Introduction

Acute lymphoblastic leukemia (ALL) is the most common cancer in children as it represents approximately 25% of cancer diagnoses among children below 15 years. Management of ALL has evolved over many decades; with a risk-based approach, treatment intensification, and better supportive care, survival rates in children have progressively risen to nearly 90%.1 L-asparaginase is an integral component of treatment for children with ALL and since its introduction by the Dana Farber group in 1977 into pediatric treatment protocols survival has significantly improved.23

There are three currently available L-asparaginase preparations approved for clinical applications: Escherichia coli-derived native E. coli asparaginase, PEGylated asparaginase (PEG asparaginase), and Erwinia chrysanthemi derived Erwinia Asparaginase. All presently available asparaginase preparations share the same mechanism of action—the deamination and depletion of asparagine, an essential amino acid for the lymphoblast. Yet, each displays a markedly different pharmacokinetic profile.45 PEG asparaginase has a significantly longer half-life and is less immunogenic than the native asparaginase.6 When used in front-line therapy to replace native asparaginase as part of combination chemotherapy, PEG asparaginase has shown comparable efficacy.7

In clinical practice, the enzyme is currently given by the intravenous (IV), intramuscular (IM), or subcutaneous route, with dosages being different across various protocols followed.8 Asparaginase activity of 100 IU/L at desired time point for the molecule is considered to be sufficient for complete asparagine depletion.9 Although this might theoretically result in different pharmacokinetic profiles, information on the comparability of the routes of administration is limited about the currently available preparations.

Therapeutic drug monitoring of serum asparaginase activity (SAA) level helps individualize asparaginase dosing. The common side effects encountered with asparaginase are hypersensitivity reactions, silent inactivation, cerebral sinus venous thrombosis, pancreatitis, hyperglycemia, hypertriglyceridemia, and liver dysfunction (hyperbilirubinemia and transaminitis). There is heterogeneity among healthcare providers in the usage of L-asparaginase concerning preparations used, doses and route of administration, therapeutic drug monitoring, and toxicity profile observed along with dilemma of choosing a bioequivalent drug. The present survey attempts to understand the asparaginase usage practice among healthcare providers in India, which will pave the way for effective designing of future clinical trials associated with pediatric oncology.

Methodology

A descriptive cross-sectional survey design was employed to assess the L-asparaginase usage practice among healthcare providers treating children with cancer in India. The survey was conducted through the smart survey platform. The potential participants for the study were faculty who had registered for National continuing medical education (CME) of Pediatric Hematology and Oncology held in December 2020 virtually. The sampling bias was avoided by sending the survey link through email to all faculty who attended the CME. The researchers sent fortnightly reminders to the participants during the data collection process to minimize the nonresponses. Data collected through this platform was digitally stored in a designated device as an encrypted file. The data was transferred and securely stored in a hard drive upon completing the data collection process.

The researchers have designed a three-part survey containing 25 questions to collect data from study participants. The first part consisted of information about the survey and consent. The second part included five questions to capture the demographic details of the survey participant, and the last part had 20 questions aimed to assess the asparaginase usage practices of the respondents. It was mandatory to answer all the 25 questions prior to submitting. Out of the 20 core questions, 14 were multiple choice questions, and the remaining 6 were dichotomous questions. A pilot survey on five pediatric oncologists was implemented to check content validity and comprehensibility, of the questionnaire, the results of which were excluded from the present data analysis.

The participant's responses to the survey questionnaire were recorded on Microsoft Excel 2016 and quantitatively analyzed using IBM SPSS 16.0. Descriptive statistics were implemented in the present study. The Institutional Ethics Committee (IEC), Kasturba Hospital and Kasturba Medical College, Manipal (IEC 532/2020) approved the study protocol.

Results

Out of the 215 participants who had registered for the CME, 120 faculty (junior and senior consultants) excluding trainees were sent the link for the survey. Of these 120 faculty, response was received from 80 healthcare providers treating children with cancer across India. The failure rate was 33%. The demographics of the healthcare providers participating in the survey is presented in Table 1.

