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

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.

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, 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
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,
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