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

Primary Purpose

Dyskeratosis Congenita, Hoyeraal Hreidarsson Syndrome, Revesz Syndrome

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
alemtuzumab
Fludarabine
Cyclosporins
Mycophenolate mofetil
Tacrolimus
Sponsored by
Boston Children's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Dyskeratosis Congenita focused on measuring dyskeratosis congenita, bone marrow failure, aplastic anemia, bone marrow transplantation, reduced intensity conditioning, campath, fludarabine, telomere

Eligibility Criteria

30 Days - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • Children's Hospital Los Angeles
  • University of Chicago
  • Massachusetts General Hospital
  • Boston Children's Hospital (pediatric patients)
  • Dana-Farber Cancer Institute (adult patients)
  • Mayo Clinic
  • Children's Mercy Hospital Kansas City
  • Hackensack University Medical Center
  • Duke University Medical Center, Pediatric BMT
  • Cincinnati Children's Hospital Medical Center
  • Children's Hospital of Philadelphia
  • Baylor College of Medicine
  • Fred Hutch/University of Washington/Seattle Children's Cancer Consortium
  • University of Wisconsin Hospital and Clinics
  • Oslo University Hospital
  • Karolinska University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

alemtuzumab/fludarabine conditioning

Arm Description

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

Outcomes

Primary Outcome Measures

Primary engraftment

Secondary Outcome Measures

Survival to day+100 post-BMT
Viral reactivation and infection
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
Secondary graft failure
Acute and chronic graft-versus-host disease (GVHD)
Engraftment monitoring (chimerism)
Immune reconstitution as assessed by quantitation of lymphocyte subsets
Number of participants with quantitative defects in lymphocyte subset numbers following BMT
Changes in pulmonary function as assessed by pulmonary function testing
Secondary malignancies
Number of patients with malignancies following BMT
Long-term survival

Full Information

First Posted
August 6, 2012
Last Updated
August 28, 2023
Sponsor
Boston Children's Hospital
Collaborators
Dana-Farber Cancer Institute, Children's Hospital Medical Center, Cincinnati, Children's Hospital Los Angeles, Fred Hutch/University of Washington/Seattle Children's 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
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1. Study Identification

Unique Protocol Identification Number
NCT01659606
Brief Title
Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
Official Title
Radiation- and Alkylator-free Hematopoietic Cell Transplantation for Bone Marrow Failure Due to Dyskeratosis Congenita / Telomere Disease
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 2012 (undefined)
Primary Completion Date
January 2024 (Anticipated)
Study Completion Date
December 2034 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Boston Children's Hospital
Collaborators
Dana-Farber Cancer Institute, Children's Hospital Medical Center, Cincinnati, Children's Hospital Los Angeles, Fred Hutch/University of Washington/Seattle Children's 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

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Dyskeratosis Congenita, Hoyeraal Hreidarsson Syndrome, Revesz Syndrome, Aplastic Anemia
Keywords
dyskeratosis congenita, bone marrow failure, aplastic anemia, bone marrow transplantation, reduced intensity conditioning, campath, fludarabine, telomere

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
alemtuzumab/fludarabine conditioning
Arm Type
Experimental
Arm Description
alemtuzumab/fludarabine conditioning; calcineurin-inhibitor/mycophenolate mofetil GVHD prophylaxis
Intervention Type
Biological
Intervention Name(s)
alemtuzumab
Other Intervention Name(s)
Campath-1H
Intervention Description
Conditioning: alemtuzumab 0.2 mg/kg/dose IV/SC x 5 doses
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
fludarabine 30 mg/m2/dose IV x 6 doses
Intervention Type
Drug
Intervention Name(s)
Cyclosporins
Other Intervention Name(s)
cyclosporine A, Neoral, Sandimmune
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil
Other Intervention Name(s)
Cellcept
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
FK506, Prograf
Primary Outcome Measure Information:
Title
Primary engraftment
Time Frame
Up to day +100 post-BMT
Secondary Outcome Measure Information:
Title
Survival to day+100 post-BMT
Time Frame
Up to day+100 post-BMT
Title
Viral reactivation and infection
Description
Number of participants with DNA virus (cytomegalovirus, Epstein Barr virus, or adenovirus) reactivation/infection detected by PCR screening will be reported.
Time Frame
Up to day +100 post-BMT
Title
Treatment related adverse events as assessed by CTCAE version 4.0
Time Frame
Up to 1 year post-BMT
Title
Secondary graft failure
Time Frame
Up to 15 years post-BMT
Title
Acute and chronic graft-versus-host disease (GVHD)
Time Frame
Up to 15 years post-BMT
Title
Engraftment monitoring (chimerism)
Time Frame
Up to 15 years post-BMT
Title
Immune reconstitution as assessed by quantitation of lymphocyte subsets
Description
Number of participants with quantitative defects in lymphocyte subset numbers following BMT
Time Frame
Up to 15 years post-BMT
Title
Changes in pulmonary function as assessed by pulmonary function testing
Time Frame
Up to 15 years post-BMT
Title
Secondary malignancies
Description
Number of patients with malignancies following BMT
Time Frame
Up to 15 years post-BMT
Title
Long-term survival
Time Frame
Up to 15 years post-BMT

10. Eligibility

Sex
All
Minimum Age & Unit of Time
30 Days
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility 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, 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Suneet Agarwal, MD, PHD
Organizational Affiliation
Boston Children's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Boston Children's Hospital (pediatric patients)
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Dana-Farber Cancer Institute (adult patients)
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Children's Mercy Hospital Kansas City
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Duke University Medical Center, Pediatric BMT
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
University of Wisconsin Hospital and Clinics
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States
Facility Name
Oslo University Hospital
City
Oslo
Country
Norway
Facility Name
Karolinska University Hospital
City
Stockholm
Country
Sweden

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
34086408
Citation
Bhoopalan SV, Wlodarski M, Reiss U, Triplett B, Sharma A. Reduced-intensity conditioning-based hematopoietic cell transplantation for dyskeratosis congenita: Single-center experience and literature review. Pediatr Blood Cancer. 2021 Oct;68(10):e29177. doi: 10.1002/pbc.29177. Epub 2021 Jun 4.
Results Reference
derived

Learn more about this trial

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

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