TY - JOUR
T1 - Intermittent Versus Continuous PEG-Asparaginase to Reduce Asparaginase-Associated Toxicities
T2 - A NOPHO ALL2008 Randomized Study
AU - Albertsen, Birgitte Klug
AU - Grell, Kathrine
AU - Abrahamsson, Jonas
AU - Lund, Bendik
AU - Vettenranta, Kim
AU - Jónsson, Ólafur G
AU - Frandsen, Thomas L
AU - Wolthers, Benjamin O
AU - Heyman, Mats
AU - Schmiegelow, Kjeld
PY - 2019
Y1 - 2019
N2 - PURPOSE 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. METHODS 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/m2) 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. RESULTS 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 (P = .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; P = .001). The experimental arm had the lowest incidences of all four toxicities, reaching significance for pancreatitis (6-month risk, 5.8% v 1.3%; P = .002). CONCLUSION 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.
AB - PURPOSE 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. METHODS 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/m2) 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. RESULTS 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 (P = .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; P = .001). The experimental arm had the lowest incidences of all four toxicities, reaching significance for pancreatitis (6-month risk, 5.8% v 1.3%; P = .002). CONCLUSION 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.
U2 - 10.1200/JCO.18.01877
DO - 10.1200/JCO.18.01877
M3 - Journal article
C2 - 30978155
SN - 0732-183X
VL - 37
SP - 1638
EP - 1646
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 9
ER -