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

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®

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.

Study Overview

• Status: Completed
• Conditions: Immunodeficiency Syndrome; Non-Cancer Diagnosis
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Fludarabine Phosphate; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Mycophenolate Mofetil; Biological: Alemtuzumab; Drug: Cyclosporine; Procedure: Allogeneic Bone Marrow Transplantation; Radiation: Total-Body Irradiation

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.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Oakland, California, United States, 94609-1809
      • Children's Hospital and Research Center at Oakland
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53201
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 54 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Treatment (chemotherapy, low dose radiation); 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.

Other: Laboratory Biomarker Analysis; Correlative study; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; Oforta; SH T 586; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo HCT; Other Names: HSC; HSCT; allogeneic stem cell transplantation; Drug: Mycophenolate Mofetil; Given PO or IV; Other Names: Cellcept; MMF; Biological: Alemtuzumab; Given IV; Other Names: Campath; Campath-1H; Monoclonal Antibody Campath-1H; MabCampath; Anti-CD52 Monoclonal Antibody; LDP-03; Drug: Cyclosporine; Given PO or IV; Other Names: 27-400; Sandimmune; Ciclosporin; CsA; Neoral; Sandimmun; Cyclosporin; Cyclosporin A; OL 27-400; SangCya; Procedure: Allogeneic Bone Marrow Transplantation; Undergo HCT; Other Names: Allo BMT; Allogeneic BMT; Radiation: Total-Body Irradiation; Undergo low dose TBI; Other Names: Whole-Body Irradiation; TOTAL 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

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI)

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (ACTUAL): March 1, 2015

Study Registration Dates

• First Submitted: November 2, 2007
• First Submitted That Met QC Criteria: November 2, 2007
• First Posted (ESTIMATE): November 4, 2007

Study Record Updates

• Last Update Posted (ACTUAL): February 17, 2020
• Last Update Submitted That Met QC Criteria: February 5, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Immunologic Deficiency Syndromes; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Fludarabine; Fludarabine phosphate; Mycophenolic Acid; Cyclosporine; Cyclosporins; Alemtuzumab
• Other Study ID Numbers: 2007.00 (OTHER: Fred Hutch/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); 2007 (King Faisal University); NCI-2009-01550 (REGISTRY: CTRP (Clinical Trial Reporting Program))