Pharmacological and clinical monitoring in children with acute lymphoblastic leukemia treated with a biogeneric PEG‐l‐asparaginase product

Abstract

Background: L-Asparaginase (ASP) plays a crucial role in the treatment of childhood acute lymphoblastic leukemia (ALL). Currently, different ASP products are available in the market, including both native and pegylated drugs. Several biogeneric Escherichia coli ASP (GEN-ASP) products have been developed in response to shortages and expensiveness of the native E. coli ASP innovator compounds, but some concerns have been raised about their quality. Recently, a number of generic pegylated ASP products (GEN-PEG-ASP) have been marketed to substitute for the innovator product (PEG-ASP). Methods: Clinical courses and serum asparaginase activity (SAA) levels were monitored in 12 children with ALL, who were treated in our institution with two doses of a GEN-PEG-ASP product, given IV at 2500 IU/m 2 during the remission induction phase. Results were compared with those obtained in a reference cohort of 35 patients treated in our institution, who received the innovator PEG-ASP product at same dosage and within the same chemotherapy background. Results: Compared to the reference cohort treated with PEG-ASP, SAA levels were significantly lower in the 12 patients receiving GEN-PEG-ASP (p < .0001); a higher proportion of ASP-associated hypersensitivity reactions (2/12 vs. 0/35; p = .061) and silent inactivation (3/12 vs. 0/35; p = .014) were observed in comparison with the reference cohort. Conclusions: Our results highlighted different pharmacological profiles and different rates of hypersensitivity reactions and silent inactivation in the GEN-PEG-ASP cohort compared to those treated with the innovator product. Our findings suggest that a rigorous clinical attention and a thorough pharmacological monitoring are advisable in patients treated with GEN-PEG-ASP products.

An acute lymphoblastic leukemia cell‐based preclinical assay revealed functional differences between commercial brands of L‐asparaginase administered in Colombia

“…Here, biogeneric formulations take on an important role in providing a better chance of a cure to all children and adolescents with cancer, described in the World Health Organization (WHO) Global Initiative for Childhood Cancer. However, there are some concerns about the quality of these drugs, using the AHA, MAAT, or Nessler methods 7–10 …”

“…However, there are some concerns about the quality of these drugs, using the AHA, MAAT, or Nessler methods. [7][8][9][10] Michalowski et al 6 found differences in L-ASNase activity after administration of different formulations in the same subject, Matteo et al 9 demonstrated variances in enzyme activity using a biogeneric E. coli PEG-L-ASNases, and Sankaran et al 3 reported differences in activity using formulations of native E. coli L-ASNase. These results of enzyme activity in the serum of patients correlate with our findings in our cell-based method and raise concerns about the quality of some formulations administered to patients in low-and middle-income countries.…”

“…Michalowski et al 6 . found differences in L‐ASNase activity after administration of different formulations in the same subject, Matteo et al 9 . demonstrated variances in enzyme activity using a biogeneric E. coli PEG‐L‐ASNases, and Sankaran et al 3 .…”

“…Recent reports have generated concerns among clinicians about the possible ineffectiveness of the drugs they are administering to their patients 5,6 . Various in vitro methods are used to evaluate the activity of L‐ASNases, such as aspartic acid β‐hydroxamate (AHA), MAAT, or Nessler 7–10 . Although these methods determine enzyme activity in patient serum, they do not directly give information about the activity of the original enzyme batch.…”

“…5,6 Various in vitro methods are used to evaluate the activity of L-ASNases, such as aspartic acid β-hydroxamate (AHA), MAAT, or Nessler. [7][8][9][10] Although these methods determine enzyme activity in patient serum, they do not directly give information about the activity of the original enzyme batch. For this reason, our goal was to establish a preclinical methodology that would allow us to analyze the activity against ALL cells of different commercial formulations of L-ASNases distributed in Colombia.…”