NCT03663933

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

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

• Status: Active Not Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 71 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 4 Years
• Healthy volunteers: Accepted

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

Detailed 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 adenosine deaminase 2 (ADA2) deficiency (biallelic mutations in CECR1 (ADA2) and/or phenotypically with low ADA2 level) leading to neutropenia requiring chronic granulocyte colony-stimulating factor (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 human leukocyte antigen (HLA)-matched related or unrelated donor, or an HLA-haploidentical related donor * Adequate end-organ function * Not pregnant or breastfeeding * Human immunodeficiency virus (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 intravenous (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 deoxyribonucleic acid (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 * Graft-versus-host disease (GVHD) prophylaxis: * Post-transplant cyclophosphamide (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 mycophenolate mofetil (MMF) on days +5 through +25.

Conditions

• Lymphoproliferative Disorders
• Autoimmune Lymphoproliferative
• Primary T-cell Immunodeficiency Disorders
• Immune System Diseases
• Common Variable Immunodeficiency

Interventions

Type	Name	Description
DRUG	e-ATG	During Immunosuppression Only Conditioning (IOC) and Reduced Intensity Conditioning (RIC).
PROCEDURE	Immunosuppression Only Conditioning	Equine anti-thymocyte globulin (e-ATG) 40 mg/kg intravenous (IV) once daily for days -14 and -13. Prednisone: Tapering doses, given orally daily, and given prior to each daily dose of e-ATG on days -14 and -13, Pentostatin:4 mg/m\^2/day IV on days -9 and -5, cyclophosphamide:5 mg/kg orally daily on days -9 through -2.
PROCEDURE	Reduced Intensity Conditioning	Equine anti-thymocyte globulin (e-ATG) 40 mg/kg intravenous (IV) once daily for days -14 and -13. Prednisone: Tapering doses, given orally daily, and given prior to each daily dose of e-ATG on days -14 and -13, Pentostatin:4 mg/m\^2/day IV on days -11 and -7, cyclophosphamide: 5 mg/kg orally daily on days -11 through -4, Busulfan IV, pharmacokinetically dosed, on days -3 and -2.
DRUG	GVHD Prophylaxis	High-dose, post-transplantation cyclophosphamide (PTCy) 25-50 mg/kg on days +3 and +4, Mesna: 25-50 mg/kg weight-based dosing, Tacrolimus 0.02 mg/kg on days +5 through +90, and mycophenolate mofetil (MMF) 15 mg/kg on days +5 through +25.
PROCEDURE	Allogeneic HSC	Stem cell transplant
DRUG	Bisulfan	During Reduced Intensity Conditioning (RIC).
DRUG	Prednisone	During Immunosuppression Only Conditioning (IOC) and Reduced Intensity Conditioning (RIC).
DRUG	Cyclophosphamide	During Immunosuppression Only Conditioning (IOC), Reduced Intensity Conditioning (RIC) and Graft-versus-host disease prophylaxis (GVHD).
DRUG	MMF	During Graft-versus-host disease prophylaxis (GVHD).
DRUG	Mesna	During Graft-versus-host disease prophylaxis (GVHD).
DRUG	Tacrolimus	During Graft-versus-host disease prophylaxis (GVHD).
DRUG	Pentostatin	During Immunosuppression Only Conditioning (IOC) and Reduced Intensity Conditioning (RIC).
DIAGNOSTIC_TEST	PFTs	Screening ≤4 weeks pretreatment (rx), Day +180 (≤ 14 days), Day +36 (± 21 days), Day +548 (18 months) (± 28 days), and at 2 years and yearly thereafter through +5 years (± 56 days).
DIAGNOSTIC_TEST	DEXA	Baseline, Day +365 (± 21 days), at 2 years and yearly thereafter through +5 years (± 56 days), and as clinically indicated after hematopoietic cell transplant (HCT).
PROCEDURE	Bone Marrow Aspirate & Biopsy	Baseline, Day +60 (± 3 days) and Day +365 (±21 days).
DIAGNOSTIC_TEST	EKG	Baseline
DIAGNOSTIC_TEST	2D ECHO	Screening ≤4 weeks pretreatment (rx), Day +180 (≤ 14 days), Day +36 (± 21 days), Day +548 (18 months) (± 28 days), and at 2 years and yearly thereafter through +5 years (± 56 days).

Timeline

• Start date: 2018-09-04
• Primary completion: 2025-04-03
• Completion: 2030-04-03
• First posted: 2018-09-10
• Last updated: 2026-03-17
• Results posted: 2026-03-17

Locations

2 sites across 1 country: United States

Regulatory

• FDA-regulated drug study