Bishwaranjan Jana

Assessing the feasibility and affordability of indigenous generic PEG-Asparaginase for improved outcomes in ALL treatment Samik Samaddar1, Arko Bhowal2, Ritam Siddhanta3, Subhajit Kundu3, Bishwaranjan Jana1, Neerajana Datta1 and Jasmeet Sidhu2 1Clinical Research Unit 2Leukemia Cell Biology 3Tata Medical Center Bio-Repository TATA TRANSLATIONAL CANCER RESEARCH CENTRE TATA MEDICAL CENTER INTRODUCTION OBJECTIVES Asparaginase (ASNase) therapy has been a key component of chemotherapeutic regimen for Acute Lymphoblastic Leukemia (ALL) for the last 50 years. Asparaginase causes systemic depletion of L-asparagine, with consequent disruption in protein synthesis, leading to growth arrest and eventual apoptosis of susceptible leukaemic blasts. Therefore, the pharmacodynamic goal of ASNase therapy is sustained plasma ASNase activity, which can be an indicator of complete asparagine depletion. Asparaginase • • • • Longer half-life Sufficient therapeutic activity Less immunogenic Cost-effective PEG Asparaginase (HAMSYL) Of the two commercially available formulations, PEGylated ASNase has a longer half-life and is comparatively less immunogenic than native ASNase in ALL management. However, high price and non-availability of the innovator pegaspargase is a limiting factor. Therefore, indigenously manufactured generic PEG ASNase could be a cost-effective alternative for patients with ALL, especially in low- and middle-income countries. Vial Donation (Gennova Biopharmaceuticals) Vial sharing (Single use) Here we share our clinical experience with a generic PEG ASNase Hamsyl (Gennova Biopharmaceuticals) that had earlier demonstrated equivalent pharmacokinetics to the innovator pegasparagase [1]. We determine the cost feasibility along with assessment of therapeutic activity and toxicity. METHODS Feasibility Therapeutic drug activity Toxicity Cost benefit & comparison (PEG / Native ASNase) Trough (Day 14±2) plasma Asparaginase Activity (≥100 IU/m2) Hypersensitivity, Pancreatitis, Thrombosis, Cholestatic jaundice ASPARAGINASE DOSING/SAMPLING SCHEMA Study Design and Patients: In this prospective observational study, patients 1-18 years of age with ALL were treated on ICiCLe-ALL-2014 protocol [2]. The study patients were diagnosed between September 2020 to November 2021. All patients in the cohort had completed the 35-day induction treatment phase. The patients were administered PEG ASNase Hamsyl at 1000 IU/m2/dose by intramuscular injection. Informed written consent/assent was obtained from parent/patient as appropriate and approval was obtained from the Institutional Ethics Committee before the study commence. INDUCTION CONSOLIDATION 35 Days DELAYED INTENSIFICATION ** * 63 Days 49 Days Standard Risk D4 D16 D18 D30 Intermediate Risk D9 D4 D23 D 37 Bioanalysis: Plasma L-ASNase was quantified spectrophotometrically using the aspartic acid-𝛽hydroxamate (AHA)-indooxine assay [3]. A trough (day 14±2) plasma ASNase activity of ≥100 IU/L is considered an adequate therapeutic activity[4]. D18 High Risk D9 D23 D 37 Monitoring Toxicity: Asparaginase associated serious adverse events (SAEs) observed during the study were graded according to the National Cancer Institute CTCAE, version 5.0. D44 D16 D30 D4 D18 D58 * Interim Maintenance; No ASNase doses; ** Maintenance; No ASNase doses Days of ASNase administration; Days of ASNase sample collection RESULTS Table 1. Patient Demographics Study duration Sept, 2020 – Nov, 2021 Vial donation and sharing reduces cost burden considerably PEG Asparaginase demonstrates satisfactory therapeutic activity Table 2. Average theoretical cost vs Average actual cost for PEG Asparaginase Fig 1. Plasma Asparaginase activity: Induction vs Delayed Intensification Average Total Average Actual % Cost Theoretical Cost Cost Incurred Incurred (INR) (INR) Risk Group