Haploidentical Transplantation in Severe Aplastic Anemia

Study Overview
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Brief Summary
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This is a prospective case-control study on SAA patients treated with HSCT, order to further discuss and assess the safety, feasibility and effectiveness of HFD-HSCT which performed with reduced-intensity fludarabine-based conditioning regimen.Our findings would indicate that SAA patients who lack MSD benefited most if HFD-HSCT was performed with reduced-intensity fludarabine-based conditioning regimen, and our improved outcomes with HFD-HSCT may lead to a salvaged therapy and an expanded direct role for SAA in the future.

Official Title
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A Research on Haploidentical Transplantation in Severe Aplastic Anemia Using Reduced-intensity Fludarabine-based Conditioning

Conditions
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Severe Aplastic Anemia

Intervention / Treatment
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* Other: MSD-HSCT
* Other: HFD-HSCT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (i) Diagnosis of SAA, very SAA or SAA and paroxysmal nocturnal hemoglobinuria (PNH) according to the International Aplastic Anemia Study Group; (ii) SAA patients no response to previous IST; (iii) adequate performance status [Eastern Cooperative Oncology Group (ECOG) score 0-2]. Exclusion Criteria: (i) Congenital forms of aplastic anemia; (ii)Patients with any severe pulmonary, cardiac, liver, or renal diseases or active infection.
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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients with SAA
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: MSD-HSCT<br>This group received treatment of matched sibling donor - hematopoietic stem cell transplantation (MSD-HSCT). | Other: MSD-HSCT<br>* Conditioning regimens: (A) Patients had SAA and PNH, or heavy transfusion (RBC≥25U), or failed rabbit ATG therapy, and received 0.8 mg/kg/6h busulfan (days -7 to -6), 30mg/m2/day fludarabine (days -5 to -2), 25 mg/kg/day cyclophosphamide (days -5 to -2) and 2.5 mg/kg/day r-ATG (days -5 to -2). (B) The other patients with SAA or VSAA received same procedure but without busulfan; Allogeneic HSC infusion: Doner BM cells were harvested to achieve a target mononuclear cell count (MNC) of 2-4 × 108 per kilogram of recipient weight. The target MNC from PB was 4-6× 108 per kilogram of recipient weight; Prophylaxis and treatment of GVHD: GVHD prophylaxis consisted of intravenous CSP 2-3 mg/kg/day in divided doses beginning on the day before transplantation (day -5) and the target concentration was adjusted to 150-250 ng/ml. The oral MMF dose was 20 mg/kg/day from day -1 and was tapered off after 1 months if no aGVHD was observed.<br>|
| Experimental: HFD-HSCT<br>This group received treatment of haploid family donor - hematopoietic stem cell transplantation (HFD-HSCT). | Other: HFD-HSCT<br>* Conditioning regimens: (A) Patients had SAA and PNH, or heavy transfusion (RBC≥25U), or failed rabbit ATG therapy, and received 0.8 mg/kg/6h busulfan (days -7 to -6), 35mg/m2/day fludarabine (days -5 to -2), 25 mg/kg/day cyclophosphamide (days -5 to -2) and 2.5 mg/kg/day r-ATG (days -5 to -2). (B) The other patients with SAA or VSAA received same procedure but without busulfan; Allogeneic HSC infusion: Doner BM cells were harvested to achieve a target mononuclear cell count (MNC) of 2-4 × 108 per kilogram of recipient weight. The target MNC from PB was 4-6× 108 per kilogram of recipient weight; Prophylaxis and treatment of GVHD: GVHD prophylaxis consisted of intravenous CSP 2-3 mg/kg/day in divided doses beginning on the day before transplantation (day -5) and the target concentration was adjusted to 200-300 ng/ml. The oral MMF dose was 20 mg/kg/day from day -3 and was tapered off after 2 months if no aGVHD was observed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Engraftment | Neutrophil engraftment was defined as the first of three consecutive days in which the neutrophil counts (ANC) exceeded 0.50 × 109/L, and platelet engraftment was defined as the first of five consecutive days in which the platelet count exceeded 20 × 109/L without transfusion. GF was classified as follows: (1) primary non-engraftment (failure to reach a neutrophil count of 0.5×109/L after transplant); (2) rejection (decrease in blood counts to < 0.5×109/L neutrophils, after achieving a neutrophil count of 0.5×109/L); (3) late graft failure (decrease of blood counts after day 100 to < 1.0×109/L neutrophils and < 30×109/L platelets). | In the first months after infusion | 
| Toxicity grading | The transplantation-related toxicity (TRT) was graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0. Organ damage due to GVHD or infectious complications were excluded. | TRT was defined as toxic effects occurring within 40 days after HSCT | 
| Chimerism analyses +30 | Chimerism would be evaluated in recipient BM cells usually on days +30 after HSCT using cytogenetic G-banding or fluorescence in situ hybridization. Sex-matched donor-recipient chimerism was assessed using PCR-based analyses of polymorphic minisatellite or microsatellite regions. HLA typing was performed for patients with HLA-haploidentical donors. | Days +30 after HSCT | 
| Chimerism analyses +100 | Chimerism would be evaluated in recipient BM cells usually on days +180 after HSCT using cytogenetic G-banding or fluorescence in situ hybridization. Sex-matched donor-recipient chimerism was assessed using PCR-based analyses of polymorphic minisatellite or microsatellite regions. HLA typing was performed for patients with HLA-haploidentical donors. | Days +100 after HSCT | 
| Chimerism analyses +180 | Chimerism would be evaluated in recipient BM cells usually on days +100 after HSCT using cytogenetic G-banding or fluorescence in situ hybridization. Sex-matched donor-recipient chimerism was assessed using PCR-based analyses of polymorphic minisatellite or microsatellite regions. HLA typing was performed for patients with HLA-haploidentical donors. | Days +180 after HSCT | 
| Chimerism analyses +365 | Chimerism would be evaluated in recipient BM cells usually on days +365 after HSCT using cytogenetic G-banding or fluorescence in situ hybridization. Sex-matched donor-recipient chimerism was assessed using PCR-based analyses of polymorphic minisatellite or microsatellite regions. HLA typing was performed for patients with HLA-haploidentical donors. | Days +365 after HSCT | 
| OS 1-year | OS was defined as the time from transplantation to death from any cause or the last follow-up. | 1-year after HSCT | 
| OS 2-year | OS was defined as the time from transplantation to death from any cause or the last follow-up. | 2-year after HSCT | 
| OS 5-year | OS was defined as the time from transplantation to death from any cause or the last follow-up. | 5-year after HSCT | 
| EFS 1-year | EFS was defined as survival with a response to therapy. Death, GF and relapse were considered as treatment failure. EFS was defined as survival with a response to therapy. Death, GF and relapse were considered as treatment failure. | 1-year after HSCT | 
| EFS 2-year | EFS was defined as survival with a response to therapy. Death, GF and relapse were considered as treatment failure. | 2-year after HSCT | 
| EFS 5-year | EFS was defined as survival with a response to therapy. Death, GF and relapse were considered as treatment failure. | 5-year after HSCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Severe aplastic anemia, Haploidentical, Hematopoietic stem cell transplantation