Intermittent Versus Continuous PEG-Asparaginase to Reduce Asparaginase-Associated Toxicities: A NOPHO ALL2008 Randomized Study

• Published in: Journal of clinical oncology Vol. 37; no. 19; pp. 1638 - 1646
• Main Authors: Albertsen, Birgitte Klug, Grell, Kathrine, Abrahamsson, Jonas, Lund, Bendik, Vettenranta, Kim, Jónsson, Ólafur G, Frandsen, Thomas L, Wolthers, Benjamin O, Heyman, Mats, Schmiegelow, Kjeld
• Format: Journal Article
• Language: English
• Published: United States 01.07.2019
• Subjects: 5 consecutive trials; acute lymphoblastic-leukemia; bfm study-group; Cancer and Oncology; Cancer och onkologi; cancer-institute; children; intensification; Medicin och hälsovetenskap; nordic society; Oncology; pancreatitis; pediatric hematology; young-adults
• ISSN: 0732-183X; 1527-7755; 1527-7755
• DOI: 10.1200/jco.18.01877

Asparaginase is an essential drug in childhood acute lymphoblastic leukemia (ALL) therapy and is frequently given for months to obtain continuous asparagine depletion. We randomly assigned patients to continuous versus intermittent pegylated-asparaginase (PEG-asp) treatment, hypothesizing there would be decreased toxicity with unchanged efficacy. Children (median age, 4.2 years) treated for non-high-risk ALL according to the Nordic Society for Pediatric Hematology and Oncology ALL2008 protocol received five intramuscular PEG-asp injections (1,000 IU/m ) every two weeks and were then randomly assigned to additional three doses (6-week intervals [experimental arm], n = 309) versus 10 doses (2-week intervals [standard arm], n = 316). The primary end point was noninferior (6% margin) disease-free survival. Toxicity reduction was a secondary end point. Occurrence of asparaginase-associated hypersensitivity, pancreatitis, osteonecrosis, and thromboembolism were prospectively registered. After a median follow-up of 4.1 years, the 5-year disease-free survival was 92.2% (95% CI, 88.6 to 95.8) and 90.8% (95% CI, 87.0 to 94.6) in the experimental and standard arms, respectively. The 3-year cumulative incidence of any first asparaginase-associated toxicity (hypersensitivity [n = 13]; osteonecrosis [n = 29]; pancreatitis [n = 24]; thromboembolism [n = 17]) was 9.3% in the experimental arm and 18.1% in the standard arm ( = .001). Asparaginase-associated toxicity reduction was confirmed in sex- and risk-group-adjusted Cox regression analysis stratified by age (≥ 10 and < 10 years; hazard ratio, 0.48; = .001). The experimental arm had the lowest incidences of all four toxicities, reaching significance for pancreatitis (6-month risk, 5.8% 1.3%; = .002). The excellent cure rates and reduced toxicity risk support the use of intermittent PEG-asp therapy after the first 10 weeks in future childhood ALL trials that apply prolonged PEG-asp therapy.