Impact of Asparaginase Discontinuation on Outcome in Childhood Acute Lymphoblastic Leukemia: A Report From the Children’s Oncology Group

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.

Pediatric acute lymphoblastic leukemia

“…Discontinuation of planned asparaginase doses is associated with worse prognosis in high-risk patients. 107 In cases of allergy to pegaspargase or native E. coli asparaginase, Erwinia asparaginase (Erwinase) is considered an acceptable alternative. However, Erwinase is more expensive, is intermittently unavailable, and requires frequent administration because of its short half-life.…”

Increasing completion of asparaginase treatment in childhood acute lymphoblastic leukaemia (ALL): summary of an expert panel discussion

“…This was also the case for patients with hypersensitivity reactions who were shifted to formulations with a shorter half-life, for example, Erwinia asparaginase. 4 An earlier Dana-Farber Cancer Institute (DFCI) ALL Consortium study (91-01) showed that patients who tolerated 25 or fewer weeks of asparaginase had a significantly worse outcome than those who received at least 26 weeks of asparaginase. 3 Noteworthy, 30 weeks of PEG asparaginase exposure were associated to a similar EFS whether asparaginase was administered at 2 or 6 weeks intervals.…”

“…This has led to an unmodified outcome in two large COG studies devoted to National Cancer Institute (NCI) standard risk B-ALL (AALL0331) and NCI high risk B-ALL (AALL0232). 4 Premedication could lead to a further reduction of IRRs (see the section on Premedication below). 21 Also it has to be recognised that regular shortages of Erwinia asparaginase are occurring worldwide.…”

“…21 Importantly, this strategy requires as an indispensable prerequisite to have a tight real-time TDM in place for each PEG asparaginase dose administered to detect silent inactivation. 4…”

“…Failure to receive the entire prescribed course of asparaginase therapy has been associated with lower cure rates in multiple childhood ALL studies. [2][3][4][5][6] Therefore, guidelines to ensure that patients receive the full course are crucial.…”