Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies

This is a standard of care treatment guideline for allogeneic hematopoetic stem cell transplant (HSCT) in patients with primary immune deficiencies.

Study Overview

• Status: Recruiting
• Conditions: Common Variable Immunodeficiency; Chronic Granulomatous Disease; Hemophagocytic Lymphohistiocytosis; Wiskott-Aldrich Syndrome; X-linked Lymphoproliferative Disease; Langerhan's Cell Histiocytosis; Chediak-Higashi Syndrome; Griscelli Syndrome; Bare Lymphocyte Syndrome; SCID; Omenn's Syndrome; Reticular Dysgenesis; CD40 Ligand Deficiency; Hyper IgM Syndrome
• Intervention / Treatment: Drug: Alemtuzumab 0.3 mg; Drug: Cyclophosphamide; Drug: Busulfan; Biological: Stem Cell Transplantation; Drug: Busulfan; Drug: MESNA; Drug: Fludarabine phosphate 40 mg; Drug: Melphalan; Drug: Alemtuzumab 0.2 mg; Drug: Fludarabine phosphate 30 mg

Detailed Description

Based on diagnosis and clinical history, a determination of the most appropriate regimen will be made based on the following prep plans:

Arm A: Fully Myeloablative Preparative Regimen, Arm B: Reduced Toxicity Ablative Preparative Regimen, Arm C: Reduced Intensity Conditioning, Arm D: No Preparative Regimen

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Christen Ebens, MD; Phone Number: 612-626-2778; Email: ebens012@umn.edu

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • Masonic Cancer Center, University of Minnesota
      • Contact: Christen Ebens, MD; Phone Number: 612-626-2778; Email: ebens012@umn.edu
      • Principal Investigator: Christen Ebens, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 50 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of immunodeficiency or histiocytic disorder including the following:

  • Severe combined immunodeficiency (SCID - all variants)
  • Second bone marrow transplant (BMT) for SCID (after graft rejection)
  • Omenn's Syndrome
  • Reticular dysgenesis
  • Wiskott-Aldrich syndrome
  • Major histocompatibility complex (MHC) Class II deficiency (bare lymphocyte syndrome)
  • Hyper IgM Syndrome (CD40 Ligand Deficiency)
  • Common variable immunodeficiency (CVID) with severe phenotype
  • Chronic Granulomatous Disease (CGD)
  • Other severe Combined Immune Deficiencies (CID)
  • Hemophagocytic Lymphohistiocytosis (HLH)
  • X-linked Lymphoproliferative Disease (XLP)
  • Chediak-Higashi Syndrome (CHS)
  • Griscelli Syndrome
  • Langerhans Cell Histiocytosis (LCH)

• Acceptable stem cell sources include:

  • HLA identical or 1 antigen matched sibling donor eligible to donate bone marrow
  • HLA identical or up to a 1 antigen mismatched unrelated BM donor
  • Sibling donor cord blood with acceptable HLA match and cell dose as per current institutional standards
  • Single unrelated umbilical cord blood unit with 0-2 antigen mismatch and minimum cell dose of >5 x 10^7 nucleated cells/kg as per current institutional guidelines

  • Double unrelated umbilical cord blood units that are:

    • up to 2 antigen mismatched to the patient
    • up to 2 antigen mismatched to each other
    • minimum cell dose of at least one single unit must be ≥ 3.5 x 10^7 nucleated cells/kg
    • combined dose of both units must provide a total cell dose of ≥ 5 x 10^7 nucleated cells/kg
• Age: 0 to 50 years
• Adequate organ function and performance status.

