Anti–Escherichia coli asparaginase antibody levels determine the activity of second-line treatment with pegylated E coli asparaginase: a retrospective analysis within the ALL-BFM trials

Abstract

Hypersensitivity reactions limit the use of the antileukemic enzyme asparaginase (ASE). We evaluated Ab levels against Escherichia coli ASE and ASE activity in 1221 serum samples from 329 patients with acute lymphoblastic leukemia who had received ASE treatment according to the ALL-BFM 2000 or the ALL-REZ BFM 2002 protocol for primary or relapsed disease. ASE activity during first-line treatment with native E coli ASE and second-line treatment with pegylated E coli ASE was inversely related to anti-E coli ASE Ab levels (P < .0001; Spearman rank order correlation). An effect on ASE activity during second-line treatment with pegylated E coli ASE was, however, only observed when anti-E coli ASE Ab levels were high (> 200 AU/mL). In the presence of moderate or intermediate Ab levels (6.25-200 AU/mL) the switch from native to pegylated E coli ASE resulted in a significant increase of ASE activity above the threshold of 100 U/L (P < .05). Erwinia chrysanthemi ASE activity was not correlated with anti-E coli ASE Ab levels. Erwinia ASE was found to be the best ASE alternative if Ab levels against E coli ASE exceed 200 AU/mL. This retrospective analysis is the first to describe the relationship between the level of anti-E coli ASE Abs and serum activity of pegylated E coli ASE used second-line after native E coli ASE. These studies are registered at http://clinicaltrials.org as NTC00430118 and NCT00114348. (Blood. 2011;118(22): 5774-5782)

A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia

“…Sixth, our study shows that the presence of AAAs is related to allergy to and silent inactivation of asparaginase as shown by others, 10,20 but predicting asparaginase allergy or silent inactivation based on antibody formation is hampered by low specificity (64%) of the test. The specificity of the Coli-AAA test in intensification was higher, 73%, but still not perfect.…”

“…In the PEGasparaginase study, the PEGasparaginase activity trough levels and AAAs were measured in serum at the start of intensification (week 0); in weeks 2,4,6,8,10,14,16,24,26, and 28; and also 1 week after administration in weeks 3, 9, 15, and 25. Serum asparagine, aspartic acid, glutamine, and glutamic acid levels were measured at weeks 0, 2, 4, 14, and 24 during PEGasparaginase therapy.…”

“…9 Clinical allergy is associated with inactivation of asparaginase by antibodies. 10,11 Formation of asparaginase antibodies (AAAs) can also neutralize The online version of this article contains a data supplement.…”

Acute Lymphoblastic Leukemia

“…201,202 Moreover, a recent study showed that high anti-asparaginase antibody level after initial therapy with native E coli asparaginase was associated with decreased asparaginase activity during subsequent therapy with PEG-asparaginase. 203 In contrast, no cross-reactivity between antibodies against native E coli asparaginase and Erwinia asparaginase was reported, 201,202 and enzyme activity of Erwinia asparaginase was not affected by the presence of anti-E coli asparaginase antibodies. 203 A study from the DFCI ALL Consortium showed the feasibility and activity of using Erwinia asparaginase in pediatric and adolescent patients who developed hypersensitivity reactions to E coli asparaginase during frontline therapy; importantly, treatment with Erwinia asparaginase did not negatively impact EFS outcomes in these patients.…”

“…203 In contrast, no cross-reactivity between antibodies against native E coli asparaginase and Erwinia asparaginase was reported, 201,202 and enzyme activity of Erwinia asparaginase was not affected by the presence of anti-E coli asparaginase antibodies. 203 A study from the DFCI ALL Consortium showed the feasibility and activity of using Erwinia asparaginase in pediatric and adolescent patients who developed hypersensitivity reactions to E coli asparaginase during frontline therapy; importantly, treatment with Erwinia asparaginase did not negatively impact EFS outcomes in these patients. 204 Thus, for patients who develop severe hypersensitivity reactions during treatment with E coli asparaginase (either to the native or pegylated formulation), the use of E coli-derived formulations should be stopped and Erwinia asparaginase should be substituted (see "Sup-portive Care: Asparaginase Toxicity Management" on page 868).…”