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

Официальное название

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

Обзор

This study is being done to see if the investigators can take peripheral blood stem cells from either an adult family member or a closely matched unrelated donor, and run them through a special lab instrument to remove alpha/beta T cells and B cells and then give them to the patient to treat disease. This is an experimental way of doing a hematopoietic stem cell transplant (HSCT). The investigators want to see if the new stem cells will grow without bad graft vs. host disease (GVHD). This treatment approach is experimental in the United States.

Подробное описание

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 cells 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 that 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.

Вмешательства

• Биопрепарат 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.
• Устройство 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.

Первичные конечные точки

• Incidence of grade III-IV acute graft-versus-host disease (GVHD) [Срок оценки: 100 days post transplantation]
• Incidence of extensive chronic GVHD [Срок оценки: up to 2 years]
• Incidence of graft failure [Срок оценки: up to 2 years after graft]
• Incidence of Treatment Related Mortality (TRM) [Срок оценки: Day +100 post-HSCT]

Вторичные конечные точки (12)

• Time to neutrophil engraftment [Срок оценки: up to 28 days following HSCT]
• Time to platelet engraftment [Срок оценки: up to 28 days following HSCT]
• Percentage donor chimerism using Short Tandem Repeat (STR) [Срок оценки: up to 12 months following HSCT]
• Kinetics of lymphocyte reconstitution via immunophenotyping using flow cytometry [Срок оценки: up to 12 months following HSCT]
• CliniMACS system efficiency: Percentage of viable CD34+ cells recovered after the TCRαβ+ and CD19+ depletion procedure [Срок оценки: up to 12 months following HSCT]
• CliniMACS system efficiency: log depletion value for CD19/CD20+ B cells after the TCRαβ+ and CD19+ depletion procedure [Срок оценки: Day 0]
• CliniMACS system efficiency: log depletion value of TCRαβ+ T cells after the TCRαβ+ and CD19+ depletion procedure [Срок оценки: Day 0]
• CliniMACS system efficiency: number of viable blood cell subsets after the TCRαβ+ and CD19+ depletion procedure [Срок оценки: Day 0]
• Correlation between GVHD incidence and donor killer-cell immunoglobulin-like receptor (KIR) haplotype content [Срок оценки: up to 2 years]
• Correlation between GVHD incidence and killer-cell immunoglobulin-like receptor (KIR)/KIR-ligand mismatch between donor and recipient. [Срок оценки: up to 2 years]
• Event free survival [Срок оценки: up to 1 years]
• Overall survival (OS) [Срок оценки: up to 2 years]

Критерии участия

Критерии включения

• 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 must be unaffected or 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)
• Severe acquired aplastic anemia
• 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
• Inborn Errors of Immunity (IEI) or Primary Immune Regulatory Disorders (PIRD)

• Wiskott-Aldrich syndrome (WAS)
• Chronic granulomatous disease (CGD)
• Severe combined immunodeficiency (SCID)
• Primary hemophagocytic lymphohistiocytosis (HLH)
• Age ≤ 25 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)

Критерии исключения

• 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).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT04806347 · 2020-1251 · 2020-1251 · A536755 · Protocol Version 6 · NCI-2021-02128 · UW19113

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