Haploidentical HCT for Severe Aplastic Anemia

Phase 2

Recruiting

• Conditions: Aplastic Anemia; Bone Marrow Failure Syndrome
• Interventions: Drug: Anti-Thymocyte Globulin (Rabbit); Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mesna; Drug: G-CSF; Radiation: Total Lymphoid Irradiation (TLI); Device: CliniMACS; Biological: HPC, A Infusion; Biological: CD45RA-depleted DLI

• Registration Number: NCT04558736
• Lead Sponsor: St. Jude Children's Research Hospital

Brief Summary

This study is a prospective, single center phase II clinical trial in which patients with Severe Aplastic Anemia (SAA) ) will receive a haploidentical transplantation. The purpose of this study is to learn more about newer methods of transplanting blood forming cells donated by a family member that is not fully matched to the patient. This includes studying the effects of the chemotherapy, radiation, the transplanted cell product and additional white blood cell (lymphocyte) infusions on the patient's body, disease and overall survival. The primary objective is to assess the rate of engraftment at 30 days and overall survival (OS) and event free survival (EFS) at 1 year post-hematopoietic cell transplantation (HCT).

Primary Objectives

* To estimate the rate of engraftment at 30 days after TCR αβ+ T-cell-depleted graft infusion in patients receiving a single dose of post graft infusion cyclophosphamide.

* To estimate the overall survival and event free survival at 1-year post transplantation.

Secondary Objectives

* To calculate the incidence of acute and chronic GVHD after HCT.

* To calculate the rate of secondary graft rejection at 1-year post transplantation

* To calculate the cumulative incidence of viral reactivation (CMV, EBV and adenovirus).

* To describe the immune reconstitution after TCR αβ+ T-cell-depleted graft infusion at 1 month, 3 months, 6 months, 9 months, and 1 year.

Exploratory Objectives

* To longitudinally assess the phenotype and epigenetic profile of T-cells in SAA patients receiving HCT for SAA.

* To assess the phenotype and epigenetic profile of T-cells in DLI administered to SAA patients post HCT.

* To longitudinally assess CD8 T cell differentiation status in SAA patients using an epigenetic atlas of human CD8 T cell differentiation.

* To examine the effector functions and proliferative capacity of CD8 T cells isolated from SAA patients before and after DLI.

* Quantify donor derived Treg cells at different time points in patients received HCT.

* Determine Treg activation status at different stages after HCT.

* Are specific features of the DLI product associated with particular immune repertoire profiles post-transplant?

* How does the diversity and functional profile of the DLI product alter the response to pathogens in the recipient?

* Do baseline features of the recipient's innate and adaptive immune cells correlate with post-transplant immune repertoires and response profiles?

Detailed Description

Immunosuppressant therapy (IST) is the main treatment for SAA for patients who do not have an HLA-matched sibling donor available for transplant. But some patients with SAA do not respond to IST and some others relapse after IST. HCT using an unrelated but HLA-matched donor is the only curative option for these patients but many patients lack a suitable HLA-matched donor. St Jude is trying to increase donor options for these patients by using novel therapeutic strategies by combining two widely used of GVHD prophylaxis methods: i) selective T cell depletion and ii) use of post-transplant cyclophosphamide. This will allow expansion of the donor pool to include haploidentical donors as well as reduce the risk of GVHD. The goal of this protocol is to test whether combining these GVHD prophylaxis approaches will allow use of haploidentical donors, reduce risk of GVHD, reduce transfusion dependence and improve immune reconstitution.

For this study chemotherapy, antibodies and radiation will be given to prepare the body to receive donor cells. Participants will then be given the donor cell infusion.

Patients will receive two types of donor blood cell products - a progenitor blood cell infusion and then a donor lymphocyte infusion. Both the progenitor blood cell and the donor lymphocyte infusion will be processed in a laboratory at St. Jude using a machine called the CliniMACS™.

In this clinical trial, participants will receive a special type of progenitor blood cells (called TCRαβ- depleted blood cells) from the donor.

After the donor progenitor cells have started to grow within the body (engraftment), participants will receive a second product that contains mature immune cells. These immune cells called CD45RA-depleted lymphocytes or donor lymphocyte infusion (DLI) will help fight infections in the body after the transplant and strengthen the developing immune system.

Study Timeline

• Study First Submitted: 2020-09-09
• Study First Submitted QC: 2020-09-15
• Study First Posted: 2020-09-22
• Study Start: 2021-01-21
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-03
• Last Update Posted: 2025-07-04
• Primary Completion: 2029-07-01
• Study Completion: 2030-07-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 21

