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
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
71
During Immunosuppression Only Conditioning (IOC) and Reduced Intensity Conditioning (RIC).
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.
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.
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.
Stem cell transplant
During Reduced Intensity Conditioning (RIC).
During Immunosuppression Only Conditioning (IOC) and Reduced Intensity Conditioning (RIC).
During Immunosuppression Only Conditioning (IOC), Reduced Intensity Conditioning (RIC) and Graft-versus-host disease prophylaxis (GVHD).
During Graft-versus-host disease prophylaxis (GVHD).
During Graft-versus-host disease prophylaxis (GVHD).
During Graft-versus-host disease prophylaxis (GVHD).
During Immunosuppression Only Conditioning (IOC) and Reduced Intensity Conditioning (RIC).
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).
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).
Baseline, Day +60 (± 3 days) and Day +365 (±21 days).
Baseline
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).
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
National Marrow Donor Program
Minneapolis, Minnesota, United States
Percentage of Recipients Who Are Alive With >50% Donor T Cell Chimerism and Graft-failure Free at 180 Days Post Hematopoietic Cell Transplant (HCT) Reported With an 80% Confidence Interval
Percentage of recipients with \> 50% donor T cell chimerism and without death or graft failure. A graft failure event is defined as either primary or secondary graft failure, in the absence of a recurrent marrow malignancy.
Time frame: Day +180 post-HCT
Percentage of Recipients Who Are Alive With >50% Donor T Cell Chimerism and Graft-failure Free at 180 Days Post Hematopoietic Cell Transplant (HCT) Reported With a 95% Confidence Interval
Percentage of recipients with \> 50% donor T cell chimerism and without death or graft failure. A graft failure event is defined as either primary or secondary graft failure, in the absence of a recurrent marrow malignancy.
Time frame: Day +180 post -HCT
Cumulative Incidence of Transplant-related Mortality
Cumulative incidence of transplant-related mortality at 180 days and 1-year post-transplant. Transplant related mortality is defined as any death that occurs outside the setting of the hematopoietic cell transplant (HCT) post-allogeneic relapse of a pre-transplant malignancy or lymphoid disorder.
Time frame: Day +180, and 1-year post-transplant
Cumulative Incidence of Secondary Graft Failure
Cumulative incidence of secondary graft failure at 1-year post-transplant. Secondary graft failure is defined as initial blood or marrow donor myeloid chimerism ≥5%, declining to \<5% on subsequent measurements. \<5% indicates graft failure (undesirable outcome).
Time frame: 1-, 3-, and 5-years post-transplant
Percent Probability of Overall Survival (OS)
OS is defined as the time in whole days from hematopoietic cell transplantation (HCT) to death from any cause, with surviving recipients censored at the time of last contact.
Time frame: 1-, 3-, and 5-years post-transplant
Percentage of Participants Who Achieve Chimerism at Stated Days Between Those Who Have Failed by Day 60 or Have Not
Percentage of participants who achieve early chimerism (\>50% T cell chimerism) at stated days between those who have failed by day 60 or have not. Comparison to be performed using Fisher's exact test. Chimerism is the percentage of donor cells in the peripheral blood.
Time frame: Day +21, +28, +35, +42, and +60 after hematopoietic cell transplant (HCT)
Percentage of Donor T-cell Populations at Days +28, +42, +60, +100, +180, and 1-year Post Hematopoietic Cell Transplant (HCT)
The percentage of donor T-cell populations at days +28, +42, +60, +100, +180, and 1-year post hematopoietic cell transplant.
Time frame: Days +28, +42, +60, +100, +180, and 1-year post hematopoietic cell transplant
Cumulative Incidence of Chronic Graft-versus-host Disease (cGVHD)
Cumulative incidence curves of chronic graft versus host disease and two-sided 95% confidence intervals at 1 and 2-years post -transplant. cGVHD was scored according to the 2014 National Institutes of Health (NIH) Consensus Criteria for Clinical Trials in Chronic GVHD. Eight organs will be scored on a 0-3 scale.
