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.

• alemtuzumab (Biological), also known as Campath-1H: Conditioning: alemtuzumab 0.2 mg/kg/dose IV/SC x 5 doses
• Fludarabine (Drug), also known as Fludara: fludarabine 30 mg/m2/dose IV x 6 doses
• Cyclosporins (Drug), also known as cyclosporine A, Neoral, Sandimmune
• Mycophenolate mofetil (Drug), also known as Cellcept
• Tacrolimus (Drug), also known as FK506, Prograf

Primary outcomes

• Primary engraftment [Up to day +100 post-BMT]

Secondary outcomes

• Survival to day+100 post-BMT [Up to day+100 post-BMT]
• Viral reactivation and infection [Up to day +100 post-BMT]: Number of participants with DNA virus (cytomegalovirus, Epstein Barr virus, or adenovirus) reactivation/infection detected by PCR screening will be reported.
• 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 [Up to 15 years post-BMT]: Number of participants with quantitative defects in lymphocyte subset numbers following BMT
• Changes in pulmonary function as assessed by pulmonary function testing [Up to 15 years post-BMT]
• Secondary malignancies [Up to 15 years post-BMT]: Number of patients with malignancies following BMT
• Long-term survival [Up to 15 years post-BMT]

Sex: All, ages: 30 Days to 65 Years

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.

• Results publication: 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. PMID 34086408

• Suneet Agarwal, MD, PHD, Principal investigator, Boston Children's Hospital