Real-time Therapeutic Drug Monitoring (TDM) of Asparaginase

To initiate the access process, kindly provide your email, full name, and the name of the center where you are employed. Once we receive this information, we will proceed with facilitating your access to REDCap. Please send the required details to either Biomedical Laboratory Scientist Dorte Emilie Wulff at dorwul@rm.dk or Research Nurse Karen Møller at karemoel@rm.dk

Your username and password will be sent to the email address provided. Please check your inbox for further instructions on accessing the platform. If you encounter any issues or have any questions, feel free to reach out to us for assistance.

Remember to adhere to the requirement of logging in every six months to maintain your access privileges, as failure to do so may result in automatic suspension.

https://redcap.au.dk/

Follow these steps:

1. Navigate to the "Add/Edit Records" section.
2. Enter the patient's information, including their Castor number, NOPHO number, or initials along with their birthdate.
3. 3 Click on "Add/Edit Records" to proceed with the registration.

If the patient doesn't have a Castor or NOPHO number, you can use their name or initials along with their birthdate for registration purposes.

Introduction

Under the "Introduction" tab, patient data is recorded. This page is only required for the first sampling:

Sample

In the "Sample" section, you'll be entering crucial information about individual blood samples. Here are some key points to remember:

1. Reference Previous Asparaginase Treatments:

• Ensure to incorporate data from previous asparaginase treatments for each sampling instance.
• Note that the sample date and the date of asparaginase treatment often vary.

2. Specify Method of Asparaginase Administration:

• Clearly indicate whether asparaginase was administered intravenously (i.v.) or intramuscularly (i.m.).

3. Indicate Number of Doses Administered:

• Specify the number of doses of asparaginase administered to the patient.

4. Denote Premedication Administration:

• If premedication was given for a particular dose, ensure to indicate it in the sample information.

• If you couldn't take a sample within 1 hour after administration (e.g., 2 or 3 hours later), mark it as an NA sample and provide information like "taken 2 hours after infusion" in the comments.
• If a patient has an allergic reaction to the infusion and can't complete the entire treatment, select "reduced dose" and specify the given dose in percentage.
• If addressing side effects related to a preparation given date, ensure the same side effects are filled in under all samples referring to the same preparation given date.

If the patient has side effects these must be registered under the following:

When "yes" for side effects a drop down menu will open with options for side effect, severity, description and date. Please fill out as detailed as possible.

In the event of an allergic reaction:

If asparaginase is administered intravenously (i.v.), a sample should be collected immediately after the infusion is halted. Additionally, if feasible, an extra sample should be taken either later the same day or the following day, and again 7 days after the reaction to identify increased clearance.

If asparaginase is administered intramuscularly (i.m.), a sample should be obtained one day after the administration of asparaginase. Moreover, if possible, an additional sample should be collected two days after administration, and again 7 days after the reaction to identify increased clearance.

Recommendation

The "Recommendation" tab is used by Aarhus University Hospital, Denmark, to enter the recommendation after the blood sample analysis is available.

Possible recommendations from the Asparaginase Team are:

• Continue PEG-asparaginase treatment
• Re-expose to PEG-asparaginase is recommended
• Change to Erwinase – inactivation of PEG-asparaginase verfied
• Change to Erwinase – inactivation of PEG-asparaginase NOT verfied (too small a volume given)
• Silent inactivation of PEG-Asparaginase - change to Erwinase
• Change to i.v. administration of PEG-Asp due to low activity levels
• Continue Erwinase treatment 
• Re-expose to Erwinase is recommended
• Silent inactivation of Erwinase - stop further Erwinase treatment
• Sample not received
• Not possible to evaluate (usually because too little of the dose has been given (i.e.1-10%), or the sample has been taken >14 days after administration of the last PEG-Asparaginase dose, or >-2-3 days after administration of the last Erwinase dose)
• Send a new sample as soon as possible
• No response from the site (the site has been contacted by e-mail for additional clinical information for being able to give a reliable recommendation, and the site has not answered)
• Baseline sample (a sample before the first dose or >18 days after the previous PEG-asparaginase dose should not be drawn, as the activity level will always be zero and adds no information)

Erwinase:

Sampling during Erwinase treatment is described in ALLTogether TDM ASP v2.1 incl. Down 01OCT2021_Clean on the ALLTogether portal.

This sampling schedule describes the minimal sampling and shipment in batches.’

At the Asparaginase Lab in Aarhus we offer the execution of additional analyses, and recommend sampling of trough activity levels before the second, fourth, sixth dose and then before every third dose. In case of reduction of the dose, we recommend sampling before the subsequent two doses.

To receive alerts when a recommendation becomes available for a specific patient in REDCap, kindly provide the email address where you wish to receive the alerts. You can send this information to Biomedical Laboratory Scientist Dorte Emilie Wulff at dorwul@rm.dk.

Confirmation

The Confirmation tab is used to view and acknowledge that the recommendation has been read and followed by the site:

Sample overview for the patient

Sample overview

ALLTogether; Sampling during PEG-asparaginase treatment for patients < 25 years (pdf)

ALLTogether; Sampling during PEG-asparaginase treatment for patients > 25 years (pdf)

ALLTogether; Sampling during PEG-asparaginase treatment for patients with Down syndrome (pdf)

For the analysis of PEG-Asparaginase and Erwinase activity levels, EDTA-plasma is required. Follow these steps:

1. Centrifuge the blood sample at 2000 g for 10-15 minutes at room temperature.
2. Subsequently, divide the supernatant into 2 cryotubes and ensure prompt shipment.
3. The sample material remains stable for at least 8 days at room temperature, including shipping time.

