Stem Cell Transplant for Hemoglobinopathy

• ClinicalTrials.gov Identifier: NCT00176852
• Recruitment Status: Completed
• First Posted: September 15, 2005
• Results First Posted: May 9, 2017
• Last Update Posted: February 27, 2020
• Sponsor: Masonic Cancer Center, University of Minnesota
• Collaborator: National Marrow Donor Program
• Information provided by (Responsible Party): Masonic Cancer Center, University of Minnesota

Tracking Information

• First Submitted Date: September 12, 2005
• First Posted Date: September 15, 2005
• Results First Submitted Date: March 28, 2017
• Results First Posted Date: May 9, 2017
• Last Update Posted Date: February 27, 2020
• Study Start Date: June 2002
• Actual Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 28, 2017)

Number of Patients Who Experienced Grade 3-5 Treatment Related Toxicity [ Time Frame: 1 year ]

In general, grade 3 equates to moderate, grade 4 to severe and grade 5 to death.

• Original Primary Outcome Measures (submitted: September 12, 2005): Efficacy is defined as continued neutrophil engraftment with at least 10% donor cells by d100.

Current Secondary Outcome Measures (submitted: February 13, 2020)

• The Incidence of Chimerism at 100 Days [ Time Frame: 100 days ]
  The number of patients whose blood and/or bone marrow contains > 10% donor cells.
• The Incidence of Chimerism at 6 Months [ Time Frame: 6 months ]
  The number of patients whose blood and/or bone marrow contains > 10% donor cells.
• The Incidence of Chimerism at 1 Year [ Time Frame: 1 year ]
  The number of patients whose blood and/or bone marrow contains > 10% donor cells.
• The Incidence of Grade 2-4 Acute Graft Versus Host Disease (Acute GVHD) [ Time Frame: 100 days ]
  The number of patients who experienced grades 2-4 Acute GVHD. Acute GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. Grades 2-4 equate to mild to severe disease. Symptoms typically appear within weeks after transplant.
• The Incidence of Grade 3-4 Acute Graft Versus Host Disease (Acute GVHD) [ Time Frame: 100 days ]
  The number of patients who experienced grades 3-4 Acute GVHD. Acute GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. IGrades 3-4 equate to moderate to severe disease. Symptoms typically appear within weeks after transplant.
• The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD) [ Time Frame: 6 months ]
  The number of patients who experienced Chronic GVHD. Chronic GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. Chronic GVHD can appear at any time after allogeneic transplant or several years after transplant.
• The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD) [ Time Frame: 1 year ]
  The number of patients who experienced Chronic GVHD. Chronic GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. Chronic GVHD can appear at any time after allogeneic transplant or several years after transplant.
• Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment [ Time Frame: pre-transplant ]
  The measure for quality of life used in this study is the Karnofsky Performance Score. The Karnofsky Performance Score runs from 100 to 0, where 100 is "perfect" health and 0 is death.
• Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment [ Time Frame: 1 year ]
  The measure for quality of life used in this study is the Karnofsky Performance Score. The Karnofsky Performance Score runs from 100 to 0, where 100 is "perfect" health and 0 is death.
• Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment [ Time Frame: 2 years ]
  The measure for quality of life used in this study is the Karnofsky Performance Score. The Karnofsky Performance Score runs from 100 to 0, where 100 is "perfect" health and 0 is death.
• Determine Physical Characteristics and Biologic Effects of Mixed Populations of Donor and Host Red Blood Cells [ Time Frame: During study ]
• Determine the Concentration of Campath in the Serum [ Time Frame: Day 0 ]
• Overall Survival [ Time Frame: 100 days ]
  Number of patients alive 100 days after transplant.
• Overall Survival [ Time Frame: 1 year ]
  Number of patients alive 1 year after transplant.
• Disease Free Survival [ Time Frame: 100 days ]
  Number of patients alive without disease 100 days after transplant.
• Disease Free Survival [ Time Frame: 1 year ]
  Number of patients alive without disease 1 year after transplant.

