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

Sponsor

Boston Children's Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT01659606

Collaborator

Dana-Farber Cancer Institute (Other), Children's Hospital Medical Center, Cincinnati (Other), Children's Hospital Los Angeles (Other), Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium (Other), Baylor College of Medicine (Other), Children's Hospital of Philadelphia (Other), University of Wisconsin, Madison (Other), Karolinska University Hospital (Other), Hackensack Meridian Health (Other), Duke University (Other), Oslo University Hospital (Other), Children's Mercy Hospital Kansas City (Other), Mayo Clinic (Other), University of Chicago (Other), Massachusetts General Hospital (Other)

Enrollment

Locations

Arm

269

Duration (Months)

2.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Dyskeratosis Congenita Hoyeraal Hreidarsson Syndrome Revesz Syndrome Aplastic Anemia	Biological: alemtuzumab Drug: Fludarabine Drug: Cyclosporins Drug: Mycophenolate mofetil Drug: Tacrolimus	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Radiation- and Alkylator-free Hematopoietic Cell Transplantation for Bone Marrow Failure Due to Dyskeratosis Congenita / Telomere Disease

Study Start Date :

Jul 1, 2012

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2034

Arms and Interventions

Arm	Intervention/Treatment
Experimental: alemtuzumab/fludarabine conditioning alemtuzumab/fludarabine conditioning; calcineurin-inhibitor/mycophenolate mofetil GVHD prophylaxis	Biological: alemtuzumab Conditioning: alemtuzumab 0.2 mg/kg/dose IV/SC x 5 doses Other Names: Campath-1H Drug: Fludarabine fludarabine 30 mg/m2/dose IV x 6 doses Other Names: Fludara Drug: Cyclosporins Other Names: cyclosporine A Neoral Sandimmune Drug: Mycophenolate mofetil Other Names: Cellcept Drug: Tacrolimus Other Names: FK506 Prograf

Arm

Intervention/Treatment

Experimental: alemtuzumab/fludarabine conditioning

alemtuzumab/fludarabine conditioning; calcineurin-inhibitor/mycophenolate mofetil GVHD prophylaxis

Biological: alemtuzumab

Conditioning: alemtuzumab 0.2 mg/kg/dose IV/SC x 5 doses

Other Names:

Campath-1H

Drug: Fludarabine

fludarabine 30 mg/m2/dose IV x 6 doses

Other Names:

Fludara

Drug: Cyclosporins

Other Names:

cyclosporine A

Neoral

Sandimmune

Drug: Mycophenolate mofetil

Other Names:

Cellcept

Drug: Tacrolimus

Other Names:

FK506

Prograf

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Days to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
2	University of Chicago	Chicago	Illinois	United States	60637
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
4	Boston Children's Hospital (pediatric patients)	Boston	Massachusetts	United States	02115
5	Dana-Farber Cancer Institute (adult patients)	Boston	Massachusetts	United States	02115
6	Mayo Clinic	Rochester	Minnesota	United States	55905
7	Children's Mercy Hospital Kansas City	Kansas City	Missouri	United States	64108
8	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
9	Duke University Medical Center, Pediatric BMT	Durham	North Carolina	United States	27705
10	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
11	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
12	Baylor College of Medicine	Houston	Texas	United States	77030
13	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109
14	University of Wisconsin Hospital and Clinics, American Family Children's Hospital	Madison	Wisconsin	United States	53792
15	Oslo University Hospital	Oslo		Norway
16	Karolinska University Hospital	Stockholm		Sweden

Sponsors and Collaborators

Boston Children's Hospital
Dana-Farber Cancer Institute
Children's Hospital Medical Center, Cincinnati
Children's Hospital Los Angeles
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Baylor College of Medicine
Children's Hospital of Philadelphia
University of Wisconsin, Madison
Karolinska University Hospital
Hackensack Meridian Health
Duke University
Oslo University Hospital
Children's Mercy Hospital Kansas City
Mayo Clinic
University of Chicago
Massachusetts General Hospital