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Haploidentical HCT	Anti-Thymocyte Globulin (Rabbit)	To assess the safety and efficacy of haploidentical donor transplantation for patients with severe aplastic anemia who lack an available HLA-matched donor. The goal of this study is to develop a novel, reduced-toxicity, post-transplant pharmacologic immunosuppression (GVHD prophylaxis)- free, highly tolerogenic haploidentical transplant regimen that is associated with few post- transplant complications or late toxicities and is available promptly to all patients, irrespective of matched donor availability. Cells for infusion are prepared using the CliniMACS System.
Haploidentical HCT	Fludarabine	To assess the safety and efficacy of haploidentical donor transplantation for patients with severe aplastic anemia who lack an available HLA-matched donor. The goal of this study is to develop a novel, reduced-toxicity, post-transplant pharmacologic immunosuppression (GVHD prophylaxis)- free, highly tolerogenic haploidentical transplant regimen that is associated with few post- transplant complications or late toxicities and is available promptly to all patients, irrespective of matched donor availability. Cells for infusion are prepared using the CliniMACS System.
Haploidentical HCT	Cyclophosphamide	To assess the safety and efficacy of haploidentical donor transplantation for patients with severe aplastic anemia who lack an available HLA-matched donor. The goal of this study is to develop a novel, reduced-toxicity, post-transplant pharmacologic immunosuppression (GVHD prophylaxis)- free, highly tolerogenic haploidentical transplant regimen that is associated with few post- transplant complications or late toxicities and is available promptly to all patients, irrespective of matched donor availability. Cells for infusion are prepared using the CliniMACS System.
Haploidentical HCT	Mesna	To assess the safety and efficacy of haploidentical donor transplantation for patients with severe aplastic anemia who lack an available HLA-matched donor. The goal of this study is to develop a novel, reduced-toxicity, post-transplant pharmacologic immunosuppression (GVHD prophylaxis)- free, highly tolerogenic haploidentical transplant regimen that is associated with few post- transplant complications or late toxicities and is available promptly to all patients, irrespective of matched donor availability. Cells for infusion are prepared using the CliniMACS System.
Haploidentical HCT	Total Lymphoid Irradiation (TLI)	To assess the safety and efficacy of haploidentical donor transplantation for patients with severe aplastic anemia who lack an available HLA-matched donor. The goal of this study is to develop a novel, reduced-toxicity, post-transplant pharmacologic immunosuppression (GVHD prophylaxis)- free, highly tolerogenic haploidentical transplant regimen that is associated with few post- transplant complications or late toxicities and is available promptly to all patients, irrespective of matched donor availability. Cells for infusion are prepared using the CliniMACS System.
Haploidentical HCT	CliniMACS	To assess the safety and efficacy of haploidentical donor transplantation for patients with severe aplastic anemia who lack an available HLA-matched donor. The goal of this study is to develop a novel, reduced-toxicity, post-transplant pharmacologic immunosuppression (GVHD prophylaxis)- free, highly tolerogenic haploidentical transplant regimen that is associated with few post- transplant complications or late toxicities and is available promptly to all patients, irrespective of matched donor availability. Cells for infusion are prepared using the CliniMACS System.
Haploidentical HCT	HPC, A Infusion	To assess the safety and efficacy of haploidentical donor transplantation for patients with severe aplastic anemia who lack an available HLA-matched donor. The goal of this study is to develop a novel, reduced-toxicity, post-transplant pharmacologic immunosuppression (GVHD prophylaxis)- free, highly tolerogenic haploidentical transplant regimen that is associated with few post- transplant complications or late toxicities and is available promptly to all patients, irrespective of matched donor availability. Cells for infusion are prepared using the CliniMACS System.
Haploidentical HCT	CD45RA-depleted DLI	To assess the safety and efficacy of haploidentical donor transplantation for patients with severe aplastic anemia who lack an available HLA-matched donor. The goal of this study is to develop a novel, reduced-toxicity, post-transplant pharmacologic immunosuppression (GVHD prophylaxis)- free, highly tolerogenic haploidentical transplant regimen that is associated with few post- transplant complications or late toxicities and is available promptly to all patients, irrespective of matched donor availability. Cells for infusion are prepared using the CliniMACS System.
Haploidentical HCT	G-CSF	To assess the safety and efficacy of haploidentical donor transplantation for patients with severe aplastic anemia who lack an available HLA-matched donor. The goal of this study is to develop a novel, reduced-toxicity, post-transplant pharmacologic immunosuppression (GVHD prophylaxis)- free, highly tolerogenic haploidentical transplant regimen that is associated with few post- transplant complications or late toxicities and is available promptly to all patients, irrespective of matched donor availability. Cells for infusion are prepared using the CliniMACS System.

Primary Outcome Measures

Name	Time	Method
Engraftment	30 days	Rate of patients engrafting at day 30 after TCR αβ+ T-cell-depleted graft infusion in patients receiving a single dose of post graft infusion cyclophosphamide.
Overall and event free survival	1 year	Rate of overall survival and event free survival at 1-year post transplantation.

Secondary Outcome Measures

Name	Time	Method
Graft rejection	1 year	Rate of secondary graft rejection at 1-year post transplantation
Immune reconstitution	1 year	We will record immune reconstitution parameters, including the order and magnitude of recovery of the different subtypes of leukocytes. Results will be summarized by descriptive statistics. The pattern of immune reconstitution will be evaluated using longitudinal approaches such as mixed effect models or generalized estimating equation (GEE) approach.
Viral reactivation	1 year	Cumulative incidence of viral reactivation post-transplant (CMV, EBV and adenovirus)
Graft vs host disease	1 year	Incidence of acute and chronic GVHD after hematopoietic cell transplant

Trial Locations

Locations (1)

St. Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States