Review question
How much asparaginase, a key drug in the treatment of the blood cancer acute lymphoblastic leukaemia (ALL), is optimal to ensure the best possible survival while minimising asparaginase-related toxicities?
Background
ALL is a subtype of blood cancer arising from malignant transformation of immature white blood cells of lymphoid origin. ALL is the commonest childhood cancer. Use of the anti-leukaemic medicine asparaginase has been of crucial importance for the advancement of the treatment of childhood ALL and has led to significantly improved survival over time. Asparaginase is a cornerstone in the treatment of ALL. The most used preparation is PEG-asparaginase. Although the benefits from asparaginase are high, the drug has been linked to many severe toxicities. Agreement on optimal dose of PEG-asparaginase has never been reached.
What did we do?
We searched for all currently available trials in childhood ALL that compared different PEG-asparaginase treatments. We looked at how the number of PEG-asparaginase doses affected survival and the risk of toxicities associated with asparaginase treatment. We included three trials in the review, which compared three different PEG-asparaginase treatments. As the trials had many differences, it was not possible to combine them into an overall analysis, and we have summarised the trials separately.
What did we find?
The three trials included the following comparisons:
(i) intermittent PEG-asparaginase treatment (eight doses of PEG-asparaginase, 1000 IU/m2) compared to continuous PEG-asparaginase treatment (15 doses of PEG-asparaginase, 1000 IU/m2) in 631 children with non-high-risk ALL, aged one to 17.9 years;
(ii) low-risk standard treatment with additional PEG-asparaginase (six doses, 2500 IU/m2) compared to low-risk standard treatment (two doses, 2500 IU/m2) in 1857 children aged one to nine years with standard low-risk ALL; and
(iii) a subtype of PEG-asparaginase called calaspargase (11 doses, 2500 IU/m2) compared to PEG-asparaginase (16 doses, 2500 IU/m2) in 239 people with standard- and high-risk ALL, aged one to 21 years.
Main results
We were not able to draw any clear conclusions because we were not able to combine the results of the studies in any analyses. However, the three studies showed that there was probably little to no difference in survival estimates when different PEG-asparaginase treatments were compared. Two studies found that there was probably an increased risk of overall toxicity and pancreatitis in people given the most intensive asparaginase treatment.
Limitations of the evidence
We only have limited or moderate confidence in the evidence because deaths and toxic side effects were rare, so there was uncertainty in the findings. None of the included trials had important design limitations, meaning that the trials were conducted in a way that likely did not skew the results.
How up to date is this evidence?
The evidence is up to date to November 2021.
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.
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.
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).
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.
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.
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.
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.