Remission Induction for Newly Diagnosed ALL
Several forms of L-asparaginase are available for use in the treatment of children with ALL in the United States. PEG-L-asparaginase, a form of L-asparaginase in which the Escherichia coli-derived enzyme is modified by the covalent attachment of polyethylene glycol, is the most common preparation used during both induction and postinduction phases of treatment in newly diagnosed patients. PEG-L-asparaginase has a much longer serum half-life than native E. coli L-asparaginase, producing prolonged asparagine depletion following a single injection. A single intramuscular (IM) dose of PEG-L-asparaginase given in conjunction with vincristine and prednisone during induction therapy appeared to have similar activity and toxicity as nine doses of IM E. coli L-asparaginase (3 times a week for 3 weeks). Studies have shown that a single dose of PEG-L-asparaginase given either IM or intravenously (IV) as part of multiagent induction results in serum enzyme activity (>100 IU/mL) in nearly all patients for at least 2 to 3 weeks.[18,19,20] The toxicity of PEG-L-asparaginase seems to be similar to that observed with native E. coli asparaginase. In a randomized comparison of PEG-L-asparaginase versus native E. coli asparaginase in which each agent was to be given for a 30-week period following achievement of remission, similar outcome and similar rates of asparaginase-related toxicities were observed for both groups of patients. In another randomized trial in which patients with standard-risk ALL were randomly assigned to receive PEG-L-asparaginase versus native E. coli asparaginase in induction and each of two delayed intensification courses, the use of PEG-L-asparaginase was associated with more rapid blast clearance and a lower incidence of neutralizing antibodies. It is safe to give IV PEG-L-asparaginase in pediatric patients.[19,20] Pharmacokinetics and toxicity profiles are similar for IV and IM PEG-L-asparaginase administration.
Patients with an allergic reaction to PEG-L-asparaginase should be switched to Erwinia L-asparaginase. The half-life of Erwinia L-asparaginase (0.65 days) is much shorter than that of native E. coli (1.2 days) or PEG-L-asparaginase (5.7 days). If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration and a higher dose to achieve adequate asparagine depletion. In two studies, newly diagnosed patients randomly assigned to receive Erwinia L-asparaginase on the same schedule and dosage as E. coli L-asparaginase had a significantly worse EFS.[22,23] However, when administered more frequently (twice weekly), the use of Erwinia asparaginase did not adversely impact EFS in patients experiencing an allergic reaction to E. coli L-asparaginase.
More than 95% of children with newly diagnosed ALL will achieve a CR within the first 4 weeks of treatment. Of the 2% to 4% of patients who fail to achieve CR within the first 4 weeks, approximately half will experience a toxic death during the induction phase (usually due to infection) and the other half will have resistant disease (persistent morphologic leukemia).[23,25,26]; [Level of evidence: 3iA] Patients with persistent leukemia at the end of the 4-week induction phase have a poor prognosis and may benefit from an allogeneic stem cell transplant once CR is achieved.[28,29,30]