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The treatment of acute lymphoblastic leukemia (ALL) is frequently complicated by toxicity, including venous thromboembolism (VTE) affecting roughly 8% of patients. VTE can lead to post-thrombotic syndrome (PTS), a group of signs and symptoms developed as a complication to deep venous thrombosis (DVT), imposing risk of permanent disability and reduced quality of life (QoL). PTS prevalence ranges from 0% to 70%, reflecting very heterogenous cohorts and assessment tools. We aimed to estimate sequelae, including PTS and QoL in children and adults (<45 years old) who had a DVT during ALL treatment. PTS and QoL scores were obtained through use of Villalta and Modified Villalta Scale, PedsQL, and Short Form-36 questionnaires. The cohort comprised 20 children (<18 years) and seven adults (median age: 12.9 years, range: 2-44 years) at the time of DVT diagnosis. In total, 25 ALL survivors underwent PTS examination. The examination took place when survivors were 7-48 years (median age: 20.3 years, median follow-up time 6.8 years). QoL was assessed correlating cases with three matching ALL survivors without VTE. Two adults (15.4%) showed mild or moderate PTS. Eight children (66.7%) were diagnosed with mild PTS, while three cases had collaterals as sole symptoms. Pain or symptoms affecting daily life were reported by 16%. No difference in QoL was found (p = .9). This study underscores the need for comprehensive population-based investigations with validation of PTS instruments in ALL survivors., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Asparaginase has played a crucial role in the improvement of survival in children with acute lymphoblastic leukaemia (ALL), which is the commonest cancer among children. Survival rates have steadily increased over decades since the introduction of asparaginase to ALL therapy, and overall survival rates reach 90% with the best contemporary protocols. Currently, polyethylene glycolated native Escherichia coli-derived L-asparaginase (PEG-asparaginase) is the preferred first-line asparaginase preparation. Besides its clinical benefits, PEG-asparaginase is well known for severe toxicities. Agreement on the optimal dose, treatment duration, and frequency of administration has never been reached among clinicians., Objectives: Primary objective To assess the effect of the number of PEG-asparaginase doses on survival and relapse in children and adolescents with ALL. Secondary objectives To assess the association between the number of doses of PEG-asparaginase and asparaginase-associated toxicities (e.g. hypersensitivity, thromboembolism, pancreatitis and osteonecrosis). To undertake a network meta-analysis at dose-level in order to generate rankings of the number of doses of PEG-asparaginase used in the treatment for ALL, according to their benefits (survival and relapse) and harms (toxicity)., Search Methods: We searched CENTRAL, PubMed, Embase, Web of Science databases and three trials registers in November 2021, together with reference checking, citation searching and contact with study authors to identify additional studies., Selection Criteria: We included randomised controlled trials (RCTs) comparing different PEG-asparaginase treatment regimens in children and adolescents (< 18 years of age) with first-line ALL treated with multiagent chemotherapy including PEG-asparaginase., Data Collection and Analysis: Using a standardised data collection form, two review authors independently screened and selected studies, extracted data, assessed risk of bias for each outcome using a standardised tool (RoB 2.0) and assessed the certainty of evidence for each outcome using the GRADE approach. Primary outcomes included overall survival, event-free survival and leukaemic relapse. Secondary outcomes included asparaginase-associated toxicities (hypersensitivity, thromboembolism, pancreatitis, sinusoidal obstruction syndrome and osteonecrosis as well as overall asparaginase-associated toxicity). We conducted the review and performed the analyses in accordance with the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions., Main Results: We included three RCTs in the review, and identified an additional four ongoing studies. We judged outcomes of two RCTs to be at low risk of bias in all the Cochrane risk of bias (RoB 2) domains. We rated the remaining study as having some concerns regarding bias. Due to concerns about imprecision, we rated all outcomes as having low- to moderate-certainty evidence.  