Alpha/Beta T-cell Depleted Blood-forming Stem Cell Transplant From Related or Unrelated Donors for Blood Diseases in Children and Young Adults

Overview

This single institution, phase I clinical trial will determine the safety and feasibility of employing T-cell receptor (TCR) αβ+ and CD19+ (Cluster of Differentiation ) depleted hematopoietic stem cell transplantation (HSCT) using peripheral blood stem cells (PBMC) from closely matched unrelated donors or haploidentical donors to treat non-malignant hematologic diseases in children and young adults. Allogeneic hematopoietic stem cell transplantation has become a curative option for children and adolescents with a variety of otherwise fatal conditions. To reduce the incidence and severity of graft-versus-host disease (GVHD) associated with allogeneic hematopoietic stem cell transplantation, donor grafts are depleted of T cells, either using CD34+ selection or CD3+/CD19+ depletion of grafts. However, these selection processes also deplete the graft of protective cell subsets, such as γδ T cells, natural killer(NK) cells, monocytes and dendritic cells, which play important roles in the immune response to infectious agents. Moreover, the presence of NK cells and γδ T in donor grafts is associated with more rapid immune reconstitution after HSCT transplantation. In order to retain these protective immune cell subsets, this trial will use a novel, highly selective graft engineering process using the Miltenyi CliniMACS system that selectively depletes αβ-T cells and B cells which are responsible for GVHD and Epstein Barr Virus (EBV)-related post-transplantation lymphoproliferative disorder, respectively. Prior to transplantation, patients will be treated with a conditioning regimen, specific for the original disorder. The primary objective of this study is evaluation of the safety and feasibility of HSCT using TCRαβ+/CD19+ depleted hematopoietic stem cells to treat non-malignant hematologic diseases. This will be assessed by evaluating the incidence of graft failure, grade III-IV acute GVHD and chronic GVHD and TRM. Secondary objectives include the evaluation of immune reconstitution and incidence of post-transplant infections, adverse events, serious adverse events, overall and disease-free survival and the efficiency of graft processing by the CliniMACS System.

Full Title of Study: “TCRαβ+ and CD19+ Depleted Hematopoietic Stem Cell Transplant From Closely Matched Unrelated Donors or Haploidentical Related Donors for Hematologic Diseases in Children and Young Adults”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: March 2028

Interventions

  • Biological: TCRαβ+/CD19+ depleted Hematopoietic stem cell (HSC) graft
    • After undergoing a disease specific conditioning regimen (standard of care), participants will receive peripheral blood stem cell transplant from a haploidentical donor or closely matched unrelated donor, depleted of TCR αβ+ and CD19+ cells using the CliniMACS TCR α/β-biotin and CD19 Systems.
  • Device: CliniMACS® System
    • The CliniMACS Cell Selection System is based on magnetic-activated cell sorting mechanism. The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures.

Arms, Groups and Cohorts

  • Experimental: Treatment arm
    • Participants will undergo a conditioning regimen, specific for the original disease, After that peripheral blood stem cell transplant from a haploidentical donor or closely matched unrelated donor, depleted of TCRαβ+ and CD19+ cells using the CliniMACS TCR α/β-biotin and CD19 Systems will be administered intravenously on Day 0 to all participants.

Clinical Trial Outcome Measures

Primary Measures

  • Incidence of grade III-IV acute graft-versus-host disease (GVHD)
    • Time Frame: 100 days post transplantation
    • Acute GVHD will be assessed and graded according to the Keystone Consensus Criteria for staging and grading of acute graft-versus-host disease.
  • Incidence of extensive chronic GVHD
    • Time Frame: up to 2 years
    • Chronic GVHD will be assessed according to the current CIBMTR (Center for International Blood and Marrow Transplant Research) manual reflecting a grading system published by Sullivan KM (Sullivan 1981).
  • Incidence of graft failure
    • Time Frame: up to 2 years after graft
    • Graft failure – defined as failure to achieve ANC > 500 /µL at Day +28 or initial neutrophil engraftment followed by a decline in ANC < 500 /µL that is unresponsive to growth factor therapy (secondary graft failure).
  • Incidence of Treatment related mortality(TRM)
    • Time Frame: Day +100 post-HSCT
    • TRM – defined as death from any cause other than disease progression.

