TY - JOUR
T1 - Impact of asparaginase discontinuation on outcome in childhood acute lymphoblastic leukemia
T2 - A report from the children’s oncology group
AU - Gupta, Sumit
AU - Wang, Cindy
AU - Raetz, Elizabeth A.
AU - Schore, Reuven
AU - Salzer, Wanda L.
AU - Larsen, Eric C.
AU - Maloney, Kelly W.
AU - Mattano, Len A.
AU - Carroll, William L.
AU - Winick, Naomi J.
AU - Hunger, Stephen P.
AU - Loh, Mignon L.
AU - Devidas, Meenakshi
N1 - Publisher Copyright:
Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
PY - 2020/4/10
Y1 - 2020/4/10
N2 - PURPOSE Asparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity. Erwinia chrysanthemi ASNase (Erwinia) substitution was approved in 2011 for allergic reactions. Erwinia has, however, been intermittently unavailable because of drug supply issues. The impact of Erwinia substitution or complete ASNase discontinuation is unknown. METHODS Patients aged 1-30.99 years in frontline Children’s Oncology Group trials for B-cell acute lymphoblastic leukemia between 2004 and 2011 (National Cancer Institute [NCI] standard risk [SR]: AALL0331; NCI high risk: AALL0232) were included. The number of prescribed pegaspargase (PEG-ASNase) doses varied by trial and strata. Maintenance therapy did not contain ASNase. Landmark analyses at maintenance compared disease-free survival (DFS) among those receiving all prescribed PEG-ASNase doses versus switching to Erwinia but receiving all doses versus not receiving all ASNase doses. RESULTS We included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG-ASNase discontinuation was 12.2% 6 4.6% in AALL0331 and 25.4% 6 0.8% in AALL0232. In multivariable analyses, NCI high-risk patients not receiving all prescribed ASNase doses had inferior DFS (hazard ratio [HR], 1.5; 95% CI, 1.2 to 1.9; P 5 .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with Erwinia substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6; P 5 .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6; P 5 .23), except when restricted to those with slow early response, who were prescribed more ASNase because of therapy intensification (HR, 1.7; 95% CI, 1.1 to 2.7; P 5 .03). CONCLUSION Discontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of Erwinia shortages.
AB - PURPOSE Asparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity. Erwinia chrysanthemi ASNase (Erwinia) substitution was approved in 2011 for allergic reactions. Erwinia has, however, been intermittently unavailable because of drug supply issues. The impact of Erwinia substitution or complete ASNase discontinuation is unknown. METHODS Patients aged 1-30.99 years in frontline Children’s Oncology Group trials for B-cell acute lymphoblastic leukemia between 2004 and 2011 (National Cancer Institute [NCI] standard risk [SR]: AALL0331; NCI high risk: AALL0232) were included. The number of prescribed pegaspargase (PEG-ASNase) doses varied by trial and strata. Maintenance therapy did not contain ASNase. Landmark analyses at maintenance compared disease-free survival (DFS) among those receiving all prescribed PEG-ASNase doses versus switching to Erwinia but receiving all doses versus not receiving all ASNase doses. RESULTS We included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG-ASNase discontinuation was 12.2% 6 4.6% in AALL0331 and 25.4% 6 0.8% in AALL0232. In multivariable analyses, NCI high-risk patients not receiving all prescribed ASNase doses had inferior DFS (hazard ratio [HR], 1.5; 95% CI, 1.2 to 1.9; P 5 .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with Erwinia substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6; P 5 .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6; P 5 .23), except when restricted to those with slow early response, who were prescribed more ASNase because of therapy intensification (HR, 1.7; 95% CI, 1.1 to 2.7; P 5 .03). CONCLUSION Discontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of Erwinia shortages.
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U2 - 10.1200/JCO.19.03024
DO - 10.1200/JCO.19.03024
M3 - Article
C2 - 32275469
AN - SCOPUS:85086052878
SN - 0732-183X
VL - 38
SP - 1897
EP - 1905
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 17
ER -