Hematopoietic Stem Cell Transplant for Dyskeratosis Congenita or Severe Aplastic Anemia

Study Overview
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Brief Summary
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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.

Official Title
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Hematopoietic Stem Cell Transplant for Dyskeratosis Congenita or Severe Aplastic Anemia

Conditions
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Dyskeratosis Congenita, Aplastic Anemia

Intervention / Treatment
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* Drug: Alemtuzumab
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Radiation: Total Body Irradiation
* Biological: Stem Cell Transplant
* Drug: Anti-thymocyte globulin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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severe aplastic anemia, Hematopoietic Stem Cell Transplant