Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by a Donor Stem Cell Transplant in Treating Patients With Immunodeficiency or Other Nonmalignant Inherited Disorders

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies fludarabine phosphate and total-body irradiation with or without alemtuzumab followed by donor stem cell transplant to see how well it works in treating patients with immunodeficiency or other nonmalignant inherited disorders. Giving chemotherapy, such as fludarabine phosphate, a monoclonal antibody such as alemtuzumab, and radiation therapy before a donor stem cell transplant helps stop the growth of abnormal cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining abnormal cells.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Improve donor chimerism levels in patients with inherited nonmalignant disorders undergoing hematopoietic cell transplantation (HCT) using a reduced intensity conditioning regimen either through the addition of Campath (alemtuzumab) or a slightly higher dose of total-body irradiation (TBI). SECONDARY OBJECTIVES: I. Decrease the incidence and severity of acute and chronic graft-versus-host disease (GVHD) through use of marrow as the stem cell source and Campath. II. Assess disease response following HCT. III. Immune reconstitution following HCT. IV. Incidence of infections. V. Overall survival. VI. Percent of patients with cluster of differentiation (CD)33/CD19 donor chimerism > 50%. OUTLINE: CONDITIONING REGIMEN: Patients with no life-threatening viral or fungal infections within 1 month before the planned hematopoietic cell transplantation (HCT) receive alemtuzumab intravenously (IV) over 6 hours on day -10 and fludarabine phosphate IV over 30 minutes on days -4 to -2. They also undergo low-dose TBI on day 0. Patients with hemophagocytic lymphohistiocytosis (HLH), immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, DiGeorge syndrome, or life-threatening viral or fungal infections within 1 month before the planned HCT receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo 2 low doses of TBI on day 0. HEMATOPOIETIC CELL TRANSPLANTATION: Patients undergo HCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine IV or orally (PO) 2-3 times daily beginning on day -3 and continuing until day 100 followed by a taper until day 180. They also receive mycophenolate mofetil IV or PO 3 times daily beginning on day 0 and continuing until day 40 followed by a taper until day 96. After completion of HCT, patients are followed up at day 84, at 6, 12, 18 and 24 months post-transplantation, and then once a year for 3 years.

Official Title
-----------------
Hematopoietic Cell Transplantation for Treatment of Patients With Primary Immunodeficiencies and Other Nonmalignant Inherited Disorders Using Low-Dose TBI and Fludarabine With or Without Campath®

Conditions
-----------------
Immunodeficiency Syndrome, Non-Cancer Diagnosis

Intervention / Treatment
-----------------
* Biological: Alemtuzumab
* Procedure: Allogeneic Bone Marrow Transplantation
* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Cyclosporine
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Mycophenolate Mofetil
* Radiation: Total-Body Irradiation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Primary immunodeficiency disorder or other nonmalignant inherited disease (except aplastic anemia and Fanconi anemia) treatable by allogeneic HCT Patients with pre-existing medical conditions or other factors that renders them at high risk for regimen related toxicity or ineligible for a conventional myeloablative HCT Donors: Related donor who is human leukocyte antigen (HLA) genotypically identical at least at one haplotype and may be genotypically or phenotypically identical for serological typing for HLA-A, B, -C, and at the allele level for -DRB1 and -DQB1; related donors must be a match or a single allele mismatch at HLA-A, B, and C (at highest resolution available at the time of donor selection) and matched at DRB1 and DQB1 by deoxyribonucleic acid (DNA) typing Donors: Unrelated donors who are prospectively: Matched for HLA-A, B, C, DRB1 and DQB1 by DNA typing at the highest resolution routinely available at the time of donor selection Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing (no mismatching for DRB1 or DQB1 is allowed) Exclusion Criteria: Patients with Aplastic anemia and Fanconi anemia Patients with metabolic storage diseases who have severe central nervous system (CNS) involvement of disease, defined as intelligence quotient (IQ) score < 70 Cardiac ejection fraction < 30% or, if unable to obtain ejection fraction, shortening fraction of < 26%) on multi-gated acquisition (MUGA) scan or cardiac echo, symptomatic coronary artery disease, other cardiac failure requiring therapy; patients with a history of, or current cardiac disease should be evaluated with appropriate cardiac studies and/or cardiology consult; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist Poorly controlled hypertension despite anti-hypertensive medications Patients with clinical or laboratory evidence of liver disease will need to be evaluated for the cause of the liver disease, its clinical severity in terms of liver function and the degree of portal hypertension; patients will be excluded if they are found to have: fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3mg/dl, or symptomatic biliary disease (Patients will be allowed on to the protocol with liver problems if gastroenterology approves the patient for HCT) Patients who are positive for human immunodeficiency virus (HIV) Females who are pregnant or breast-feeding Fertile men or women who are unwilling to use contraceptives during HCT and up to 12 months post-treatment Patients with fungal pneumonia with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month will not be eligible for this protocol (either regimen A or B) Donors: Identical twin Donors: Pregnancy Donors: HIV positive Donors: A positive anti-donor cytotoxic cross match is absolute donor exclusion Donors: If a patient is homozygous at a particular loci, mismatching at that loci is not allowed due to an isolated graft rejection vector, i.e., patient A*0101 and the donor is A*0101, A*0201; such a mismatch may increase the risk of graft rejection; if patient and donor pairs are both homozygous at a mismatched loci, they are considered a two-HLA antigen mismatch, i.e., the patient is A*0101 and the donor is A*0201, and this type of mismatch is not allowed Donor: Donor < 6 months old, > 75 years old

