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Abstract Cerebral sinovenous thrombosis (CSVT) is a serious complication during asparaginase therapy in patients with acute lymphoblastic leukaemia (ALL). We identified 46 patients with CSVT among 2651 patients (1‒45 years) treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2008 and 2018. CSVT cases were prospectively registered in the NOPHO database with retrospective updates. We examined the frequency of asparaginase re‐exposure after CSVT, potential factors associated with asparaginase truncation, and sequelae after CSVT. This work was supported by the Danish Cancer Society and the Danish Childhood Cancer Foundation. The 2.5‐year cumulative incidence of CSVT was 1.9% (95% confidence interval 1.4%–2.5%). The majority of patients (74%, n = 31) were re‐exposed to asparaginase (with low‐molecular‐weight heparin coverage), one of whom had a second CSVT, without neurological sequelae. Patients re‐exposed to asparaginase were earlier in ALL treatment and lacked more asparaginase doses than non‐re‐exposed patients at CSVT diagnosis (median 50 vs. 81 days, p = 0.03; mean 11.2 vs. 8.4 asparaginase doses, p = 0.04). No other examined factors had an impact on asparaginase re‐exposure. At the last follow‐up (median 4.5 years after CSVT), 61% of patients had normal neurological status, and 57% had complete recanalisation of CSVT, with no significant difference between patients re‐exposed and non‐re‐exposed to asparaginase. Our results indicate that re‐exposure to asparaginase is safe after CSVT during anticoagulation.

Abstract Background Pulmonary embolism (PE) is a serious complication of acute lymphoblastic leukemia (ALL). We examined the cumulative incidence and clinical presentation of PE in a well‐defined cohort of patients with ALL aged 1‐45 years treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. Methods As part of the mandatory toxicity reporting of NOPHO ALL2008, thromboembolism including PE was reported consecutively. The cumulative incidence of first‐time PE was calculated using the Aalen‐Johansen estimator during a 2.5‐year period from ALL diagnosis. We used Fisher’s exact test to examine categorical variables and Cox logistic regression to estimate hazard ratios (HRs) for PE. Results PE was diagnosed in 32 of 1685 patients. The 2.5‐year cumulative incidence of first‐time PE increased with age: 0.43% (95% CI, 0.18‐1.03) in children aged 1‐9 years, 3.28% (95% CI, 1.72‐6.22) in children aged 10‐17 years, and 7.22% (95% CI, 4.61‐11.21) in adults aged 18‐45 years. The majority of PEs, 78% (25/32), occurred during asparaginase treatment. HRs adjusted for age and sex were associated with male sex (HR, 2.4; 95% CI, 1.0‐5.6) and older age (10‐17 years: HR 7.5; 95% CI, 2.5‐22.2), 18‐45 years: HR, 16.5; 95% CI, 6.1‐44.5). In two‐thirds of the patients (63%; 17/27), PE and its treatment had no impact on the administered doses of asparaginase. PE‐associated 30‐day mortality was 9.4% (95% CI, 1.9‐25.0). Conclusions Awareness of PE is warranted during ALL treatment. Larger multicenter studies are needed to examine predictors of PE in ALL.

Maintenance therapy containing methotrexate and 6-mercapto - purine 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- mercapto purine, we added low-dose 6-thioguanine to methotrexate/6- mercapto purine 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/m2/day, maximum: 12.5 mg/m2/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/m2/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/mg DNA higher [95% confidence interval: 160-341; P

BackgroundThe 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.ObjectivesTo assess the incidence of hepatotoxicity in patients treated with 6TG, and to explore if a safe dose of continuous 6TG can be established.Data sourcesDatabases, conference proceedings, and reference lists of included studies were systematically searched for 6TG and synonyms from 1998-2018.MethodsWe 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 conclusionsWe 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.