One study compared intermittent PEG-asparaginase treatment (eight doses of PEG-asparaginase, 1000 IU/m 2 , intramuscular (IM) administration) versus continuous PEG-asparaginase treatment (15 doses of PEG-asparaginase, 1000 IU/m 2 , IM) in 625 participants with non-high risk ALL aged 1.0 to 17.9 years. We found that treatment with eight doses probably results in little to no difference in event-free survival compared to treatment with 15 doses (RR 1.01, 95% CI 0.97 to 1.06; moderate-certainty evidence). Compared to treatment with 15 doses, treatment with eight doses may result in either no difference or a slight reduction in hypersensitivity (RR 0.64, 95% CI 0.21 to 1.93; low-certainty evidence), thromboembolism (RR 0.55, 95% CI 0.22 to 1.36; low-certainty evidence) or osteonecrosis (RR 0.68, 95% CI 0.35 to 1.32; low-certainty evidence). Furthermore, we found that treatment with eight doses probably reduces pancreatitis (RR 0.31, 95% CI 0.12 to 0.75; moderate-certainty evidence) and asparaginase-associated toxicity (RR 0.53, 95% CI 0.35 to 0.78; moderate-certainty evidence) compared to treatment with 15 doses. One study compared low-risk standard treatment with additional PEG-asparaginase (six doses, 2500 IU/m 2 , IM) versus low-risk standard treatment (two doses, 2500 IU/m 2 , IM) in 1857 participants aged one to nine years old with standard low-risk ALL. We found that, compared to treatment with two doses, treatment with six doses probably results in little to no difference in overall survival (RR 0.99, 95% CI 0.98 to 1.00; moderate-certainty evidence) and event-free survival (RR 1.01, 95% CI 0.99 to 1.04; moderate-certainty evidence), and may result in either no difference or a slight increase in osteonecrosis (RR 1.65, 95% CI 0.91 to 3.00; low-certainty evidence). Furthermore, we found that treatment with six doses probably increases hypersensitivity (RR 12.05, 95% CI 5.27 to 27.58; moderate-certainty evidence), pancreatitis (RR 4.84, 95% CI 2.15 to 10.85; moderate-certainty evidence) and asparaginase-associated toxicity (RR 4.49, 95% CI 3.05 to 6.59; moderate-certainty evidence) compared to treatment with two doses. One trial compared calaspargase (11 doses, 2500 IU/m 2 , intravenous (IV)) versus PEG-asparaginase (16 doses, 2500 IU/m 2 , IV) in 239 participants aged one to 21 years with standard- and high-risk ALL and lymphoblastic lymphoma. We found that treatment with 11 doses of calaspargase probably results in little to no difference in event-free survival compared to treatment with 16 doses of PEG-asparaginase (RR 1.06, 95% CI 0.97 to 1.16; moderate-certainty evidence). However, treatment with 11 doses of calaspargase probably reduces leukaemic relapse compared to treatment with 16 doses of PEG-asparaginase (RR 0.32, 95% CI 0.12 to 0.83; moderate-certainty evidence). Furthermore, we found that treatment with 11 doses of calaspargase results in either no difference or a slight reduction in hypersensitivity (RR 1.17, 95% CI 0.64 to 2.13; low-certainty evidence), pancreatitis (RR 0.85, 95% CI 0.47 to 1.52; low-certainty evidence), thromboembolism (RR 0.83, 95% CI 0.48 to 1.42; low-certainty evidence), osteonecrosis (RR 0.63, 95% CI 0.15 to 2.56; low-certainty evidence) and asparaginase-associated toxicity (RR 1.00, 95% CI 0.71 to 1.40; low-certainty evidence) compared to treatment with 16 doses of PEG-asparaginase., Authors' Conclusions: We were not able to conduct a network meta-analysis, and could not draw clear conclusions because it was not possible to rank the interventions. Overall, we found that different numbers of doses of PEG-asparaginase probably result in little to no difference in event-free survival across all studies. In two studies, we found that a higher number of PEG-asparaginase doses probably increases pancreatitis and asparaginase-associated toxicities., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

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., Competing Interests: Birgitte Klug Albertsen: Sponsor of the investigator‐initiated trial NOR‐GRASPALL2016. Speaker and/or Advisory Board Honoraria from Erytech (2020) and Servier (2021). Kirsten Brunsvig Jarvis: Honoraria from Bayer (2021). Sonata Trakymiene: Honoraria from Bayer HealthCare, Novo Nordisk, Octapharma, Roche, and Takeda, served on advisory board committees for Novo Nordisk and Roche. Remaining authors declare they have no conflicts of interest., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Asparaginase is essential in treating acute lymphoblastic leukaemia (ALL). Asparaginase-related hypersensitivity causes treatment discontinuation, which is associated with decreased event-free survival. To continue asparaginase treatment after hypersensitivity, a formulation of asparaginase encapsulated in erythrocytes (eryaspase) was developed. In NOR-GRASPALL 