Last updated on February 2018

International Chronic Myeloid Leukemia Pediatric Study

Brief description of study

The purpose of the study is to describe and characterize CML in a large pediatric cohort of patients.

Detailed Study Description

International study of CML in children and adolescents

  1. Rational and objectives 1.1 Rational: Chronic myeloid leukaemia (CML) is a malignant disease of the hematopoietic system characterized by the presence a reciprocal translocation between chromosome 9 and 22. CML is a very rare disease in children and adolescents, accounting for 2% to 3% of leukemias in this age range, with an annual incidence of 1 case per million children (1,2,3). A recent report of the French National Registry of childhood leukemia and lymphoma revealed an incidence of 0.6 case per million children under 15 years of age between 1990 and 1999 in France. Characteristics of CML seem to differ in this age range compared with adults (5). In Europe, very few children and adolescents with CML is included in national trials nor are they recorded in regional or national registries. A European CML-Registry was established to improve the knowledge concerning this disease but only patients aged 18 years and over are registered. In Europe, a national registry was recently set up in UK to collect prospectively data in patients less than 15 years of age with CML. However, limited information is available concerning the epidemiology and the characteristics of CML in childhood.
     There are currently two main treatment options in children with CML. The first option is
     allogeneic hematopoietic transplantation which is a potentially curative therapy in
     children with a suitable donor. Transplantation with a matched unrelated donor resulted
     in an overall survival rate of 66% at 3 years in children with CML in first chronic
     phase (6). A 5-year overall survival rate of 73 % was reported in those transplanted
     with a matched sibling donor (7). The second option is treatment with imatinib mesylate,
     an orally administered antityrosine kinase. Imatinib mesylate is well tolerated and
     cytogenetic and molecular remissions can be achieved in a significant percentage of
     children with CML (8, 9). However, the ability of imatinib mesylate to cure the disease
     remains unknown.

     In adults with CML, Sokal and Hasford reported 2 distinct staging systems able to
     distinguish patient groups with different survival. These scoring systems were
     determined in cohorts of patients including adults and children, but the data of the
     younger patients were not analysed separately. Moreover, the Sokal score was determined
     in patients treated with busulfan or hydroxyurea and the Hasford score in patients
     receiving IFN therapy. Identification of prognosis factors and determination of a
     prognostic scoring system in children and adolescents with CML are essential to optimize
     individual treatment strategy in this age group. All these points justify the need for
     an international network to better describe this rare disease in children and
     adolescents and to optimize individual treatment strategy.

     1.2 Objectives.

     The main objectives of the study are the followings:

     -  To describe the characteristics of CML in a large cohort of patients less than 18
      years of age

     -  To describe the treatment policies.

     -  To identify prognostic factors in this age-group

     -  To determine prognostic scoring systems in this population in order to optimize
      individual treatment choices.

     -  To determine side effects and long term effects of treatments, mainly the tyrosine
      kinase inhibitor effect, on growth and development of a pediatric population

2. Population. All patients less than 18 years of age with newly diagnosed Philadelphia

     positive and/or bcr-abl positive CML are eligible whatever the phase of the disease, the
     type of treatment and the enrollment or not in a clinical study.

     However their data will be collected only if requirements concerning ethics and policy
     agreement are fulfilled (see section 9)

3. Method The study is strictly observational. Retrospective and prospective data will be collected from patient flow charts and/or existing databases.

     A steering committee (SC) including A Biondi, E De Bont, MF Dresse, J de la Fuente, M
     Suttorp, J Guilhot and F Millot will promote the international study of CML in children
     and adolescents. The SC will include representatives of each country involved in the
     study. The SC will agree on policy, support its implementation, initiate research, and
     raise public awareness about the study by presentations and publications.A scientific
     committee (SciC) will be set up. By laws regarding data property,analysis and
     publication will be decided by the scientific committee and the steering committee. For
     each objective of the study, there will be a working party (WP),which will be open to
     all interested participants in the study.Data will be provided by clinicians and
     biologists involved in pediatric haematology.The data base of the study will be set up
     in the Clinical Investigation Center(CIC INSERM 802)of the University Hospital of
     Poitiers(France)which will be the International Central Data Center(ICDC) of the study
     in charge of and centralizing the data. Sophie Zin Ka Yeu will be the responsible for
     the monitoring,E Ducasse for data base management and J Guilhot for the statistical
     analysis. The study is international.A National Coordinating Center and a leader will be
     identified in each participating country. The National Coordinating Center will be in
     charge of collecting data for his country. Each leader of the National Coordinating
     Center will be in charge of registering the patients and sending the data to the ICDC
     (CIC INSERM 802, Poitiers, France). To avoid double entry, the location of the medical
     center where the CML of the patient was diagnosed will be recorded in the case report
     form. Moreover, notification of new cases may be cross checked by national coordinators
     with their own national registry when available (for example with the Registre national
     des hmopathies malignes de l'enfant in France).

4. Origin and type of data:

Data will include:

  • Identification number
  • Demographic data
  • Date of birth
  • Sex
  • Medical data Ethnicity will be collected because of variation in terms of clinical characteristics (height for example) and pharmacokinetic of medication of the different groups of children potentially involved. Identifying biological results will not be collected.
     The ICDC will collect only data which is strictly anonymized by the national
     coordinating centers. Patients will be identified by a code including 2 to 3 letters for
     the country and 4 digits for the patient number (ex: FR/0001 for the first registered
     Patient in France). No initial of patients will be used. As country coordinator for
     France, F Millot will also collect initials of French patients in order to avoid double
     registration. These initials will not be computerized. The international ID number will
     be immediately provided.

5. Circulation of the data The data is centralized in the ICDC of the study. The ICDC is

     located in the Clinical Research Investigation Center of the University Hospital of
     Poitiers (France).

     Retrospective data:the data will be collected in a one step procedure. Prospective
     data:The data will be collected using a two step procedures.

     1. Notification of the cases:

      New cases will be notified by physicians and biologists involved in pediatric
      hematology to their National Coordinating Center; at regular intervals these cases
      will then be referred by this coordinating center to the ICDC.

     2. Full data collection:

     The data will be collected from the clinical chart of the patients. The complete data
     will be send to each National Coordinating Center and then centralized at regular
     intervals subsequently in the ICDC. Follow up will be required twice a year. For each
     case of CML, a yet to be fixed sum of money will be transferred from the ICDC to the
     National Coordinating Center at notification of the case and when complete data transfer
     will be performed.

     To avoid extra work, data already computerized will be accepted if it fulfilled the
     requirements of ethics, confidentiality and partnership rules as mentioned in paragraph

     When available agreement between parties, data may come from case report form of
     patients included in clinical studies or other Registries. Data will be sent by regular
     mail, fax or electronic file by the national coordinators to the ARC of the study at the
     ICDC. Data received by mail will be transferred by copy using disks (CD-Rom or external
     disk) to the data-manager and destroyed from the computer with mail box. Data will be
     entered in a Microsoft ACCESS database in the ICDC. Data base will be implemented in a
     PC (I) (Windows) located in a room dedicated for the purpose of the work. A second PC
     (II) in the same place will be used for duplication, backup, quality control and
     analysis of the data. None of these 2 PCs will offer connections such as Internet, or
     Intranet. The use of an electronic case Report form (e-CRF) is not planned. A secure
     access building and rooms of the ICDC is organized; specific password and login for the
     computers are used. At regular interval a secure storage of the data will be performed
     and located in the secure IDCD room organized for this purpose. Access to the data will
     be restricted to the coordinator of the study, the ARC, the data manager, the
     biostatistician, and Health Authorities, if needed.

6. Study duration and organization The expected start date is August 1, 2009. The planned

     study duration is about 5 years. Study prolongation will depend on the funding linked to
     the effective participation of the centres in the study.

7. Analysis of the data Data will be analysed using mainly SAS software (SAS institute,

     CARY, NC, USA). Final analyses will be provided within 5 years from start of the study.
     Analysis will be mainly descriptive. Date of inclusion in the study is defined as the
     date of reception of the notification of case by the ICDC. For the purpose of
     descriptive analysis, all parameters will be analysed at regular intervals: number of
     registered cases, baseline characteristics, follow-up and outcome variables. Categorical
     data will be presented with frequency, percentage and 95 % confidence interval.
     Quantitative variable will be presented with median and range, mean and standard
     deviation when relevant. Survival data and issue to events (time to response or
     side-effects, loss and duration of response); will be analysed by the Kaplan Meier and
     competing risks methods. For prognosis factors identification, exploratory analyses will
     be performed as appropriate. The final statistical plan will be validated by the
     steering committee and the scientific committee.

     Reports will be provided every 6 months and by the end of the study by the ARC, the data
     manager, the biostatistician and Dr F. Millot, coordinator of the study. These reports
     will be sent to the national coordinators and to the participants. Results could be
     presented in Workshops, meetings and could be published with the agreement of the
     steering and scientific committees. All reports and publications will remain anonymous.

8. Number of Patients :

     A proximately 100 to 150 patients per year are expected. As the number of cases of
     children and adolescent with CML being low, no strict calculation was made. The
     objective is to collect a maximum of cases to improve the power of the study.

9. Ethical Considerations The children, according to their age, and their parents will be

     informed about the study and its procedures, according to the European policy regarding
     collection and transfer data for research purpose. Informed consent (parents and, when
     possible, children) will have to be provided.

Anonymized data will be collected and presented in this study. Rules will be in accordance with the Principles and Guideline of the European Community concerning clinical studies and data collection and the French Law "Informatique, fichiers et libert" (January 6, 1978, updated.It is the responsibility of each national coordinator to provide insurance concerning the participation of the members of his groups according these rules and the local rules required by his own country.

Clinical Study Identifier: NCT01281735

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