Allogeneic Hematopoietic Cell Transplantation for Disorders of T-cell Proliferation and/or Dysregulation

  • STATUS
    Recruiting
  • End date
    May 1, 2025
  • participants needed
    177
  • sponsor
    National Cancer Institute (NCI)
Updated on 1 May 2021
anesthesia
electrocardiogram
fever
estimated creatinine clearance
oxygen saturation
urine tests
graft versus host disease
tacrolimus
anemia
mycophenolate mofetil
cyclophosphamide
bone marrow transplant
busulfan
ejection fraction
granulocyte colony stimulating factor
prednisone
chest x-ray
deficiency
cell transplantation
x-rays
bone marrow procedure
shortening fraction
reduced intensity conditioning
antithymocyte globulin
thrombocytopenia
hemolysis
schwartz
shots
blood transfusion
chemotherapy regimen
pulmonary function tests
immunosuppression
mesna
urine test
therapeutic agents
lymphoproliferative disorder
neutropenia
immune globulin
hla typing
hemophagocytic lymphohistiocytosis
ada2 deficiency

Summary

Background

Blood stem cells in the bone marrow make all the cells to normally defend a body against disease. Allogeneic blood or marrow transplant is when these stem cells are transferred from one person to another. Researchers think this treatment can provide a new, healthy immune system to correct T-cell problems in some people.

Objective

To see if allogeneic blood or bone marrow transplant is safe and effective in treating people with T-cell problems.

Eligibility

Donors: Healthy people ages 4 and older

Recipients: People the same age with abnormal T-cell function causing health problems

Design

All participants will be screened with:

  • Medical history
  • Physical exam
  • Blood, heart, and urine tests

Donors will also have an electrocardiogram and chest x-ray. They may have veins tested or a pre-anesthesia test.

Recipients will also have lung tests.

Some participants will have scans and/or bone marrow collected by needle in the hip bones.

Donors will learn about medicines and activities to avoid and repeat some screening tests.

Some donors will stay in the hospital overnight and have bone marrow collected with anesthesia.

Other donors will get shots for several days to stimulate cells. They will have blood removed by plastic tube (IV) in an arm vein. A machine will remove stem cells and return the rest of the blood to the other arm.

Recipients will have:

  • More bone marrow and a small fragment of bone removed
  • Dental, diet, and social worker consultations
  • Scans
  • Chemotherapy and antibody therapy for 2 weeks
  • Catheter inserted in a chest or neck vein to receive donor stem cells
  • A hospital stay for several weeks with more medicines and procedures
  • Multiple follow-up visits

Description

Background
  • Disorders of T-cell proliferation and/or dysregulation (TCP/D) can lead to T-cell lymphoproliferative disorders, autoimmunity, infection, and aberrant immune activation with resulting organ dysfunction, morbidity, and mortality.
  • Allogeneic hematopoietic cell transplantation (HCT) has the potential to cure disorders of TCP/D.
  • Subjects with TCP/D may be at higher risk for graft rejection and/or disease relapse.

Primary Objective:

  • Separately by arm: To estimate the percentage of recipients with >50% donor T cell chimerism and graft-failure free survival at day +180 post-HCT
    Eligibility
  • Age greater than or equal to 4 years
  • TCP/D deemed to be of sufficient past severity to warrant HCT that meets at least one of the criteria below:
  • Identified germline T-cell activating mutation in the PI3k pathway
  • Identified ADA2 deficiency (biallelic mutations in CECR1 (ADA2) and/or phenotypically with low ADA2 level) leading to neutropenia requiring chronic GCSF therapy or to transfusion-dependent anemia or thrombocytopenia
  • T-cell infiltration of liver, spleen, lymph nodes, marrow, lungs, gut, or other organs by T cells, as evidenced by laboratory, radiographic, and/or anatomic pathology evaluation, resulting in organ dysfunction and/or organomegaly
  • Latent herpesvirus infection in T lymphocytes
  • History of or active evidence of hemophagocytic lymphohistiocytosis (HLH)
  • Recurrent or prolonged fevers attributed to immune dysregulation
  • T-cell population in blood and/or marrow with immunophenotype of large granular lymphocytes (LGL), with or without clonality or lymphocytosis
  • T-cell lymphoproliferative disorder in the setting of an underlying immune defect
  • Immune-mediated cytopenias of one lineage requiring transfusion or GCSF support or of 2 or 3 lineages with or without transfusion or support
  • Chronic active Epstein-Barr virus (EBV)
  • At least one potentially suitable 7-8/8 HLA-matched related or unrelated donor, or an HLA-haploidentical related donor
  • Adequate end-organ function
  • Not pregnant or breastfeeding
  • HIV negative
  • Disease status: Subjects with malignancy should be referred in remission for evaluation if possible, although the aggressive nature of many of these diseases necessitates the potential need to enroll subjects onto study and treat with standard therapies before proceeding to protocol therapy (HCT)
    Design
  • There will be two arms that vary in conditioning intensity - an immunosuppression-only conditioning (IOC) arm for high-risk subjects and a reduced-intensity conditioning (RIC) arm.
  • IOC arm: equine anti-thymocyte globulin (e-ATG) 40 mg/kg/day IV on days -14 and -13, pentostatin 4 mg/m^2/day IV on days -9 and -5, low-dose cyclophosphamide orally daily on days -9 through -2
  • RIC arm: e-ATG 40 mg/kg/day IV on days -14 and -13, pentostatin 4 mg/m^2/day IV on days -11 and -7, low-dose cyclophosphamide orally daily on days -11 through -4; busulfan IV, pharmacokinetically dosed, on days -3 and -2.

