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

Radiation- and Alkylator-free Hematopoietic Cell Transplantation for Bone Marrow Failure Due to Dyskeratosis Congenita / Telomere Disease

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Aplastic Anemia; Dyskeratosis Congenita; Hoyeraal Hreidarsson Syndrome; Revesz Syndrome
• Intervention / Treatment: Drug: Tacrolimus; Biological: alemtuzumab; Drug: Fludarabine; Drug: Cyclosporins; Drug: Mycophenolate mofetil

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.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway
    • Oslo University Hospital
• Sweden
  • Stockholm, Sweden
    • Karolinska University Hospital
• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital (pediatric patients)
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute (adult patients)
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital Kansas City
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington/Seattle Children's Cancer Consortium
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: alemtuzumab/fludarabine conditioning; alemtuzumab/fludarabine conditioning; calcineurin-inhibitor/mycophenolate mofetil GVHD prophylaxis	Drug: Tacrolimus; Other Names: Prograf; FK506; Biological: alemtuzumab; Conditioning: alemtuzumab 0.2 mg/kg/dose IV/SC x 5 doses; Other Names: Campath-1H; Drug: Fludarabine; fludarabine 30 mg/m2/dose IV x 6 doses; Other Names: Fludara; Drug: Cyclosporins; Other Names: Sandimmune; cyclosporine A; Neoral; Drug: Mycophenolate mofetil; Other Names: Cellcept

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Primary engraftment	Up to day +100 post-BMT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival to day+100 post-BMT		Up to day+100 post-BMT
Viral reactivation and infection	Number of participants with DNA virus (cytomegalovirus, Epstein Barr virus, or adenovirus) reactivation/infection detected by PCR screening will be reported.	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
Engraftment monitoring (chimerism)		Up to 15 years post-BMT
Immune reconstitution as assessed by quantitation of lymphocyte subsets	Number of participants with quantitative defects in lymphocyte subset numbers following BMT	Up to 15 years post-BMT
Changes in pulmonary function as assessed by pulmonary function testing		Up to 15 years post-BMT
Secondary malignancies	Number of patients with malignancies following BMT	Up to 15 years post-BMT
Long-term survival		Up to 15 years post-BMT

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Collaborators: Massachusetts General Hospital; Karolinska University Hospital; Baylor College of Medicine; Children's Hospital of Philadelphia; Oslo University Hospital; Dana-Farber Cancer Institute; University of Chicago; University of Wisconsin, Madison; Children's Hospital Medical Center, Cincinnati; Children's Mercy Hospital Kansas City; Hackensack Meridian Health; Fred Hutch/University of Washington/Seattle Children's Cancer Consortium
• Investigators: Principal Investigator: Suneet Agarwal, MD, PHD, Boston Children's Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2012
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2034

Study Registration Dates

• First Submitted: August 6, 2012
• First Submitted That Met QC Criteria: August 6, 2012
• First Posted (Estimated): August 8, 2012

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: bone marrow failure; aplastic anemia; dyskeratosis congenita; bone marrow transplantation; reduced intensity conditioning; campath; fludarabine; telomere
• Additional Relevant MeSH Terms: Congenital Bone Marrow Failure Syndromes; Genetic Diseases, Inborn; Hematologic Diseases; Skin Diseases; Congenital Abnormalities; Bone Marrow Diseases; Anemia; Skin Diseases, Genetic; Genetic Diseases, X-Linked; Skin Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin and Connective Tissue Diseases; Hemic and Lymphatic Diseases; Bone Marrow Failure Disorders; Anemia, Aplastic; Dyskeratosis Congenita; Revesz Debuse syndrome; Hoyeraal Hreidarsson syndrome; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Fatty Acids; Lipids; Acids, Acyclic; Carboxylic Acids; Polycyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Macrolides; Lactones; Macrocyclic Compounds; Peptides, Cyclic; Caproates; Alemtuzumab; Mycophenolic Acid; Tacrolimus; Cyclosporine; Cyclosporins; fludarabine; fludarabine phosphate
• Other Study ID Numbers: 12-950; IRB-P00003466 (Other Identifier: Boston Children's Hospital)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No