---

You can get the PDF-brochure, here

Introduction

François-Xavier Mahon and Mathieu Molimard

Dear Colleagues,

As you know, imatinib is the current first-line treatment of choice for chronic myeloid leukemia. We now have the opportunity to be able to determine trough imatinib plasma levels for patients receiving imatinib. If you wish to use this service, please find enclosed a brochure that will explain how to process samples.

We are sure that you are all convinced by this ‘pharmacological’ tool in light of your own experience and recently published results, but let me remind you about the main situations where it is indicated:

• You suspect that a patient may be non-adherent to imatinib
• You suspect that a patient may be experiencing a drug–drug interaction
• A patient is not responding to imatinib as well as he/she should be
• A patient is experiencing unusually severe side effects for the administered dose

Other situations are also interesting, and allow us all to gain experience with this treatment and insights into how treatment might be optimized. It is of great benefit to patients that the European Leukemia Network supports this service, and we would like to thank everyone who has participated in this project.

Best regards,


Professor François-Xavier Mahon Professor Mathieu Molimard

Pharmacological monitoring laboratories:

Guidelines for participation

Background

The European Treatment and Outcome Study for chronic myeloid leukemia (EUTOS for CML) is a scientific collaboration between the European LeukemiaNet (ELN) and Novartis. Its main purpose is to support the optimization of treatment for CML.

There are multiple projects planned within the EUTOS for CML program. One of these is a pharmacological monitoring project, designed to increase the provision of plasma imatinib monitoring, free of charge, across Europe. The guidelines below are intended for laboratories that wish to offer this monitoring service.

Project aims

The aims of the pharmacological monitoring project are:

• To provide a Europe-wide monitoring service free of charge (sample transportation and plasma-level determination) for a period of 3 years.
• To construct a database that will verify the imatinib therapeutic threshold by following patients with trough plasma levels < 1000 ng/mL
• To identify and certify laboratories across Europe, and establish imatinib plasma-level determination services within the respective countries, in collaboration with the central facility in Bordeaux, France (laboratory of Prof. Mathieu Molimard, Department of Clinical Pharmacology and Toxicology, Pellegrin Hospital and University Victor Segalen, Bordeaux).

Organizational structure

• The Pharmacological Monitoring project will be overseen by a Steering Committee, initially consisting of Prof. Francois Guilhot (Université de Poitiers, Poitiers, France), Prof. Francois-Xavier Mahon (Université Victor Segalen, Bordeaux, France), and Dr Peter Schuld (Novartis).
• The Steering Committee will lead the implementation of the Pharmacological Monitoring project. In particular, it will be responsible for nominating and certifying laboratories for participation within the project.
• It is anticipated that 1–2 laboratories will be selected per participating country. However, numbers may vary at the discretion of the Steering Committee.
• All participating laboratories need to belong to the ELN. Details of how to join may be obtained from the ELN or Novartis.

Plasma-level determination protocol

1. Laboratories will adopt the same protocol for trough imatinib plasma concentration determination as is used at the central monitoring facility in Bordeaux, France.
2. Details of this protocol can be found in: Titier K, Picard S, Ducint D, et al. Quantification of imatinib in human plasma by high-performance liquid chromatography - tandem mass spectrometry. Ther Drug Monit 2005; 27:634-640.
3. A brief summary of the protocol is given below:
   - The methodology is based on a high-performance liquid chromatography tandem mass spectrometry for imatinib therapeutic drug monitoring in plasma.
   - After a liquid-liquid extraction, the imatinib and its deuterated internal standard are eluted on an Xterra® RP18 column with a gradient of acetonitrile-ammonium formiate buffer (4 mmol/L, pH 3.2).
   - Imatinib is detected by electrospray ionization mass spectrometry with multiple reaction monitoring mode.
   - The calibration curves should be linear over the range 10-5000 ng/mL.
   - The limit of quantification is set to 10 ng/mL.
   - Imatinib-associated materials will be provided by Novartis.
   - Requests should be directed to Dr Peter Schuld (peter.schuld@novartis.com).
4. Imatinib-associated materials will be provided by Novartis. Requests should be directed to Dr Peter Schuld (peter.schuld@novartis.com).

Quality control

Laboratories will be free to adapt the protocol to the equipment at their disposal. However, a cross-check of the results will be organized by the Bordeaux center before dosing laboratories can receive certification.

The Bordeaux center will prepare and send a linear range of 8 spiked blank plasma samples (corresponding to part of the calibration range used) and 12 non-linear plasma samples (from either pooled or single patient plasma, spiked plasma or internal controls used at the Bordeaux center).

A system of regular quality-control checks will also be put in place. Every 2 months, 3 samples will be sent to the dosing laboratories (either pooled or single patient plasma or spiked plasma).

Reimbursement

Plasma-level determination and shipment costs will be covered by the Bordeaux center.

Pharmacological monitoring:

A guide to submitting blood samples for imatinib testing

Through the European Treatment and Outcome Study (EUTOS) for CML program, the European LeukemiaNet and Novartis are pleased to offer plasma imatinib monitoring free of charge (for sample transportation and dosing).

Follow this simple protocol for taking and submitting plasma samples:

1. Draw a 5 mL blood sample into a heparinized vial immediately prior to the patient taking their daily dose of imatinib (i.e. 24 ± 3 hours after the previous dose).
2. Centrifuge for at least 5 minutes at 4000 rpm. Separate the plasma supernatant into vials, and retain.
3. If necessary, samples may be stored at 4 °C for up to 1 week (e.g. if shipments are to be pooled).
4. Complete a Monitoring Request Form (included)
5. Ship the sample and Monitoring Request Form to Prof. Mathieu Molimard at the Bordeaux University Hospital,* using the address given on the Monitoring Request Form.
   a) The sample should be sent within approved packaging
   b) Please use the approved carrier
   c) While in transit, the sample should kept at ambient temperature (< 30 °C)

*Initially, all samples will be processed in Bordeaux. However, additional centers across Europe are currently being certified. Novartis representatives will update you on your nearest laboratory once the certification process is complete.

Any questions?

Please direct all queries to the team at the central facility in Bordeaux. They may be contacted directly at imatinib@chu-bordeaux.fr

Monitoring Request Form:

Explanatory notes

Send the sample and Monitoring Request Form to this address. Give details of the patient’s name and personal details. Note down the contact information for your facility or unit, so that we can contact you with any queries, and with the results of the imatinib blood-level testing. Give details of the exact time and date at which the blood sample was drawn, and the time and date of the last dose of imatinib taken by the patient prior to sampling. Sampling should be done 24 ± 3 hours after the last dose. Tick the box or boxes that most closely match your reasons for wanting to monitor the blood imatinib level in this patient. Tick the boxes that match the most recently measured cytogenetic and molecular responses observed in the patient (if available). Give details of the patient’s current treatment regimen, any incidents that occurred during sampling that could affect the results, and any BCR-ABL mutations the patient is known to have.

Pharmacological monitoring:

Which patients should be considered?

Through the European Treatment and Outcome Study (EUTOS) for CML program, the European LeukemiaNet and Novartis are pleased to offer plasma imatinib monitoring free of charge (for sample transportation and dosing).

The pharmacological monitoring project has been designed to help physicians optimize treatment with imatinib. A number of factors may affect imatinib blood levels, including pharmacokinetic factors such as drug–drug interactions, and patient-related factors such as adherence. If a patient is not responding to imatinib as expected, it is essential to determine whether this is due to inadequate blood levels of the drug. It should not be assumed that patients have become resistant to imatinib.

Imatinib blood-level testing should be considered in patients who:

• You suspect may not be adhering to their imatinib regimen;
• You suspect may be experiencing a drug–drug interaction;
• Are not responding to GLIVEC treatment as well as you would expect; or
• Are experiencing side effects that are unusually severe for the dose of imatinib they are taking.

If your patient fits into one of these four categories, imatinib blood-level testing may help you to understand why they are not doing as well as expected.