Original Secondary Outcome Measures (submitted: September 12, 2005)

• Determine the incidence of chimerism at 100 days, 6 months and 1 year.
• Determine the incidence of grade 2-4 and 3-4 acute GVHD at 100 days.
• Determine the incidence of chronic GVHD at 6 months and 1 year.
• Determine the physical characteristics and biologic effects of mixed populations of donor and host red blood cells (RBCs).
• Compare the quality of life (QOL) at 1, 2 and 5 years with the pre-transplant assessment.
• Determine overall and disease free survival at 100 days and 1 year.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Sickle Cell Disease
• Thalassemia
• Severe Congenital Neutropenia
• Diamond-Blackfan Anemia
• Shwachman-Diamond Syndrome

Intervention

• Drug: Busulfan, Fludarabine, ATG, TLI
  Busulfan 0.8 mg/kg/dose intravenous (IV) Days -8 and -7 Fludarabine 35 mg/m2 IV Days -6 through -2 Antithymocyte globulin (ATG) 30 mg/kg IV Days -2 and -1 Total lymphoid radiation 300 cGy
  Other Names:

  • Busulfex
  • Fludara
  • ATG
  • Total lymphoid Irradiation
• Drug: Busulfan, Cyclophosphamide, ATG, GCSF
  Busulfan 0.8 mg/kg/dose intravenous (IV) Days -9 through -6 Cyclophosphamide 50 mg/kg IV Days -5 through -2 ATG 30 mg/kg IV Day -1 GCSF 5 mcg/kg/day IV until ANC >2500 x 2 days.
  Other Names:

  • Busulfex
  • Cytoxan
  • antithymocyte globulin
  • granulocyte colony-stimulating factor
• Drug: Campath, Fludarabine, Cyclophosphamide
  Receives Campath-1H 0.2 mg/kg Days -10 through -6, Fludarabine 35 mg/m2 intravenous (IV) Days -6 through -2, total body irradiation (TBI) 300 cGy Day -1.
  Other Names:

  • Fludara
  • alemtuzumab
  • Cytoxan
• Radiation: Total Body Irradiation
  300 cGY Day -1
  Other Name: TBI
• Procedure: Stem cell infusion
  Given Day 0
  Other Name: bone marrow transplant

Study Arms

• RIC Bu/Flu (A) (discontinued)
  Full Preparative Regimen for subjects with matched donors using Busulfan on Day -8 and -7, Fludarabine on Day -6 through -2, antithymocyte globulin (ATG) on Day -2 through -1, total lymphoid radiation (TLI) on Day -1, stem cell infusion on Day 0.
  Intervention: Drug: Busulfan, Fludarabine, ATG, TLI
• Experimental: MA Bu/Cy (B)
  Myeloablative Preparative Regimen for subjects with HLA identical sibling donors consists of Busulfan on day -9 through -6, Cyclophosphamide on day -5 through -2, ATG on day -3 through -1, stem cell infusion on Day 0 and Granulocyte Colony Stimulating Factor on day -3 until ANC >2500 x 2 days.
  Interventions:

  • Drug: Busulfan, Cyclophosphamide, ATG, GCSF
  • Radiation: Total Body Irradiation
  • Procedure: Stem cell infusion
• Experimental: RIC Cy/Flu/TBI (A2)
  Patients with sickle cell disease or thalassemia who do not have an HLA-identical sibling donor or who has pre-existing organ dysfunction making myeloablative condition ineligible will receive Campath on day -10 through -6, Cyclophosphamide on day -7, Fludarabine on day -6 through -2, total body irradiation (TBI) on day -1, stem cell infusion on Day 0.
  Interventions:

  • Drug: Campath, Fludarabine, Cyclophosphamide
  • Radiation: Total Body Irradiation
  • Procedure: Stem cell infusion

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 28, 2017): 22
• Original Enrollment (submitted: September 12, 2005): 30
• Actual Study Completion Date: January 2020
• Actual Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 50 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00176852
• Other Study ID Numbers: MT2002-07; 0206M26241 ( Other Identifier: IRB, University of Minnesota )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Masonic Cancer Center, University of Minnesota
• Original Responsible Party: Not Provided
• Current Study Sponsor: Masonic Cancer Center, University of Minnesota
• Original Study Sponsor: Baker, K. Scott, MD
• Collaborators: National Marrow Donor Program

Investigators

• Principal Investigator: Angela Smith, MD; Masonic Cancer Center, University of Minnesota

• PRS Account: Masonic Cancer Center, University of Minnesota
• Verification Date: February 2020