Exclusion Criteria

• pregnant or breastfeeding
• active, uncontrolled infection and/or HIV positive
• acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Arm A: Fully Myeloablative regimen; For use in patients with diseases including Wiskott-Aldrich syndrome, MHC Class II deficiency, hypomorphic SCID, etc. Receives Alemtuzumab 0.3 mg/kg intravenously (IV) on days -12 through -10, cyclophosphamide 50 mg/kg IV plus MESNA on days -9 through -6, busulfan 0.8 or 1.1 mg/kg IV on days -5 through -2 and stem cell infusion on day 0.	Drug: Alemtuzumab 0.3 mg; 0.3 mg/kg intravenously (IV) on days -12 through -10; Other Names: Campath-1H; Drug: Cyclophosphamide; cyclophosphamide 50 mg/kg IV on days -9 through -6; Other Names: Cytoxan; Drug: Busulfan; busulfan 0.8 or 1.1 mg/kg IV on days -5 through -2; Other Names: Myerlan; Biological: Stem Cell Transplantation; Unrelated donor bone marrow will be collected in the usual manner using established parameters determined by the National Marrow Donor Program. A minimum of 3 x 10^8 nucleated cells/kg recipient weight will be collected with a goal of ≥ 5 x 10^8 nucleated cells/kg recipient weight. Umbilical cord blood selection will be per the current University of Minnesota Cord Blood Unit Selection algorithm. One or two units may be used to obtain the minimum cell dose. One of the UCB units selected for transplantation must contain ≥ 3.5 x 10^7 nucleated cells/kg recipient weight based on cell numbers at time of cryopreservation, and the total combined cell dose of both units must be > 5.0 x 10^7 nucleated cells/kg.; Drug: Busulfan; busulfan 0.8 or 1.1 mg/kg IV on days -9 through -6; Other Names: Myerlan; Drug: MESNA; administered as per the standard institutional protocol.; Other Names: Mesnex; mercaptoethane sulfonate Na (Na being the symbol for sodium)
Other: Arm B: Reduced Toxicity Ablative Regimen; For use in patients with diseases including SCID, CGD, CHS and other CID. Receives Alemtuzumab 0.3 mg/kg intravenously (IV) on days -12 through -10, busulfan 0.8 or 1.1 mg/kg IV on days -9 through -6, fludarabine phosphate 40 mg/m^2 IV on days -5 through -2 and stem cell infusion on day 0.	Drug: Alemtuzumab 0.3 mg; 0.3 mg/kg intravenously (IV) on days -12 through -10; Other Names: Campath-1H; Drug: Busulfan; busulfan 0.8 or 1.1 mg/kg IV on days -5 through -2; Other Names: Myerlan; Biological: Stem Cell Transplantation; Unrelated donor bone marrow will be collected in the usual manner using established parameters determined by the National Marrow Donor Program. A minimum of 3 x 10^8 nucleated cells/kg recipient weight will be collected with a goal of ≥ 5 x 10^8 nucleated cells/kg recipient weight. Umbilical cord blood selection will be per the current University of Minnesota Cord Blood Unit Selection algorithm. One or two units may be used to obtain the minimum cell dose. One of the UCB units selected for transplantation must contain ≥ 3.5 x 10^7 nucleated cells/kg recipient weight based on cell numbers at time of cryopreservation, and the total combined cell dose of both units must be > 5.0 x 10^7 nucleated cells/kg.; Drug: Busulfan; busulfan 0.8 or 1.1 mg/kg IV on days -9 through -6; Other Names: Myerlan; Drug: Fludarabine phosphate 40 mg; 40 mg/m^2 IV on days -5 through -2 (for children < 6 months and/or < 10 kg weight dose at 1.33 mg/kg); Other Names: Fludara
Other: Arm C: Reduced Intensity Conditioning; For use in patients with diseases including HLH. Receives Alemtuzumab 0.2 mg/kg intravenously (IV) on days -14 through -10, fludarabine phosphate 30 mg/m^2 IV on days -8 through -4, melphalan 140 mg/m^2 IV on day -3 and stem cell infusion on day 0.	Biological: Stem Cell Transplantation; Unrelated donor bone marrow will be collected in the usual manner using established parameters determined by the National Marrow Donor Program. A minimum of 3 x 10^8 nucleated cells/kg recipient weight will be collected with a goal of ≥ 5 x 10^8 nucleated cells/kg recipient weight. Umbilical cord blood selection will be per the current University of Minnesota Cord Blood Unit Selection algorithm. One or two units may be used to obtain the minimum cell dose. One of the UCB units selected for transplantation must contain ≥ 3.5 x 10^7 nucleated cells/kg recipient weight based on cell numbers at time of cryopreservation, and the total combined cell dose of both units must be > 5.0 x 10^7 nucleated cells/kg.; Drug: Melphalan; 140 mg/m^2 IV on day -3; Other Names: Alkeran; Drug: Alemtuzumab 0.2 mg; 0.2 mg/kg intravenously (IV) on days -14 through -10; Other Names: Campath 1-H; Drug: Fludarabine phosphate 30 mg; fludarabine 30 mg/m^2 IV on days -8 through -4; Other Names: Fludara
Other: Arm D: No Preparative Regimen; For use in patients with complete SCID phenotype with no evidence of maternal engraftment or residual immune function who will be receiving their stem cell transplantation from a genotypically matched donor.	Biological: Stem Cell Transplantation; Unrelated donor bone marrow will be collected in the usual manner using established parameters determined by the National Marrow Donor Program. A minimum of 3 x 10^8 nucleated cells/kg recipient weight will be collected with a goal of ≥ 5 x 10^8 nucleated cells/kg recipient weight. Umbilical cord blood selection will be per the current University of Minnesota Cord Blood Unit Selection algorithm. One or two units may be used to obtain the minimum cell dose. One of the UCB units selected for transplantation must contain ≥ 3.5 x 10^7 nucleated cells/kg recipient weight based on cell numbers at time of cryopreservation, and the total combined cell dose of both units must be > 5.0 x 10^7 nucleated cells/kg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neutrophil Engraftment	Neutrophil engraftment is defined as the first day of three consecutive days where the neutrophil count (absolute neutrophil count) is 500 cells/mm3 (0.5 x 109/L) or greater.	Day 42

