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

NCT01659606 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: 12-950IRB-P00003466
• Study Type: interventional
• Target: 40
• Locations: 3 countries
• Sites: 13

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.

Conditions

Dyskeratosis Congenita; Hoyeraal Hreidarsson Syndrome; Revesz Syndrome; Aplastic Anemia

Keywords

dyskeratosis congenita; bone marrow failure; aplastic anemia; bone marrow transplantation; reduced intensity conditioning; campath; fludarabine; telomere

Outcome Measures

Primary Outcomes (1)

• Primary engraftment

  Up to day +100 post-BMT

Secondary Outcomes (10)

• Survival to day+100 post-BMT

  Up to day+100 post-BMT

• Viral reactivation and infection

  Up to day +100 post-BMT

• Treatment related adverse events as assessed by CTCAE version 4.0

  Up to 1 year post-BMT

• Secondary graft failure

  Up to 15 years post-BMT

• Acute and chronic graft-versus-host disease (GVHD)

  Up to 15 years post-BMT

Study Arms (1)

alemtuzumab/fludarabine conditioning

EXPERIMENTAL

alemtuzumab/fludarabine conditioning; calcineurin-inhibitor/mycophenolate mofetil GVHD prophylaxis

Biological: alemtuzumab; Drug: Fludarabine; Drug: Cyclosporins; Drug: Mycophenolate mofetil; Drug: Tacrolimus

Interventions

Mycophenolate mofetil DRUG

Also known as: Cellcept

alemtuzumab/fludarabine conditioning

Tacrolimus DRUG

Also known as: FK506, Prograf

alemtuzumab/fludarabine conditioning

alemtuzumab BIOLOGICAL

Conditioning: alemtuzumab 0.2 mg/kg/dose IV/SC x 5 doses

Also known as: Campath-1H

alemtuzumab/fludarabine conditioning

Fludarabine DRUG

fludarabine 30 mg/m2/dose IV x 6 doses

Also known as: Fludara

alemtuzumab/fludarabine conditioning

Cyclosporins DRUG

Also known as: cyclosporine A, Neoral, Sandimmune

alemtuzumab/fludarabine conditioning

Eligibility Criteria

• Age: 30 Days - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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, ACD, NAF1, STN1, or ZCCHC8, 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

You may not qualify if:

• 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, mycophenolate mofetil or both cyclosporine and tacrolimus.
• Positive patient anti-donor HLA antibody, which is deemed clinically significant.
• Prior allogeneic marrow or stem cell transplantation.
• Prior solid organ transplantation.

Sponsors & Collaborators

• Boston Children's Hospital: lead
• Dana-Farber Cancer Institute: collaborator
• Children's Hospital Medical Center, Cincinnati: collaborator
• Baylor College of Medicine: collaborator
• Children's Hospital of Philadelphia: collaborator
• University of Wisconsin, Madison: collaborator
• Karolinska University Hospital: collaborator
• Hackensack Meridian Health: collaborator
• Oslo University Hospital: collaborator
• Children's Mercy Hospital Kansas City: collaborator
• University of Chicago: collaborator
• Massachusetts General Hospital: collaborator
• Fred Hutch/University of Washington/Seattle Children's Cancer Consortium: collaborator

Study Sites (13)

University of Chicago

Chicago, Illinois, 60637, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Boston Children's Hospital (pediatric patients)

Boston, Massachusetts, 02115, United States

Location

Dana-Farber Cancer Institute (adult patients)

Boston, Massachusetts, 02115, United States

Location

Children's Mercy Hospital Kansas City

Kansas City, Missouri, 64108, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium

Seattle, Washington, 98109, United States

Location

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

Oslo University Hospital

Oslo, Norway

Location

Karolinska University Hospital

Stockholm, Sweden

Location

Related Publications (1)

• Bhoopalan SV, Wlodarski M, Reiss U, Triplett B, Sharma A. Reduced-intensity conditioning-based hematopoietic cell transplantation for dyskeratosis congenita: Single-center experience and literature review. Pediatr Blood Cancer. 2021 Oct;68(10):e29177. doi: 10.1002/pbc.29177. Epub 2021 Jun 4.

  PMID: 34086408 DERIVED

MeSH Terms

Conditions

Dyskeratosis Congenita; Hoyeraal Hreidarsson syndrome; Revesz Debuse syndrome; Anemia, Aplastic; Bone Marrow Failure Disorders

Interventions

Alemtuzumab; fludarabine; fludarabine phosphate; Cyclosporins; Cyclosporine; Mycophenolic Acid; Tacrolimus

Condition Hierarchy (Ancestors)

Congenital Bone Marrow Failure Syndromes; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Skin Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Skin Diseases, Genetic; Skin Diseases; Skin and Connective Tissue Diseases; Anemia

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Macrolides; Lactones

Study Officials

• Suneet Agarwal, MD, PHD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Study Record Dates

• First Submitted: August 6, 2012
• First Posted: August 8, 2012
• Study Start: July 1, 2012
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2034
• Last Updated: March 27, 2026

Record last verified: 2025-01

Locations

US (11); NO (1); SE (1)