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

NCT ID: NCT01659606

Last Updated: 2026-01-09

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-31
• Study Completion Date: 2034-12-31

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.

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.

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

alemtuzumab/fludarabine conditioning

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

Group Type: EXPERIMENTAL

alemtuzumab

Intervention Type: BIOLOGICAL

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

Fludarabine

Intervention Type: DRUG

fludarabine 30 mg/m2/dose IV x 6 doses

Cyclosporins

Intervention Type: DRUG

Mycophenolate mofetil

Intervention Type: DRUG

Tacrolimus

Intervention Type: DRUG

Interventions

alemtuzumab

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

Intervention Type: BIOLOGICAL

Fludarabine

fludarabine 30 mg/m2/dose IV x 6 doses

Intervention Type: DRUG

Cyclosporins

Intervention Type: DRUG

Mycophenolate mofetil

Intervention Type: DRUG

Tacrolimus

Intervention Type: DRUG

Other Intervention Names

Campath-1H; Fludara; cyclosporine A; Neoral; Sandimmune; Cellcept; FK506; Prograf

Eligibility Criteria

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, 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

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, 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.

• Minimum Eligible Age: 30 Days
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Baylor College of Medicine

OTHER

Sponsor Role: collaborator

Children's Hospital of Philadelphia

OTHER

Sponsor Role: collaborator

University of Wisconsin, Madison

OTHER

Sponsor Role: collaborator

Karolinska University Hospital

OTHER

Sponsor Role: collaborator

Hackensack Meridian Health

OTHER

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: collaborator

Oslo University Hospital

OTHER

Sponsor Role: collaborator

Children's Mercy Hospital Kansas City

OTHER

Sponsor Role: collaborator

Mayo Clinic

OTHER

Sponsor Role: collaborator

University of Chicago

OTHER

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: collaborator

Boston Children's Hospital

OTHER

Sponsor Role: lead

Dana-Farber Cancer Institute

OTHER

Sponsor Role: collaborator

Children's Hospital Medical Center, Cincinnati

OTHER

Sponsor Role: collaborator

Children's Hospital Los Angeles

OTHER

Sponsor Role: collaborator

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

UNKNOWN

Sponsor Role: collaborator

Responsible Party

Suneet Agarwal

Associate Professor of Pediatrics

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Suneet Agarwal, MD, PHD

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

Locations

Children's Hospital Los Angeles

Los Angeles, California, United States

University of Chicago

Chicago, Illinois, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Boston Children's Hospital (pediatric patients)

Boston, Massachusetts, United States

Dana-Farber Cancer Institute (adult patients)

Boston, Massachusetts, United States

Children's Mercy Hospital Kansas City

Kansas City, Missouri, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Baylor College of Medicine

Houston, Texas, United States

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

Seattle, Washington, United States

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States

Oslo University Hospital

Oslo, , Norway

Karolinska University Hospital

Stockholm, , Sweden

Countries

United States; Norway; Sweden

References

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.

Reference Type: DERIVED

PMID: 34086408 (View on PubMed)

Other Identifiers

IRB-P00003466

Identifier Type: OTHER

Identifier Source: secondary_id

12-950

Identifier Type: -

Identifier Source: org_study_id