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

This study is currently recruiting participants.
Verified July 2017 by Suneet Agarwal, Boston Children's Hospital
ClinicalTrials.gov Identifier:
First Posted: August 8, 2012
Last Update Posted: July 25, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
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
Information provided by (Responsible Party):
Suneet Agarwal, Boston Children's Hospital
August 6, 2012
August 8, 2012
July 25, 2017
July 2012
December 2019   (Final data collection date for primary outcome measure)
Primary engraftment [ Time Frame: Up to day +100 post-BMT ]
  • Day +100 Post-transplant Survival [ Time Frame: 100 days post bone marrow infusion ]
    To determine feasibility, in terms of the proportion of patients who survive to Day+100 post-transplant, of a reduced intensity conditioning regimen in allogeneic HCT for BMF due to DC.
  • Primary engraftment [ Time Frame: Days +30 and +100 after bone marrow infusion ]
    To maintain a primary engraftment rate of not less than 65% using a reduced intensity conditioning regimen in allogeneic HCT for BMF due to DC. A subject will be considered to have engrafted if the patient has neutrophil engraftment defined as the achievement of an ANC > 0.5 x 10^9/L for three consecutive measurements as of Day+30 post-transplant; and if the patient has peripheral blood chimerism > 50% donor neutrophil cells on two occasions from Day +30 to Day +100 post-transplant
Complete list of historical versions of study NCT01659606 on ClinicalTrials.gov Archive Site
  • 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 ]
  • Secondary graft failure [ Time Frame: Days +30, +60, +100, +180, +365, yearly for next 14 years ]
    Secondary graft failure is defined by (1) initial neutrophil engraftment followed by subsequent decline in the ANC to < 0.5 x 10^9/L for 3 consecutive measurements on different days, unresponsive to growth factor therapy, and/or (2) chimerism 51-100% donor neutrophil cells by Day +100 followed by decline to ≤50% donor neutrophil cells on two subsequent evaluations.
  • Regimen-related toxicity [ Time Frame: Ongoing assessments in year 1 of study ]
    Toxicities will be monitored and reported from the time of enrollment onward. Toxicities other than GVHD will be scored according to the NCI's CTCAE version 4.0. Data will be collected on adverse event (AE) by code, description, category, grade, attribution, start and end dates, and whether the AE was anticipated. Major regimen-related toxicity is defined by those toxicities with an attribution level of "probably" or "definitely" related to protocol therapy and a severity of grade 4 or 5 in any organ system. The assessment for toxicities will be carried out until day +365 post-transplant.
  • Acute and chronic graft-versus-host disease (GVHD) [ Time Frame: Weekly through day +100, day +180, day +365, yearly for 14 years ]
    Acute and chronic GVHD will be assessed and graded according to the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Manual of Procedures (MOP) v. 2.0.
  • Viral reactivation and infection [ Time Frame: Weekly through day+100 post-transplant ]
    Cytomegalovirus, Epstein Barr virus, adenovirus, and HHV6 reactivation/infection will be routinely screened by PCR based assays of blood up to day +100 post-transplant, with more focused molecular, histological or microbiological assessments based on clinical concern as needed.
  • Peripheral blood neutrophil and T cell chimerism [ Time Frame: Day +30, day +60, day +100, day +180, day +365, yearly for 14 years ]
    Peripheral blood cell subset chimerism will be monitored on Days +30, +60, +100, +180, +365 post-transplant, and yearly thereafter. Chimerism will be quantified on neutrophil (CD15+) and T lymphocytes (CD3+) subsets.
  • Pulmonary function [ Time Frame: baseline, day +60, day +100, day +180, day +365, yearly up to 14 years thereafter ]
    Pulmonary function testing (PFTs) by spirometry and diffusion capacity for carbon monoxide will be performed on subjects who are 5 years old and over (at the time of testing) and who are able to comply with testing.
  • Long-term overall survival [ Time Frame: up to 15 years after transplant ]
    Post-transplant overall survival is defined as time from transplant to death from any cause for up to fifteen years after transplant.
  • Malignancies [ Time Frame: up to 15 years after transplant ]
    The occurrence and type of malignancies will be ascertained based on patient report and medical records in follow-up visits up to fifteen years post-transplant.
Not Provided
Not Provided
Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
Radiation- and Alkylator-free Hematopoietic Cell Transplantation for Bone Marrow Failure Due to Dyskeratosis Congenita / Telomere Disease
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.
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.
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Dyskeratosis Congenita
  • Hoyeraal Hreidarsson Syndrome
  • Revesz Syndrome
  • Aplastic Anemia
  • 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
Experimental: alemtuzumab/fludarabine conditioning
alemtuzumab/fludarabine conditioning; cyclosporins/mycophenolate mofetil GVHD prophylaxis
  • Biological: alemtuzumab
  • Drug: Fludarabine
  • Drug: Cyclosporins
  • Drug: Mycophenolate mofetil
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
December 2034
December 2019   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
up to 65 Years   (Child, Adult)
Contact: Suneet Agarwal, MD, PHD 617-919-7579 suneet.agarwal@childrens.harvard.edu
United States
IRB-P00003466 ( Other Identifier: Boston Children's Hospital )
Not Provided
Plan to Share IPD: Undecided
Suneet Agarwal, Boston Children's Hospital
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
Principal Investigator: Suneet Agarwal, MD, PHD Boston Children’s Hospital
Boston Children’s Hospital
July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP