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Stem Cell Transplant for Bone Marrow Failure Syndromes

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00176878
Recruitment Status : Completed
First Posted : September 15, 2005
Results First Posted : August 6, 2009
Last Update Posted : December 28, 2017
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota

Brief Summary:
The researchers hypothesize that it will be possible to perform unrelated bone marrow or cord blood transplants in a safer manner by using less intensive therapy yet still achieve an acceptable level of donor cell engraftment for non-malignant congenital bone marrow failure disorders.

Condition or disease Intervention/treatment Phase
Diamond-Blackfan Anemia Kostmann's Neutropenia Shwachman-Diamond Syndrome Procedure: Stem cell transplant Drug: Fludarabine monophosphate Procedure: Total lymphoid irradiation Drug: Busulfan Biological: anti-thymocyte globulin Phase 2 Phase 3

Detailed Description:

Prior to transplantation, subjects will receive the drugs busulfan (orally or through the catheter), as well as fludarabine and anti-thymocyte globulin (ATG) via the catheter. Busulfan, fludarabine and ATG will be given with Total Lymphoid Irradiation (TLI) to help the new donor bone marrow take and grow after transplantation.

Those patients receiving donor marrow will have the T cells (a type of white blood cell in the donor marrow) removed to lower the risk that the new marrow will react to their body, a condition called Graft-Versus-Host-Disease (GVHD). After bone marrow transplantation, subjects will receive drugs to help prevent GVHD, including cyclosporin and mycophenolate mofetil (MMF).

Blood samples are taken at day 28, day 60, day 100, 1 year and as required by medical status yearly for five years after transplant to evaluate how well the new marrow is growing. A bone marrow biopsy is required at day 21, at day 100 and 1 year.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Bone Marrow Transplantation for Non-Malignant Congenital Bone Marrow Failure Disorders
Study Start Date : June 2000
Actual Primary Completion Date : March 2009
Actual Study Completion Date : March 2009

Arm Intervention/treatment
Experimental: Bone Marrow Failure Disorders
Patients with Diamond-Blackfan Anemia, Kostmann's Neutropenia, Shwachman-Diamond Syndrome
Procedure: Stem cell transplant
Stem cell transplant on Day 0 - healthy marrow from an unrelated individual. A minimum of 1.0 x 10^9/kg nucleated cells/kg ideal body weight will be collected with a goal of 2.0 x 10^9/kg.
Other Name: BMT

Drug: Fludarabine monophosphate
fludarabine 175 mg/m^2 (total) on Days -6 through -3.
Other Name: Fludara

Procedure: Total lymphoid irradiation
Dose 500 cGy radiation therapy to specific areas of the body
Other Name: TLI

Drug: Busulfan
Busulfan 8 mg/kg (total) on Days - 8 and -7 (orally or through the catheter),
Other Name: Busulfex

Biological: anti-thymocyte globulin
anti-thymocyte globulin (ATG) 15 mg/kg on days -2 and -1 via catheter
Other Name: ATG

Primary Outcome Measures :
  1. Number of Patients Alive (Survival) at 2 Years [ Time Frame: 2 years ]
    Calculated from day 1 of transplant to last contact.

Secondary Outcome Measures :
  1. Number of Patients Alive at Three Years (Survival) [ Time Frame: 3 years ]
    Number of subjects who survived 3 years post-transplant.

  2. Number of Patients With Succcessful Engraftment After Transplantation [ Time Frame: 42 Days ]
    Number of patients who received non-genotypic identical marrow or cord blood cells using a "non-myeloablative" preparative regimen and exhibited engraftment at Day 42.

  3. Number of Patients With Grade 2-4 Acute Graft Versus Host Disease [ Time Frame: 100 Days ]
    Number of patients with Grade 2, 3 and 4 Acute (normally observed within the first 100 days) Graft Versus Host Disease. Acute GVHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GVHD usually have a poor prognosis. Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening.

  4. Number of Patients With Chronic Graft Versus Host Disease [ Time Frame: 2 years ]
    Number of patients who exhibited chronic (normally occurs after 100 days) Graft Versus Host Disease at 2 years post transplant. Chronic graft-versus-host-disease, over its long-term course, can also cause damage to the connective tissue and exocrine glands.

  5. Number of Patients With Disease Recurrence [ Time Frame: 2 years ]
    Number of patients who exhibited disease recurrence at 2 years.

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Ages Eligible for Study:   up to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients eligible for transplantation under this protocol will be <35 years of age, and will be diagnosed with:

    • a bone marrow failure syndrome unresponsive to available therapy, including but not limited to Diamond-Blackfan anemia, Shwachman Diamond syndrome or Kostmann's neutropenia but exclusive of aplastic anemia.
  • Diamond Blackfan Anemia:

    • Patients must show evidence of steroid resistance requiring equivalent of >6 transfusions yearly despite steroid therapy.
    • Evidence of developing aplasia or myelodysplasia will also be criteria for transplantation.
  • Kostmann's Neutropenia, Shwachman-Diamond syndrome:

    • Patients must have been previously diagnosed as having a clinical picture characteristic of Shwachman-Diamond syndrome (exocrine pancreatic insufficiency, growth retardation, metaphyseal dysostosis, neutropenia), or must have a bone marrow aspirate consistent with Kostmann's neutropenia, with no evidence of acute leukemia.
    • Patients must have failed therapy with granulocyte-colony stimulating factor (G-CSF), as determined by an inability to maintain an absolute neutrophil count (ANC) >750 cells/ml(3), or manifesting recurrent infections despite G-CSF administration resulting in life threatening infections or repeated hospitalizations (<4 /year).

Exclusion Criteria:

  • Patients >35 years of age
  • Karnofsky score <70%
  • Hepatic dysfunction as determined by bilirubin >3.0, ALT >150, or active hepatitis
  • Pulmonary function tests with forced volume vital capacity (FVC) and forced expiratory volume (FEV) <70%; O2 saturation <94%
  • Renal dysfunction with glomerular filtration rate (GFR) <30% of predicted.
  • Cardiac compromise, with left ejection fraction <45%.
  • Severe, stable neurologic impairment.
  • Human immunodeficiency virus (HIV) positivity.
  • Pregnant or lactating females

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00176878

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United States, Minnesota
University of Minnesota Medical Center
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
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Principal Investigator: Paul Orchard, MD University of Minnesota Medical Center

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Responsible Party: Masonic Cancer Center, University of Minnesota Identifier: NCT00176878     History of Changes
Obsolete Identifiers: NCT00005895
Other Study ID Numbers: MT2000-18
9504M09637 ( Other Identifier: IRB, University of Minnesota )
First Posted: September 15, 2005    Key Record Dates
Results First Posted: August 6, 2009
Last Update Posted: December 28, 2017
Last Verified: December 2017
Keywords provided by Masonic Cancer Center, University of Minnesota:
Stem cell transplant
T-cell depletion
bone marrow failure disorders
Additional relevant MeSH terms:
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Anemia, Diamond-Blackfan
Pathologic Processes
Leukocyte Disorders
Hematologic Diseases
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Red-Cell Aplasia, Pure
Bone Marrow Diseases
Genetic Diseases, Inborn
Fludarabine phosphate
Antilymphocyte Serum
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Alkylating Agents
Antineoplastic Agents, Alkylating
Myeloablative Agonists