Overview

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

Status:
Recruiting
Trial end date:
2025-05-01
Target enrollment:
0
Participant gender:
All
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
Phase:
Phase 2
Accepts Healthy Volunteers?
Accepts Healthy Volunteers
Details
Lead Sponsor:
National Cancer Institute (NCI)
Criteria
- INCLUSION CRITERIA - RECIPIENT:

- 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 EBV

- At least one potential 7-8/8 HLA-matched related (excluding an identical twin) or
unrelated donor (at HLA-A, -B, -C, and -DR), or an HLA-haploidentical related donor,
based on initial low resolution unrelated donor search and/or at least one
biologically- related family member who has at least a 25% chance of being at minimum
an HLA- haploidentical match and is potentially suitable to donate based on reported
family history. HLA typing of potential donors and/or mutation testing does not need
to be completed for eligibility.

- Adequate end-organ function, as measured by:

- Left ventricular ejection fraction (LVEF) greater than or equal to 40% by 2D
echocardiogram ECHO, or left ventricular shortening fraction greater than or
equal to 20% by ECHO for subjects receiving RIC, or LVEF greater than or equal to
30% if the subject has radiologic evidence of aortic, renal, or coronary artery
vasculitis. LVEF greater than or equal to 30% for subjects receiving IOC.

- Pulmonary function tests: DLco (corrected for hemoglobin) and FEV1 greater than
or equal to 40% of predicted for the RIC arm, and greater than or equal to 30%
predicted for the IOC arm; or in pediatric subjects, if unable to perform
pulmonary function tests, there should be no evidence of dyspnea at rest, no
requirement for supplemental oxygen, and oxygen saturation >92% on room air.
Calculations will be based on the USA- ITS-NIH reference.

- Bilirubin less than or equal to 3.0 mg/dL (unless due to Gilbert s syndrome or
hemolysis) for subjects receiving RIC and bilirubin greater than or equal to 5.0
mg/dL for subjects receiving IOC (unless due to Gilbert s syndrome or hemolysis);
ALT and AST greater than or equal to 5 x ULN for subjects receiving RIC or
greater than or equal to 10 x ULN for subjects receiving IOC. Subjects who are
above these bilirubin, ALT, or AST thresholds may be eligible for the RIC or IOC
arm if evaluated by a hepatologist who deems the liver function test
abnormalities to be potentially reversible with HCT.

- Estimated creatinine clearance of greater than or equal to 50 mL/min/1.73 m^2,
calculated using eGRF in the clinical lab for adults and the Schwartz formula for
pediatric subjects, if eGFR not reported by the clinical lab.

- Adequate central venous access potential

- Karnofsky (adults) or Lansky (children) performance status of greater than or equal to
50% or ECOG performance status of 2 or less for the RIC arm and greater than or equal
to 30% or ECOG performance status of 3 or less for the IOC arm

- Ability of subject or parent/legal guardian to understand and the willingness to sign
a written informed consent document

- Not pregnant or breastfeeding. As therapeutic agents used in this trial may be harmful
to a fetus, women of childbearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for at least one year post-allo HCT. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in the study, she
should inform her treating physician immediately.

- Disease status: Subjects with lymphoproliferative disorder (LPD), LGL, HLH, or other
TCP/D disorders requiring standard therapies to prepare for HCT should be referred in
remission if possible. However, these diseases are often aggressive and require swift
evaluation for HCT while concurrently attempting to establish disease control through
the administration of standard therapies. If ongoing therapy for the underlying
disease outside of the NIH is not in the best interest of the subject according to the
clinical judgment of the PI, then the subject may receive standard treatment for
his/her underlying TCP/D disorder as a bridge to HCT on this protocol, prior to
starting the research phase of the study. If it becomes apparent that the subject will
not be able to proceed to HCT, then he/she must come off study. Subjects receiving
standard therapy will be told about the therapy, associated risks, potential benefits,
alternatives to the proposed therapy, and the availability of receiving the same
treatment elsewhere, outside of a research protocol.

EXCLUSION CRITERIA - RECIPIENT:

- Subjects who are receiving any other investigational agents, with the exception of
virus- specific cytotoxic T-cells for the treatment of viral infection/reactivation
prior to allo HCT.

- Prohibitive allergy to a study drug or to compounds of similar chemical or biologic
composition of the agents (e-ATG, steroids, cyclophosphamide, busulfan, pentostatin,
tacrolimus, MMF, G-CSF) used in the study.

- Active psychiatric disorder which is deemed by the PI to have significant risk of
compromising compliance with the transplant protocol or which does not allow for
appropriate informed consent

- HIV positive or other acquired immunodeficiency that, as determined by the PI,
interferes with the assessment of TCP/D severity and/or the attribution of clinical
manifestations of immunodeficiency to a disorder of TCP/D.

- MagT1 mutation and active need to take anti-platelet agents and/or therapeutic anti-
coagulation that cannot be interrupted during aplasia

INCLUSION CRITERIA RELATED DONOR

- Age greater than or equal to 4 years

- Related donor deemed suitable and eligible, and willing to donate, per clinical
evaluations who are additionally willing to donate blood, urine, and marrow specimens
for research. Related donors will be evaluated in accordance with existing Standard
Policies and Procedures for determination of eligibility and suitability for clinical
donation. Note that participation in this study is offered to all related donors, but
is not required for clinical donation, so it is possible that not all related donors
will enroll onto this study.

EXCLUSION CRITERIA - RELATED DONOR:

-None

INCLUSION CRITERIA - UNRELATED DONOR:

-Unrelated donors will be evaluated in accordance with existing NMDP Standard Policies and
Procedures, available at: http://bethematch.org/About-Us/Global-
transplant-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 DONOR:

-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.