Hematopoietic Stem Cell Transplant for Dyskeratosis Congenita or Severe Aplastic Anemia

Not Applicable

Completed

Conditions: Aplastic Anemia
Dyskeratosis Congenita

Interventions: Drug: Alemtuzumab
Drug: Fludarabine
Drug: Cyclophosphamide
Biological: Stem Cell Transplant
Radiation: Total Body Irradiation
Drug: Anti-thymocyte globulin

Registration Number: NCT02162420

Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 61

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm A Dyskeratosis Congenita (DKC) (non-haploidentical donor)	Alemtuzumab	Fludarabine based preparative regimen, including alemtuzumab, cyclophosphamide, fludarabine, followed by stem cell transplant for the treatment of dyskeratosis congenita.
Arm A Dyskeratosis Congenita (DKC) (non-haploidentical donor)	Fludarabine	Fludarabine based preparative regimen, including alemtuzumab, cyclophosphamide, fludarabine, followed by stem cell transplant for the treatment of dyskeratosis congenita.
Arm A Dyskeratosis Congenita (DKC) (non-haploidentical donor)	Cyclophosphamide	Fludarabine based preparative regimen, including alemtuzumab, cyclophosphamide, fludarabine, followed by stem cell transplant for the treatment of dyskeratosis congenita.
Arm A Dyskeratosis Congenita (DKC) (non-haploidentical donor)	Stem Cell Transplant	Fludarabine based preparative regimen, including alemtuzumab, cyclophosphamide, fludarabine, followed by stem cell transplant for the treatment of dyskeratosis congenita.
Arm B: Severe Aplastic Anemia (SAA ) (non-matched related, non-haploidentical donor)	Alemtuzumab	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm B: Severe Aplastic Anemia (SAA ) (non-matched related, non-haploidentical donor)	Fludarabine	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm B: Severe Aplastic Anemia (SAA ) (non-matched related, non-haploidentical donor)	Cyclophosphamide	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm B: Severe Aplastic Anemia (SAA ) (non-matched related, non-haploidentical donor)	Total Body Irradiation	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm B: Severe Aplastic Anemia (SAA ) (non-matched related, non-haploidentical donor)	Stem Cell Transplant	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm B: Severe Aplastic Anemia (SAA ) (non-matched related, non-haploidentical donor)	Anti-thymocyte globulin	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm C: Severe Aplastic Anemia (matched related donor)	Alemtuzumab	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm C: Severe Aplastic Anemia (matched related donor)	Fludarabine	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm C: Severe Aplastic Anemia (matched related donor)	Cyclophosphamide	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm C: Severe Aplastic Anemia (matched related donor)	Total Body Irradiation	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm C: Severe Aplastic Anemia (matched related donor)	Stem Cell Transplant	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm C: Severe Aplastic Anemia (matched related donor)	Anti-thymocyte globulin	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm D: Dyskeratosis Congenita (DKC), PTCy platform	Alemtuzumab	Fludarabine based preparative regimen, including alemtuzumab, cyclophosphamide, fludarabine, followed by stem cell transplant for the treatment of dyskeratosis congenita.
Arm D: Dyskeratosis Congenita (DKC), PTCy platform	Fludarabine	Fludarabine based preparative regimen, including alemtuzumab, cyclophosphamide, fludarabine, followed by stem cell transplant for the treatment of dyskeratosis congenita.
Arm D: Dyskeratosis Congenita (DKC), PTCy platform	Cyclophosphamide	Fludarabine based preparative regimen, including alemtuzumab, cyclophosphamide, fludarabine, followed by stem cell transplant for the treatment of dyskeratosis congenita.
Arm D: Dyskeratosis Congenita (DKC), PTCy platform	Stem Cell Transplant	Fludarabine based preparative regimen, including alemtuzumab, cyclophosphamide, fludarabine, followed by stem cell transplant for the treatment of dyskeratosis congenita.
Arm E: Severe Aplastic Anemia (SAA), PTCy platform	Alemtuzumab	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm E: Severe Aplastic Anemia (SAA), PTCy platform	Fludarabine	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm E: Severe Aplastic Anemia (SAA), PTCy platform	Cyclophosphamide	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm E: Severe Aplastic Anemia (SAA), PTCy platform	Total Body Irradiation	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm E: Severe Aplastic Anemia (SAA), PTCy platform	Stem Cell Transplant	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Arm E: Severe Aplastic Anemia (SAA), PTCy platform	Anti-thymocyte globulin	Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.

Primary Outcome Measures

Name	Time	Method
Incidence of Neutrophil Engraftment	Day 42	Incidence of neutrophil engraftment by day 42.
Incidence of Platelet Engraftment	1 year	Incidence of platelet engraftment at 1 year

Secondary Outcome Measures

Name	Time	Method
Incidence of Regimen Related Mortality	Day 100	Incidence of regimen related mortality by day 100.
Incidence of Acute Graft-versus-host Disease	Day 100	Incidence of acute graft-versus-host disease by day 100.
Incidence of Chronic Graft-versus-host Disease	1 Year	Incidence of chronic graft-versus-host disease by 1 year
Incidence of Secondary Malignancies	1 Year	Incidence of secondary malingancies