Asparaginase Antibody and Asparaginase Activity in Children With Higher-Risk Acute Lymphoblastic Leukemia

Abstract

We investigated the anti-asparaginase antibody (Ab) and asparaginase enzymatic activity in the sera of 1,001 patients (CCG-1961) with high-risk acute lymphoblastic leukemia (HR-ALL). Patients received nine doses of native Escherichia coli asparaginase during induction. Half of rapid early responders (RER) were randomly assigned to standard intensity arms and continued to receive native asparaginase. The other RER patients and all slow early responders received 6 or 10 doses of PEG-asparaginase. Serum samples (n = 3,193) were assayed for determination of asparaginase Ab titers and enzymatic activity. Three hundred ninety of 1,001 patients (39%) had no elevation of Ab among multiple evaluations-that is, were Ab-negative (<1.1 over negative control)-and 611 patients (61%) had an elevated Ab titer (>1.1). Among these 611 patients, 447 had no measurable asparaginase activity during therapy. Patients who were Ab-positive but had no clinical allergies continued to receive E. coli asparaginase, the activity of which declined precipitately. No detectable asparaginase activity was found in 81 of 88 Ab-positive patients shortly after asparaginase injections (94% neutralizing Ab). The Ab-positive patients with clinical allergies subsequently were given Erwinase and achieved substantial activity (0.1-0.4 IU/ml). An interim analysis of 280 patients who were followed for 30 months from induction demonstrated that the Ab-positive titers during interim maintenance-1 and in delayed intensification-1 were associated with an increased rate of events. The CCG-1961 treatment schedule was very immunogenic, plausibly due to initially administrated native asparaginase. Anti-asparaginase Ab was associated with undetectable asparaginase activity and may be correlated with adverse outcomes in HR ALL.

Pediatric T‐cell post‐transplant lymphoproliferative disorder after solid organ transplantation

“…She had an initial significant decrease in size of the abdominal masses, but re-evaluation after cycle #3 showed regrowth of the abdominal adenopathy. She then received four-drug acute lymphoblastic leukemia (ALL)-like induction chemotherapy with vincristine, daunorubicin, PEG asparaginase and prednisone with intrathecal methotrexate [10]. She had a dramatic response to this therapy with complete disappearance of abdominal disease.…”

“…Her pre-transplant EBV status was unknown. ALL induction therapy, as given in case #1 [10], was complicated by pancreatitis, and posterior reversible encephalopathy syndrome. Following completion of induction chemotherapy she had complete resolution of abdominal nodal disease, but the abnormal T-cell clone persisted at a low-level in the marrow and CSF in conjunction with interstitial lung disease.…”

Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation

“…Children and adolescents with ALL who receive an inadequate course of planned asparaginase therapy due to either intolerable side effects or silent inactivation have been shown to have inferior outcomes compared with those who receive the majority of intended doses of asparaginase, highlighting the importance of maximizing the delivery of planned asparaginase therapy. [1][2][3] L-asparaginase preparations are bacterial enzymes derived from either Escherichia coli (E. coli) or Erwinia chrysanthemi (Erwinia). E. coli-derived preparations include native E. coli-asparaginase, no longer available in the United States, and pegylated formulations (pegaspargase), in which the E. coli-derived enzyme is modified by the covalent attachment of polyethylene glycol.…”

Microbial Amidases and their Industrial Applications: A Review

“…Another mechanism appears to be the production of anti-asparaginase antibodies in the host cells, which neutralize L-asparaginases impeding their enzymatic activity (Chakrabarti and Schuster). Some studies have shown that the incidence of hypersensitivity to asparaginase is similar between age groups; others suggested that infants and younger patients develop antibody and hypersensitivity reactions less frequently than teenagers and adult patients [79]. Antibodies produced in response to asparaginase do not always lead to clinical hypersensitivity instead cause rapid inactivation of the asparaginase, resulting in Sub optimal asparagines depletion.…”