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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2015 by Boston Children’s Hospital
Information provided by (Responsible Party):
Suneet Agarwal, Children's Hospital Boston
ClinicalTrials.gov Identifier:
First received: August 6, 2012
Last updated: September 14, 2015
Last verified: September 2015
Dyskeratosis congenita is a disease that affects numerous parts of the body, most typically causing failure of the blood system. Lung disease and a predisposition to cancer are also frequent causes of illness and death. Bone marrow transplantation (BMT) can cure the blood system but can make the lung disease and cancer predisposition worse, because of 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 agents in patients with DC, and still have a successful BMT. In this protocol we will test whether a regimen that avoids 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: Open Label
Primary Purpose: Treatment
Official Title: Non-TBI and Alkylator-free Conditioning for Allogeneic Bone Marrow Transplantation for Bone Marrow Failure Due to Dyskeratosis Congenita / Telomere Disease

Resource links provided by NLM:

Further study details as provided by Boston Children’s Hospital:

Primary Outcome Measures:
  • 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

Secondary Outcome Measures:
  • 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.

Estimated Enrollment: 10
Study Start Date: July 2012
Estimated Study Completion Date: October 2032
Estimated Primary Completion Date: October 2017 (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
Starting Day -2 beginning at 1.5 mg/kg IV twice per day, infused over 2 hours, titrated to maintain a serum trough level of 150 -200 ng/ml. CSA will be administered for a minimum of 6 months and then tapered over 10 weeks.
Other Names:
  • cyclosporine A
  • Neoral
  • Sandimmune
Drug: Mycophenolate mofetil
15 mg/kg IV three times a day from day 0 to day +53
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.

Ages Eligible for Study:   up to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Bone marrow cellularity: 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 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.
  • Matched unrelated donor must consent to 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.
  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

Contact: Suneet Agarwal, MD, PHD 617-919-7579 suneet.agarwal@childrens.harvard.edu
Contact: Leslie E Lehmann, MD 617-632-4882 leslie_lehmann@dfci.harvard.edu

United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Principal Investigator: Suneet Agarwal, MD, PHD         
Principal Investigator: Leslie E Lehmann, MD         
Sub-Investigator: Inga Hofmann, MD, PHD         
Sub-Investigator: Steven Margossian, MD, PHD         
Sub-Investigator: Christine Duncan, MD         
Sub-Investigator: Wendy London, PHD         
Sponsors and Collaborators
Boston Children’s Hospital
Principal Investigator: Suneet Agarwal, MD, PHD Boston Children’s Hospital
Principal Investigator: Leslie E Lehmann, MD Dana-Farber Cancer Institute
  More Information

Responsible Party: Suneet Agarwal, Assistant Professor of Pediatrics, Children's Hospital Boston
ClinicalTrials.gov Identifier: NCT01659606     History of Changes
Other Study ID Numbers: 12-950  IRB-P00003466 
Study First Received: August 6, 2012
Last Updated: September 14, 2015

Keywords provided by Boston Children’s Hospital:
dyskeratosis congenita
bone marrow failure
aplastic anemia
bone marrow transplantation
reduced intensity conditioning

Additional relevant MeSH terms:
Fetal Diseases
Anemia, Aplastic
Dyskeratosis Congenita
Fetal Growth Retardation
Intellectual Disability
Pathologic Processes
Hematologic Diseases
Bone Marrow Diseases
Skin Abnormalities
Congenital Abnormalities
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Skin Diseases, Genetic
Skin 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 January 19, 2017