4 DISCUSSION
This survey investigated Asparaginase usage practice among healthcare providers treating children with cancer in India. Despite Asparaginase being ta prime catalyst in improving the outcome of pediatric ALL, there is a wide variation in its usage practice in India. PEGylated Asparaginase has replaced native Asparaginase for treatment of pediatric ALL because of its prolonged effect, lower incidence of silent antibodies, similar safety profile, and convenience.6Many international pediatric ALL trials have shown promising outcomes with PEGylated Asparaginase.10,11 Despite this in India, most survey participants use native formulation probably due to the higher cost and non-availability of PEGylated formulation under certain national health schemes. As per this study, respondents majorly utilised the IM route, perhaps because this method is less time-consuming, does not require a test dose to be given and has ease of administration especially in high-volume centers. There was no statistically significant difference in reporting of mean hypersensitivity reaction rate between the IM and IV route, which is in accordance with the randomised study by the Dana Farber group.12
Incidence of hypersensitivity reaction varies depending on formulation, route, and frequency of administration. These hypersensitivity reactions are mediated by neutralising antibodies in most instances. However, with the use of intravenous PEGylated Asparaginase, a distinct type of acute clinical reaction (a non-allergic infusion reaction) is becoming increasingly recognised, and it is nearly impossible to distinguish this reaction from allergic hypersensitivity clinically. In this survey, hypersensitivity reaction was the most common adverse event noticed by participants, even for PEGylated Asparaginase during induction chemotherapy. As per a well-known study, a policy of universal premedication to prevent infusion-related reaction with therapeutic drug monitoring might significantly benefit our patient.13
As per the study findings, more than 90% of participants did not carry out therapeutic drug monitoring, but nearly 50% of participants felt that it would benefit their clinical decision. A study highlights the importance of therapeutic drug monitoring in individualised PEGylated Asparaginase dose.14 However, in the present study, participants opted to pre-medicate while re-challenging Asparaginase without monitoring drug level, which might mask allergic reaction resulting in sub therapeutic levels hampering desired outcomes. As per the experiences from two oncology centre in India, there was a concern regarding unsatisfactory quality and therapeutic activity of biogeneric native Asparaginase marketed in India.15,16A prospective observational study from North India demonstrated that achievement of adequate SAA level with generic brands of PEGylated Asparaginase. This could be the way forward for LMIC to utilise economical generic brands along with therapeutic drug monitoring.17
The side effect profile seen in India is almost similar to the side effect seen worldwide.18 Apart from an allergic reaction, another common reason for discontinuing Asparaginase therapy is pancreatitis; nearly 75% of survey participants were not re-exposing the drug following an episode of Asparaginase-associated pancreatitis. There is a significant negative impact of discontinuing Asparaginase, especially in high-risk patients.19 Hence, the decision to discontinue should be taken with caution, considering the severity of the initial episode and additional risk factors for pancreatitis.20 There is a need for prospective studies to define “re-challenge strategy” following Asparaginase-associated pancreatitis.
The present survey utilized an online method to obtain information from participants across the country. There were instances of multiple participants from the same institute/hospital vis-a-vis, no representation from a few institutions. Although the data from the survey can be utilised for identifying research gaps and proposing research questions, the survey results cannot be extrapolated for clinical use.
In conclusion, this survey shows a wide variation in L-Asparaginase usage among healthcare providers caring for children with cancer in our country concerning the formulation, dose and route of administration. As L-Asparaginase is the pivotal component of ALL therapy, uniformity in its usage and dosing is the need of the hour. With the availability of multiple generic brands, therapeutic drug monitoring of SAA should be a critical step towards improving outcomes in ALL in our country. We need prospective nationwide studies to define optimal asparagine depletion and the level of enzyme activity required in our population.