL or inflammatory bowel disorder (IBD) treated with 6TG, excluding studies with 6TG as part of an intensive chemotherapy regimen. We uploaded a protocol to PROSPERO (registration number CRD42018089424). Database and manual searches yielded 1823 unique records. Of these, 395 full-texts were screened for eligibility. Finally, 134 reports representing 42 studies were included.</p><p>Results and conclusions</p><p>We included data from 42 studies of ALL and IBD patients; four randomised controlled trials (RCTs) including 3,993 patients, 20 observational studies including 796 patients, and 18 case reports including 60 patients. Hepatotoxicity in the form of sinusoidal obstruction syndrome (SOS) occurred in 9–25% of the ALL patients in two of the four included RCTs using 6TG doses of 40–60 mg/m²/day, and long-term hepatotoxicity in the form of nodular regenerative hyperplasia (NRH) was reported in 2.5%. In IBD patients treated with 6TG doses of approximately 23 mg/m²/day, NRH occurred in 14% of patients. At a 6TG dose of approximately 12 mg/m²/day, NRH was reported in 6% of IBD patients, which is similar to the background incidence. According to this review, doses at or below 12 mg/m²/day are rarely associated with notable hepatotoxicity and can probably be considered safe.</p></div

Ciclosporin does not attenuate intracranial hypertension in rats with acute hyperammonaemia

AIM: To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin-4 expression in a rat model with acute hyperammonaemia. METHODS: Twenty-four male Wistar rats with portacaval anastomosis were randomised into four groups receiving ciclosporin or vehicle and ammonia or saline infusion. Ciclosporin or vehicle was given intrathecally prior to the ammonia or saline infusion. The ammonia or saline infusion was given intravenously for 4 h, while intracranial pressure and arterial pressure was recorded. At the end of the experiment, cerebral cortex and cerebellar brain tissue was analysed for water and aquaporin-4 content. RESULTS: The following intracranial pressures were found at the end of the experiment: ammonia + ciclosporin: 10.0 ± 1.7 mmHg, ammonia + vehicle: 6.8 ± 1.0 mmHg, saline + ciclosporin: 3.1 ± 0.5 mmHg, saline + vehicle: 3.3 ± 0.6 mmHg. Ammonia infusion had a significant effect on intracranial pressure and brain water content, which both were higher in the groups receiving ammonia (P < 0.001, two-way analysis of variance). Treatment with ciclosporin resulted in relevant tissue concentrations of ciclosporin (> 0.2 micromolar) but did not reduce intracranial pressure after 4 h. Furthermore, ciclosporin did not attenuate the increase in cerebral water content, and did not affect aquaporin-4 expression. CONCLUSION: Intrathecal administration of ciclosporin does not attenuate intracranial hypertension or brain oedema in rats with portacaval anastomosis and 4 h of ammonia infusion

Increments in DNA-thioguanine level during thiopurine-enhanced maintenance therapy of acute lymphoblastic leukemia

Maintenance therapy containing methotrexate and 6-mercaptopurine is essential to cure acute lymphoblastic leukemia (ALL). Cytotoxicity is elicited by incorporation of thioguanine nucleotides into DNA (DNA-TG), and higher leukocyte DNA-TG is associated with increased relapse-free survival. As 6-thioguanine provides 6-fold higher cytosolic levels of thioguanine nucleotides than does 6-mercaptopurine, we added low-dose 6-thioguanine to methotrexate/6-mercaptopurine maintenance therapy to explore if this combination results in significantly higher DNA-TG. The target population of the "Thiopurine Enhanced ALL Maintenance therapy" (TEAM) study was 30 patients with non-high-risk ALL, aged 1-45 years on methotrexate/6-mercaptopurine maintenance therapy receiving no other systemic chemotherapy. Incremental doses of 6-thioguanine were added to methotrexate/6-mercaptopurine maintenance therapy (starting 6-thioguanine dose: 2.5 mg/m(2)/day, maximum: 12.5 mg/m(2)/day). The primary endpoint was DNA-TG increments. Thirty-four patients were included, and 30 patients completed maintenance therapy according to the TEAM strategy. Of these 30 patients, 26 (87%) tolerated 10.0-12.5 mg/m(2)/day as the maximum 6-thioguanine dose. TEAM resulted in significantly higher DNA-TG levels compared to those in both TEAM patients before their inclusion in TEAM (on average 251 fmol/mu g DNA higher [95% confidence interval: 160-341; PPeer reviewe