Last updated on March 2020

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

Brief description of study


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.


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


Donors: Healthy people ages 4 and older

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


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...

Detailed Study Description

  • 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
  • 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)
  • 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 IOC arm), tacrolimus on days +5 through +90, and MMF on days +5 through +25.

Clinical Study Identifier: NCT03663933

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