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

A Phase II Prospective Study Evaluating Selective Depletion of CD45RA+ (Naïve) T Cells (TND) From Peripheral Blood Stem Cell (PBSC) Grafts for Prevention of Graft Versus Host Disease (GVHD) in Non-Malignant Diseases (NMDs)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Hemoglobinopathies; Immune Dysregulation; Bone Marrow Failure; Hemophagocytic Lymphohistiocytosis (HLH); Autoimmune Cytopenia; Non Malignant Disorders; Primary Immune Deficiency (PID)
• Intervention / Treatment: Biological: ALLOGENEIC CD34+ ENRICHED AND CD45RA- DEPLETED PBSCs

Detailed Description

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
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Madhavi Lakkaraja, MD, MPH; Phone Number: 206-667-7166; Email: mlakkara@fredhutch.org

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Arm A (HLA-Haploidentical or mismatched unrelated donor); Conditioning regimen for HLA-Haploidentical or mismatched unrelated donor consisting of Cyclophosphamide (50 mg/kg x1 day), Fludarabine 35 mg/m2/day x 5 days, Thiotepa (5 mg/kg/day x 2 days), TBI (200 cGy x 2). Tacrolimus starting Day -1, MMF D0-35.	Biological: ALLOGENEIC CD34+ ENRICHED AND CD45RA- DEPLETED PBSCs; CD34-selected graft with CD45RA- depleted peripheral blood stem cells given to patients with Non-Malignant Diseases
Other: Arm B (HLA-matched related or matched unrelated donor ); Conditioning regimen for HLA-matched related or matched unrelated donor consisting of Cyclophosphamide (50 mg/kg x1 day), Fludarabine (30 mg/m2/day x 5 days), Thiotepa (5 mg/kg/day x 2 days), TBI (200 cGy x 2). Tacrolimus starting Day -1, MMF D0-35.	Biological: ALLOGENEIC CD34+ ENRICHED AND CD45RA- DEPLETED PBSCs; CD34-selected graft with CD45RA- depleted peripheral blood stem cells given to patients with Non-Malignant Diseases

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GVHD-free Survival	Free of grade III-IV acute and NIH chronic (moderate-severe) GVHD requiring systemic immunosuppression	1 year post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		1 year post-transplant
Transplant related mortality		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.	Day 42 post-transplant
Graft rejection	Graft rejection defined as <5% donor CD3 T cell and CD33 myeloid chimerism	Day 100 post-transplant
Incidence of chronic GVHD	Defined and graded based on NIH criteria and graded operationally as the occurrence of compatible symptoms	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	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	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	2 years post-transplant

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Investigators: Principal Investigator: Madhavi Lakkaraja, MD, MPH, Fred Hutch Cancer Center

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2031
• Study Completion (Estimated): September 1, 2035

Study Registration Dates

• First Submitted: June 16, 2026
• First Submitted That Met QC Criteria: June 16, 2026
• First Posted (Actual): June 22, 2026

Study Record Updates

• Last Update Posted (Actual): June 22, 2026
• Last Update Submitted That Met QC Criteria: June 16, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Immune System Diseases; Hematologic Diseases; Immunologic Deficiency Syndromes; Lymphatic Diseases; Bone Marrow Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Primary Immunodeficiency Diseases; Bone Marrow Failure Disorders; Hemoglobinopathies; Lymphohistiocytosis, Hemophagocytic
• Other Study ID Numbers: 20798; RG1126016 (Other Identifier: Fred Hutch Cancer Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No