2016 (NCT03267030) the safety and efficacy of eryaspase was evaluated in 55 patients (aged 1-45 years; median: 6.1 years) with non-high-risk ALL and hypersensitivity to asparaginase conjugated with polyethylene glycol (PEG-asparaginase). Eryaspase (150 u/kg) was scheduled to complete the intended course of asparaginase (1-7 doses) in two Nordic/Baltic treatment protocols. Forty-nine (96.1%) patients had asparaginase enzyme activity (AEA) ≥100 iu/l 14 ± 2 days after the first eryaspase infusion [median AEA 511 iu/l; interquartile range (IQR), 291-780], whereas six of nine (66.7%) patients had AEA ≥100 iu/l 14 ± 2 days after the fourth infusion (median AEA 932 iu/l; IQR, 496-163). The mean terminal half-life of eryaspase following the first infusion was 15.3 ± 15.5 days. Few asparaginase-related adverse events were reported; five patients (9.1%) developed clinical allergy associated with enzyme inactivation. Replacement therapy was successfully completed in 50 patients (90.9%). Eryaspase was well tolerated, and most patients had AEA levels above the therapeutic target after the first infusion. The half-life of eryaspase confirmed that a 2-week schedule is appropriate., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Endothelial dysfunction has not previously been investigated as a thrombogenic risk factor among patients with acute lymphoblastic leukemia (ALL), known to be at high risk of thromboembolism. We retrospectively explored the association between three circulating biomarkers of endothelial dysfunction (thrombomodulin, syndecan-1, VEGFR-1) measured in prospectively collected blood samples and risk of thromboembolism in 55 cases and 165 time-matched controls, treated according to the NOPHO ALL2008 protocol. In age-, sex-, and risk group-adjusted analysis, increasing levels of thrombomodulin and VEGFR-1 were independently associated with increased odds of developing thromboembolism (OR 1.37 per 1 ng/mL [95% CI 1.20‒1.56, P < 0.0001] and OR 1.21 per 100 pg/mL [95% CI 1.02‒1.21, P = 0.005], respectively). These associations remained significant when including only samples drawn >30 days before thromboembolic diagnosis. Thrombomodulin levels were on average 3.2 ng/mL (95% CI 2.6-8.2 ng/mL) higher in samples with measurable asparaginase activity (P < 0.0001). Among single nucleotide variants located in or neighboring coding genes for the three biomarkers, none were significantly associated with odds of thromboembolism. If results are validated in another cohort, thrombomodulin and VEGFR-1 could serve as predictive biomarkers, identifying patients in need of preemptive antithrombotic prophylaxis., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Asparaginase treatment is a mainstay in contemporary treatment of acute lymphoblastic leukemia (ALL), but substantial asparaginase-related toxicity may lead to jeopardized protocol compliance and compromises survival. We investigated the association between risk of asparaginase-associated toxicities (AspTox) and asparaginase enzyme activity (AEA) levels in 1155 children aged 1.0 to 17.9 years, diagnosed with ALL between July 2008 and March 2016, and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. Patients with ≥2 blood samples for AEA measurement drawn 14 ± 2 days after asparaginase administration were included (6944 trough values). AEA was measurable (or >0 IU/L) in 955 patients, whereas 200 patients (17.3%) had asparaginase inactivation and few AspTox recorded. A time-dependent multiple Cox model of time to any first asparaginase-associated toxicity adjusted for sex and age was used. For patients with measurable AEA, we found a hazard ratio (HR) of 1.17 per 100 IU/L increase in median AEA (95% confidence interval [CI], 0.98-1.41; P = .09). For pancreatitis, thromboembolism, and osteonecrosis, the HRs were 1.40 (95% CI, 1.12-1.75; P = .002), 0.99 (95% CI, 0.70-1.40; P = .96), and 1.36 (95% CI, 1.04-1.77; P = .02) per 100 IU/L increase in median AEA, respectively. No significant decrease in the risk of leukemic relapse was found: HR 0.88 per 100 IU/L increase in AEA (95% CI, 0.66-1.16; P = .35). In conclusion, these results emphasize that overall AspTox and relapse are not associated with AEA levels, yet the risk of pancreatitis and osteonecrosis increases with increasing AEA levels., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The risk of venous thromboembolism is increased in adults and enhanced by asparaginase-based chemotherapy, and venous thromboembolism introduces a secondary risk of treatment delay and premature discontinuation of key anti-leukaemic agents, potentially compromising survival. Yet, the trade-off between benefits and harms of primary thromboprophylaxis in adults with acute lymphoblastic leukaemia (ALL) treated according to asparaginase-based regimens is uncertain.  