Ensure that cryotubes are labeled with the date, patient initials, date of birth, and the Castor number. In the case of two asparaginase samples from the same patient on the same date, distinguish them with "before or after asparaginase treatment" for accurate assessment of results. If the patient lacks a Castor number, label the cryotubes with the patient's name and birthdate.

Corresponding information must be filled in the requisition form, matching the details marked on the asparaginase sample. The patient's name and other information used during patient registration in REDCap should also mirror these details.

Note: Register the samples in REDCap TDM of Asparaginase before dispatching them for analysis.

This official requisition form for ALLTogether's TDM of Asparaginase sampling ensures the submission of essential information, enabling precise treatment recommendations.

3c3c (download Lab Requisition Form)

Note:

• Ensure Consistent Patient ID: Maintain uniform patient identification across the requisition form, sample labeling, and REDCap
• Emphasize Date of Sampling: Highlight the date of sample collection as crucial information, including the timeframe before or within one hour after administration.
• Complete All Requested Data: Fill in all required information diligently. Make a specific note if requesting measurement for Erwinase instead of PEG-Asparaginase

To ensure smooth processing of samples sent from a non-EU country to Denmark, please adhere to the following guidelines:

• All sites from a non-EU country sending samples to Aarhus must complete a proforma invoice using the provided template.
• Make sure the proforma invoice is visible from outside the package and includes the procedure code 4000C16, SE number 29762929, and the unit value of 1 DKK/NOK/Euro.

Norway - Invoice.pdf

Please ensure that all necessary information regarding the hypersensitivity reaction is filled in under the "Side effects since the last dose" section. This includes specifying the severity of the hypersensitivity reaction, which should be graded according to the PdL toxicity consensus definition as described in REDCap.

If the entire prescribed dose was not administered, please indicate "Reduced dose" and state the percentage of the prescribed dose that was given. This information is crucial for making accurate treatment recommendations.

By providing comprehensive details regarding hypersensitivity reactions and any deviations from the prescribed dose, it is easier for us to assess the patient's condition and provide an appropriate recommendations.

Hypersensitivity reactions can occur due to the administration of asparaginase, as it is a foreign protein for the human body. These reactions often manifest following an asparaginase-free phase, particularly during ALLTogether1 post-induction/start of consolidation 2. To mitigate the risk of hypersensitivity reactions or reduce their severity, it was decided within the ALLTogether Consortium, starting from October 2021, to administer premedication before PEG-asparaginase post-induction. This proactive measure aims to enhance patient safety and minimize adverse reactions associated with asparaginase treatment.

When a patient develops clinical symptoms of a hypersensitivity reaction, asparaginase enzyme activity levels must be measured to distinguish between hypersensitivity with inactivation of the enzyme activity and an allergic-like reaction without inactivation. The sampling depends on the route of administration (IV or IM).

IV Administration:

IM Administration:

If you give PEG-Asparaginase IM, the hypersensitivity reaction usually occurs later compared to IV administration (within 2 hrs after administration. Henriksen LT et.al. PBC 2015). To identify inactivation, three samples must be taken, i.e. one, two and seven days after the reaction.

For IV as well as IM administration:

• Please provide us with as much information regarding the allergic reaction as possible.
• Information about the percentage of the prescribed dose that was given before the sampling.
• This information is necessary for the “Asparaginase Lab” being able to give a qualified recommendation for further treatment.

Patients with inactivation of PEG-asparaginase enzyme activity will switch to Erwinia asparaginase treatment.

Sampling during Erwinase Treatment – Substitution after Inactivation of PEG-Asparaginase:

During Erwinase treatment samples may be send for analysis more frequently, and especially after reduction of the dose (i.e. to 75%) due to side effects, minimum sampling after the two following doses (trough levels after 48 hrs.) is recommended.

ALLTogether TDM ASP v2.1 incl Down 01OCT2021 Clean.pdf

If the Erwinase dose is reduced, for instance, to 75%, it's imperative to monitor trough levels before the two subsequent doses to ensure trough levels remain above 100 IU/L.

Erwinase is typically administered every second day. However, if the decision is made to administer it on a Monday-Wednesday-Friday schedule, trough levels should be taken on Mondays (3 days after the last dose).

In the event that a patient develops hypersensitivity symptoms during Erwinase treatment, please provide the following details in REDCap:

1. Grade of reaction
2. Percentage of the prescribed dose administered
3. Description of the symptoms

1. Sample Timing:

• Samples should be taken within 14 days after the previous PEG-asparaginase dose.
• Sampling between doses and after the last scheduled dose, followed by a long asparaginase-free phase (>14 days), should not deviate more than +/- 1 day from the indicated time-points in the tables.

2. Adjustments:

• In special situations, such as logistical constraints, adjustments to the sampling time may be necessary. For instance, the sample on day 32 can be brought forward from day 32 to day 29.