-- Subjects will be assigned to the IOC arm if there is significant end-organ dysfunction present and it is felt that a conditioning regimen that includes busulfan would likely be associated with intolerable or life-threatening toxicities for the subject. Subjects will also be assigned to the IOC arm if they possess a DNA repair defect, telomere maintenance defect, or familial cancer predisposition syndrome that necessitates limiting chemotherapy as much as possible to prevent future cancer risk.

  • Peripheral blood stem cells are the preferred graft source, although bone marrow is permitted
  • GVHD prophylaxis:
  • PTCy on days +3 and +4 (50 mg/kg/day on RIC arm and 25 mg/kg/day on the IOC arm, with the option of 25 mg/kg/day on the RIC arm), tacrolimus on days +5 through +90, and MMF on days +5 through +25.

Details
Condition Immunodeficiency, Disorder of immune system, Lymphoproliferative Disorder, Common Variable Immunodeficiency, Common Variable Immunodeficiency (CVID), Autoimmune Lymphoproliferative, Primary Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Lymphoproliferative disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, lymphoproliferative disease, immune disorder, immune disorders, immunologic disease, immune dysfunction, immune disease, immun, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders
Treatment Allogeneic HSC, GVHD Prophylaxis, Immunosuppression Only Conditioning (IOC), Reduced Intensity Conditioning (RIC)
Clinical Study IdentifierNCT03663933
SponsorNational Cancer Institute (NCI)
Last Modified on1 May 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Do you have any of these conditions: Disorder of immune system or immunologic disease or immune dysfunction or lymphoproliferative disease or Primary T-cell Immunodeficiency Disorders or ...?
Do you have any of these conditions: Primary Immunodeficiency Disorders or immunologic disease or Autoimmune Lymphoproliferative or Primary T-cell Immunodeficiency Disorders or immune dis...?
Do you have any of these conditions: Primary T-cell Immunodeficiency Disorders or immune disorders or Autoimmune Lymphoproliferative or immunologic disease or immune disease or Immunodefi...?
Do you have any of these conditions: Autoimmune Lymphoproliferative or immune disease or Immunodeficiency or immune dysfunction or Lymphoproliferative disorders or immune disorders or imm...?
Do you have any of these conditions: Common Variable Immunodeficiency (CVID) or Lymphoproliferative Disorder or Autoimmune Lymphoproliferative or Primary T-cell Immunodeficiency Disorders...?
Do you have any of these conditions: Lymphoproliferative disorders or immune disorders or immune disease or Common Variable Immunodeficiency (CVID) or Disorder of immune system or immune ...?
Do you have any of these conditions: Autoimmune Lymphoproliferative or Disorder of immune system or Lymphoproliferative disorders or immune dysfunction or immune disease or Lymphoprolifer...?
Do you have any of these conditions: immune disorder or immune disease or Common Variable Immunodeficiency (CVID) or immune disorders or lymphoproliferative disease or Immunodeficiency or...?
Do you have any of these conditions: immunologic disease or Primary T-cell Immunodeficiency Disorders or Common Variable Immunodeficiency or Autoimmune Lymphoproliferative or Common Varia...?
Is your age greater than or equal to 4 yrs?
Do you have any of these conditions: Immunodeficiency or immune disorder or Primary T-cell Immunodeficiency Disorders or Disorder of immune system or immun or Autoimmune Lymphoproliferati...?
Do you have any of these conditions: lymphoproliferative disease or Common Variable Immunodeficiency or immune disease or Lymphoproliferative disorders or Disorder of immune system or imm...?
Do you have any of these conditions: lymphoproliferative disease or immune disorders or immune disorder or immunologic disease or Common Variable Immunodeficiency (CVID) or Primary Immuno...?
Do you have any of these conditions: lymphoproliferative disease or Common Variable Immunodeficiency or Common Variable Immunodeficiency (CVID) or immunologic disease or Autoimmune Lympho...?
Do you have any of these conditions: Lymphoproliferative Disorder or Disorder of immune system or Primary Immunodeficiency Disorders or immune disorders or immunologic disease or lymphopr...?
Do you have any of these conditions: Common Variable Immunodeficiency (CVID) or Primary T-cell Immunodeficiency Disorders or Immunodeficiency or Autoimmune Lymphoproliferative or Lymphopr...?
Gender: Male or Female
Unrelated donors will be evaluated in accordance with existing NMDP Standard Policies and Procedures, available at: <http://bethematch.org/About-Us/Globaltransplant> -network/Standards/, except for the additional requirement of EBV serostatus testing for clinical purposes of donor selection. Note that participation in this study is offered to all unrelated donors but not required for clinical donation, so it is possible that not all unrelated donors will enroll on this study. Unrelated donors only enroll if they contribute research specimens, which is optional

Exclusion Criteria

Unrelated donors: failure to qualify as a National Marrow Donor Program (NMDP) donor per current NMDP Standards, available at
<http://bethematch.org/About-Us/Global-transplant-network/Standards/>
Exceptions to donor eligibility (e.g. foreign travel, tattoos) do not
automatically exclude the donor and will be reviewed by the PI
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