A prospective, open-label, randomised, parallel design study of 4 generic formulations of intramuscular L-asparaginase in childhood precursor B-cell acute lymphoblastic leukaemia (ALL)

Autor: Suja Johnson, Chetan Dhamne, Hari Sankaran, Khushboo A. Gandhi, Pallavi Rane, Nirmaly Roy Moulik, Shraddha Mahesh Jadhav, Murari Gurjar, Gaurav Narula, Shripad Banavali, Vikram Gota
Rok vydání: 2022
Předmět:
Zdroj: Cancer Chemotherapy and Pharmacology. 90:445-453
ISSN: 1432-0843
0344-5704
Popis: L-asparaginase is an essential medicine for childhood ALL. The quality of generic L-asparaginase available in India is a matter of concern. We compared four commonly used generic formulations of L-asparaginase in India.We conducted a prospective, open-label, randomised trial of four generic formulations of asparaginase for the treatment of patients with newly diagnosed intermediate-risk B-ALL. Patients were randomly assigned in a 1:1:1:1 ratio to receive generic asparaginase at a dose of at 10,000 IU/m 2 on days 9, 12, 15, and 18 of a 35-day cycle (Induction treatment). The primary end points were to determine the difference in the asparaginase activity and asparagine depletion. Historical patients who received L-asparaginase Medac (innovator) served as controls.A total of 48 patients underwent randomization; 12 patients each in the four arms. Failure to achieve predefined activity threshold of 100 IU/L was observed in 9/40 samples of Generic A (22·5%), 23/40 of Generic B (57·5%), and 43/44 (98%) each of Generic C and D. All 27 samples from seven historical patients who were administered Medac had activity gt; 100 IU/L. The average activity was significantly higher for Genericm A, 154 (70·3, 285·4) IU/L followed by Generic B 84·5(44·2, 289·1) IU/L, Generic C 45(14·4, 58·4) IU/L, and Generic D 20·4(13, 35) IU/L. Only 6 patients had asparaginase activity gt; 100 IU/L on each of the four occasions (Generic A = 5; Generic B = 1), and none of them developed Anti-Asparaginase Antibodies (AAA). On the other hand, AAA was observed in 12/36 patients who had at least one level lt; 100 IU/L (P lt; 0·05): Generic A 3/5, Generic B = 3/9, Generic D (4/11), and Generic C (5/11).Generic A and B had better trough asparaginase activity compared to Generic D and C. Overall, generic formulations had lower asparaginase activity which raises serious clinical concerns regarding their quality. Until strict regulatory enforcement improves the quality of these generics, dose adaptive approaches coupled with therapeutic drug monitoring need to be considered.
Databáze: OpenAIRE
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