Efficacy of Basiliximab in the Prevention of Acute Graft-versus-host Disease in Unrelated Allogeneic Hematopoietic Stem Cell Transplantation Therapy for Thalassemia Major

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the basiliximab for prevention of graft-versus-host disease in unrelated allo-genetic hematopoietic stem cell transplantation for thalassemia major. The objective was to evaluate the effect and safety of basiliximab for acute graft-versus-host disease.

Detailed Description
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Allo-geneic stem cell transplantation(allo-HSCT) cure thalassemia major by destroying the original hematopoietic and immune systems with a large dose of chemotherapy, rebuilding a new system to correct the abnormal hematopoietic globin chain synthesis which leads to hemolysis. Currently, it is the only curative means. According to donors, allo-HSCT could be sibling allogeneic hematopoietic stem cell transplantation and unrelated allogeneic hematopoietic stem cell transplantation(URD-HSCT). URD-HSCT could expand the range of treatment among β-thalassemia major patients. As recently reported , 68 cases of thalassemia patients at the median age of 15 (2 to 37 ) received unrelated donor BMT. According to Pesaro rating classification, 14 patients were attributed to type Ⅰ, 16 cases Ⅱ type , 38 cases type III, overall survival and thalassemia free survival rates were 79.3% and 65.8%. A survey among 59 evaluable patients indicated that grade Ⅱ   Ⅳ aGVHD occurred in 24 cases (40%) , in which 10 cases (17%) were grade Ⅲ   Ⅳ aGVHD. Similar results were seen in other reports, 21 patients received unrelated donor BMT, with a 2-year thalassemia free survival rate of 71%. GVHD happened in 3 cases, and 3 patients died. Our institution has conducted a total of 10 cases of URD-HSCT to treat severe thalassemia, using methotrexate + cyclosporine A+ mycophenolate mofetil to prevent graft-versus-host disease, 9 cases of disease-free survival, 1 case with graft rejection. Incidence of Ⅲ-Ⅳ severe acute graft-versus-host disease (aGVHD) was 20%. Severe aGVHD incidence was 20%. Our research group has found there is a high risk to develop aGVHD, especially severe aGVHD for heavy thalassemia patients who receive URD-HSCT, which seriously affects the prognosis and survival, while increasing medical costs and the financial burden on the patients' families. The key factor affecting URD-HSCT's success is GVHD. Thus effective prevention and treatment of GVHD is a prerequisite to ensure a successful transplant. CD25 is a humanized monoclonal IgG1,with murine anti-human IL-2RA chain complement determining region retained. IL-2RA chain expressed only on the surface of activated cytotoxic T cells, which could convert the IL-2R complexes into a higher affinity. The feature that IL-2RA distributes only on the surface of activated lymphocytes indicates it's a ideal target when designing the policy to scavenge antigen-specific allogeneic reactive T cells. In vitro experiments, CD25 monoclonal antibody binds specifically with IL-2RA+ cells by inhibiting IL-2 binding to its receptor competitively. Basiliximab has now been used as first-line medication for aGVHD treatment, as well as the combined prevention of hematologic malignancies URD-HSCT treatment . However as for thalassemia major URD-HSCT, few cases have been reported. This study was aimed at the high incidence of aGVHD, especially severe aGVHD in thalassemia major URD-HSCT. Basiliximab was added to the original prevention program. The aGVHD incidence, implantation rate, transplant-related mortality, infection incidence would be observed. It is hopeful to reduce the aGVHD incidence after URD-HSCT and promote curative effect.

Official Title
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Efficacy of Basiliximab in the Prevention of Acute Graft-versus-host Disease in Unrelated Allogeneic Hematopoietic Stem Cell Transplantation Therapy for Thalassemia Major Treatment: a Multi-center, Open, Randomized, Controlled Clinical Study

Conditions
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Beta-Thalassemia Major

Intervention / Treatment
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* Drug: Basiliximab,
* Drug: cyclosporine A
* Drug: Methotrexate
* Drug: Mycophenolate mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 2 to 18 years old Gender: Male or female Thalassemia major Donor and recipient sides 10/10 consistency Unrelated allogeneic peripheral blood stem cell transplantation In good general condition , ECOG score ≤ 1 Normal heart function: ejection fraction ≥ 50% Normal liver and renal function: Serum bilirubin ≤ 35μmol / L, AST / ALT less than 2 times the upper limit , serum creatinine under 2 times the upper limit Enrolled subjects or their families signed informed consent Exclusion Criteria: severe infection uncontrolled before transplantation severe allergic on Basiliximab (anaphylactic shock or laryngeal edema) sibling allogeneic hematopoietic stem cell transplantation Cardiac dysfunction (ejection fraction <50%) Renal insufficiency (serum creatinine> 130umol / L) Hepatic dysfunction (total bilirubin> 34umol / L, ALT, AST> 2 times the upper limit of normal) Previously history of allogeneic hematopoietic stem cell transplantation Other circumstances which do not meet the inclusion criteria

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: group A<br>The patients were used cycloaporine A:2mg/kg combined with methotrexate 15mg/m2 +1d，10mg/m2 +3,+6,+11d,mycophenolate mofetil: 0.25g/d, -1d to 90d and basiliximab: 10mg each time, 0d and +4 d for prevention of graft-versus-host-disease. | Drug: Basiliximab,<br>* Basiliximab was used 10mg each time on 0d(after transplantation) and +4 d .<br>* Other names: Simulect;Drug: cyclosporine A<br>* Specifically cyclosporine A was used by intravenous drip infusion on 2mg/kg dosage from -1d and change to 5mg/kg twice oral when gastrointestinal function recovers. The blood concentrations of cyclosporine A was maintained 150-250ng/ml.<br>* Other names: cyclosporin;Drug: Methotrexate<br>* Methotrexate was used 15mg/m2 on +1d and 10mg/m2 on +3,+6,+11d by intravenous for prevention of graft-versus-host-disease.<br>* Other names: Ametnopterin;Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil was used 0.25g qd from 0d to 3 months for prevention of graft-versus-host-disease.<br>* Other names: cellcept;|
| Experimental: group B<br>The patients were used cyclosporine A 2mg/kg,methotrexate,15mg/m2 +1d，10mg/m2 +3,+6,+11d,mycophenolate mofetil: 0.25g/d, -1d to 90d for prevention of graft-versus-host-disease. | Drug: cyclosporine A<br>* Specifically cyclosporine A was used by intravenous drip infusion on 2mg/kg dosage from -1d and change to 5mg/kg twice oral when gastrointestinal function recovers. The blood concentrations of cyclosporine A was maintained 150-250ng/ml.<br>* Other names: cyclosporin;Drug: Methotrexate<br>* Methotrexate was used 15mg/m2 on +1d and 10mg/m2 on +3,+6,+11d by intravenous for prevention of graft-versus-host-disease.<br>* Other names: Ametnopterin;Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil was used 0.25g qd from 0d to 3 months for prevention of graft-versus-host-disease.<br>* Other names: cellcept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| acute graft-versus-host disease incidence |  | two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Implantation rate |  | two years | 
| Transplanted-related mortality |  | two years | 
| Infection incidence |  | two years | 
| Chronic graft-versus-host-disease incidence |  | two years | 
| Overall survival |  | two years | 
| Disease-free-survival |  | two years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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beta-Thalassemia major