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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)

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Abstract

Aims

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.

Materials and methods

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.

Results

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 > 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 > 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 < 100 IU/L (P < 0·05): Generic A 3/5, Generic B = 3/9, Generic D (4/11), and Generic C (5/11).

Conclusion

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.

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Data availability

All the data collected are available in this article and the appendix.

Abbreviations

AHA:

Aspartate beta hydroxamate

ANOVA:

Analysis of variance

CDSCO:

Central drugs standard control organisation

CSF:

Cerebrospinal fluid

E. coli :

Escherichia coli

HIC:

High-income countries

IR:

Intermediate risk

IQR:

Interquartile range

LC–MS/MS:

Liquid chromatography–mass spectrometry

LMIC:

Low–middle-income countries

pre-B-ALL:

B-cell acute lymphoblastic leukaemia

SLA:

State licensing agencies

UPLC:

Ultra-performance liquid chromatography

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Acknowledgements

The ImPaCCT Foundation is kindly acknowledged for its financial support. We are also grateful to Cadila Pharmacauticals Ltd., Naprod Lifesciences Pvt. Ltd., Sun Pharma Laboratories Ltd., and Zydus Oncosciences for supplying L-asparaginase vials to the trial participants.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, 410210, India

    Suja Johnson, Khushboo A. Gandhi, Pallavi Rane, Nirmaly Roy Moulik, Shraddha Mahesh Jadhav, Murari Gurjar & Vikram Gota

  2. Department of Paediatric Oncology, Tata Memorial Centre, Mumbai, India

    Chetan Dhamne, Hari Sankaran, Nirmaly Roy Moulik, Gaurav Narula & Shripad Banavali

  3. Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, 400094, India

    Chetan Dhamne, Gaurav Narula, Shripad Banavali & Vikram Gota

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  1. Suja Johnson
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Correspondence to Vikram Gota.

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Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical approval

The study was approved by the Institutional Ethics Committee of Tata Memorial Hospital. All trial participants provided written informed consent prior to their enrolment. The study was carried out in accordance with the Declaration of Helsinki and International Conference on Harmonization—Good Clinical Practice (ICH‐GCP) guidelines.

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Johnson, S., Dhamne, C., Sankaran, H. et al. 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). Cancer Chemother Pharmacol 90, 445–453 (2022). https://doi.org/10.1007/s00280-022-04482-8

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