Effectiveness and safety of thioguanine as a maintenance therapy of inflammatory bowel disease: Systematic review, meta-analysis and meta-regression.

INTRODUCTION: Thiopurines are an important therapy for the maintenance of remission in inflammatory bowel disease (IBD). However, the use of thioguanine has been limited by concerns regarding its toxicity. We performed a systematic review to evaluate its effectiveness and safety in IBD. METHODS: Electronic databases were searched to identify studies reporting clinical responses and/or adverse events of thioguanine therapy in IBD. We calculated the pooled clinical response and clinical remission rates of thioguanine in IBD. Subgroup analyses were done for the dosage of thioguanine and the type of studies (prospective or retrospective). Meta-Regression was used to analyze the impact of dose on clinical efficacy and occurrence of nodular regenerative hyperplasia. RESULTS: A total of 32 studies were included. The pooled clinical response rate of thioguanine therapy in IBD was 0.66 (95% C.I. 0.62 - 0.70; I2 = 16%). The pooled clinical response rate with low-dose was similar to high-dose thioguanine therapy [0.65 (95% C.I. 0.59 - 0.70; I2 = 24%) and 0.68 (95% C.I. 0.61 - 0.75; I2 = 18%) respectively]. The pooled remission maintenance rate was 0.71 (95% C.I. 0.58 - 0.81; I2 = 86%). The pooled rates of occurrence of nodular regenerative hyperplasia, liver function tests abnormalities and cytopenia were 0.04 (95% C.I. 0.02 - 0.08; I2 = 75%), 0.11 (95% C.I. 0.08 - 0.16; I2 = 72%) and 0.06 (95% C.I. 0.04 - 0.09; I2 = 62%) respectively. Meta-regression suggested that the risk of nodular regenerative hyperplasia is related to the dose of thioguanine. CONCLUSION: TG is an efficacious and well-tolerated drug in most patients with IBD. Nodular regenerative hyperplasia, cytopenias, and liver function abnormalities occur in a small subset. Future studies should look into TG as primary therapy in IBD.

Skin Toxicity Due to Mercaptopurine in Maintenance Therapy Among Children With Acute Lymphoblastic Leukemia.

Mercaptopurine is a crucial component in the treatment of acute lymphoblastic leukemia. It is associated with toxicities that can delay treatment. Mercaptopurine is metabolized into 6-thioguanine nucleotides and 6-methylomercaptopurine nucleotides (6MMPN). Accumulation of 6MMPN has previously been associated with hepatotoxicity, pancreatitis, and hypoglycemia. However, skin toxicity has rarely been reported. We report 5 cases of elevated 6MMPN levels associated with cutaneous manifestations.

Exposure to Thioguanine During 117 Pregnancies in Women With Inflammatory Bowel Disease.

BACKGROUND: Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth. METHODS: In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications, and neonatal outcomes were collected. RESULTS: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most [78%] had Crohn's disease and the mean age at delivery was 31 years. In 18 pregnancies [15%], IBD flared. Obstetric and infectious complications were seen in 15% [n = 17] and 7% [n = 8] of pregnancies, respectively. Ten pregnancies [8.5%] resulted in a first trimester miscarriage, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. CONCLUSION: In this large case series, the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes.

Low-dose thioguanine guided by therapeutic drug monitoring is a safe and effective alternative in inflammatory bowel disease patients intolerant to conventional thiopurines.

BACKGROUND: Thioguanine is an alternative thiopurine for inflammatory bowel disease (IBD) patients. AIMS: To evaluate the short-term efficacy and safety of low-dose therapeutic drug-monitored (TDM) thioguanine. METHODS: A retrospective evaluation of IBD patients intolerant to conventional thiopurines started on thioguanine from 2017 to 2019 with dosing guided by TDM was conducted. Clinical response was defined for ulcerative colitis (UC) as a reduction of partial Mayo score ≥3 with reduction in rectal bleeding score of at least 1 and a final rectal bleeding subscore of 0-1 at Week 12 of therapy. Crohn disease (CD) response was defined as a reduction of Harvey-Bradshaw index ≥3 (HBI) at Week 12 of therapy. Remission was defined in UC as partial Mayo score of <2 and in CD as HBI score of <5. RESULTS: Forty-six patients were included in the study. The median thioguanine dose was 20 mg/day (standard deviation 7.3; range: 10-40 mg/day) with a median 6-thioguanine nucleotide level of 577 pmol/8 × 108 (interquartile range (IQR) IQR 378.5-878.75) for CD and 677.5 pmol/8 × 108 (IQR 523.25-842.25) for UC. The overall clinical response rate was 62% (13/21), intention to treat (ITT). Maintenance of remission was 76% (19/25, ITT). Thirty-seven percent (17/46) of patients experienced an adverse effect. No early cases of nodular regenerative hyperplasia (NRH) were seen. CONCLUSION: Thioguanine was tolerated well in 63% of patients. A clinical response was seen in 62% of patients, and maintenance of remission was high at 76%. No cases of early NRH were seen. Longer-term follow up is required to ensure safety and to assess durability of response.