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Graft Failure	Graft failure is defined as not accepting donated cells. The donated cells do not make the new white blood cells, red blood cells and platelets.	Day 100
Incidence of Chimerism	a state in bone marrow transplantation in which bone marrow and host cells exist compatibly without signs of graft-versus-host rejection disease.	Day 100, 6 Months, 1 Year
Incidence of Acute Graft-Versus-Host Disease	Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.	Day 100
Incidence of Chronic Graft-Versus-Host Disease	Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host.	6 Months and 1 Year
Incidence of Transplant-Related Mortality	In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation.	6 Months
Disease-Free Survival	the length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works.	6 Months
Overall Survival	Overall survival will be defined as time from enrollment to date of death or censored at the date of last documented contact for patients still alive.	6 Months

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Christen Ebens, MD, Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2012
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: July 25, 2012
• First Submitted That Met QC Criteria: July 26, 2012
• First Posted (Estimated): July 27, 2012

Study Record Updates

• Last Update Posted (Estimated): January 26, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: immunodeficiency disorder; histiocytic disorder
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Respiratory Tract Diseases; Immune System Diseases; Lymphatic Diseases; Immunoproliferative Disorders; Lung Diseases; Eye Diseases; Disease Attributes; Disease; Hematologic Diseases; Infant, Newborn, Diseases; Blood Coagulation Disorders, Inherited; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Protein Disorders; Eye Diseases, Hereditary; Blood Coagulation Disorders; DNA Repair-Deficiency Disorders; Leukopenia; Leukocyte Disorders; Lung Diseases, Interstitial; Phagocyte Bactericidal Dysfunction; Histiocytosis, Non-Langerhans-Cell; Lymphopenia; Albinism; Chronic Disease; Dysgammaglobulinemia; Syndrome; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases; Granulomatous Disease, Chronic; Lymphoproliferative Disorders; Histiocytosis, Langerhans-Cell; Histiocytosis; Lymphohistiocytosis, Hemophagocytic; Severe Combined Immunodeficiency; Wiskott-Aldrich Syndrome; Common Variable Immunodeficiency; Chediak-Higashi Syndrome; Hyper-IgM Immunodeficiency Syndrome; Hyper-IgM Immunodeficiency Syndrome, Type 1; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Melphalan; Fludarabine; Fludarabine phosphate; Busulfan; Alemtuzumab; Vidarabine; Mesna
• Other Study ID Numbers: 2012OC055; MT2012-10C (Other Identifier: Blood and Marrow Transplantation Program)