Time frame: 1 and 2-years post-transplant
Cumulative Incidence of Acute Graft-versus-host Disease (aGVHD) at 1 Year
Cumulative incidence curves of acute graft versus host disease and two-sided 95% confidence intervals at 1-year post transplant according to Keystone Criteria of the 1994 Consensus Conference on Acute GVHD Grading. Acute GVHD is defined as any grade, grade 2, 3, or 4 and grade 3-4 acute GVHD. The Keystone criteria provide the basis for grading acute GVHD as follows: Organ-Specific Staging: Each affected organ (skin, liver, gut) is staged 0 (absent) to 4 (severe). Overall Grading (I-IV): Based on the most severe organ involvement. Skin (Grade 0-4): Based on % body surface area (BSA) involvement (e.g., \<25% for Grade 1, \>50% for Grade 3, bullae for Grade 4). Liver (Grade 0-4): Based on total serum bilirubin levels (e.g., 2-2.9 mg/dL for Grade 1, \>15 mg/dL for Grade 4). Gut (Grade 0-4): Based on diarrhea volume and severity (e.g., \>500 mL/day for Grade 1, \>2000 mL/day or ileus/severe pain for Grade 4). Upper GI: Included for classification, with specific criteria for staging.
Time frame: 1-year post-transplant
Percent Probability Event-free Survival (EFS)
EFS is defined as the time from transplant to death of any cause or other event, including disease relapse, graft failure, grade 3-4 acute graft versus host disease (GVHD), chronic GVHD requiring systemic therapy, or receipt of post-transplant donor cell infusion.
Time frame: 1, 3, and 5-years post-transplant
Cumulative Incidence of Primary Graft Failure at Day +60
Primary graft failure at day +60 estimated using cumulative incidence curves and 95% two-sided confidence intervals. Primary graft failure is defined as \< 5% donor myeloid chimerism in blood and/or bone marrow on all evaluations up to and including day +60, in the absence of a recurrent marrow malignancy.
Time frame: Day +60
Percentage of Participants With Lymphoproliferative Disease/Lymphoma Relapse at 1, 3, and 5-years Post-hematopoietic Cell Transplant (HCT)
Lymphoproliferative disease/lymphoma relapse at 1, 3, and 5-years post-HCT estimated using cumulative incidence curves and two-sided 95% confidence intervals at each timepoint.
Time frame: 1, 3, and 5 years post-HCT
Percent Probability Graft Versus Host Disease (GVHD)-Free Graft Failure-free Survival (GGFS)
Probabilities of GGFS were estimated using the Kaplan-Meier method. GGFS is
Time frame: 1, 3, and 5 years post-hematopoietic cell transplant (HCT)
Percent Probability of Graft Versus Host Disease (GVHD)-Free Relapse-free Survival (GRFS)
GRFS was estimated using the Kaplan-Meier method. Relapse free survival is
Time frame: 1, 3 and 5-years post-hematopoietic cell transplant (HCT)
Cumulative Incidences of Cytomegalovirus (CMV), BK Virus (BK), Adenovirus, Human Herpes Virus 6 (HHV6), JC Virus (JCV), and Epstein-Barr Virus (EBV) Detection in Blood at Day +100 Post-HCT
Cumulative incidences of CMV, BK, adenovirus, HHV6, JCV, and EBV detection in blood at day +100 post-HCT estimated using cumulative incidence curves along with two-sided 95% confidence intervals.
Time frame: day +100 post-HCT
Percentage of Donor B-cell Populations at Days +28, +42, +60, +100, +180, and 1-year Post-transplant
The percentage of donor B-cell populations at days +28, +42, +60, +100, +180, and 1-year post-transplant.
Time frame: Days +28, +42, +60, +100, +180, and 1-year post-transplant
Percentage of Donor Natural Killer (NK-) Cell Populations at Days +28, +42, +60, +100, +180, and 1-year Post Transplant
Percentage of donor natural killer (NK-) cell populations at days +28, +42, +60, +100, +180, and 1-year post transplant.
Time frame: Days +28, +42, +60, +100, +180, and 1-year post transplant
Percentage of Donor Myeloid Cell Populations at Days +28, +42, +60, +100, +180, and 1-year Post Transplant
Percentage of donor myeloid cell populations at days +28, +42, +60, +100, +180, and 1-year post transplant.
Time frame: Days +28, +42, +60, +100, +180, and 1-year post transplant
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