Sinusoidal Obstruction Syndrome of the Liver Associated With 6-Mercaptopurine During Maintenance in a Child With T-cell Acute Lymphoblastic Leukemia.

Sinusoidal obstruction syndrome (SOS) of the liver is a complication of chemotherapy most often encountered with hematopoietic stem cell transplant due to high-dose conditioning regimens, but it can also occur with regimens outside of the transplant setting. Mild-to-moderate SOS is a well-described 6-thioguanine toxicity; however, it has rarely been reported as secondary to 6-mercaptopurine, a related thiopurine. This report details a case of a 10-year-old male with T-cell acute lymphoblastic leukemia who developed severe SOS during maintenance therapy with 6-mercaptopurine, and a review of the related literature.

Safety of Thioguanine in Pediatric Inflammatory Bowel Disease: A Multi-Center Case Series.

OBJECTIVES: Thioguanine (TG) has been shown as a safe alternative in adults with inflammatory bowel disease (IBD) who did not tolerate conventional thiopurines [azathioprine (AZA)/mercaptopurine]. However, data in pediatric IBD are scarce. Therefore, we aimed to assess the safety of TG as maintenance therapy. METHODS: A retrospective, multicenter cohort study of children with IBD on TG was performed in the Netherlands. TG-related adverse events (AE) were assessed and listed according to the common terminology criteria for AE. RESULTS: Thirty-six children with IBD (median age 14.5 years) on TG (median dose 15 mg/day) were included in 6 centers. Five AE occurred during follow-up [pancreatitis (grade 3), hepatotoxicity (grade 3) (n = 2), Clostridium difficile infection (grade 2), and abdominal pain (grade 2)]. All patients (n = 8) with a previously AZA-induced pancreatitis did not redevelop pancreatitis on TG. CONCLUSIONS: In pediatric IBD, TG seems a safe alternative in case of AZA-induced pancreatitis. Further research assessing long-term TG-related safety and efficacy is needed.

DNA-Thioguanine Nucleotides as a Marker for Thiopurine Induced Late Leukopenia after Dose Optimizing by NUDT15 C415T in Chinese Patients with IBD.

Thiopurine dose optimization by thiopurine-S-methyltransferase (TPMT) or nudix hydrolase-15 (NUDT15) significantly reduced early leucopenia in Asia. However, it fails to avoid the late incidence (> 2 months). Although laboratory monitoring of 6-thioguanine nucleotides (6TGN) to optimize thiopurine dose was suggested in White patients the exact association between leucopenia and 6TGN was controversial in Asian patients. In the present study, we aimed to explore whether DNA-thioguanine nucleotides (DNA-TGs) in leukocytes, compared with 6TGN in erythrocytes, can be a better biomarker for late leucopenia. This was a prospective, observational study. Patients with inflammatory bowel disease (IBD) prescribed thiopurine from February 2019 to December 2019 were recruited. Thiopurine dose was optimized by NUDT15 C415T (rs116855232). DNA-TG and 6TGN levels were determined at the time of late leucopenia or 2 months after the stable dose was obtained. A total of 308 patients were included. Thiopurine induced late leucopenia (white blood cells < 3.5 × 109 /L) were observed in 43 patients (14.0%), who had significantly higher DNA-TG concentration than those without leucopenia (P = 4.1 × 10-9 , 423.3 (~ 342.2 to 565.7) vs. 270.5 (~ 188.1 to 394.3) fmol/µg DNA). No difference in 6TGN concentrations between leucopenia and non-leucopenia was found. With a DNA-TG threshold of 340.1 fmol/µg DNA, 83.7% of leucopenia cases could be identified. Multivariate analysis showed that DNA-TG was an independent risk factor for late leucopenia. Quantification of DNA-TG, rather than 6TGN, can be applied to gauge thiopurine therapy after NUDT15 screening in Chinese patients with IBD.

Favourable Tolerability and Drug Survival of Tioguanine Versus Methotrexate After Failure of Conventional Thiopurines in Crohn's Disease.

