A Trial of Plerixafor/G-CSF as Additional Agents for Conditioning Before TCR Alpha/Beta Depleted HSCT in WAS Patients

Study Overview
=================
Brief Summary
-----------------
Treatment Study to assess of safety and efficiency of conditioning with Plerixafor and G-CSF as additional agents for prevention of graft failure after transplantation with TCR alpha/beta grafts depletion in patient with Wiskott-Aldrich syndrome.

Detailed Description
-----------------
Severe graft dysfunction, such as the degree of donor chimerism predominantly in the myeloid compartment is one of major problem in patients with Wiskott-Aldrich syndrome (WAS), especially after hematopoietic stem cell transplantation (HSCT) from alternative donor. It often leads to the development of severe thrombocytopenia or even transplants rejection. In this study the hypothesis is that the use of plerixafor and G-CSF as additional agents in conditioning regimen would offers advantages due to lowing risk of mixed chimerism after HSCT. This effect is based on the fact that simultaneous use of plerixafor with G-CSF is efficient in inducing stem cell release and opening of bone marrow (BM) niches. Moreover, stem cell release probably leads to liberation of host stem cells from the anti-apoptotic effects of the BM stroma for the more powerful effect of chemotherapy. In this study, the investigators use TCR alpha/beta grafts depletion of the grafts as basic technology for HSCT from haploidentical and unrelated donors approved in Institution. Thus, the purpose of this study is to evaluate the safety and efficiency of myeloablative conditioning with Plerixafor and G-CSF as additional agents for prevention of graft failure after transplantation with TCR alpha/beta grafts depletion in patients with Wiskott-Aldrich syndrome.

Official Title
-----------------
A Trial of Plerixafor With G-CSF as Additional Agents in Conditioning Regimen for Prevention of Graft Failure After Transplantation With TCR Alpha/Beta Grafts Depletion in Patients With Wiskott-Aldrich Syndrome.

Conditions
-----------------
Wiskott-Aldrich Syndrome, Hematopoietic Stem Cell Transplantation, Graft Failure

Intervention / Treatment
-----------------
* Biological: G-CSF for Conditioning before HSCT.
* Biological: Plerixafor for Conditioning before HSCT.


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients aged ≥ 1 months and < 19 years Patients diagnosed with Wiskott-Aldrich syndrome eligible for an allogeneic transplantation and lacking a related HLA-matched donor Lansky/Karnofsky score > 40, WHO > 4 Signed written informed consent Exclusion Criteria: Dysfunction of liver (ALT/AST > 5 times normal value, or bilirubin > 3 times normal value), or of renal function (creatinine clearance < 30 ml / min) Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or left ventricular ejection fraction <40%) Serious concurrent uncontrolled medical disorder Lack of parents' informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 19 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: Plerixafor/G-CSF for HSCT conditioning<br>Myeloablative conditioning regimen with Plerixafor and G-CSF as addition agents before stem cell transplantation in WAS patients. | Biological: G-CSF for Conditioning before HSCT.<br>* Mobilization of hematopoietic stem (HSC) into circulation<br>Biological: Plerixafor for Conditioning before HSCT.<br>* Directed inhibition of CXC chemokine receptor type 4 (CXCR4) for opening enough BM niches for adequate donor HSC engraftment.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival (EFS) | The EFS probability compared with historical control. We mean event as patient's death, second transplantation or persistence of severe thrombocytopenia | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | The OS probability compared with historical control. | 24 months | 
| Percentage of patients with full/mixed donor chimerism | Evaluation of the percentage of patients with the full/mixed donor chimerism (whole blood and CD3+ lineage). In addition, patients will be divided in accordance with % of donors cells: >95%; 50%-95%; 10%-49%; <10%. All data will be compared with historical control | 12 months | 
| Transplant related mortality (TRM) | The TRM probability compared with historical control. | 24 months | 
| Severe thrombocytopenia (ST) | The ST probability after HSCT compared with historical control | 24 months | 
| Autoimmune complications (AC) | The AC probability after HSCT compared with historical control | 24 months | 
| Acute Graft Versus Host Diseases (aGVHD) | Cumulative Incidence and severity of aGVHD | 12 months | 
| Chronic Graft Versus Host Diseases (cGVHD) | Cumulative Incidence and severity of cGVHD | 24 months | 
| Plerixafor related complications (PRC) | PRC: severity, features, incidence | 2 week |