Clinical trial NCT01659606: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: 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
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
Collaborators: name: Dana-Farber Cancer Institute
name: Children's Hospital Medical Center, Cincinnati
name: Children's Hospital Los Angeles
name: Fred Hutch/University of Washington/Seattle Children's Cancer Consortium
name: Baylor College of Medicine
name: Children's Hospital of Philadelphia
name: University of Wisconsin, Madison
name: Karolinska University Hospital
name: Hackensack Meridian Health
name: Duke University
name: Oslo University Hospital
name: Children's Mercy Hospital Kansas City
name: Mayo Clinic
name: University of Chicago
name: Massachusetts General Hospital
First posted: 2012-08-08
Enrollment: 40
Sex: ALL
Minimum age (years): 30
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Primary engraftment
timeFrame: Up to day +100 post-BMT
Secondary outcomes:
measure: Survival to day+100 post-BMT
timeFrame: Up to day+100 post-BMT
measure: Viral reactivation and infection
timeFrame: Up to day +100 post-BMT
measure: Treatment related adverse events as assessed by CTCAE version 4.0
timeFrame: Up to 1 year post-BMT
measure: Secondary graft failure
timeFrame: Up to 15 years post-BMT
measure: Acute and chronic graft-versus-host disease (GVHD)
timeFrame: Up to 15 years post-BMT
measure: Engraftment monitoring (chimerism)
timeFrame: Up to 15 years post-BMT
measure: Immune reconstitution as assessed by quantitation of lymphocyte subsets
timeFrame: Up to 15 years post-BMT
measure: Changes in pulmonary function as assessed by pulmonary function testing
timeFrame: Up to 15 years post-BMT
measure: Secondary malignancies
timeFrame: Up to 15 years post-BMT
measure: Long-term survival
timeFrame: Up to 15 years post-BMT
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital (pediatric patients)
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute (adult patients)
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital Kansas City
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Durham
country: United States
facility: Duke University Medical Center, Pediatric BMT
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Fred Hutch/University of Washington/Seattle Children's Cancer Consortium
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
Study officials:
affiliation: Boston Children's Hospital
name: Suneet Agarwal, MD, PHD
role: PRINCIPAL_INVESTIGATOR
References:
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.