BACKGROUND AND AIMS: Both methotrexate and tioguanine can be considered as treatment options in patients with Crohn's disease after failure of conventional thiopurines. This study aimed to compare tolerability and drug survival of methotrexate and tioguanine therapy after failure of conventional thiopurines in patients with Crohn's disease. METHODS: We conducted a retrospective, multicentre study, including patients with Crohn's disease initiating monotherapy methotrexate or tioguanine after failure [all causes] of conventional thiopurines. Follow-up duration was 104 weeks or until treatment discontinuation. The primary outcome was cumulative therapy discontinuation incidence due to adverse events. Secondary outcomes included total number of [serious] adverse events, and ongoing monotherapy. RESULTS: In total, 219 patients starting either methotrexate [n = 105] or tioguanine [n = 114] were included. In all 65 [29.7%] patients (methotrexate 43.8% [46/105 people], tioguanine 16.7% [19/114 people], p <0.001) discontinued their treatment due to adverse events during follow-up. Median time until discontinuation due to adverse events was 16 weeks (interquartile range [IQR] 7-38, p = 0.812). Serious adverse events were not significantly different. Patients treated with methotrexate experienced adverse events more often [methotrexate 83%, tioguanine 46%, p <0.001]. Total monotherapy drug survival after 104 weeks was 22% for methotrexate and 46% for tioguanine [p <0.001]. CONCLUSIONS: We observed a higher cumulative discontinuation incidence due to adverse events for methotrexate [44%] compared with tioguanine [17%] in Crohn's disease patients after failure of conventional thiopurines. The total adverse events incidence during methotrexate use was higher, whereas serious adverse events incidence was similar. These favourable results for tioguanine treatment may guide the selection of immunosuppressive therapy after failure of conventional thiopurines.

Therapeutic drug monitoring of thiopurines: Effect of reduced 6-thioguanine nucleotide target levels in inflammatory bowel disease patients.

AIMS: The effect of the Dutch nationwide adjustment of reducing 6-thioguanine nucleotide (6-TGN) target values (from 600-1200 to 320-630 pmol/8 × 108 red blood cells [RBC]) on toxicity and clinical outcome of thiopurine treatment in patients with inflammatory bowel disease has not yet been established. Therefore, the authors determined the incidence of toxicity-induced discontinuations and efficacy at both target concentrations. METHODS: This retrospective study was performed in inflammatory bowel disease patients treated with azathioprine or mercaptopurine. Two groups were defined: the former target (FT) group with target concentrations of 600-1200 pmol/8 × 108 RBC and the adjusted target (AT) group with target concentrations of 320-630 pmol/8 × 108 RBC. Patients were followed for maximum 52 weeks or until discontinuation of thiopurine therapy. Data were collected from the local hospital electronic health software of Rijnstate Hospital. RESULTS: In total, 151 patients were included, 76 in the FT group and 75 in the AT group. At week 52, 100 out of 151 patients (66%) of the total population discontinued thiopurine therapy. Forty-eight of the discontinuations were due toxicity (48%). The incidence of toxicity induced discontinuations was 35% in the AT group vs. 47% in the FT group (P = .25). No loss of efficacy was seen in the AT group. CONCLUSION: After reduction of the target range, there was a trend towards fewer toxicity-induced discontinuations, albeit not statistically significant. In addition, this study did not find any indication that the reduction of the target range diminished efficacy.

Two Cases of Veno-occlusive Disease/Sinusoidal Obstruction Syndrome After Thioguanine Treatment for Acute Lymphoblastic Leukemia.

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation conditioning or high-dose chemotherapy. The underlying pathogenesis involves toxic injury to hepatocytes and sinusoidal endothelial cells. Presenting symptoms include ascites, weight gain, hepatomegaly, and hyperbilirubinemia. Severe VOD/SOS with multiorgan failure has a mortality rate of >80% if left untreated. Thioguanine, a chemotherapy drug used to treat acute lymphoblastic leukemia, has been shown to cause VOD/SOS. Here, we describe cases of 2 patients who developed very severe VOD/SOS after starting thioguanine for acute lymphoblastic leukemia; both achieved complete remission with defibrotide and experienced no defibrotide-related adverse events.

Understanding thiopurine methyltransferase polymorphisms for the targeted treatment of hematologic malignancies.

