Naive T Cell Deplete Grafts for GVHD Prevention in Non-Malignant Diseases

Phase 2Not Yet RecruitingNCT07660783

Fred Hutchinson Cancer Center40 enrolled

Overview

This phase II trial investigates how well a naive T cell depleted graft work for the reduction of graft versus host disease in patients with non-malignant diseases requiring hematopoietic cell transplantation. Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells.

OUTLINE: Patients will receive CD34+ enriched CD45RA-depleted donor T-lymphocytes IV on day 0. For conditioning, patients receive cyclophosphamide by IV on day -8, fludarabine by IV on day -7 to day -3, thiotepa IV on day -7 and day -6, and undergo total-body irradiation (TBI) for 2 doses on day -2 and day -1. GVHD Prophylaxis: All patients also receive tacrolimus IV continuously starting on day -1, and mycophenolate mofetil (MMF) starting day 0 through day 35. If there is no evidence of grade II-IV acute GVHD on or prior to day 100, tacrolimus is tapered. All patients also undergo bone marrow aspiration/biopsy and collection of blood samples throughout the trial. After completion of study treatment, patients are followed up at days 7, 14, 21, 28, 56, 80, 180, and 270 and at 1, 1.5, and 2 years.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Eligibility

Sex: ALLMin age: 6 MonthsMax age: 50 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Considered appropriate candidate for allogeneic HCT following low dose (4Gy) TBI containing-conditioning and have one of the following diagnoses: A) BMF B)Hemoglobinopathies C)PID D) Autoimmune cytopenias E) Immune dysregulation F) HLH G) Other NMD treatable by HCT and NMD that is not clearly defined (a patient with a NMD for whom genetic testing has been done and a genetic mutation responsible for their NMD phenotype has not been identified) are eligible for the study following discussion with and approval by the protocol PI * Patients aged 6 months- 5 years old (inclusive) at the time of informed consent * Patient with suitable HCT donor (see inclusion criteria below) * Recipient informed consent/assent (13 years and older), and/or legal guardian permission must be obtained Exclusion Criteria: * Patient with aplastic anemia * Patients with severe combined immunodeficiency (SCID) * Fanconi anemia * Dyskeratosis congenita * Patient weight \> 100 kg * Patients who are positive for HIV-1, HIV-2 * Patients with current neoplastic disorders * Patients with uncontrolled infections for whom HCT is considered contraindicated by the consulting infectious disease physician. * Patients with organ dysfunction including A) Renal insufficiency B) Impaired cardiac function C)Impaired pulmonary function D) Liver dysfunction * Patients who are pregnant or breast-feeding * Patients on other experimental protocols for prevention of GVHD * Patients of childbearing age who are presumed to be fertile and are unwilling to use an effective birth control method or refrain from sexual intercourse during and for 12 months post-HCT * Patients with any other significant medical conditions that would make them unsuitable for transplantation, as determined by the PI * Patients with a known hypersensitivity to tacrolimus or MMF

Outcomes

Primary Outcomes

GVHD-free Survival

Free of grade III-IV acute and NIH chronic (moderate-severe) GVHD requiring systemic immunosuppression

Time frame: 1 year post-transplant

Secondary Outcomes

Overall survival

Time frame: 1 year post-transplant

Transplant related mortality

Time frame: Day 100 post-transplant and 1 year post-transplant

Graft failure

Graft failure defined as failure to achieve an ANC ≥ 0.5 × 109/L before death or second HCT, or decrease to ANC \<0.1 × 109/L for 14 consecutive days (date of graft failure defined as the 14th day) after an established donor graft despite daily administration of G-CSF (SC or IV) and ≤ average 20% bone marrow cellularity on bone marrow aspirate or biopsy any time in the first 2 years following HCT. If a patient dies from organ toxicity and/or infection prior to day 28 without ANC ≥ 0.5 × 109/L this will not be considered graft failure. If the graft failure is attributed to viral infection, multi-organ failure or drug effect it will still be considered graft failure if it meets the definition of graft failure specified above.

Time frame: Day 42 post-transplant

Graft rejection

Graft rejection defined as \<5% donor CD3 T cell and CD33 myeloid chimerism

Time frame: Day 100 post-transplant

Incidence of chronic GVHD

Defined and graded based on NIH criteria and graded operationally as the occurrence of compatible symptoms

Time frame: At 1 year and 2 years post transplant

Prednisone for GVHD

Number of participants alive and off prednisone (or equivalent systemic corticosteroid) for the treatment of GVHD

Time frame: Every 3 months post-transplant for the first 2 years

Incidence of opportunistic infections requiring treatment

Proportion of participants who experience viral infections/reactivations. * of participants with \>/= grade 1-3 viral infections * of participants with CMV grade 2-3 * of participants with EBV grade 2-3 * of participants with ADV, HHV-6 or BK \>/= grade 2 * of participants with definite (confirmed organism) viral respiratory tract infection requiring hospital admission for \>/= 7 days or causing death between day 90 and day 365 post-transplant

Time frame: First year post-transplant

Peripheral blood donor chimerism

Full donor chimerism will be defined as CD33 and CD3 ≥95%. Mixed chimerism will be defined as CD33 OR CD3 \<95% but \>5%. Actual chimerism values will be reported and summarized as well as dichotomized according to the 'full chimerism' and 'mixed chimerism' labels

Time frame: 2 years post-transplant