Clinical trial NCT00176852: Stem Cell Transplant for Hemoglobinopathy
Official title: Allogeneic Hematopoietic Stem Cell Transplant for Patients With High Risk Hemoglobinopathy Using a Preparative Regimen to Achieve Stable Mixed Chimerism
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Sickle Cell Disease
Thalassemia
Severe Congenital Neutropenia
Diamond-Blackfan Anemia
Shwachman-Diamond Syndrome
Keywords: high risk hemoglobinopathy
stem cell transplant
donor lymphocyte infusion
transfusion dependent
stem cell donor
cord blood
marrow
transfusion dependent non-malignant hematologic disorders
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
Collaborators: name: National Marrow Donor Program
First posted: 2005-09-15
Enrollment: 22
Sex: ALL
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study tests the clinical outcomes of one of two preparative regimens (determined by available donor source) in patients with non-malignant hemoglobinopathies. The researchers hypothesize that these regimens will have a positive effect on post transplant engraftment and the incidence of graft-versus-host-disease.

Regimen A2 has replaced Regimen A in this study. Two patients were treated on Regimen A but did not have evidence of initial engraftment thus triggering the stopping rule for that arm of this study.

Detailed description: Prior to transplantation, subjects will receive either:

Cyclophosphamide, Fludarabine, Campath, Total body irradiation (TBI)

Or

Busulfan, Cyclophosphamide, antithymocyte globulin (ATG), granulocyte colony-stimulating factor (GSCF)

These drugs (and the radiation) are being given to help the new stem cells take and grow. On the day of transplantation, subjects will receive stem cells transfused via intravenous (IV) catheter.

After stem cell transplantation, subjects will be given cyclosporine-A and mycophenolate (MMF)/or Methylprednisone/or Methotrexate to reduce the risk of graft-versus-host disease, the complication that occurs when the donor's stem cells react against the patient.

Eligibility criteria: Inclusion Criteria:

* Patients with Sickle Cell Disease/Thalassemia (SCD/THAL) 0-50 years of age with an acceptable stem cell donor and disease characteristic defined by the following:

  * Stroke, central nervous system (CNS) hemorrhage or a neurologic event lasting longer than 24 hours, or abnormal cerebral magnetic resonance imaging (MRI) or cerebral arteriogram or MRI angiographic study and impaired neuropsychological testing
  * Acute chest syndrome with a history of recurrent hospitalizations or exchange transfusions
  * Recurrent vaso-occlusive pain 3 or more episodes per year for 3 years or more years or recurrent priapism,
  * Impaired neuropsychological function and abnormal cerebral MRI scan
  * Stage I or II sickle lung disease,
  * Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate \[GFR\] 30-50% of the predicted normal value)
  * Bilateral proliferative retinopathy and major visual impairment in at least one eye
  * Osteonecrosis of multiple joints with documented destructive changes
  * Requirement for chronic transfusions but with red blood cell (RBC) alloimmunization \>2 antibodies during long term transfusion therapy
* Patients with transfusion dependent alpha- or beta-thalassemia 0-35 years of age with an acceptable stem cell donor as defined in the criteria in section above.
* Patients with other non-malignant hematologic disorders that are transfusion-dependent or involve other potentially life-threatening cytopenias (including but not limited to Severe Congenital Neutropenia, Diamond-Blackfan Anemia and Shwachman-Diamond Syndrome) who are 0-35 years of age with an acceptable stem cell donor
* Second Transplants

  * Patients with sickle cell disease or thalassemia who have failed to engraft or have autologous recovery after a myeloablative SCT regimen or non-myeloablative regimen are eligible for this protocol.
  * Regimen A2 will be utilized for patients with sickle cell disease or thalassemia who do not have an HLA-identical sibling donor or for any patient who has pre-existing organ dysfunction making them ineligible for a myeloablative preparative regimen.
  * Regimen B will be utilized for patients with sickle cell disease or thalassemia who have an HLA-identical sibling donor.
  * Patients must meet above criteria.
  * If the patient has received prior radiation therapy, eligibility to receive additional radiation therapy must be determined by Dr. Dusenbery
  * If first transplant was a non-myeloablative regimen, the second transplant can occur at any time
  * If the first transplant was a myeloablative regimen, then the second transplant must be \> 6 months from the first transplant

Exclusion Criteria:

* Patients with one or more of the following:
* Karnofsky or Lansky performance score \<70
* Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy
* Stage III-IV lung disease
* GFR\<30% predicted
* Pregnant or lactating females
* Active serious infection whereby patient has been on intravenous antibiotics for one week prior to study entry. Any patient with AIDS or ARC or HIV seropositivity
* Psychologically incapable of undergoing bone marrow transplant (BMT) with associated strict isolation or documented history of medical non-compliance
* Patients not able to receive total lymphocytic irradiation (TLI) due to prior radiation therapy

Primary outcomes:
measure: Number of Patients Who Experienced Grade 3-5 Treatment Related Toxicity
timeFrame: 1 year
Secondary outcomes:
measure: The Incidence of Chimerism at 100 Days
timeFrame: 100 days
measure: The Incidence of Chimerism at 6 Months
timeFrame: 6 months
measure: The Incidence of Chimerism at 1 Year
timeFrame: 1 year
measure: The Incidence of Grade 2-4 Acute Graft Versus Host Disease (Acute GVHD)
timeFrame: 100 days
measure: The Incidence of Grade 3-4 Acute Graft Versus Host Disease (Acute GVHD)
timeFrame: 100 days
measure: The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD)
timeFrame: 6 months
measure: The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD)
timeFrame: 1 year
measure: Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment
timeFrame: pre-transplant
measure: Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment
timeFrame: 1 year
measure: Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment
timeFrame: 2 years
measure: Determine Physical Characteristics and Biologic Effects of Mixed Populations of Donor and Host Red Blood Cells
timeFrame: During study
measure: Determine the Concentration of Campath in the Serum
timeFrame: Day 0
measure: Overall Survival
timeFrame: 100 days
measure: Overall Survival
timeFrame: 1 year
measure: Disease Free Survival
timeFrame: 100 days
measure: Disease Free Survival
timeFrame: 1 year
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Angela Smith, MD
role: PRINCIPAL_INVESTIGATOR
References: