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Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01659606
Recruitment Status : Recruiting
First Posted : August 8, 2012
Last Update Posted : April 4, 2019
Dana-Farber Cancer Institute
Children's Hospital Medical Center, Cincinnati
Children's Hospital Los Angeles
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Baylor College of Medicine
Children's Hospital of Philadelphia
Memorial Sloan Kettering Cancer Center
University of Wisconsin, Madison
Karolinska University Hospital
Information provided by (Responsible Party):
Suneet Agarwal, Boston Children’s Hospital

Brief Summary:
Dyskeratosis congenita is a disease that affects numerous parts of the body, most typically causing failure of the blood system. Lung disease, liver disease and cancer are other frequent causes of illness and death. Bone marrow transplantation (BMT) can cure the blood system but can make the lung and liver disease and risk of cancer worse, because of DNA damaging agents such as alkylators and radiation that are typically used in the procedure. Based on the biology of DC, we hypothesize that it may be possible to avoid these DNA damaging agents in patients with DC, and still have a successful BMT. In this protocol we will test whether a regimen that avoids DNA alkylators and radiation can permit successful BMT without compromising survival in patients with DC.

Condition or disease Intervention/treatment Phase
Dyskeratosis Congenita Hoyeraal Hreidarsson Syndrome Revesz Syndrome Aplastic Anemia Biological: alemtuzumab Drug: Fludarabine Drug: Cyclosporins Drug: Mycophenolate mofetil Phase 2

Detailed Description:
Dyskeratosis congenita (DC) is an inherited multisystem disorder, which classically presents with a clinical triad of skin pigment abnormalities, nail dystrophy, and oral leukoplakia. DC is part of a spectrum of telomere biology disorders, which include some forms of inherited idiopathic aplastic anemia, myelodysplastic syndrome, and pulmonary fibrosis and the congenital diseases Hoyeraal-Hreidarsson syndrome and Revesz syndrome. Progressive bone marrow failure (BMF) occurs in more than 80% of patients under 30 years of age and is the primary cause of morbidity and mortality, followed by pulmonary failure and malignancies. Allogeneic hematopoietic cell transplantation (HCT) is curative for the hematological defects, but several studies have demonstrated poor outcomes in DC patients due to increased early and late complications. A predisposition to pulmonary failure, vascular disease and secondary malignancies may contribute to the high incidence of fatal complications following HCT in DC patients, and provides an impetus to reduce exposure to chemotherapy and radiotherapy in preparative regimens. Recent studies suggest that fludarabine-based conditioning regimens provide stable engraftment and may avoid the toxicities seen after HCT for DC, but studies to date are limited to case reports, retrospective studies and a single prospective trial. In this study, we propose to prospectively evaluate the efficacy of a fludarabine- and antibody-based conditioning regimen in HCT for DC patients, with the goals of maintaining donor hematopoiesis and transfusion independence while decreasing early and late complications of HCT for DC.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Radiation- and Alkylator-free Hematopoietic Cell Transplantation for Bone Marrow Failure Due to Dyskeratosis Congenita / Telomere Disease
Study Start Date : July 2012
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2034

Arm Intervention/treatment
Experimental: alemtuzumab/fludarabine conditioning
alemtuzumab/fludarabine conditioning; cyclosporins/mycophenolate mofetil GVHD prophylaxis
Biological: alemtuzumab
Conditioning: alemtuzumab 0.2 mg/kg/dose IV x 5 doses
Other Name: Campath-1H

Drug: Fludarabine
fludarabine 30 mg/m2/dose IV x 6 doses
Other Name: Fludara

Drug: Cyclosporins
Other Names:
  • cyclosporine A
  • Neoral
  • Sandimmune

Drug: Mycophenolate mofetil
Other Name: Cellcept

Primary Outcome Measures :
  1. Primary engraftment [ Time Frame: Up to day +100 post-BMT ]

Secondary Outcome Measures :
  1. Survival to day+100 post-BMT [ Time Frame: Up to day+100 post-BMT ]
  2. Viral reactivation and infection [ Time Frame: Up to day +100 post-BMT ]
    Number of participants with DNA virus (cytomegalovirus, Epstein Barr virus, or adenovirus) reactivation/infection detected by PCR screening will be reported.

  3. Treatment related adverse events as assessed by CTCAE version 4.0 [ Time Frame: Up to 1 year post-BMT ]
  4. Secondary graft failure [ Time Frame: Up to 15 years post-BMT ]
  5. Acute and chronic graft-versus-host disease (GVHD) [ Time Frame: Up to 15 years post-BMT ]
  6. Engraftment monitoring (chimerism) [ Time Frame: Up to 15 years post-BMT ]
  7. Immune reconstitution as assessed by quantitation of lymphocyte subsets [ Time Frame: Up to 15 years post-BMT ]
    Number of participants with quantitative defects in lymphocyte subset numbers following BMT

  8. Changes in pulmonary function as assessed by pulmonary function testing [ Time Frame: Up to 15 years post-BMT ]
  9. Secondary malignancies [ Time Frame: Up to 15 years post-BMT ]
    Number of patients with malignancies following BMT

  10. Long-term survival [ Time Frame: Up to 15 years post-BMT ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   up to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Bone marrow hypocellular for age
  • Moderate or severe aplastic anemia defined by one of the following: peripheral blood neutrophils < 0.5 x 10^9/L; platelets < 30 x 10^9/L or platelet transfusion dependence; reticulocytes < 50 x 10^9/L in anemic patients or red cell transfusion dependence
  • Diagnosis of dyskeratosis congenita based on clinical triad of abnormalities of skin pigmentation, nail dystrophy, oral leukoplakia; OR one of clinical triad and presence of two or more associated features; OR a pathogenic mutation in DKC1,TERC, TERT, NOP10, NHP2, TCAB1, TINF2, CTC1, PARN, RTEL1, or ACD as reported by a CLIA-approved laboratory; OR age-adjusted mean telomere length < 1%ile in peripheral blood lymphocytes as reported by a CLIA-approved laboratory; OR Hoyeraal-Hreidarsson syndrome; OR Revesz syndrome
  • Availability of a related or unrelated donor with a 7/8 or 8/8 match for HLA-A, B, C, and DRB1.
  • Patient and/or legal guardian must be able to sign informed consent.
  • Donor must provide a marrow allograft.
  • Diagnosis of Fanconi anemia must be excluded by mitomycin C or diepoxybutane chromosomal breakage testing on peripheral blood at a CLIA-approved laboratory (not required for patients with a genetic mutation consistent with DC)
  • Adequate renal function with glomerular filtration rate equal to or greater than 30 ml/min/1.73 m2

Exclusion Criteria:

  • Clonal cytogenetic abnormalities associated with MDS or AML on bone marrow examination.
  • Karnofsky/Lansky performance status < 40.
  • Uncontrolled bacterial, viral or fungal infections.
  • Positive test for the human immunodeficiency virus (HIV).
  • Pregnancy or breastfeeding.
  • Known severe or life-threatening allergy or intolerance to fludarabine, alemtuzumab, cyclosporine, or mycophenolate mofetil.
  • Positive patient anti-donor HLA antibody, which is deemed clinically significant.
  • Prior allogeneic marrow or stem cell transplantation.
  • Prior solid organ transplantation

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): NCT01659606

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Contact: Suneet Agarwal, MD, PHD 617-919-7579

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United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Kimberly Arieli    323-361-5744   
Principal Investigator: Michael Pulsipher, MD         
United States, Massachusetts
Boston Children's Hospital (pediatric patients) Recruiting
Boston, Massachusetts, United States, 02115
Contact: Suneet Agarwal, MD, PHD    617-919-7579   
Contact: Leslie Lehmann, MD   
Principal Investigator: Suneet Agarwal, MD, PHD         
Sub-Investigator: Leslie Lehmann, MD         
Dana-Farber Cancer Institute (adult patients) Recruiting
Boston, Massachusetts, United States, 02115
Contact: Suneet Agarwal, MD, PHD   
Contact: Joseph Antin, MD   
Principal Investigator: Suneet Agarwal, MD, PHD         
Sub-Investigator: Joseph Antin, MD         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Farid Boulad, MD    212-639-6684   
Principal Investigator: Farid Boulad, MD         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Kasiani Myers, MD   
Principal Investigator: Kasiani Myers, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Barb McGlynn    215-590-1303   
Principal Investigator: Tim Olson, MD, PHD         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Ghadir Sasa, MD    832-824-4524   
Principal Investigator: Ghadir Sasa, MD         
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Lauri Burroughs, MD    206-667-2396   
Principal Investigator: Lauri Burroughs, MD         
United States, Wisconsin
University of Wisconsin Hospital and Clinics, American Family Children's Hospital Recruiting
Madison, Wisconsin, United States, 53792
Contact: Jenny Weiland    608-890-8070   
Contact: Peds Hem Onc Main Office    608-263-6200   
Principal Investigator: Inga Hoffman, MD         
Karolinska University Hospital Recruiting
Stockholm, Sweden
Contact: Mikael Sundin, MD, PHD    +46 8 585 848 43   
Principal Investigator: Mikael Sundin, MD, PHD         
Sponsors and Collaborators
Boston Children’s Hospital
Dana-Farber Cancer Institute
Children's Hospital Medical Center, Cincinnati
Children's Hospital Los Angeles
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Baylor College of Medicine
Children's Hospital of Philadelphia
Memorial Sloan Kettering Cancer Center
University of Wisconsin, Madison
Karolinska University Hospital
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Principal Investigator: Suneet Agarwal, MD, PHD Boston Children’s Hospital

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Responsible Party: Suneet Agarwal, Assistant Professor of Pediatrics, Boston Children’s Hospital Identifier: NCT01659606    
Other Study ID Numbers: 12-950
IRB-P00003466 ( Other Identifier: Boston Children's Hospital )
First Posted: August 8, 2012    Key Record Dates
Last Update Posted: April 4, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Suneet Agarwal, Boston Children’s Hospital:
dyskeratosis congenita
bone marrow failure
aplastic anemia
bone marrow transplantation
reduced intensity conditioning
Additional relevant MeSH terms:
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Anemia, Aplastic
Dyskeratosis Congenita
Pathologic Processes
Hematologic Diseases
Bone Marrow Diseases
Skin Abnormalities
Congenital Abnormalities
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Skin Diseases, Genetic
Skin Diseases
Mycophenolic Acid
Fludarabine phosphate
Alkylating Agents
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents