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.