Five-year single-center study of asparaginase therapy within the ALL-BFM 2000 trial - Schrey - 2011 - Pediatric Blood & Cancer - Wiley Online Library

Recently published in Pediatric Blood and Cancer:

The german ALL-BFM2000 trial reported on the relation between asparaginase activity monitoring in children during the treatment for acute leukemia.
Asparaginase (ASNase) has been a core element in the treatment of acute lymphoblastic leukemia (ALL) in children and adults over the last decades. It reduces the exogenous supply of asparagine (ASN) by catalyzing the hydrolysis of ASN, a non-essential amino acid, to aspartic acid and ammonia. Relative deficiencies of endogenous ASN synthesis lead to apoptosis and impaired protein synthesis in the leukaemic blast. The two critical issues about ASNase for cancer treatment are toxicity and insufficient activity. Toxicity is mostly due to the inhibition of protein synthesis and includes hypoalbuminemia, liver enzyme elevation, pancreatitis, hyperglycemia, thrombosis and hemorrhage. Especially during the induction phase, when the drug is co-administered with steroids, ASNase related toxicity can necessitate the withdrawal of ASNase from treatment. An aggravating factor consists in the fact that steroid induced toxicity is in some cases comparably additive (i.e., thromboembolic events, hyperglycemia) to ASNase side effects. Another major limiting factor of ASNase treatment consists in hypersensitivity reactions. The probability of allergic reactions increases with the number of administrations. It is known that up to 30% of patients develop an allergic reaction to first-line E. coli ASNase.
The Berlin-Frankfurt-Muenster (BFM) protocol for the treatment of childhood leukemia employed different combinations of multi-agent chemotherapy in risk-adapted regimes. The ALL-BFM 2000 trial protocol uses Escherichia coli derived asparaginase (E. coli ASNase produced by Kyowa Hakko; Asparaginase medac®) for first-line treatment in the induction phase; in case of insufficient activity or allergic reactions to E. coli ASNase, this is followed by re-intensification with a pegylated form of the E. coli ASNase (PEG ASNase, Oncaspar®). Third-line treatment, usually given for re-intensification and after an allergic reaction to and/or silent inactivation of E. coli preparations, employs Erwinia chrysanthemi asparaginase (Erwinase®). As all preparations are of bacterial origin, common side effects are hypersensitivity reactions by antibody formation or the phenomenon of silent inactivation, that is, insufficient asparaginase activity, without clinical signs of allergy.
An important prognostic milestone in ALL therapy is day of the end of induction therapy (day 33 on the BFM regimens) when the measurement of minimal residual disease (MRD) (negative or not negative) and the randomization according to three different risk categories (SR, MR, HR) take place. The report found no significant relationship between MRD marker positivity or different risk categories and differences in ASNase activity on day +3 after the administration of 5,000 U/m²E. coli ASNase, taken throughout the induction element. This indicates that, while sufficient ASNase treatment is in fact important, there is no apparent correlation between high ASNase trough levels and MRD.
With regard to the patients who relapsed, the report found that the number of patients with sufficient ASNase activity throughout the ASNase containing elements is comparable to the total group, especially concerning induction. This indicates that the occurrence of relapses cannot easily be attributed to inadequate ASNase therapy.
This important report from the BFM group trial highlights the importance of ASNase therapy in ALL, but shows that monitoring of enzymatic activity levels are not well correlated with biological response or relapse.

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Five-year single-center study of asparaginase therapy within the ALL-BFM 2000 trial - Schrey - 2011 - Pediatric Blood & Cancer - Wiley Online Library