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

• ClinicalTrials.gov Identifier: NCT02342145
• Recruitment Status: Unknown
• First Posted: January 19, 2015
• Last Update Posted: January 19, 2015
• Sponsor: Affiliated hospital of guangxi medical university,china
• Collaborators: Union hospital of Fujian Medical University; Zhongshan Hospital Xiamen University; The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School; Kunming general Hospital of Chengdu Military Region
• Information provided by (Responsible Party): Affiliated hospital of guangxi medical university,china, First Affiliated Hospital of Guangxi Medical University

Tracking Information

• First Submitted Date: January 14, 2015
• First Posted Date: January 19, 2015
• Last Update Posted Date: January 19, 2015
• Study Start Date: June 2014
• Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: January 16, 2015): acute graft-versus-host disease incidence [ Time Frame: two years ]
• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: January 16, 2015)

• Implantation rate [ Time Frame: two years ]
• Transplanted-related mortality [ Time Frame: two years ]
• Infection incidence [ Time Frame: two years ]
• Chronic graft-versus-host-disease incidence [ Time Frame: two years ]
• Overall survival [ Time Frame: two years ]
• Disease-free-survival [ Time Frame: two years ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy of Basiliximab in the Prevention of Acute Graft-versus-host Disease in Unrelated Allogeneic Hematopoietic Stem Cell Transplantation Therapy for Thalassemia Major
• Official Title: 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
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Beta-Thalassemia Major

Intervention

• Drug: Basiliximab,
  Basiliximab was used 10mg each time on 0d(after transplantation) and +4 d .
  Other Names:

  • chimeric mouse-human antiCD25
  • Simulect
• Drug: cyclosporine A
  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.
  Other Name: cyclosporin
• Drug: Methotrexate
  Methotrexate was used 15mg/m2 on +1d and 10mg/m2 on +3,+6,+11d by intravenous for prevention of graft-versus-host-disease.
  Other Name: Ametnopterin
• Drug: Mycophenolate mofetil
  Mycophenolate mofetil was used 0.25g qd from 0d to 3 months for prevention of graft-versus-host-disease.
  Other Name: cellcept

Study Arms

• Active Comparator: group A
  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.
  Interventions:

  • Drug: Basiliximab,
  • Drug: cyclosporine A
  • Drug: Methotrexate
  • Drug: Mycophenolate mofetil
• Experimental: group B
  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.
  Interventions:

  • Drug: cyclosporine A
  • Drug: Methotrexate
  • Drug: Mycophenolate mofetil

Publications *

• Smiers FJ, Krishnamurti L, Lucarelli G. Hematopoietic stem cell transplantation for hemoglobinopathies: current practice and emerging trends. Pediatr Clin North Am. 2010 Feb;57(1):181-205. doi: 10.1016/j.pcl.2010.01.003.
• Wang HX, Yan HM, Wang ZD, Xue M, Liu J, Guo ZK. Haploidentical hematopoietic stem cell transplantation in hematologic malignancies with G-CSF mobilized bone marrow plus peripheral blood stem cells grafts without T cell depletion: a single center report of 29 cases. Leuk Lymphoma. 2012 Apr;53(4):654-9. doi: 10.3109/10428194.2011.624225. Epub 2011 Dec 5.
• Hu LD, Chen H, Jiang M, Li BT, Yu ZY, Li YH. [The role of CD25 antibody in unrelated hematopoietic stem cell transplantation]. Zhonghua Nei Ke Za Zhi. 2005 Nov;44(11):848-50. Chinese.
• Feng Z, Sun E, Lan H, Zhang C, Li Q, Zhu W. Unrelated donor bone marrow transplantation for beta-thalassemia major: an experience from China. Bone Marrow Transplant. 2006 Jan;37(2):171-4. doi: 10.1038/sj.bmt.1705193.
• Hongeng S, Pakakasama S, Chuansumrit A, Sirachainan N, Kitpoka P, Udomsubpayakul U, Ungkanont A, Jootar S. Outcomes of transplantation with related- and unrelated-donor stem cells in children with severe thalassemia. Biol Blood Marrow Transplant. 2006 Jun;12(6):683-7. doi: 10.1016/j.bbmt.2006.02.008.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: January 16, 2015): 40
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2018
• Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age: 2 to 18 years old
2. Gender: Male or female
3. Thalassemia major
4. Donor and recipient sides 10/10 consistency
5. Unrelated allogeneic peripheral blood stem cell transplantation
6. In good general condition , ECOG score ≤ 1
7. Normal heart function: ejection fraction ≥ 50%
8. 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
9. Enrolled subjects or their families signed informed consent

Exclusion Criteria:

1. severe infection uncontrolled before transplantation
2. severe allergic on Basiliximab (anaphylactic shock or laryngeal edema)
3. sibling allogeneic hematopoietic stem cell transplantation
4. Cardiac dysfunction (ejection fraction <50%)
5. Renal insufficiency (serum creatinine> 130umol / L)
6. Hepatic dysfunction (total bilirubin> 34umol / L, ALT, AST> 2 times the upper limit of normal)
7. Previously history of allogeneic hematopoietic stem cell transplantation
8. Other circumstances which do not meet the inclusion criteria

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 18 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT02342145
• Other Study ID Numbers: gxmuh-2014-14
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Affiliated hospital of guangxi medical university,china, First Affiliated Hospital of Guangxi Medical University
• Original Responsible Party: Same as current
• Current Study Sponsor: Affiliated hospital of guangxi medical university,china
• Original Study Sponsor: Same as current

Collaborators

• Union hospital of Fujian Medical University
• Zhongshan Hospital Xiamen University
• The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
• Kunming general Hospital of Chengdu Military Region

Investigators

• Principal Investigator: yongrong lai, PhD; Guangxi Medical University

• PRS Account: First Affiliated Hospital of Guangxi Medical University
• Verification Date: January 2015