Allogeneic Stem Cell Transplantation for Children With CML

Study Overview
=================
Brief Summary
-----------------
In children and adolescents with chronic myeloid leukaemia (CML) stem cell transplantation (SCT) may be a valid alternative to the life-long treatment with tyrosinkinase inhibitors (TKI). This trial aims to evaluate the use of a reduced intensity conditioning regimen (RIC), consisting of fludarabine, melphalan and thiotepa in order to minimize transplant related mortality and toxic late effects. Strict post-transplant monitoring and reintroduction of TKI as well as donor lymphocyte infusions (DLI) in case of relevant residual disease are part of the protocol.

Detailed Description
-----------------
Chronic myeloid leukaemia (CML) is a rare disease in children with an incidence of 3-5% of all paediatric leukaemias. Since the introduction of tyrosinkinase inhibitors (TKI) stem cell transplantation (SCT) is no longer the first choice treatment for patients with early phase CML. However life-long treatment with TKI may not be feasable in several cases due to side effects such as growth retardation, non-compliance and resistance. This protocol evaluates the feasibility of SCT following a reduced intensity conditioning regimen (RIC) consisting of fludarabine, melphalan, thiotepa and thymoglobuline (ATG). Matched siblings and matched unrelated donors are permitted for stem cell donation. In case of unrelated donors tissue typing has to be done by high resolution molecular typing. Donors with 10/10 or 9/10 identical allels in the human leukocyte antigen (HLA) system are accepted. Preferred stem cell source is bone marrow but peripheral blood stem cells and umbilical cord blood are also allowed. Graft-versus-Host-Disease (GvHD)-prophylaxis is achieved with cyclosporine A and mycophenolate mofetil. Monitoring of the breakpoint cluster region - Abelson (BCR/ABL) rearrangement is performed monthly in the first year after SCT. In case of BCR/ABL positivity TKI are given in the first year after SCT. Followed by donor lymphocyte infusions (DLI) later on if BCR/ABL positivity persists.

Official Title
-----------------
Allogeneic Stem Cell Transplantation for Children and Adolescents With CML: Conditioning Regimen, Donor Selection, Supportive Care and Diagnostic Procedures

Conditions
-----------------
Chronic Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: Fludarabine
* Drug: Thiotepa
* Drug: Melphalan
* Drug: ATG
* Drug: Cyclosporine A
* Drug: Mycophenolate mofetil
* Biological: bone marrow or peripheral blood stem cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: children and adolescents with BCR/ABL positive CML in chronic phase, who are eligible for allogeneic stem cell transplantation, irrespective of the previous treatment strategy availability of a HLA matched sibling donor (MSD), a matched family donor, a matched unrelated donor or a matched unrelated cord blood (MD) informed consent Exclusion Criteria: unavailability of MSD or MD patients in accelerated phase or blast crisis pregnancy previous autologous or allogeneic SCT no informed consent

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single arm<br>Fludarabine intravenous - daily dose: 40mg/sqm on day -7, -6, -5, -4; Thiotepa intravenous - daily dose: 2 x 5mg/kg on day -3; Melphalan intravenous - daily dose: 140/mg/sqm on day - 2; ATG intravenous - dose according to local standards on day -3, -2, -1; bone marrow or peripheral blood stem cells of an HLA identical sibling or matched unrelated donor on day 0; GvHD propyhlaxis with Mycophenolate Mofetil and Cyclosporine A | Drug: Fludarabine<br>* infusion<br>* Other names: Fludara;Drug: Thiotepa<br>* infusion<br>* Other names: TESPA;Drug: Melphalan<br>* infusion<br>* Other names: Alkeran;Drug: ATG<br>* infusion<br>* Other names: Thymoglobulin;Drug: Cyclosporine A<br>* infusion, orally if possible<br>* Other names: Sandimmune;Drug: Mycophenolate mofetil<br>* infusion<br>* Other names: CellCept;Biological: bone marrow or peripheral blood stem cells<br>* infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| transplant related mortality |  | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival |  | five years | 
| event free survival |  | five years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stem cell transplantation, pediatrics