Ages Eligible for Study
-----------------
Maximum Age: 54 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, low dose radiation)<br>CONDITIONING REGIMEN: *Patients with no life-threatening viral or fungal infections within 1 month before the planned HCT receive alemtuzumab IV over 6 hours on day -10 and fludarabine phosphate IV over 30 minutes on days -4 to -2. They also undergo low-dose TBI on day 0. Patients with HLH, IPEX syndrome, DiGeorge syndrome, or life-threatening viral or fungal infections within 1 month before the planned HCT receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo 2 low doses of TBI on day 0. HEMATOPOIETIC CELL TRANSPLANTATION: Patients undergo HCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine IV or PO 2-3 times daily beginning on day -3 and continuing until day 100 followed by a taper until day 180. They also receive mycophenolate mofetil IV or PO 3 times daily beginning on day 0 and continuing until day 40 followed by a taper until day 96. | Biological: Alemtuzumab<br>* Given IV<br>* Other names: Monoclonal Antibody Campath-1H;Procedure: Allogeneic Bone Marrow Transplantation<br>* Undergo HCT<br>* Other names: Allogeneic BMT;Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo HCT<br>* Other names: HSCT;Drug: Cyclosporine<br>* Given PO or IV<br>* Other names: SangCya;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative study<br>Drug: Mycophenolate Mofetil<br>* Given PO or IV<br>* Other names: MMF;Radiation: Total-Body Irradiation<br>* Undergo low dose TBI<br>* Other names: Whole-Body Irradiation;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Achieve Greater Than 50% Donor T-cell Chimerism | The study will be considered a success and the protocol worthy of further study if there is sufficient evidence that this rate is greater than the 50% rate observed in the most recently transplanted patients with nonmalignant disorders. Analyses will be carried out separately for the alemtuzumab recipients and the TBI recipients. We will be 80% confidence of success if a one-sided 80% confidence interval for the proportion of patients with successful chimerism exceeds 50%. Cumulative incidence will be used to evaluate the probability of chimerism. | At 1 year post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Number of patients alive at 1 year | 1 year | 
| Immune Reconstitution by 1 Year Post Transplant | Number of patients with normal range CD3 at 1 year post transplant | 1 year | 
| Disease Response by 1 Year Post Transplant | Number of patients at 1 year with disease response (defined as no clinical evidence of active disease and/or sufficient level of donor chimerisms to prevent disease recurrence) | 1 year | 
| Greater Than 50% CD33+ Donor Chimerisms at 1 Year Post Transplant | Number of patients who achieve greater than 50% CD33+ donor chimerisms at 1 year post transplant. | 1 year | 
| Greater Than 50% CD19+ Donor Chimerisms at 1 Year Post Transplant | Number of Patients Who Achieve Greater Than 50% CD19+ Donor Chimerisms at 1 Year Post Transplant | 1 year | 
| Clinical Significant Infection, Requiring Treatment, Within 100 Days Post Transplant | Number of patients who experienced a clinical significant infection, requiring treatment, within 100 days post transplant. | 100 days | 
| Number of Patients Diagnosed With Acute GVHD | Number of patients diagnosed with acute GVHD by Day 100 post transplant | Day 100 | 
| Number of Patients Diagnosed With Overall Grade 1 or Grade 2 Acute GVHD | Number of patients diagnosed with overall grade I or grade II acute GVHD by Day 100 post transplant | Day 100 | 
| Number of Patients Diagnosed With Overall Grade III or Grade IV Acute GVHD | Number of patients diagnosed with overall Grade III or Grade IV Acute GVHD by Day 100 post transplant | Day 100 | 
| Number of Patients Diagnosed With Chronic GVHD | Number of patients diagnosed with chronic GVHD within 1 year post transplant | 1 year |