Page 56 - Haematologica Vol. 110 - January 2025

ARTICLE - IVIG prophylaxis in pediatric ALL
K.A. Thus et al.
numbers of B cells, declining serum immunoglobulin (IgG) levels and low specific antibody levels.5,6 Theoretically, the increased risk of infections could be partially overcome by raising the low IgG levels with supplementary intravenous immunoglobulins (IVIG).
In patients with primary immunodeficiency leading to agammaglobulinemia, prophylactic administration of IVIG has been shown to be effective in preventing infections.7 In adults, it has been demonstrated that IVIG prophylax- is can reduce the number of infections in patients with lymphoproliferative diseases with hypogammaglobulin- emia.8,9 Currently, it is unknown whether prophylactic administration of IVIG could prevent infections during ALL treatment. Since it is an expensive treatment and its administration can lead to adverse events, the value of IVIG for infection prevention during ALL treatment needs to be established.
The trial reported here investigated the role of IVIG pro- phylaxis in children with newly diagnosed ALL, treated according to the DCOG ALL-11 protocol. It is the first mul- ticenter, randomized trial investigating the effect of IVIG in patients with ALL on number of admissions for fever, blood culture results, adaptations in chemotherapy, and relapse risk.
Methods
Trial design
This multicenter, open-label, randomized trial was a sub- trial of the Dutch multicenter ALL study (DCOG ALL-11), described in detail in the trial register (trial registration number: EudraCT 2012-000067-25, NL3227 [clinicaltrial- register.nl]) and by Pieters et al.3 In this IVIG subtrial, per- formed across six centers in the Netherlands (described in the Online Supplementary Data), patients were randomly assigned to IVIG prophylaxis or the control group. The trial was approved by the medical ethics committee of the Erasmus Medical Center Rotterdam and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all study participants and/or their legal guardians.
Endpoints
The primary goal was to evaluate the number of infectious episodes for which patients were admitted to hospital. As, in practice, this means an admission for fever, the primary endpoint was number of admissions for fever. Secondary endpoint, was number of therapeutic antibiotic courses, blood culture results, number of admissions to an Intensive Care Unit (ICU) because of fever, number of chemotherapy adaptations due to admission for fever, 5-year cumulative incidence of relapse, disease-free survival (with events defined as relapse, secondary malignancy or death in re- mission), and overall survival from the date of diagnosis.
Patients
All patients, aged 1-19 years, in the medium-risk group of the DCOG ALL-11 trial were considered eligible for inclusion (for detailed inclusion and exclusion criteria see the Online Supplementary Data). Randomization was performed at the start of ALL treatment, before risk stratification in DCOG ALL-11 was done. Patients subsequently stratified according to standard- or high-risk ALL treatment then went off study.
Procedures
Patients randomized to the IVIG prophylaxis group started IVIG prophylaxis on day 22 after diagnosis. Patients received 0.7 g/kg per infusion IVIG (Nanogam, Prothya Biosolutions), with a maximum of 50 g per infusion, every 3 weeks until week 104 of ALL treatment. Details regarding the criteria to start IVIG infusions are provided in the Online Supple- mentary Data. If an IVIG infusion had to be postponed for a period of more than 8 weeks since the preceding infusion, the patient was withdrawn from the study. Patients in the control arm were allowed to receive IVIG treatment under strict criteria (see Online Supplementary Data).
Data were gathered in case report files, as described in detail in the Online Supplementary Data. Side effects were documented according to Common Toxicity Criteria for Adverse Events, version 4.03. Severe adverse events were defined in the DCOG ALL-11 study.
Sample size calculation and statistical analysis
By performing Monte Carlo simulations with 10,000 rep- lications, a sample size of 70 patients per arm was esti- mated to detect a reduction of admissions for fever, with a power of 80% and a one-sided test with a=5%. Details about the sample size calculation are reported in the Online Supplementary Data.
Analyses were performed according to the intention-to-treat principle and per-protocol principle (patients who followed the IVIG protocol for at least 1 year after diagnosis). The patients’ characteristics were compared using a Pearson χ2 test for categorical variables and a t test for continuous variables. Due to the presence of overdispersion, a negative binomial regression model was used to study the effect of IVIG prophylaxis on outcomes; age was included as a categorical variable in all models. The difference in du- ration of admission was compared using a Mann-Whitney U test. The cumulative incidence of relapse, disease-free survival and overall survival were estimated with the Ka- plan-Meier methodology. A log-rank test was applied to compare differences between estimated survival curves. The total percentage of relapses was computed for each group. A two-sided P value <0.05 was considered statis- tically significant. Statistical analyses were performed in SPSS version 26 and in the R software environment.10 The MASS library was used to estimate the negative binomial regression model.
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