Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies

This study is currently recruiting participants.
Verified October 2013 by Masonic Cancer Center, University of Minnesota
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT01652092
First received: July 25, 2012
Last updated: October 9, 2013
Last verified: October 2013
  Purpose

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


Condition Intervention
Severe Combined Immunodeficiency
Omenn's Syndrome
Reticular Dysgenesis
Wiskott-Aldrich Syndrome
Bare Lymphocyte Syndrome
MHC Class II Deficiency
Common Variable Immunodeficiency
Chronic Granulomatous Disease
CD40 Ligand Deficiency
Hyper IgM Syndrome
X-linked Lymphoproliferative Disease
Hemophagocytic Lymphohistiocytosis
Combined Immune Deficiencies
Griscelli Syndrome
Chediak-Higashi Syndrome
Langerhan's Cell Histiocytosis
Drug: Alemtuzumab 0.3 mg
Drug: Cyclophosphamide
Drug: Busulfan
Biological: Stem Cell Transplantation
Drug: Fludarabine phosphate 40 mg
Drug: Melphalan
Drug: Alemtuzumab 0.2 mg
Drug: Fludarabine phosphate 30 mg
Drug: MESNA

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies

Resource links provided by NLM:


Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Neutrophil Engraftment [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Incidence of Graft Failure [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
    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.

  • Incidence of Chimerism [ Time Frame: Day 100, 6 Months, 1 Year ] [ Designated as safety issue: No ]
    a state in bone marrow transplantation in which bone marrow and host cells exist compatibly without signs of graft-versus-host rejection disease.

  • Incidence of Acute Graft-Versus-Host Disease [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.

  • Incidence of Chronic Graft-Versus-Host Disease [ Time Frame: 6 Months and 1 Year ] [ Designated as safety issue: Yes ]
    Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host.

  • Incidence of Transplant-Related Mortality [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]
    In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation.

  • Disease-Free Survival [ Time Frame: 6 Months ] [ Designated as safety issue: No ]
    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.

  • Overall Survival [ Time Frame: 6 Months ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 30
Study Start Date: September 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Arm A: Fully Myeloablative Preparative 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 Name: Campath-1H
Drug: Cyclophosphamide
cyclophosphamide 50 mg/kg IV on days -9 through -6
Other Name: Cytoxan
Drug: Busulfan
busulfan 0.8 or 1.1 mg/kg IV on days -5 through -2
Other Name: 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: MESNA
administered as per the standard institutional protocol.
Other Names:
  • mercaptoethane sulfonate Na (Na being the symbol for sodium)
  • Mesnex
Arm B: Reduced Toxicity Ablative Preparative 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 Name: Campath-1H
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: Fludarabine phosphate 40 mg
40 mg/m^2 IV on days -5 through -2
Other Name: Fludara
Drug: Busulfan
busulfan 0.8 or 1.1 mg/kg IV on days -9 through -6
Other Name: Myerlan
Arm C: Reduced Intensity Conditioning
For use in patients with diseases including HLH. Receives Alemtuzumab 0.2 mg/kg intravenously (IV) on days -10 through -6, fludarabine phosphate 30 mg/m^2 IV on days -6 through -3, melphalan 140 mg/m^2 IV on day -2 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 -2
Other Name: Alkeran
Drug: Alemtuzumab 0.2 mg
0.2 mg/kg intravenously (IV) on days -10 through -6
Other Name: Campath 1-H
Drug: Fludarabine phosphate 30 mg
fludarabine 30 mg/m^2 IV on days -6 through -3
Other Name: Fludara
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.


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

  Eligibility

Ages Eligible for Study:   up to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  • Performance status: Karnofsky Performance status must be at least 70% for patients > 16 years of age or Lansky Play Score ≥ 70 for patients > 16 years of age
  • Consent: able to provide appropriate voluntary written consent
  • Organ Function

    • Renal: glomerular filtration rate (GFR) ≥ 30% of predicted and serum creatinine ≤ 2 x upper limit of normal for age
    • Hepatic: aspartate aminotransferase/alanine aminotransferase (AST or ALT) ≤ 5 x upper limit of normal (ULN) and bilirubin ≤ 5 x ULN
    • Cardiac: cardiac function ≥ 40% normal by echocardiogram

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

Donor Section Criteria:

  • in general good health, in the opinion of the evaluating health care professional
  • adequate partial prothrombin time (PTT), hemoglobin, white blood cell, and platelet counts
  • for females of child bearing potential not pregnant or breastfeeding (must have a negative pregnancy test within 7 days of donation)
  • no active infection
  • voluntary written consent

In the case where more than one donor meets the eligibility criteria, donor selection will be guided by the following considerations:

  • Class I HLA Antigens: It will always be preferable to have a donor that is an allele match at HLA-A, -B and -C. However, acceptable donors may have up to two Class I allele mismatches (A, B or C), or a single HLA-A, -B, or -C allele and/or antigen mismatch, although in either situation the class II HLA-DR must be allele matched.
  • Class II HLA Antigen (HLA-DR): The preferred donor will be a full HLA-DR allele match. However, a single allele DR mismatch donor will be acceptable provided the donor is a full allele match at HLA-A, -B, and -C. Class II antigen mismatched donors are not acceptable.
  • HLA A, B, DRB1 identical sibling donor is preferable to an unrelated donor

    • Homozygous normal donor is preferable to heterozygote (carrier)
    • ABO-compatible donor is preferable to ABO-incompatible donor
    • Younger donor is preferable to older
    • Cytomegalovirus seronegative donor is preferable to cytomegalovirus (CMV) seropositive donor, if the patient is CMV negative
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01652092

Contacts
Contact: Angela R. Smith, M.D. 612-626-2778 smith719@umn.edu

Locations
United States, Minnesota
Masonic Cancer Center, University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Angela R. Smith, M.D.    612-626-2778    smith719@umn.edu   
Principal Investigator: Angela R. Smith, M.D.         
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
Principal Investigator: Angela R. Smith, M.D. Masonic Cancer Center, University of Minnesota
  More Information

No publications provided

Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT01652092     History of Changes
Other Study ID Numbers: 2012OC055, MT2012-10C
Study First Received: July 25, 2012
Last Updated: October 9, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Masonic Cancer Center, University of Minnesota:
immunodeficiency disorder
histiocytic disorder

Additional relevant MeSH terms:
Chediak-Higashi Syndrome
Immunologic Deficiency Syndromes
Wiskott-Aldrich Syndrome
Hyper-IgM Immunodeficiency Syndrome
Hyper-IgM Immunodeficiency Syndrome, Type 1
Congenital Abnormalities
Common Variable Immunodeficiency
Granulomatous Disease, Chronic
Histiocytosis
Histiocytosis, Langerhans-Cell
Lymphohistiocytosis, Hemophagocytic
Lymphoproliferative Disorders
Severe Combined Immunodeficiency
Leukopenia
Granuloma
Phagocyte Bactericidal Dysfunction
Leukocyte Disorders
Hematologic Diseases
Immune System Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Lymphatic Diseases
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Histiocytosis, Non-Langerhans-Cell
Immunoproliferative Disorders
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hemorrhagic Disorders

ClinicalTrials.gov processed this record on April 17, 2014