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

Purpose

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	Intervention	Phase
Dyskeratosis Congenita Hoyeraal Hreidarsson Syndrome Revesz Syndrome Aplastic Anemia	Biological: alemtuzumab Drug: Fludarabine Drug: Cyclosporins Drug: Mycophenolate mofetil	Phase 2


Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: No masking Primary Purpose: Treatment
Official Title:	Radiation- and Alkylator-free Hematopoietic Cell Transplantation for Bone Marrow Failure Due to Dyskeratosis Congenita / Telomere Disease

Resource links provided by NLM:

Genetics Home Reference related topics: dyskeratosis congenita

MedlinePlus related topics: Bone Marrow Transplantation

Drug Information available for: Fludarabine Fludarabine phosphate Alemtuzumab

Genetic and Rare Diseases Information Center resources: Aplastic Anemia Dyskeratosis Congenita Hoyeraal Hreidarsson Syndrome Revesz Syndrome Microcephaly Microencephaly

U.S. FDA Resources

Further study details as provided by Suneet Agarwal, Boston Children's Hospital:

Primary Outcome Measures:

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

Secondary Outcome Measures:

Survival to day+100 post-BMT [ Time Frame: Up to day+100 post-BMT ]
Viral reactivation and infection [ Time Frame: 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 [ Time Frame: Up to 1 year post-BMT ]
Secondary graft failure [ Time Frame: Up to 15 years post-BMT ]
Acute and chronic graft-versus-host disease (GVHD) [ Time Frame: Up to 15 years post-BMT ]
Engraftment monitoring (chimerism) [ Time Frame: Up to 15 years post-BMT ]
Immune reconstitution as assessed by quantitation of lymphocyte subsets [ Time Frame: 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 [ Time Frame: Up to 15 years post-BMT ]
Secondary malignancies [ Time Frame: Up to 15 years post-BMT ]
Number of patients with malignancies following BMT
Long-term survival [ Time Frame: Up to 15 years post-BMT ]


Estimated Enrollment:	20
Study Start Date:	July 2012
Estimated Study Completion Date:	December 2034
Estimated Primary Completion Date:	December 2019 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: alemtuzumab/fludarabine conditioning alemtuzumab/fludarabine conditioning; cyclosporins/mycophenolate mofetil GVHD prophylaxis	Biological: alemtuzumab Conditioning: alemtuzumab 0.2 mg/kg/dose IV x 5 doses Other Name: Campath-1H Drug: Fludarabine fludarabine 30 mg/m2/dose IV x 6 doses Other Name: Fludara Drug: Cyclosporins Other Names: cyclosporine A Neoral Sandimmune Drug: Mycophenolate mofetil Other Name: Cellcept

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.

Eligibility


Ages Eligible for Study:	up to 65 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01659606

Contacts


Contact: Suneet Agarwal, MD, PHD	617-919-7579	suneet.agarwal@childrens.harvard.edu

Locations


United States, California
Children's Hospital Los Angeles	Recruiting
Los Angeles, California, United States, 90027
Contact: Andrew Dietz, MD adietz@chla.usc.edu
Principal Investigator: Andrew Dietz, MD
United States, Massachusetts
Boston Children's Hospital (pediatric patients)	Recruiting
Boston, Massachusetts, United States, 02115
Contact: Suneet Agarwal, MD, PHD 617-919-7579 suneet.agarwal@childrens.harvard.edu
Contact: Leslie Lehmann, MD leslie_lehmann@dfci.harvard.edu
Principal Investigator: Suneet Agarwal, MD, PHD
Sub-Investigator: Leslie Lehmann, MD
Dana-Farber Cancer Institute (adult patients)	Recruiting
Boston, Massachusetts, United States, 02115
Contact: Suneet Agarwal, MD, PHD suneet.agarwal@childrens.harvard.edu
Contact: Joseph Antin, MD Joseph_Antin@dfci.harvard.edu
Principal Investigator: Suneet Agarwal, MD, PHD
Sub-Investigator: Joseph Antin, MD
United States, Ohio
Cincinnati Children's Hospital Medical Center	Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Kasiani Myers, MD Kasiani.Myers@cchmc.org
Principal Investigator: Kasiani Myers, MD
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Recruiting
Seattle, Washington, United States, 98109
Contact: Lauri Burroughs, MD 206-667-2396 lburroug@fhcrc.org
Principal Investigator: Lauri Burroughs, MD

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

Investigators


Principal Investigator:	Suneet Agarwal, MD, PHD	Boston Children’s Hospital

More Information


Responsible Party:	Suneet Agarwal, Assistant Professor of Pediatrics, Boston Children's Hospital
ClinicalTrials.gov Identifier:	NCT01659606 History of Changes
Other Study ID Numbers:	12-950 IRB-P00003466 ( Other Identifier: Boston Children's Hospital )
Study First Received:	August 6, 2012
Last Updated:	June 7, 2017
Individual Participant Data
Plan to Share IPD:	Undecided

Keywords provided by Suneet Agarwal, Boston Children's Hospital:


dyskeratosis congenita bone marrow failure aplastic anemia bone marrow transplantation	reduced intensity conditioning campath fludarabine telomere

Additional relevant MeSH terms:


Syndrome Anemia, Aplastic Dyskeratosis Congenita Fetal Growth Retardation Intellectual Disability Microcephaly Disease Pathologic Processes Anemia Hematologic Diseases Bone Marrow Diseases Skin Abnormalities Congenital Abnormalities Genetic Diseases, X-Linked Genetic Diseases, Inborn	Skin Diseases, Genetic Skin Diseases Fetal Diseases Pregnancy Complications Growth Disorders Neurobehavioral Manifestations Neurologic Manifestations Nervous System Diseases Signs and Symptoms Neurodevelopmental Disorders Mental Disorders Craniofacial Abnormalities Musculoskeletal Abnormalities Musculoskeletal Diseases Malformations of Cortical Development, Group I

ClinicalTrials.gov processed this record on June 26, 2017