Secondary Measures

  • Time to neutrophil engraftment
    • Time Frame: up to 28 days following HSCT
    • The time to neutrophil engraftment is defined as the post-transplant day that is the first of 3 consecutive days with an absolute neutrophil count (ANC) of >500/µL as assessed by CBC.
  • Time to platelet engraftment
    • Time Frame: up to 28 days following HSCT
    • The time to platelet engraftment is defined as the post-transplant day that is the first of 3 consecutive days with a platelet count ≥ 20,000/µL as assessed by complete blood count(CBC), without platelet support (transfusion) for 7 days.
  • Percentage donor chimerism using Short tandem repeat (STR)
    • Time Frame: up to 12 months following HSCT
    • Short tandem repeat (STR) analysis will provide the percentage donor chimerism at specific time points post-transplant.
  • Kinetics of lymphocyte reconstitution via immunophenotyping using flow cytometry
    • Time Frame: up to 12 months following HSCT
    • Lymphocyte reconstitution will be assessed at specific time points post-HSCT, expressed as the percentage of white blood cells comprised of T, B and NK cell subsets.
  • CliniMACS system efficiency: Percentage of viable CD34+ cells recovered after the TCRαβ+ and CD19+ depletion procedure
    • Time Frame: up to 12 months following HSCT
  • CliniMACS system efficiency: log depletion value for CD19+ cells after the TCRαβ+ and CD19+ depletion procedure
    • Time Frame: Day 0
  • CliniMACS system efficiency: log depletion value of TCRαβ+ cells after the TCRαβ+ and CD19+ depletion procedure
    • Time Frame: Day 0
  • CliniMACS system efficiency: number of viable blood cell subsets after the TCRαβ+ and CD19+ depletion procedure
    • Time Frame: Day 0
    • Number of viable CD34+ blood stem cells, CD20+ B cells, CD3-CD56+ NK cells, TCRαβ+ T cells, and TCRγδ+ T cells in the HSC graft after the TCRαβ+ and CD19+ depletion procedure
  • Correlation between GVHD incidence and donor killer-cell immunoglobulin-like receptor (KIR) haplotype content
    • Time Frame: up to 2 years
  • Correlation between GVHD incidence and killer-cell immunoglobulin-like receptor (KIR)/KIR-ligand mismatch between donor and recipient.
    • Time Frame: up to 2 years
  • Event free survival
    • Time Frame: up to 1 years
    • An event is defined as death, graft failure or stable mixed chimerism with disease recurrence.
  • Overall survival (OS)
    • Time Frame: up to 2 years
  • Incidence of symptomatic bacterial/fungal and viral reactivation requiring therapy
    • Time Frame: up to 1 year
    • The incidence of infections (symptomatic bacterial/fungal and viral reactivation requiring therapy) will be used as an additional safety measure
  • Number of participants with adverse events related to infusion of the HSC graft
    • Time Frame: Day 0
  • Incidence of serious adverse events
    • Time Frame: up to 2 years

Participating in This Clinical Trial

Inclusion Criteria

  • No Human leukocyte antigen (HLA) identical sibling available AND – NO HLA matched unrelated donor available OR urgent need of HSCT precludes time necessary to search for suitable HLA matched unrelated donor AND – Haploidentical donor OR closely matched unrelated donor available and willing to undergo mobilization and apheresis – If subject has genetically confirmed inherited bone marrow failure, related donor must be evaluated for this disorder and testing must be negative. – If subject has sickle cell disease, donor may have only sickle cell trait – Patient must be diagnosed with one of the following diseases or disorders: Hemoglobinopathies – Sickle Cell Disease for patients ≤ 21 years of age for whom hydroxyurea has been trialed for at least six months, and failed – Thalassemia Major for patients ≤ 21 years of age Acquired Bone Marrow Failure Syndromes – Paroxysmal Nocturnal Hemoglobinuria with bone marrow failure – Myelodysplastic Syndromes (lower risk) Inherited Bone Marrow Failure Syndromes – Fanconi Anemia – Diamond Blackfan Anemia – Dyskeratosis Congenita and related telomere disorders – Congenital Thrombocytopenia Syndromes – Severe Congenital Neutropenia – Shwachman-Diamond Syndrome – Age ≤ 40 years (except patients with hemoglobinopathies) – Life Expectancy ≥ 3 months – Karnofsky (patients > 16 years)/Lansky (patients ≤ 16 years) index ≥ 60 – Organ Function Requirements Renal Function – Creatinine clearance or radioisotope Glomerular Filtration Rate (GFR) greater than or equal to 60 ml/min/1.73m^2 Liver Function – Total bilirubin < 3 mg/dL – Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase; synonymous with ALT (SCPT) ≤ 3 x Upper Limit of Normal(ULN) for age Cardiac Function – Ejection fraction of > 40% by Multiple gated acquisition scan (MUGA) or echocardiogram Pulmonary Function – No evidence of dyspnea at rest – No supplemental oxygen requirement – If measured, carbon monoxide diffusion capacity (DLCO) > 50% – Willing to use effective birth control method if patient is of reproductive potential – Informed consent obtained (patient or legal representative) Exclusion Criteria:

  • Pregnant – HIV infection – Uncontrolled, serious active infection at screening – Significant serious intercurrent illnesses – Enrollment in any other treatment study that would interfere with the endpoints of this study according to judgement of Principal Investigator(or PI designee).

Gender Eligibility: All

Minimum Age: 3 Months

Maximum Age: 40 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Wisconsin, Madison
  • Collaborator
    • University of Wisconsin Carbone Cancer Center (UWCCC)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Kenneth DeSantes, MD, Principal Investigator, University of Wisconsin, Madison
    • Jacques Galipeau, MD, Study Director, University of Wisconsin, Madison
  • Overall Contact(s)
    • Jenny Weiland, 608-890-8070, PedsHemOncResearch@lists.wisc.edu

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