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Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
Trial Status: closed to accrual
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.
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 sponsor and potential other locations can be found on ClinicalTrials.gov for NCT01659606.
Locations matching your search criteria
United States
California
Los Angeles
Children's Hospital Los Angeles
Status: Approved
Name Not Available
Pennsylvania
Philadelphia
Children's Hospital of Philadelphia
Status: Active
Name Not Available
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.
