Hematopoietic Stem Cell Transplant for Dyskeratosis Congenita or Severe Aplastic Anemia

Fludarabine-based preparative regimen followed by an allogeneic hematopoietic stem cell transplant using related or unrelated donor in persons 0-70 years of age diagnosed with dyskeratosis congenita or severe aplastic anemia who have bone marrow failure characterized by a requirement for red blood cell and platelet transfusions. Three different preparative regimens are included based on disease and donor type.

Study Overview

• Status: Recruiting
• Conditions: Aplastic Anemia; Dyskeratosis Congenita
• Intervention / Treatment: Drug: Alemtuzumab; Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Stem Cell Transplant; Radiation: Total Body Irradiation; Drug: Anti-thymocyte globulin

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Timothy Krepski; Phone Number: 612-273-2800; Email: tkrepsk1@fairview.org

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • University of Minnesota Medical Center, Fairview
      • Contact: Timothy Krepski; Phone Number: 612-273-2800; Email: tkrepsk1@fairview.org
      • Principal Investigator: Jakub Tolar, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged 0 - 70 years
• Acceptable hematopoeitic stem cell donor

• Dyskeratosis Congenita (DC) with evidence of BM failure defined as:

  • requirement for red blood cell and/or platelet transfusions or
  • requirement for G-CSF or GM-CSF or erythropoietin or

  • refractory cytopenias having one of the following three

    • platelets <50,000/uL or transfusion dependent
    • absolute neutrophil count <500/uL without hematopoietic growth factor support
    • hemoglobin <9g/uL or transfusion dependent

• Diagnosis of DC with a triad of mucocutaneous features:

  • oral leukoplakia
  • nail dystrophy
  • abnormal reticular skin hyperpigmentation, or

• Diagnosis of DC with one of the following:

  • short telomeres (under a research study)
  • mutation in telomerase holoenzyme (DKC1, TERT, TERC, NOP10, NHP2, TCAB1)
  • mutation in shelterin complex (TINF2)
  • mutation in telomere-capping complex (CTC1)

• Severe Aplastic Anemia (SAA) primary transplant with evidence of BM failure:

  • Refractory cytopenia defined by bone marrow cellularity <50% (with < 30% residual hematopoietic cells)

• Diagnosis of SAA with refractory cytopenias having one of the following three:

  • platelets <20,000/uL or transfusion dependent
  • absolute neutrophil count <500/uL without hematopoietic growth factor support
  • absolute reticulocyte count <20,000/uL

• Severe Aplastic Anemia (SAA) requiring a 2nd transplant

  • Graft failure as defined by blood/marrow chimerism of < 5%
• Early myelodysplastic features
• With or without clonal cytogenetic abnormalities

• Adequate organ function defined as:

  • cardiac: left ventricular ejection fraction ≥ 35% with no evidence of decompensated heart failure
  • pulmonary: DLCO ≥30% predicted, no supplemental oxygen requirement
  • renal: Glomerular filtration rate (GFR) ≥30% predicted
• Voluntary written consent

Exclusion Criteria:

• Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy
• Pregnant or lactating
• Uncontrolled infection
• Prior radiation therapy (applies to SAA patients only)
• Diagnosis of Fanconi anemia based on DEB
• Diagnosis of dyskeratosis congenita with advanced MDS or acute myeloid leukemia with >30% blasts

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Plan for Dyskeratosis Congenita; Fludarabine based preparative regimen, including alemtuzumab, cyclophosphamide, fludarabine, and total body irradiation, followed by stem cell transplant for the treatment of dyskeratosis congenita.	Drug: Alemtuzumab; Alemtuzumab 0.2 mg/kg IV over 2 hours on days -10 to -6 from transplant.; Drug: Fludarabine; Fludarabine 40 mg/m2 IV over 1 hour on days -6 to -2 from transplant.; Other Names: Fludara; Drug: Cyclophosphamide; Cyclophosphamide 50 mg/kg IV over 2 hours on day -7 from transplant.; Biological: Stem Cell Transplant; Stem cell transplant on day 0.; Other Names: HSCT
Experimental: Treatment for Severe Aplastic Anemia; Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.	Drug: Fludarabine; Fludarabine 40 mg/m2 IV over 1 hour on days -6 to -2 from transplant.; Other Names: Fludara; Drug: Cyclophosphamide; Cyclophosphamide 50 mg/kg IV over 2 hours on day -7 from transplant.; Biological: Stem Cell Transplant; Stem cell transplant on day 0.; Other Names: HSCT; Radiation: Total Body Irradiation; TBI 200 cGy as a single fraction on day -1 from transplant.; Other Names: TBI; Drug: Anti-thymocyte globulin; ATG (Thymoglobulin - Rabbit ) 3 mg/kg IV on days -5 to -3 from stem cell transplant.; Other Names: Rabbit ATG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of neutrophil engraftment	Incidence of neutrophil engraftment by day 42.	Day 42
Incidence of platelet engraftment	Incidence of platelet engraftment at 1 year	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of regimen related mortality	Incidence of regimen related mortality by day 100.	Day 100
Incidence of acute graft-versus-host disease	Incidence of acute graft-versus-host disease by day 100.	Day 100
Incidence of chronic graft-versus-host disease	Incidence of chronic graft-versus-host disease by 6 months	6 Months
Incidence of chronic graft-versus-host disease	Incidence of chronic graft-versus-host disease by 1 year	1 Year
Incidence of secondary malignancies	Incidence of secondary malingancies	1 Year

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Jakub Tolar, MD, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2015
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: June 10, 2014
• First Submitted That Met QC Criteria: June 10, 2014
• First Posted (Estimated): June 12, 2014

Study Record Updates

• Last Update Posted (Estimated): January 26, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Hematopoietic Stem Cell Transplant; severe aplastic anemia
• Additional Relevant MeSH Terms: Skin Diseases; Congenital Abnormalities; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Skin Diseases, Genetic; Skin Abnormalities; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Anemia; Anemia, Aplastic; Dyskeratosis Congenita; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Fludarabine; Antilymphocyte Serum; Alemtuzumab
• Other Study ID Numbers: 2013OC127; MT2013-34C (Other Identifier: University of Minnesota Blood and Marrow Transplant Program)