Last follow-up No. of patients Dec 31, 2021 80 Age (Median, IQR) 5.1 (2.75 – 8.29) years Male/ Female End of Induction remission Not in CR (<5% blasts in bone marrow aspirate) Not evaluable High Low Not evaluable 73 (91.25%) 28,579 31 Intermediate Risk (N=14, 35, 12, 23) 135,750 46,543 34 IQR (IU/L) High Risk (N=31, 155, 34, 121) 185,671 42,039 23 Very High Risk (N=14, 74, 17, 57) 287,014 65,936 23 5 (6.25%) Standard Risk 20 (25%) Intermediate Risk High Risk High Risk Not evaluable MRD: Minimal Residue Disease CR: Complete Remission 14 (17.5%) Risk Group PEG Asparaginase (Hamsyl) (INR) 1 (1.25%) Native Asparaginase (Leucoginase) (INR) Additional cost burden (PEG Asparaginase) (%) Standard Risk 28,579 (2) 19,500 (12) 32 Intermediate Risk 46,543 (3) 24,375 (15) 48 High Risk 42,039 (5) 37,375 (23) 11 65,936 (8) 53,625 (33) 19 Number in parentheses indicate total number of doses received 285.1 - - 798.8 62, 91% 20, 95% 0.0001 PEG Asparaginase is associated with less overall toxicity Table 4. Incidence of toxicity (%), Native vs PEG Asparaginase Toxicity (CTCAE ≥3) Native Asparaginase PEG Asparaginase Bionase Leucoginase 72 h (N=62) 48 h (N=72) 72 h (N=55) Hamsyl (N=80) Hypersensitivity 12 (19.4%) 8 (11.1%) 5 (9.1%) 3 (3.8%) Pancreatitis 2 (3.2%) 0 1 (1.8%) 4 (5%) Thrombosis 0 1 (1.4%) 2 (3.6%) 1 (1.2%) No Toxicity 77.4% 87.5% 85.5% 90% No incidence of cholestatic jaundice in our cohort CONCLUSIONS 37 (46.25%) 8 (10%) 21 674 100 IU/L Table 3. Cost comparison: PEG Asparaginase (average actual cost) vs Native Asparaginase (total theoretical cost) 27 (33.75%) 48 (60%) 68 395.6 N=No. of patients, doses administered, vials purchased, vials shared Very High Risk T-ALL Proportion ≥100 IU/L (n, %) p-value Higher PEG Asparaginase cost is offset by reduced hospital visits 2 (2.50%) Delayed Intensification Samples (n) Median (IU/L) 5 (6.25%) Final Risk B-Cell Precursor ALL 91,453 45/35 In CR End of Induction MRD (Detectable by FCM and/or ≥10−4 by Ig-TR) Standard Risk (N=19, 32, 10, 22) Induction Vial sharing is a labour-intensive system that requires coordinated inter-departmental effort. Along with sponsored vial donation, it has been able to reduce cost of Asparaginase therapy substantially. PEG Asparaginase shows overall satisfactory therapeutic activity, with significantly increased plasma activity post-induction. PEG Asparaginase is associated with less overall toxicity and least incidence of clinical hypersensitivity compared to native Asparaginase. Higher cost of PEG Asparaginase is offset by reduced number of doses and hospital visits and lesser incidence of overall toxicity. REFERENCES 1. Nookala Krishnamurthy, M. et al. Randomized, Parallel Group, Open-Label Bioequivalence Trial of Intramuscular Pegaspargase in Patients With Relapsed Acute Lymphoblastic Leukemia. JCO Global Oncology- (2020) doi:10.1200/GO-. Das, N. et al. Protocol for ICiCLe-ALL-14 (InPOG-ALL-15-01): a prospective, risk stratified, randomised, multicentre, open label, controlled therapeutic trial for newly diagnosed childhood acute lymphoblastic leukaemia in India. Trials 23, 102 (2022). 3. Sidhu, J. et al. Unsatisfactory quality of E. coli asparaginase biogenerics in India: Implications for clinical outcomes in acute lymphoblastic leukaemia. Paediatric Blood & Cancer 68, e29046 (2021). 4. Müller, H. J. & Boos, J. Use of L-asparaginase in childhood ALL. Crit Rev Oncol Hematol 28, 97–113 (1998 ). ACKNOWLEDGMENT Our Patients and their families Paediatric Oncology Department (TMC) TMC BioBank FUNDING ICiCLe-ALL-14 is funded by Indian Council of Medical Research and National Cancer Grid The clinical trials unit is part supported by a DBT-Wellcome Trust Margdarshi grant to Prof. Vaskar Saha Gennova Biopharmaceuticals has sponsored the vial donation system Dr. Jasmeet Sidhu is an India Alliance Early Career Clinical Fellow