Donor Stem Cell Transplant After Busulfan, Fludarabine, Methylprednisolone, and Antithymocyte Globulin in Treating Patients With Bone Marrow Failure Syndrome

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Giving low doses of chemotherapy and antithymocyte globulin before a donor stem cell transplant helps stop the growth of abnormal cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining abnormal cells (graft-versus-tumor effect). PURPOSE: This phase II trial is studying how well a donor stem cell transplant works after busulfan, fludarabine, methylprednisolone, and antithymocyte globulin in treating patients with bone marrow failure syndrome.

Detailed Description
-----------------
OBJECTIVES: To evaluate the efficacy of HLA-haploidentical familial donor hematopoietic stem cell transplantation after reduced-intensity conditioning regimen comprising busulfan, fludarabine phosphate, and anti-thymocyte globulin in patients with bone marrow failure syndromes. OUTLINE: Reduced-intensity conditioning regimen: Patients receive busulfan IV daily on days -7 and -6, fludarabine phosphate IV over 30 minutes on days -7 to -2, anti-thymocyte globulin (ATG) IV over 4 hours on days -4 to -1, and methylprednisolone IV over 30 minutes starting 30 minutes before ATG on days -4 to -1. HLA-haploidentical donor hematopoietic stem cell transplantation: Patients receive donor hematopoietic stem cells via Hickman catheter over 1 hour on days 0 or 1. Graft-versus-host-disease prophylaxis (GVHD): Patients receive cyclosporine IV over 2-4 hours every 12 hours starting on day -1 (cyclosporine can be given orally once oral medication can be tolerated) and methotrexate IV on days 2, 4 , 7, and 12. In the absence of GVHD, cyclosporine is tapered starting between days 30 to 60. After completion of study treatment, patients are followed periodically for 1 year.

Official Title
-----------------
HLA-HAPLOIDENTICAL FAMILIAL DONOR HEMATOPOIETIC CELL TRANSPLANTATION AFTER REDUCED INTENSITY CONDITIONING OF BUSULFAN, FLUDARABINE, AND ANTI-THYMOCYTE GLOBULIN FOR PATIENTS WITH BONE MARROW FAILURE SYNDROME - A PHASE 2 STUDY

Conditions
-----------------
Leukemia, Myelodysplastic Syndromes, Nonmalignant Neoplasm, Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
-----------------
* Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Diagnosis of any of the following bone marrow failure syndromes: Severe aplastic anemia, meeting 1 of the following criteria: Not responsive to immunosuppressive therapy With recurrent cytopenia after immunosuppressive therapy or allogeneic hematopoietic cell transplantation Low-risk myelodysplastic syndrome, including any of the following: Refractory anemia Refractory anemia with ringed sideroblasts Refractory cytopenia with multi-lineage dysplasia Paroxysmal nocturnal hemoglobinuria, meeting 1 of the following criteria: With thrombotic episodes With severe cytopenia No willing, suitable HLA-compatible donor in family or in donor registries Related donor with HLA-haploidentical mismatch at three or less of 6 loci Patients with very severe neutropenia (< 200/μL) or febrile episodes, who feel urgent need for allogeneic hematopoietic cell transplantation, are eligible without a search for HLA-matched unrelated donors PATIENT CHARACTERISTICS: Karnofsky performance status 70-100% Bilirubin < 2.0 mg/dL AST < 3 times upper limit of normal Creatinine < 2.0 mg/dL Ejection fraction > 40% by MUGA scan PRIOR CONCURRENT THERAPY: See Disease Characteristics

Ages Eligible for Study
-----------------
Maximum Age: 75 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

| Intervention/Treatment |
| --- |
|Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation|infusion of mobilized donor hematopoietic progenitor cells|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Donor cell engraftment | neutrophil count over 500/ul | 10-35 days after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regimen-related toxicities as assessed by NCI's Common Toxicity Criteria | various toxicities of treatment | 0-60 months after transplantation | 
| Acute and chronic GVHD | ocurrence of acute or chronic GVHD after transplantation | 15-100 days; 100 days to 4 years | 
| overall survival | patients surviving after transplantaion | 0-60 months | 
| event-free survival | patients undergoing transplantation and maintaining donor hematopoiesis | 0-60 months after transplatation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
refractory anemia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, childhood myelodysplastic syndromes, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, aplastic anemia, paroxysmal nocturnal hemoglobinuria