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.