Type and Dose of Asparaginase

The most common asparaginase used by Indian pediatric oncologists is native E. coli asparaginase. Forty-one (51.2%) respondents used the native form exclusively, whereas 21 (26.3%) respondents used PEGylated asparaginase exclusively and 18 (22.5%) respondents used both forms (Fig. 1). Erwinia asparaginase is unavailable in India and was not used. There was no statistically significant relationship between the practice setting and the type of asparaginase used by the healthcare providers (p = 0.489). There was significantly more utilization of PEG asparaginase among participants who had 5 to 10 years of experience (p = 0.04). Fifty-six (70%) respondents used 10,000U/m²/dose of native asparaginase. Sixteen (20%) and 8 (10%) respondents used native asparaginase at 6,000U/m²/dose and variable dose, respectively. Most of the participants (78%, n = 62) used a 72-hour dosing interval while administering native asparaginase. In the case of PEGylated asparaginase, 39 (48.8%), 32 (40%), and 9 (11.3%) respondents utilized 1000U/m²/dose, 2500U/m²/dose, and variable dose regimen, respectively. When asked about the preferred route of administration of asparaginase, 66% (n = 53) used the IM route and 29% (n = 23) respondents gave the drug by IV route, details of which are depicted in Fig. 2.

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Fig. 1: Frequency of utilization of different types of asparaginase (ASP). E. coli, Escherichia coli.

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Fig. 2: Preferred route of administration of asparaginase.

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Side Effect Profile

To understand the side effect profile of asparaginase, participants were asked multiple-choice questions with options consisting of various side effects of asparaginase such as hypersensitivity reaction, liver dysfunction (hyperbilirubinemia and transaminitis), hyperglycemia needing medication, cerebral sinus venous thrombosis, and pancreatitis. Further to this question elaborated the phase in which side effects were observed (induction vs. reinduction/delayed intensification), and the type of asparaginase utilized. The most common side effect observed by survey participants is hypersensitivity reaction followed by liver dysfunction. Frequency of hypersensitivity reaction was more in reinduction (40% in induction vs. 72% in reinduction with respect to native asparaginase). As per the respondents, the frequency of hypersensitive reactions was lesser with the utility of PEG asparaginase as compared with native formulation, which was statistically significant (p = 0.01). The side effect profile, route of administration, and the dose of asparaginase (native or PEGylated) lacked correlation with adverse events. The side effect profile is presented in Fig. 3.

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Fig. 3: Side effects profile of asparaginase (ASP) as observed by pediatric hematologists and oncologists in India. (A) Side effect frequency of native Escherichia coli ASP during induction. (B) Side effect frequency of native E. coli ASP during reinduction/delayed intensification. (C) Side effect frequency of PEGylated ASP during induction. (D) Side effect frequency of PEGylated ASP reinduction/delayed intensification.

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Discussion

This survey investigated asparaginase usage practice among healthcare providers treating children with cancer in India. Despite asparaginase being the 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 the treatment of pediatric ALL because of its prolonged effect, lower incidence of silent antibodies, similar safety profile, and convenience.6 Many international pediatric ALL trials have shown promising outcomes with PEGylated asparaginase.1011 Despite this in India, most survey participants use native formulation probably due to the higher cost and nonavailability of PEGylated formulation under certain national health schemes. As per this study, respondents majorly utilized 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 randomized 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 neutralizing antibodies in most instances. However, with the use of IV PEGylated asparaginase, a distinct type of acute clinical reaction (a non-allergic infusion reaction) is becoming increasingly recognized, 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 individualized PEGylated asparaginase dose.14 However, in the present study, participants opted to premedicate while rechallenging asparaginase without monitoring drug level, which might mask allergic reaction resulting in subtherapeutic levels hampering desired outcomes. As per the experiences from two oncology center in India, there was a concern regarding unsatisfactory quality and therapeutic activity of biogeneric native asparaginase marketed in India.1516 A 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 low-to-middle income country to utilize 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 utilized 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 toward 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.