INTRODUCTION: Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines (mercaptopurine (MP) and tioguanine (TG)), chemotherapeutic agents used in the treatment of acute lymphoblastic leukemia (ALL). Polymorphisms in TPMT gene encode diminished activity enzyme, enhancing accumulation of active metabolites, and partially explaining the inter-individual differences in patients' clinical response. AREAS COVERED: This review gives an overview on TPMT gene and function, and discusses the pharmacogenomic implications of TPMT variants in the prevention of severe thiopurine-induced hematological toxicities and the less known implication on TG-induced sinusoidal obstruction syndrome. Additional genetic and non-genetic factors impairing TPMT activity are considered. Literature search was done in PubMed for English articles published since1990, and on PharmGKB. EXPERT OPINION: To titrate thiopurines safely and effectively, achieve the right degree of lymphotoxic effect and avoid excessive myelosuppression, the optimal management will combine a preemptive TPMT genotyping to establish a safe initial dose with a close phenotypic monitoring of TPMT activity and/or of active metabolites during long-term treatment. Compared to current ALL protocols, replacement of TG by MP during reinduction phase in TPMT heterozygotes and novel individualized TG regimens in maintenance for TPMT wild-type subjects could be investigated to improve outcomes while avoiding risk of severe hepatotoxicity.

Efficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom.

BACKGROUND: Thioguanine (TG) is a thiopurine which has been used for patients with inflammatory bowel disease (IBD), who have failed azathioprine (AZA) or mercaptopurine (MP) due to adverse events or suboptimal response. Its widespread use has been hampered due to concerns about nodular regenerative hyperplasia (NRH) of the liver. The aim of this study was to investigate the long-term efficacy and safety of low-dose TG therapy in IBD patients failing AZA and MP. METHODS: A retrospective multicentre study was performed in IBD patients who failed prior treatment with conventional thiopurines with or without following immunomodulation (thiopurine-allopurinol, biologicals, methotrexate, tacrolimus) and were subsequently treated with TG as rescue monotherapy between 2003 and 2019 at three hospitals in the United Kingdom. Clinical response, adverse events, laboratory results, imaging and liver biopsies were retrospectively collected. RESULTS: A total of 193 patients (57% female and 64% Crohn's disease) were included, with a median daily TG dose of 20 mg (range: 20-40 mg), a median treatment duration of 23 months (IQR 10-47) and a median follow-up of 36 months (IQR 22-53). The clinical response rate at 12 months was 65 and 54% remained on TG until the end of follow-up. Adverse events consisted primarily of elevated liver tests (6%), myelotoxicity (7%) and rash (5%). NRH was histologically diagnosed in two patients and two other patients (1%) developed non-cirrhotic portal hypertension. The median 6-TGN and TPMT levels were 953 pmol/8 × 105 RBC (IQR 145-1761) and 47 mu/L (IQR 34.5-96). CONCLUSIONS: Long-term follow-up suggests that TG can be an effective and well-tolerated therapy in more than half of difficult-to-treat and multi-therapy failing IBD patients. Findings of this study indicate that TG can be used safely and the occurrence of hepatotoxicity was low. The incidence rate of NRH was within the background incidence.

Clinical efficacy and safety of 6-thioguanine in the treatment of childhood acute lymphoblastic leukemia: A protocol for systematic review and meta-analysis.

BACKGROUND: To systematic review the efficacy and safety of 6-thioguanine (6-TG) in the substitute of 6-mercaptopurine (6-MP) in the treatment for patients with childhood acute lymphoblastic leukemia (ALL) in the maintenance phase, and to explore its clinical application value. It provides theoretical guidance for the maintenance treatment of ALL in children from the perspective of evidence-based medicine. METHODS: By means of computer retrieval, Chinese databases were searched: Chinese Biomedical Database (CBM), China national knowledge internet (CNKI), Chongqing Weipu Database (VIP), and Wanfang Database; Foreign databases: PubMed, The Cochrane Library, Embase, and Web of Science were applied to find out randomized controlled trial (RCT) for 6-TG in childhood acute lymphoblastic leukemia. By manual retrieval, documents without electronic edition and related conference papers were retrieved. The retrieval time ranges from the beginning of the establishment of the databases to September 1st, 2019. According to the inclusion, and exclusion criteria by 3 researchers, the literature screening, data extraction, and research methodological quality evaluation were completed. RevMan 5.3 software was applied to evaluate the quality of the included literature, and Stata 12.0 software was used to conduct meta-analysis of the outcome indicators of the included literature. RESULTS: This study systematically evaluated the efficacy and safety of 6-TG in the substitute of 6-MP as a maintenance drug for childhood acute lymphoblastic leukemia. Through the key outcome indicators, this study is expected to draw a scientific, practical conclusion for 6-TG in the treatment of childhood acute lymphoblastic leukemia. This conclusion will provide evidence-based medical direction for clinical treatment. CONCLUSION: The efficacy and safety of 6-TG in the substitute of 6-MP in the maintenance treatment of childhood acute lymphoblastic leukemia will be confirmed through this study. The conclusions will be published in relevant academic journals. REGISTRATION: PROSPERO (registration number is CRD42020150466).

