Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
- Conditions
- Aplastic AnemiaDyskeratosis CongenitaRevesz SyndromeHoyeraal Hreidarsson Syndrome
- Interventions
- Registration Number
- NCT01659606
- Lead Sponsor
- Boston Children's Hospital
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 40
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description alemtuzumab/fludarabine conditioning alemtuzumab alemtuzumab/fludarabine conditioning; calcineurin-inhibitor/mycophenolate mofetil GVHD prophylaxis alemtuzumab/fludarabine conditioning Fludarabine alemtuzumab/fludarabine conditioning; calcineurin-inhibitor/mycophenolate mofetil GVHD prophylaxis alemtuzumab/fludarabine conditioning Tacrolimus alemtuzumab/fludarabine conditioning; calcineurin-inhibitor/mycophenolate mofetil GVHD prophylaxis alemtuzumab/fludarabine conditioning Cyclosporins alemtuzumab/fludarabine conditioning; calcineurin-inhibitor/mycophenolate mofetil GVHD prophylaxis alemtuzumab/fludarabine conditioning Mycophenolate mofetil alemtuzumab/fludarabine conditioning; calcineurin-inhibitor/mycophenolate mofetil GVHD prophylaxis
- Primary Outcome Measures
Name Time Method Primary engraftment Up to day +100 post-BMT
- Secondary Outcome Measures
Name Time Method Survival to day+100 post-BMT Up to day+100 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 Changes in pulmonary function as assessed by pulmonary function testing Up to 15 years post-BMT Long-term survival Up to 15 years 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.
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
Secondary malignancies Up to 15 years post-BMT Number of patients with malignancies following BMT
Treatment related adverse events as assessed by CTCAE version 4.0 Up to 1 year post-BMT Engraftment monitoring (chimerism) Up to 15 years post-BMT
Trial Locations
- Locations (16)
Boston Children's Hospital (pediatric patients)
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute (adult patients)
🇺🇸Boston, Massachusetts, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium
🇺🇸Seattle, Washington, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Oslo University Hospital
🇳🇴Oslo, Norway
Karolinska University Hospital
🇸🇪Stockholm, Sweden
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
University of Chicago
🇺🇸Chicago, Illinois, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Duke University Medical Center, Pediatric BMT
🇺🇸Durham, North Carolina, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Children's Mercy Hospital Kansas City
🇺🇸Kansas City, Missouri, United States
University of Wisconsin Hospital and Clinics
🇺🇸Madison, Wisconsin, United States