OBJECTIVES: The primary objectives were to assess the benefits and harms of primary thromboprophylaxis for first-time symptomatic venous thromboembolism in adults with ALL receiving asparaginase-based therapy compared with placebo or no thromboprophylaxis. The secondary objectives were to compare the benefits and harms of different groups of primary systemic thromboprophylaxis by stratifying the main results per type of drug (heparins, vitamin K antagonists, synthetic pentasaccharides, parenteral direct thrombin inhibitors, direct oral anticoagulants, and blood-derived products for antithrombin substitution)., Search Methods: We conducted a comprehensive literature search on 02 June 2020, with no language restrictions, including (1) electronic searches of Pubmed/MEDLINE; Embase/Ovid; Scopus/Elsevier; Web of Science Core Collection/Clarivate Analytics; and Cochrane Central Register of Controlled Trials (CENTRAL) and (2) handsearches of (i) reference lists of identified studies and related reviews; (ii) clinical trials registries (ClinicalTrials.gov registry; the International Standard Randomized Controlled Trial Number (ISRCTN) registry; the World Health Organisation's International Clinical Trials Registry Platform (ICTRP); and pharmaceutical manufacturers of asparaginase including Servier, Takeda, Jazz Pharmaceuticals, Ohara Pharmaceuticals, and Kyowa Pharmaceuticals), and (iii) conference proceedings (from the annual meetings of the American Society of Hematology (ASH); the European Haematology Association (EHA); the American Society of Clinical Oncology (ASCO); and the International Society on Thrombosis and Haemostasis (ISTH)). We conducted all searches from 1970 (the time of introduction of asparaginase in ALL treatment). We contacted the authors of relevant studies to identify any unpublished material, missing data, or information regarding ongoing studies., Selection Criteria: Randomised controlled trials (RCTs); including quasi-randomised, controlled clinical, cross-over, and cluster-randomised trial designs) comparing any parenteral/oral preemptive anticoagulant or mechanical intervention with placebo or no thromboprophylaxis, or comparing two different pre-emptive anticoagulant interventions in adults aged at least 18 years with ALL treated according to asparaginase-based chemotherapy regimens. For the description of harms, non-randomised observational studies with a control group were eligible for inclusion.  DATA COLLECTION AND ANALYSIS: Using a standardised data collection form, two review authors independently screened and selected studies, extracted data, assessed risk of bias for each outcome using standardised tools (RoB 2.0 tool for RCTs and ROBINS-I tool for non-randomised studies) and the certainty of evidence for each outcome using the GRADE approach. Primary outcomes included first-time symptomatic venous thromboembolism, all-cause mortality, and major bleeding. Secondary outcomes included asymptomatic venous thromboembolism, venous thromboembolism-related mortality, adverse events (i.e. clinically relevant non-major bleeding and heparin-induced thrombocytopenia for trials using heparins), and quality of life. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. For non-randomised studies, we evaluated all studies (including studies judged to be at critical risk of bias in at least one of the ROBINS-I domains) in a sensitivity analysis exploring confounding.  MAIN RESULTS: We identified 23 non-randomised studies that met the inclusion criteria of this review, of which 10 studies provided no outcome data for adults with ALL. We included the remaining 13 studies in the 'Risk of bias' assessment, in which we identified invalid control group definition in two studies and judged outcomes of nine studies to be at critical risk of bias in at least one of the ROBINS-I domains and outcomes of two studies at serious risk of bias. We did not assess the benefits of thromboprophylaxis, as no RCTs were included. In the main descriptive analysis of harms, we included two retrospective non-randomised studies with outcomes judged to be at serious risk of bias. One study evaluated antithrombin concentrates compared to no antithrombin concentrates. We are uncertain whether antithrombin concentrates have an effect on all-cause mortality (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.26 to 1.19 (intention-to-treat analysis); one study, 40 participants; very low certainty of evidence). We are uncertain whether antithrombin concentrates have an effect on venous