Pharmacodynamics and Tolerability of Twice-Weekly Erwinia Asparaginase after E. coli Asparaginase Allergy in Children with ALL.

Abstract

BACKGROUND: E.coli L-asparaginase (ASP) is an important component of multiagent chemotherapy for childhood ALL; however, allergic symptoms develop in 25–30% of patients (pts). Erwinia ASP is an alternative preparation which has been used after E.coli ASP allergy; however, it has not been previously shown how well E.coli ASP-allergic pts tolerate Erwinia ASP or whether they achieve therapeutic ASP levels.METHODS: On DFCI ALL Consortium Protocol 00–01 (2000–2005), newly diagnosed children with ALL (aged 1–18 years) received 30 weeks (wks) of IM ASP during consolidation beginning 7 weeks after diagnosis. All pts initially received weekly E.coli ASP. Nadir serum ASP concentrations were measured every 3 wks by a validated biochemical assay and antibodies to E.coli and Erwinia ASP were measured by ELISA every 6 wks. If E.coli ASP allergy developed, children received Erwinia ASP (25000 IU/m2/dose twice weekly) until 2003, when Erwinia ASP became unavailable.RESULTS: We analyzed the data of all 44 patients treated between 2000–2002 who received Erwinia ASP after E.coli ASP-allergy. Median age at diagnosis was 5.5 years. Median duration of E.coli ASP prior to development of allergy was 5 wks (range 1–23). 26 (59%) pts were positive for E.coli ASP antibodies. Erwinia ASP toxicities included: allergy in 15 (34%) pts (which occurred a median 8 wks after starting Erwinia, range 2–15.5), pancreatitis in 1 (2%) and insulin-requiring hyperglycemia in 1 (2%) pt. 18 (41%) pts became positive for Erwinia ASP antibodies, 4 of whom developed Erwinia ASP allergy. Highest nadir ASP concentrations observed after Erwinia ASP in the 44 E.coli-allergic pts are displayed in the Table (below). Prior data has suggested that a nadir serum ASP level of >=0.1 IU/mL is associated with asparagine depletion (therapeutic level).Nadir Serum ASP Levels after Erwinia ASP in E.coli ASP-allergic ptsNMedian (range) ASP Level (IU/mL)% with ASP Level >= 0.1 IU/mLAll E.coli ASP allergic pts440.231(0.00–3.33)84%Subsequent allergy to ErwiniaYes150.418 (0.00–3.33)80%No290.215 (0.00–0.93)86%E.coli ASP antibodypositive260.171 (0.00–3.33)73%negative180.318 (0.10–0.93)100%Erwinia ASP antibodyPositive180.171 (0.00–3.33)72%negative260.322 (0.00–0.93)92%Highest ASP concentration with E.coli ASP prior to allergySubtherapeutic(<0.1 IU/mL)200.221 (0.00–1.04)85%Therapeutic(>=0.1 IU/mL)240.323 (0.00–3.33)83%Excluding pts who switched to PEG when Erwinia became unavailable in 2003 (N=11), pts remained on Erwinia ASP for a median of 16 wks (range 2–28). 31 pts (70%) ultimately completed all planned 30 wks of ASP consolidation.CONCLUSIONS: We conclude that twice-weekly Erwinia ASP is well-tolerated and achieves detectable and potentially therapeutic serum ASP levels in the majority of E.coli ASP-allergic pts, including those with ASP antibodies (E.coli and/or Erwinia), pts who developed subsequent allergy to Erwinia ASP and pts who never achieved therapeutic nadir levels with prior E.coli ASP. Erwinia ASP should be considered as alternative therapy for pts with ALL who develop E.coli ASP allergy.