In a Children’s Oncology Group analysis reported in the Journal of Clinical Oncology, Gupta et al found that discontinuation of pegylated asparaginase (PEG-ASNase) was associated with poorer disease-free survival among pediatric patients with high-risk acute lymphoblastic leukemia (ALL). However, outcomes were not significantly worse in those patients who had Erwinia chrysanthemi ASNase (Erwinia) substituted for PEG-ASNase after discontinuation.
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As stated by the authors, “In patients who develop hypersensitivity to PEG-ASNase (but not other ASNase-related toxicities), substitution of subsequent doses with six Erwinia doses was approved by the U.S. Food and Drug Administration and the European Medicines Agency in 2011, and is now standard of care…Erwinia has, however, been intermittently unavailable to patients because of drug supply issues; currently, a global shortage has markedly restricted access.”
Study Details
The study involved data from patients age 1 to 30.9 years in frontline Children’s Oncology Group trials for B-cell ALL between 2004 and 2011. The patient population consisted of 5,195 patients with National Cancer Institute (NCI) standard-risk (AALL0331 study) and 3,001 patients with NCI high-risk (AALL0232 study) disease. The number of prescribed PEG-ASNase doses varied among trials and patient strata. Maintenance therapy did not include ASNase. Landmark analyses from the beginning of maintenance therapy assessed disease-free survival among patients receiving all prescribed PEG-ASNase doses vs switching to Erwinia but receiving all doses vs not receiving all ASNase doses.
Key Findings
The cumulative incidence of PEG-ASNase discontinuation was 12.2% among the NCI standard-risk patients and 25.4% among the NCI high-risk patients.
In multivariable analyses, NCI high-risk patients who did not receive all prescribed ASNase doses had poorer disease-free survival vs those receiving all prescribed PEG-ASNase doses (hazard ratio [HR] = 1.5, P = .002)
Among NCI high-risk patients, those who completed treatment courses with Erwinia substitution after PEG-ASNase discontinuation did not have significantly poorer disease-free survival vs patents who received all prescribed PEG-ASNase doses (HR = 1.1, P = .69).
Among all NCI standard-risk patients, those who did not receive all prescribed PEG-ASNase doses did not have significantly poorer disease-free survival vs those who received all prescribed doses (HR = 1.2, P = .23); however, poorer disease-free survival was observed in the subgroup of patients with slow early response, who were prescribed more ASNase for therapy intensification and did not receive all prescribed doses (HR = 1.7, P = .03). Among NCI standard-risk patients, PEG-ASNase discontinuation was not associated with overall survival among all patients or among those with slow early response.
Among NCI high-risk patients, those in whom Erwinia was substituted for PEG-ASNase did not have significantly poorer overall survival vs those who received all PEG-ASNase doses (HR = 0.8, P = .40). Failure to receive all prescribed ASNase doses vs receipt of all prescribed doses was associated with significantly poorer overall survival on univariate analysis (HR = 1.4, P = .03) but not on multivariate analysis (HR = 1.2, P = 0.19).
The investigators concluded: “Discontinuation of ASNase doses is associated with inferior [disease-free survival] in higher-risk patients. Our results illustrate the severe consequences of Erwinia shortages.”
Sumit Gupta, MD, of The Hospital for Sick Children, Toronto, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.
