key: cord-102199-mc6zruyx
authors: Toksvang, Linea Natalie; Schmidt, Magnus Strøh; Arup, Sofie; Larsen, Rikke Hebo; Frandsen, Thomas Leth; Schmiegelow, Kjeld; Rank, Cecilie Utke
title: Hepatotoxicity during 6-thioguanine treatment in inflammatory bowel disease and childhood acute lymphoblastic leukaemia: a systematic review
date: 2019-01-30
journal: bioRxiv
DOI: 10.1101/535518
sha: 
doc_id: 102199
cord_uid: mc6zruyx

Background 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. Objectives To assess the incidence of hepatotoxicity in patients treated with 6TG, and to explore if a safe dose of continuous 6TG can be established. Data sources Databases, conference proceedings, and reference lists of included studies were systematically searched for 6TG and synonyms from 1998–2018. Methods 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. Results and conclusions 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; SOS has not been reported. 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.

180 Two review authors independently evaluated risk of bias of the included reports using the Cochrane 181 Collaboration tool for RCTs. [18] The study quality assessment tools of the National Heart, Lung, 182 and Blood Institute of the National Institutes of Health (NIH) for quality assessment of 183 Observational Cohort and Cross-Sectional Studies and Controlled Intervention Studies [23] were 184 used to assess the risk of bias of observational studies. A graphic illustration of potential bias of 220 observational studies (6, (27) (28) (29) (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) (41) (42) (43) (44) (45) , and 18 were case reports (11, (46) (47) (48) (49) (50) (51) (52) (53) (54) (55) (56) (57) (58) (59) (60) (61) (62) . No similar reviews were 221 found in the database search or on PROSPERO. 14 278 The included RCTs were generally well executed with low risk of bias, except in the areas of 279 blinding participants and outcome assessment, which may lead to performance and detection bias.

280 Risk of bias assessments in the included observational studies did not result in any suspicion of 281 specific biases. The confidence in the cumulative estimate of the incidence of hepatotoxicity was 282 graded as moderate, and the use of diagnostic methods as moderate, primarily because of the 283 inconsistencies in reporting within these subjects. The confidence in the cumulative estimate of 284 dose reduction or truncation of 6TG was graded as high.

287 The findings of the present systematic review indicate that 6TG-induced hepatotoxicity in the form 288 of SOS or NRH is highly dose-dependent, and that it rarely occurs at daily doses of less than 12 289 mg/m 2 /day. Furthermore, 6TG-induced hepatotoxicity appears to be largely reversible, except at 290 high doses exceeding 40 mg/m 2 /day.

The three RCTs of childhood ALL, the COALL-92 trial, the CCG-1952 trial, and the UK MRC 293 ALL97/99 trial, respectively, have previously been included in a meta-analysis, which estimated the 294 increase in SOS between treatment arms to be a factor 7.16 (OR, 95% CI 5.66-9.06). [12] SOS was 295 highlighted as a dose-related toxicity with a multifactorial aetiology. No SOS was reported in the 296 COALL-92 trial, albeit a high frequency of discordant thrombocytopenia, which may reflect a 297 minor degree of hepatotoxicity. In that trial, vincristine and corticosteroids were not co-298 administered with 6TG -as was the case in the other two RCTs. [25] This difference in the co-299 medication has been proposed to be an explanation for the differing incidence of SOS between the 300 three RCTs. [2] 301 302 The theory that NRH is 6TG dose or ery-TGN level-dependent was first presented in 2005. [11] 303 This is supported by a mouse model, in which SOS arose from high peak concentrations of 6TG, 397 LNT created and pilot tested the data extraction form. SA, MSS and LNT extracted the data, made 398 assessments of risk of bias and confidence in cumulative evidence. LNT drafted the manuscript.

399 The manuscript was read, revised, and approved by all authors. 

setting, duration, inclusion and exclusion 155 criteria, source of funding, conflict of interest, ethical approvals, key conclusions), patient 156 characteristics (number of patients, age, sex, ethnicity, disease, comorbidity, concomitant therapy), 157 details of the interventions (duration of 6TG, dose of 6TG, cumulative dose of 6TG, maximum dose 158 of 6TG, route of administration, ery-TGN levels), comparator (comparator drug, duration of 6MP or 159 other standard of care drug, dose of 6MP or other standard of care drug, cumulative dose of 6MP or 160 other standard of care drug, maximum dose of 6MP or other drug

Incidence of any hepatotoxicity reported as SOS, veno-occlusive disease (VOD)

drug-165 induced liver injury or non-specified hepatotoxicity. Due to the lack of standardised definitions of 166 hepatotoxicity, authors of the included studies may not have used the above-mentioned terms. To 167 assess additional hepatotoxicity we therefore report any pathological findings of liver biopsies and 168 use the Ponte di Legno (PdL) toxicity working group consensus criteria for SOS, which entail 169 fulfilment of at least three out of the following five criteria: (i) hyperbilirubinaemia; (ii) 170 hepatomegaly

Furthermore, we considered an increase in alanine transaminase, aspartate transaminase, alkaline 172 phosphatase, conjugated bilirubin or total bilirubin of more than two times upper normal limit as 173 evidence of hepatotoxicity

Secondary outcomes: Diagnostic methods (number of patients who had a liver biopsy, indication 175 for liver biopsy, other diagnostic methods, study conclusions about diagnostic methods); dose 176 reduction or truncation of 6TG due to hepatotoxicity (how many patients had 6TG truncated or the 177 dose reduced

If protocols were unavailable, we compared 205 outcomes reported in the methods and results sections. We did not quantitate the impact of meta

) consistency, and (4) directness. The evidence on each outcome was graded as 'very 213 low', 'low', 'moderate' or 'high'. higher in studies on 6TG for adult IBD and childhood ALL. 6TG-related 387 hepatotoxicity persists in the form of NRH in 3% of the patients. However, the use of 6TG doses of 388 approximately 12 mg/m 2 /day or less leads to hepatotoxicity in only 6% of the adult patients, 389 corresponding to the incidence in the background population

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