A comparative analysis of tioguanine versus low-dose thiopurines combined with allopurinol in inflammatory bowel disease patients.

BACKGROUND: Both tioguanine and low-dose thiopurines combined with allopurinol (LDTA) can be considered for the treatment of inflammatory bowel disease (IBD) when conventional thiopurines fail due to adverse events. AIM: To compare the safety of tioguanine and LDTA in IBD patients. METHODS: Inflammatory bowel disease patients who failed conventional thiopurines due to adverse events and initiated LDTA in standard care were identified in the prospective ICC Registry. IBD patients who failed conventional thiopurines due to adverse events and initiated tioguanine were enrolled in three university hospitals. Patients on concomitant biologicals were excluded. The primary outcome was discontinuation of therapy due to adverse events. Secondary outcomes included: safety outcomes and surgery-, biological- and corticosteroid-free clinical remission (physician global assessment = 0) after 104 weeks. Both multiple logistic regression and propensity score matching were used to correct for confounders. RESULTS: In total, 182 IBD patients treated with tioguanine (n = 94) or LDTA (n = 88) were included with a median follow-up of 104 weeks (IQR 91-104). Of these, 19% (tioguanine: 20%, LDTA: 18%) of patients discontinued therapy due to adverse events. After adjusting for confounders, there were no differences in terms of discontinuation rate due to adverse events (OR 0.50, 95% CI 0.15-1.68, P = 0.26), adverse events (OR 0.89, 95% CI 0.44-1.81, P = 0.75), infections (OR 1.05, 95% CI 0.40-2.73, P = 0.93), hospitalisations (OR 2.00, 95% CI 0.64-6.23, P = 0.23) or clinical remission (OR 0.74, 95%CI 0.33-1.68, P = 0.48). All results are comparable with the propensity score matched cohort. CONCLUSION: Nineteen percent of IBD patients with prior failure to conventional thiopurines due to adverse events discontinued therapy with tioguanine or LDTA due to adverse events. Either therapy may be considered before escalating to biological therapy.

The continuous rediscovery and the benefit-risk ratio of thioguanine, a comprehensive review.

Introduction: In the 1950s, thioguanine (TG), a thiopurine-derivative together with azathioprine (AZA) and mercaptopurine (MP), were developed for the treatment of childhood leukemia. Over the years, the use of TG was also explored for other, mainly immune-mediated and inflammatory, diseases such as in the field of dermatology and rheumatology (e.g. psoriasis, systemic lupus erythematosus (SLE)) and gastroenterology and hepatology (e.g. inflammatory bowel diseases (IBD), autoimmune hepatitis).Areas covered: This review provides a comprehensive overview of all the clinical uses of TG and describes its mechanism of action, pharmacokinetic/pharmacodynamic features, and toxicity.Expert opinion: Thioguanine has shown beneficial clinical effects in hematological (particularly leukemia) and several immune-inflammatory diseases including psoriasis, SLE, polycythemia vera, Churg-Strauss syndrome, IBD, collagenous sprue, refractory celiac disease, and autoimmune hepatitis. Thioguanine is not effective in treating solid-cancers. At relatively low dosages, i.e. 0.2- 0.3mg/kg/day or 20 mg/day, TG has a favorable risk-benefit ratio and is a safe and effective drug in the long-term treatment of amongst other IBD patients. Thioguanine toxicity, especially myelotoxicity, and hepatotoxicity, including nodular regenerative hyperplasia (NRH) of the liver, is limited when dosed adequately. The occurrence of NRH appears dose-dependent and has been especially described during high dose TG above 40 mg/day.

Ocular hemorrhage secondary to thioguanine-associated veno-occlusive disease in a child with acute lymphoblastic leukemia in delayed intensification.

Hepatic VOD is a potentially fatal complication during stem cell transplantation and is rarely seen in the non-transplant setting. We report the case of a five-year-old boy who presented with visual complaints during delayed intensification phase of treatment for ALL. He was found to have bilateral retinal hemorrhages associated with profound thrombocytopenia due to chemotherapy. VOD was diagnosed based on EBMT criteria and was managed with supportive care. Despite resolution of VOD, his vision progressively deteriorated and resulted in blindness. This case highlights the significance of close monitoring of ALL patients in delayed intensification when they are at risk for developing VOD, the importance of refractory thrombocytopenia as a diagnostic feature and the potential for VOD to manifest with intraocular bleeding.