PEG-asparaginase treatment regimens for acute lymphoblastic leukaemia in children: a network meta-analysis.

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/m2, intramuscular (IM) administration) versus continuous PEG-asparaginase treatment (15 doses of PEG-asparaginase, 1000 IU/m2, 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/m2, IM) versus low-risk standard treatment (two doses, 2500 IU/m2, 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/m2, intravenous (IV)) versus PEG-asparaginase (16 doses, 2500 IU/m2, 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.

Prophylaxis of thromboembolism during therapy with asparaginase in adults with acute lymphoblastic leukaemia.

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.

Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia: Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age.

PURPOSE: Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored. PATIENTS AND METHODS: We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. RESULTS: Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse. CONCLUSION: Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse.