Trial Information

INTERNATIONAL STUDY of Chronic Myeloid Leukaemia (CML) Treatment and Outcomes in Children and Adolescents

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 hémopathies 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
7.

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 liberté" (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.