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Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita ID: NCT01659606


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.


Dyskeratosis Congenita

Hoyeraal Hreidarsson Syndrome

Revesz Syndrome

Severe Aplastic Anemia

Recruitment Status



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.

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

- 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

- 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


Intervention Type


Intervention Name


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Intervention Type


Intervention Name

Mycophenolate mofetil


Phase 2



Minimum Age


Maximum Age

65 Years

Download Date

June 29, 2021

Principal Investigator

Suneet Agarwal

Primary Contact Information

Suneet Agarwal, MD, PHD

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