Sumit Gupta1, Cindy Wang2, Elizabeth A Raetz3, Reuven Schore4, Wanda L Salzer5, Eric C Larsen6, Kelly W Maloney7, Len A Mattano8, William L Carroll9, Naomi J Winick10, Stephen P Hunger11, Mignon L Loh12, Meenakshi Devidas13. 1. Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. 2. Department of Biostatistics, University of Florida, Gainesville, FL. 3. Primary Children's Hospital, Salt Lake City, UT. 4. Children's National Medical Center, Washington, DC. 5. US Army Medical Research and Materiel Command, Fort Detrick, MD. 6. Department of Pediatrics, Maine Children's Cancer Program, Scarborough, ME. 7. Children's Hospital Colorado, Aurora, CO. 8. Harpoon Therapeutics Pharma Consulting, Mystic, CT. 9. Department of Pediatrics and Perlmutter Cancer Center, New York University Langone Health, New York, NY. 10. University of Texas Southwestern/Simmons Cancer Center, Dallas, TX. 11. Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. 12. Department of Pediatrics, UCSF Benoiff Childen's Hospital and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA. 13. Department of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN.
Abstract
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% ± 4.6% in AALL0331 and 25.4% ± 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 = .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 = .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6; P = .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 = .03). CONCLUSION: Discontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of Erwinia shortages.
PURPOSE:Asparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity. Erwinia chrysanthemiASNase (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% ± 4.6% in AALL0331 and 25.4% ± 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 = .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 = .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6; P = .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 = .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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