thromboembolism-related mortality (RR 0.10, 95% CI 0.01 to 1.94 (intention-to-treat analysis); one study, 40 participants; very low certainty of evidence). We do not know whether antithrombin concentrates have an effect on major bleeding, clinically relevant non-major bleeding, and quality of life in adults with ALL treated with asparaginase-based chemotherapy, as data were insufficient. The remaining study (224 participants) evaluated prophylaxis with low-molecular-weight heparin versus no prophylaxis. However, this study reported insufficient data regarding harms including all-cause mortality, major bleeding, venous thromboembolism-related mortality, clinically relevant non-major bleeding, heparin-induced thrombocytopenia, and quality of life. In the sensitivity analysis of harms, exploring the effect of confounding, we also included nine non-randomised studies with outcomes judged to be at critical risk of bias primarily due to uncontrolled confounding. Three studies (179 participants) evaluated the effect of antithrombin concentrates and six studies (1224 participants) evaluated the effect of prophylaxis with different types of heparins. When analysing all-cause mortality; venous thromboembolism-related mortality; and major bleeding (studies of heparin only) including all studies with extractable outcomes for each comparison (antithrombin and low-molecular-weight heparin), we observed small study sizes; few events; wide CIs crossing the line of no effect; and substantial heterogeneity by visual inspection of the forest plots. Although the observed heterogeneity could arise through the inclusion of a small number of studies with differences in participants; interventions; and outcome assessments, the likelihood that bias due to uncontrolled confounding was the cause of heterogeneity is inevitable. Subgroup analyses were not possible due to insufficient data.  AUTHORS' CONCLUSIONS: We do not know from the currently available evidence, if thromboprophylaxis used for adults with ALL treated according to asparaginase-based regimens is associated with clinically appreciable benefits and acceptable harms. The existing research on this question is solely of non-randomised design, seriously to critically confounded, and underpowered with substantial imprecision. Any estimates of effect based on the existing insufficient evidence is very uncertain and is likely to change with future research., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Stringent complete remission (sCR) of acute myeloid leukemia is defined as normal hematopoiesis after therapy. Less sCR, including non-sCR, was introduced as insufficient blood platelet, neutrophil, or erythrocyte recovery. These latter characteristics were defined retrospectively as postremission transfusion dependency and were suggested to be of prognostic value. In the present report, we evaluated the prognostic impact of achieving sCR and non-sCR in the Danish National Acute Leukaemia Registry, including 769 patients registered with classical CR (ie, <5% blasts in the postinduction bone marrow analysis). Individual patients were classified as having sCR (n = 360; 46.8%) or non-sCR (n = 409; 53.2%) based on data from our national laboratory and transfusion databases. Survival analysis revealed that patients achieving sCR had superior overall survival (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.10-1.64) as well as relapse-free survival (HR, 1.25; 95% CI, 1.03-1.51) compared with those with non-sCR after adjusting for covariates. Cox regression analysis regarding the impact of the stringent criteria for blood cell recovery identified these as significant and independent variables. In conclusion, this real-life register study supports the international criteria for response evaluation on prognosis and, most importantly, documents each of the 3 lineage recovery criteria as contributing independently., (© 2018 by The American Society of Hematology.)

A small group of children with acute lymphoblastic leukemia (ALL) have a preleukemic phase of pancytopenia followed by a period of spontaneous remission before the diagnosis (pre-ALL). A 6-year-old girl presented with pancytopenia, fever, and myelodysplasia. Following transient remission pre-B ALL was diagnosed 14 months later. Clonal B-lineage blasts at the period of pancytopenia were identified retrospectively. The interval between pre-ALL and ALL-diagnosis was longer than previously reported. The infection was clinically severe and might have induced a significant endogenous corticosteroids production resulting in the long-lasting remission. The case supports the adrenal and the Coley's toxin hypothesis in leukemogenesis.