Frequently asked questions

What is EUTOS for CML?

The European Treatment and Outcome Study for CML (EUTOS for CML) is a unique scientific collaboration between the European LeukemiaNet (ELN) and Novartis. It aims to use the strengths of the two organizations – the clinical expertise and experience of the ELN, allied to Novartis’ outreach potential and funding provision – to help physicians optimize the treatment of CML.

Why do we need the EUTOS for CML program?

Strategies for the management of CML have evolved rapidly over the past few years, and Europe has played a leading role in this process. The EUTOS for CML program has been created to help keep Europe at the forefront of this advancement in the coming years. Ultimately, the program will foster continued improvements in outcomes for European patients with CML.

What projects are being run within the EUTOS for CML program?

There are four key projects:

CML registry – expanding the existing European registry to facilitate the collection of baseline, treatment and outcome data from representative samples of European patients with CML Molecular monitoring – promoting quality-controlled, standardized monitoring of therapeutic outcomes at the molecular level Pharmacological monitoring – increasing the availability of therapeutic drug monitoring Spread of excellence – promoting continuing medical education and awareness of CML

Why monitor blood levels of imatinib?

Trough plasma levels of imatinib have been associated with both cytogenetic and molecular responses, with a level of around 1000 ng/mL recommended for a full molecular response.1

However, at a given dose, trough plasma levels of imatinib may vary greatly between patients. There are several potential causes, including pharmacokinetic factors such as drug–drug interactions, and patient-related factors such as adherence.

Hence, if a patient is not responding to imatinib as expected, blood-level testing is an essential tool for determining whether imatinib blood levels are adequate. It should not be assumed that the patient has become resistant to imatinib.

What is the purpose of the EUTOS for CML pharmacological monitoring project?

The aims of the project are to increase the availability of blood-level testing and to standardize the protocol across Europe. To achieve these aims, quality-controlled monitoring laboratories will be set up across the continent. While these laboratories are being certified, monitoring will be performed at a central facility in Bordeaux.

Why should I get involved?

The EUTOS for CML program has been created by the ELN and Novartis to help enhance outcomes in CML. Imatinib blood-level testing thus has the potential to improve outcomes for specific patients in your care. By taking part, you will also be helping the wider medical community to understand the epidemiology of CML, and how different interventions affect treatment success.

How much will it cost?

Pharmacological monitoring will be provided free of charge for participating centers.

Where and how can I submit samples?

Local facilities are currently being identified and certified. In the meantime, all samples will be submitted to a central facility in Bordeaux. Further details are available from the Guide to Submitting Samples contained within this pack. Alternatively, you may wish to contact your local Novartis representative.

Reference

Picard S, et al. Blood 2007;109:3496-3499.

Contact list

Local Novartis office

(CPO to insert local contacts’ names, addresses, telephone, fax and e-mail)

Bordeaux University Hospital monitoring facility

Professor Mathieu Molimard
Centre Hospitalier Universitaire De Bordeaux
Laboratoire de Pharmacologie Clinique et Toxologie
Centre Hospitalier Pellegrin – Tripode
Plateau Technique 2ème Étage
33076 Bordeaux, France
Tel: +33 (0)5 56 79 59 91
Fax: +33 (0)5 56 79 47 95
E-mail: imatinib@chu-bordeaux.fr

Pharmacological monitoring working group

Professor Francois Xavier Mahon
Université Victor Segalen
Bordeaux, France
E-mail: francois-xavier.mahon@umr5540.u-bordeaux2.fr

Professor Francois Guilhot
Université de Poitiers
Poitiers, France
E-mail: f.guilhot@chu-poitiers.fr

Dr Peter Schuld
Senior Clinical Research Manager
Novartis Pharma S.p.A.
Region Europe Business Unit Oncology
Largo Umberto Boccioni, 1
21040 Origgio (VA), Italy
Tel: +39 02 9654 2688
Fax: +39 02 9654 2668
E-mail: peter.schuld@novartis.com

Created by: A. Hellenbrecht , generated 2008/01/03 , last changed: 2008/08/21