Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant

Induction of Mixed Hematopoietic Chimerism in Patients With Severe Combined Immunodeficiency Disorders Using Allogeneic Bone Marrow and Post-Transplant Immunosuppression With Cyclosporine and Mycophenolate Mofetil

This pilot clinical trial studies total-body irradiation followed by cyclosporine and mycophenolate mofetil in treating patients with severe combined immunodeficiency (SCID) undergoing donor bone marrow transplant. Giving total-body irradiation (TBI) before a donor bone marrow transplant using stem cells that closely match the patient's stem cells, 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 mix with the patient's immune cells and help destroy any remaining abnormal cells. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

Study Overview

• Status: Completed
• Conditions: Severe Combined Immunodeficiency; Adenosine Deaminase Deficiency; Immune System Disorder; Autosomal Recessive Disorder; Purine-Nucleoside Phosphorylase Deficiency; Severe Combined Immunodeficiency With Absence of T and B Cells; X-Linked Severe Combined Immunodeficiency
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Radiation: Total-Body Irradiation; Drug: Mycophenolate Mofetil; Procedure: Allogeneic Bone Marrow Transplantation; Drug: Cyclosporine; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Detailed Description

PRIMARY OBJECTIVES:

I. To safely establish partial lymphoid chimerism (1-95% donor cluster of differentiation [CD]3+ cells) using a non-lethal conditioning regimen in patients with severe combined immunodeficiency syndrome.

II. To define the kinetics of immune reconstitution following a non-lethal conditioning regimen in patients with immunodeficiency diseases.

OUTLINE:

Patients receive cyclosporine orally (PO) or intravenously (IV) on days -3 to 100 followed by a taper until day 180 and mycophenolate mofetil PO or IV on days 0-40 with a taper until day 96 in the absence of unacceptable toxicity. Unrelated donor recipients also undergo TBI on day 0. Patients undergo bone marrow transplant on day 0.

After completion of study treatment, patients are followed up at 6 months and then yearly for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with severe combined immunodeficiency syndrome:

  • SCID with presence of B lymphocytes

    • X-linked SCID (presence of B lymphocytes)
    • Autosomal recessive SCID

• Patients with severe combined immunodeficiency syndrome:

  • SCID with absence of T and B lymphocytes

• Patients with severe combined immunodeficiency syndrome:

  • Purine metabolite deficiencies, deficiencies of the purine metabolites

    • Adenosine deaminase (ADA) deficiency
    • Purine nucleoside phosphorylase (PNP) deficiency
• DONOR: 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 other than siblings must be matched at HLA-A, B, and C (at highest resolution available at the time of donor selection) and at DRB1 and DQB1 by deoxyribonucleic acid (DNA) typing; if more than one HLA-identical sibling is available, priority will be given to the oldest normal donor
• DONOR: 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

Exclusion Criteria:

• Patients with viral associated T cell immunodeficiency disorders, such as human immunodeficiency virus (HIV)
• Patients with other disease or organ dysfunction that would limit survival to less than 30 days
• DONOR: Identical twin
• DONOR: Pregnancy
• DONOR: HIV seropositive
• DONOR: A positive anti-donor cytotoxic cross match is absolute donor exclusion
• DONOR: Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-HLA allele mismatch, i.e., the patient is A*0201, and this type of mismatch is not allowed
• 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 (cyclosporine, mycophenolate mofetil, transplant); Patients receive cyclosporine PO or IV on days -3 to 100 followed by a taper until day 180 and mycophenolate mofetil PO or IV on days 0-40 with a taper until day 96 in the absence of unacceptable toxicity. Unrelated donor recipients also undergo TBI on day 0. Patients undergo bone marrow transplant on day 0.

Other: Laboratory Biomarker Analysis; Correlative studies; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; Whole-Body Irradiation; Drug: Mycophenolate Mofetil; Given PO or IV; Other Names: Cellcept; MMF; Procedure: Allogeneic Bone Marrow Transplantation; Undergo allogeneic bone marrow transplant; Other Names: Allo BMT; Allogeneic BMT; Drug: Cyclosporine; Given PO or IV; Other Names: 27-400; Sandimmune; Ciclosporin; CsA; Neoral; Gengraf; Sandimmun; Cyclosporin; Cyclosporin A; OL 27-400; SangCya; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Undergo nonmyeloablative allogeneic hematopoietic stem cell transplant; Other Names: NST; Non-myeloablative allogeneic transplant; Nonmyeloablative Stem Cell Transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mixed hematopoietic chimerism in a population of pediatric patients with immunodeficiency diseases	It will be established whether a non-lethal conditioning regimen can successfully induce mixed hematopoietic chimerism in a population of pediatric patients with immunodeficiency diseases, without adverse effects on mortality.	Up to 5 years

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 (ACTUAL): August 11, 1997
• Primary Completion (ACTUAL): October 25, 2011
• Study Completion (ACTUAL): December 26, 2018

Study Registration Dates

• First Submitted: January 6, 2001
• First Submitted That Met QC Criteria: January 5, 2001
• First Posted (ESTIMATE): January 8, 2001

Study Record Updates

• Last Update Posted (ACTUAL): July 29, 2019
• Last Update Submitted That Met QC Criteria: July 26, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; DNA Repair-Deficiency Disorders; Primary Immunodeficiency Diseases; Disease; Immunologic Deficiency Syndromes; Immune System Diseases; Severe Combined Immunodeficiency; X-Linked Combined Immunodeficiency Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Mycophenolic Acid; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 1227.00 (OTHER: Fred Hutch/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); P01HL036444 (U.S. NIH Grant/Contract); NCI-2010-02045 (REGISTRY: CTRP (Clinical Trial Reporting Program))