Pilot Study Of Unrelated UCB Transplant for Non-Malignant Hematologic Conditions

Study Overview
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Brief Summary
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RATIONALE: Umbilical cord blood transplantation may allow doctors to give higher doses of chemotherapy or radiation therapy and kill more cancer cells. PURPOSE: This phase II trial is studying how well umbilical cord blood transplantation works in treating patients with severe aplastic anemia, malignant thymoma, or myelodysplasia.

Detailed Description
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OBJECTIVES: Determine the rates of durable engraftment in patients with severe aplastic anemia, myelodysplastic syndrome, inborn errors of metabolism, or inherited hematopoietic disorders, refractory to medical management, who are undergoing high-dose chemoradiotherapy followed by unrelated cord blood (UCB) transplantation. Evaluate the rate and quality of immunologic reconstitution in this patient population. OUTLINE: Patients are stratified according to weight (under 45 kg vs over 45 kg). Patients receive high-dose chemotherapy and/or radiotherapy as a conditioning regimen beginning 6-9 days before the umbilical cord blood transplant (UCBT). The regimen varies according to the underlying cause of the anemia, but could include busulfan, cyclophosphamide or melphalan, anti-thymocyte globulin or methylprednisolone, and/or radiation therapy. One day after the conditioning regimen is completed, patients receive the UCBT. Patients are followed weekly for 3 months, at 6 months, then every 6 months for 2.5 years, then annually thereafter. PROJECTED ACCRUAL: A total of 4-90 patients will be accrued for this study within 5 years.

Official Title
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A Pilot Study of Unrelated Umbilical Cord Blood Transplantation in Patients With Severe Aplastic Anemia, Inborn Errors in Metabolism, or Inherited Hematologic Stem Cell Disorders

Conditions
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Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases

Intervention / Treatment
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* Biological: anti-thymocyte globulin
* Drug: busulfan
* Drug: cyclophosphamide
* Drug: melphalan
* Drug: methylprednisolone
* Procedure: bone marrow ablation with stem cell support
* Procedure: umbilical cord blood transplantation
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diagnosis of severe aplastic anemia based on bone marrow cellularity of less than 20% Must meet at least two of the following criteria: Granulocyte count less than 500/mm^3 Platelet count less than 20,000/mm^3 Reticulocyte count less than 50,000/mm^3 Following etiologies eligible: Fanconi's anemia Hypoplastic leukemia Monosomy 7 Drug exposure (chloramphenicol, NSAIDS) Viral exposure (EBV, hepatitis, parvovirus, HIV) Nutritional deficiencies Thymoma Paroxysmal nocturnal hemoglobinuria Amegakaryocytic thrombocytopenia OR Histologically confirmed myelodysplastic syndrome (MDS) that is refractory to medical management or with cytogenic abnormalities predictive of transformation into acute leukemia, including 5q-, 7q-, monosomy 7, or trisomy 8 The following etiologies only are eligible: Refractory anemia Refractory anemia with ringed sideroblasts De novo primary MDS Therapy-related secondary MDS OR Confirmed diagnosis of inherited hematopoietic disorder that is refractory to medical management Following etiologies eligible: Severe combined immunodeficiency Familial erythrophagocytic lymphohistiocytosis Wiskott-Aldrich syndrome Kostmann's syndrome (infantile histiocytosis) Chronic granulomatous disease Leukocytic adhesion deficiency Chediak-Higashi syndrome Paroxysmal nocturnal hemoglobinuria Fanconi's anemia Dyskeratosis congenita Diamond-Blackfan anemia Amegakaryocytic thrombocytopenia Osteopetrosis Gaucher's disease Lesch-Nyhan syndrome Mucopolysaccharidoses Lipodoses Autologous or haploidentical related peripheral blood stem cells available as backup Serologically matched umbilical cord blood unit available in the New York Blood Center's Placental Blood Project, or other acceptable umbilical cord blood registry PATIENT CHARACTERISTICS: Age: 55 and under Performance status: Zubrod 0-1 Karnofsky 80-100% Life expectancy: At least 3 months Hematopoietic: See Disease Characteristics Hepatic: ALT/AST no greater than 4 times normal Bilirubin no greater than 2.0 mg/dL Renal: Creatinine no greater than 2.0 mg/dL Creatinine clearance at least 50 mL/min Cardiovascular: Normal cardiac function by echocardiogram or radionuclide scan Shortening fraction or ejection fraction at least 80% normal for age Non-Fanconi patients with acquired or congenital cardiomyopathy may receive melphalan as a substitute for cyclophosphamide Pulmonary: FVC and FEV_1 at least 60% of predicted for age DLCO at least 60% of predicted in adult patients Other: No active concurrent malignancy No active infection Not pregnant or nursing HIV negative Must have an available serologic matched Umbilical Cord Blood Unit (UCBU) in the New York Blood Center's Placental Blood Project, or other acceptable Umbilical Cord Blood (UCB) registry PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No concurrent cytotoxic chemotherapy Endocrine therapy: No concurrent immunosuppressive medications Radiotherapy: No concurrent radiotherapy Surgery: Not specified

Ages Eligible for Study
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Maximum Age: 55 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: anti-thymocyte globulin|The regimen varies according to the underlying cause of the anemia.Patients receive high-dose chemotherapy and/or radiotherapy as a conditioning regimen beginning 6-9 days before the umbilical cord blood transplant (UCBT).|
|Drug: busulfan|The regimen varies according to the underlying cause of the anemia.Patients receive high-dose chemotherapy and/or radiotherapy as a conditioning regimen beginning 6-9 days before the umbilical cord blood transplant (UCBT).|
|Drug: cyclophosphamide|The regimen varies according to the underlying cause of the anemia.Patients receive high-dose chemotherapy and/or radiotherapy as a conditioning regimen beginning 6-9 days before the umbilical cord blood transplant (UCBT).|
|Drug: melphalan|The regimen varies according to the underlying cause of the anemia.Patients receive high-dose chemotherapy and/or radiotherapy as a conditioning regimen beginning 6-9 days before the umbilical cord blood transplant (UCBT).|
|Drug: methylprednisolone|The regimen varies according to the underlying cause of the anemia.Patients receive high-dose chemotherapy and/or radiotherapy as a conditioning regimen beginning 6-9 days before the umbilical cord blood transplant (UCBT).|
|Procedure: bone marrow ablation with stem cell support|nan|
|Procedure: umbilical cord blood transplantation|One day after the conditioning regimen is completed, patients receive the UCBT.|
|Radiation: radiation therapy|The regimen varies according to the underlying cause of the anemia.Patients receive high-dose chemotherapy and/or radiotherapy as a conditioning regimen beginning 6-9 days before the umbilical cord blood transplant (UCBT).|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival by disease assessment |  | at 100 days and at 6, 9, 12, 18, and 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Umbilical cord blood donor engraftment by chimerism and complete blood count (CBC) at time of myeloid recovery. |  | 100 days and at 6, 9, 12, 18, and 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory anemia, refractory anemia with ringed sideroblasts, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, atypical chronic myeloid leukemia, myelodysplastic/myeloproliferative disease, unclassifiable, childhood myelodysplastic syndromes