Outcomes Following Discontinuation of E. coli- asparaginase upon Severe Allergic Reactions in Children with Acute Lymphoblastic Leukemia

Background: Discontinuation of E. coli- asparaginase in patients with acute lymphoblastic leukemia (ALL) upon severe allergic reactions is unavoidable. We aimed to examine the outcomes following E.coli- asparaginase discontinuation upon severe allergic reactions in ALL.

Patients and methods : In Taiwan Pediatric Oncology Group (TPOG)-2002-ALL protocol (enrolled 2002-2012), intramuscular E. coli- asparaginase (Kyowa Hakko, Japan) was given at 5000 IU/m² per dose thrice weekly for 3 weeks during the remission induction therapy of high-risk (HR) and very-high-risk (VHR) groups. During the first 20 weeks of continuation therapy, HR patients received weekly intramuscular E. coli- asparaginase 10,000 IU/m² per dose every week. They also received two reinduction treatments during which E.coli- asparaginase was given at 5000 IU/m² per dose thrice weekly for 3 weeks. Patients in VHR groups received one reinduction treatment during which E. coli- asparaginase was given at 5000 IU/m² per dose thrice weekly for 2 weeks. Patients in standard-risk (SR) group, received no E. coli- asparaginase in induction, but were randomized to receive one or two reinduction phases, during which E. coli- asparaginase was given at 5000 IU/m² per dose thrice weekly for 2 weeks. The scheduled cumulative doses of E.coli- asparaginase in each risk group were 30,000 IU/m2 or 60,000 IU/m² in SR, 265,000 IU/m² in HR and 75,000 IU/m² in VHR group. We evaluated outcome of children enrolled in TPOG-2002-ALL protocol who had E. coli- asparaginase discontinued due to severe allergic reactions (marked swelling and redness at the injection site or anaphylaxis) between 2002 and 2012, and compared outcomes between those who with Erwinase continued and those who without after the discontinuation of E. coli- asparaginase. The distributions of the Kaplan-Meier estimates of event-free survival (EFS) and overall survival (OS) were compared using log-rank test. Chi-square test was used to compare each parameter between groups.

Results: In 700 patients from 10 hospitals retrospectively studied, 52 patients had E. coli- asparaginase treatment discontinued due to the development of severe pancreatitis in 17 patients, severe thrombosis in 2, and severe allergic reactions in 33. In Taiwan, Erwinase has been available since 2012, and could be purchased from foreign countries before. PEG-asparaginase is not available in Taiwan. In the 33 patients had E. coli- asparaginase discontinued due to severe allergic reactions, 17 continued Erwinase and 16 did not. The parameters between these two groups were similar. They were of more HR group reflecting that HR patients received more E. coli- asparaginase than other patients. The 5-year OS did not differ significantly among the 648 patients without discontinuation (81±1.6%, mean±S.E.), the 17 with allergic reactions and continued with Erwinase (88±7.8%) and the 16 with allergic reactions not treated with Erwinase (87±8.6%). The P value for the difference between the latter two groups was 0.96. In the 16 patients who did not receive Erwinase, all the 10 patients, who had received >= 50% scheduled dose of E.coli- asparaginase before discontinuation, survived without events.

Conclusions: We suggest that patients who had received 50% or more of the scheduled doses of E. coli- asparaginase before the development of severe allergic reactions do not need to continue treatment with Erwinase. This may be helpful in those who cannot afford Erwinase or in the vast majority of the world where Erwinase is not available. It also raises a question on that how much asparaginase is enough for the treatment of childhood ALL.