L-asparaginase


Polypeptide of bacterial origin (E. coli) widely used in the treatment of acute lymphoblastic leukemia in children and adults.
 
Incidence
Highest of all antimitotic agents.
 
Intravenous route: 15 to 33%.
 
Intramuscular route: 6 to 18%.
 
Deaths reported.
 
Risk factors
Intravenous use.
 
Hiatus of 1 month or more between two courses.
 
Non-association with prednisone and vincristine.
 
Prior exposure months or years previously.
 
Clinical manifestations
General: anaphylactic shock.
 
Cutaneous: pruritus, rash, urticaria, angioedema.
 
Respiratory: laryngospasm, bronchospasm.
 
Diagnostic methods
Cutaneous testing.
 
Ineffective (false positive and negative).
 
Specific IgE.
 
Increased specific IgE antibodies found in patients in whom L-asparaginase infusions are followed by allergic reactions.
 
Specific IgM and IgG (microtiter solid-phase radioimmunoassay).
 
High titers of IgG3 or IgG4 anti L-asparaginase may predict L-asparaginase allergy.
 
Complement activation (C3d).
 
L-asparaginase-specific IgG antibodies bind and activate the complement system.
 
Mechanisms
IgE-mediated hypersensitivity: a few cases.
 
Complement activation induced by formation of immune complexes of L-asparaginase and specific IgM and IgG class antibodies.
 
Leukotriene production by bone marrow-derived mast cells.
 
Management
Avoidance, but hypersensitivity reactions to L-asparaginase do not impact on the remission duration in adults with acute lymphoblastic leukemia.
 
Use of alternative formulations:
 
  • L-asparaginase derived from Erwinia chrysantemia: fewer anaphylactic reactions and no cross-reactivity with Escherichia coli L-asparaginase
  • Polyethyleneglycol-L-asparaginase: lower immunogenicity.

Premedication (epinephrine).

Desensitization (in a 2-year-old child with myelogenous leukemia).
 
From 1.2 U/hour over 4.2 hours to 1200 U/hour over 3.8 hours. 

References

  1. Larson R.A, Fretzin M.H, Dodge R.K, Schiffer C.A, "Hypersensitivity reactions to L-asparaginase do not impact on the remission duration of adults with acute lymphoblastic leukemia", Leukemia. , 1998; 12 (5): 660-5
  2. Bonno M, Kawasaki H, Hori H, Umemoto M, Komada Y, Sakurai M, "Rapid desensitization for L-asparaginase hypersensitivity", J. Allergy. Clin. Immunol., 1998; 101 (4.1): 571-12
  3. Stone H.D Jr, Dipiro C, Davis P.C, Meyer C.F, Wray B.B, "Hypersensitivity reactions to Escherichia Coli derived polyethylene glycolated-asparaginase associated with subsequent immediate skin-test reactivity to E. Coli - derived granulocyte colony stimulating factor", J. Allergy. Clin. Immunol., 1998; 101 (3): 429-31 
  4. Ettinger L.J, Kurtzberg J, Voute P.A, Jurgens H, Halpern S.L, "An open-label multicenter study of polyethyleneglycol-L-asparaginase for the treatment of acute lymphoblastic leukemia", Cancer, 1995; 75 (5): 1176-81
  5. Fabry U, Korholz D, Jurgens H, Gobel U, Wahn V, "Anaphylaxis to L-asparaginase during treatment for acute lymphoblastic leukemia in children. Evidence of a complement activated mechanism", Pediatr. Res., 1985; 19 (4): 400-8

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.