A Phase II Prospective Study Evaluating Selective Depletion of CD45RA⁺ Naïve T Cells (TND) From Peripheral Blood Stem Cell Grafts for the Prevention of Graft-Versus-Host Disease in Older Patients With Acute Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation (HCT)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 52
- 试验地点
- 1
- 主要终点
- Graft versus host disease (GVHD) relapse-free survival
研究概览
简要总结
This phase II trial tests how well removing CD45RA positive naive T cells works to prevent graft versus host disease in older patients undergoing standard of care allogeneic hematopoietic stem cell transplantation for the treatment of acute leukemia or myelodysplastic syndrome (MDS). Allogeneic hematopoietic stem cell transplantation is when healthy cells are collected from a donor and infused into a patient to help the patient's bone marrow make more healthy cells and platelets and help destroy any remaining cancer cells. Giving chemotherapy and total-body irradiation before a stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. Sometimes the transplanted cells from a donor can attack the body's normal cells (called graft-versus-host disease). Removing the T cells from the donor cells before the transplant may stop this from happening. Giving CD45RA positive naive T cell depleted allogenic hematopoietic stem cell transplant may prevent graft versus host disease while treating acute leukemia or myelodysplastic syndrome in older adults.
详细描述
OUTLINE:
Patients receive cyclophosphamide intravenously (IV), over 1-2 hours on days -6 and -5, fludarabine IV, over 30 minutes on days -6 to -2 and total body irradiation for 1 treatment on day -1 or 0. Patients receive CD34+ enriched peripheral blood stem cells and CD45RA+ depleted cells IV on day 0. Patients undergo bone marrow aspiration/biopsy, echocardiography, and blood sample collection throughout the study.
After completion of study treatment, patients are followed up at day 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, then weekly until 1 completion of year 1 as well as at day 180 and 270, at 1.5 and 2 years and then periodically until 5 years post day 0.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •PARTICIPANT: Age > 60 years
- •PARTICIPANT: Diagnosis of acute leukemia or myelodysplastic syndrome (MDS):
- •Acute lymphocytic leukemia (ALL) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
- •Acute myeloid leukemia (AML) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
- •Other acute leukemia or related neoplasm (including but not limited to 'mixed phenotype' 'biphenotypic', 'acute undifferentiated' or 'ambiguous lineage' acute leukemia, blastic plasmacytoid dendritic cell neoplasm, lymphoblastic lymphoma, Burkitt leukemia/lymphoma, mast cell leukemia, chronic myeloid leukemia [CML] with blast crisis or other chronic myeloproliferative neoplasm) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
- •Myelodysplastic syndrome (MDS) with a history of excess blasts (≥ approximately 5% in marrow blasts by morphology) and a history of receiving cytoreductive therapy (including but not limited to BCL-2 inhibitors or cytotoxic chemotherapy) within the past 3 months
- •PARTICIPANT: Karnofsky performance status (KPS) ≥ 60% at pre-HCT evaluation
- •PARTICIPANT: Ability to provide informed consent
- •PARTICIPANT: Prior autologous or allogeneic HCT is permitted
- •DONOR: Human leukocyte antigen (HLA) matching: HLA-identical related donors or unrelated donors matched for HLA-A, -B, -C, - DRB1, and -DQB1 by high-resolution deoxyribonucleic acid (DNA) typing. A single allele-level mismatch at HLA class I is permitted
- •DONOR: Stem cell source: Donors must be able to undergo peripheral blood stem cell (PBSC) collection. Only G-CSF-mobilized PBSC are permitted as the hematopoietic stem cell (HSC) source on this protocol
排除标准
- •PARTICIPANT: Circulating blasts:
- •Acute leukemia: circulating abnormal blasts detectable by standard pathology.
- •MDS: > 5% circulating abnormal blasts by standard pathology
- •PARTICIPANT: Patients with promyelocytic leukemia (APL)
- •PARTICIPANT: Patients with active extramedullary disease are excluded. History of extramedullary disease is allowed if only minimal residual disease is present prior to HCT
- •PARTICIPANT: Ejection fraction < 35% (or shortening fraction < 26% if ejection fraction [EF] unavailable)
- •PARTICIPANT: Cardiac insufficiency requiring treatment or symptomatic coronary artery disease
- •PARTICIPANT: Patients with shortening fraction < 26% may enroll if approved by a cardiologist
- •PARTICIPANT: Carbon monoxide diffusing capability (DLCO) < 40%, total lung capacity (TLC) < 40%, forced expiratory volume in 1 second (FEV1) < 40%, and/or requiring continuous supplemental oxygen
- •PARTICIPANT: If pulmonary function tests (PFTs) cannot be obtained: any patient with room air oxygen saturation < 89% during a 6-minute walk test (6MWT) will be excluded
- •PARTICIPANT: Serum creatinine must be within institutional normal limits
- •PARTICIPANT: If serum creatinine > upper limit of normal, a 24-hour creatinine clearance will be performed; patients are excluded if < 50 mL/min/1.73 m^2
- •PARTICIPANT: Exclude patients with any of the following:
- •Fulminant liver failure.
- •Cirrhosis with evidence of portal hypertension.
- •Alcoholic hepatitis.
- •Esophageal varices or history of variceal bleeding.
- •Hepatic encephalopathy.
- •Uncorrectable synthetic dysfunction (prolonged prothrombin time).
- •Ascites due to portal hypertension.
- •Bridging fibrosis.
- •Bacterial or fungal liver abscess.
- •Biliary obstruction.
- •Chronic viral hepatitis with total bilirubin >3 mg/dL.
- •Symptomatic biliary disease
- •PARTICIPANT: Active infectious disease requiring deferral of conditioning (per Infectious disease consult). Upper respiratory tract infection is not considered to represent an uncontrolled infection in this context
- •PARTICIPANT: Fungal infection with radiologic progression despite appropriate antifungal therapy
- •PARTICIPANT: Viral infection risk: HIV-1, HIV-2, human T-lymphotropic virus (HTLV) 1 or HTLV2 positivity or active infectious hepatitis
- •PARTICIPANT: Patients with active central nervous system (CNS) leukemia at the time of treatment are excluded. A history of CNS leukemia is allowed if CNS disease has resolved prior to treatment initiation
- •PARTICIPANT: Weight > 110kg
- •PARTICIPANT: Other malignancies:
- •Active non-hematologic malignancies (except non-melanoma skin cancers).
- •Non-hematologic malignancy in remission but with > 20% risk of recurrence within 5 years.
- •Exclusion does not apply to indolent non-hematologic malignancies not requiring therapy
- •PARTICIPANT: Patients with a life expectancy < 12 months from co-existing disease other than the leukemia or MDS
- •PARTICIPANT: Hypersensitivity to cyclophosphamide, fludarabine, tacrolimus or mycophenolate mofetil (MMF)
- •PARTICIPANT: Inability to provide informed consent
- •PARTICIPANT: Alternative treatment: Patients who are suitable for and willing to receive a standard high intensity (myeloablative) preparative regimen
- •DONOR: Stem cell source restriction: Donors (or centers) that can exclusively provide bone marrow harvests
- •DONOR: Medical contraindications: HIV-1, HIV-2, HTLV-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection
- •DONOR: Preexisting immunoreactivity:
- •Determined per institutional standard practices.
- •For patients with a 10/10 HLA allele-level match, panel reactive antibody (PRA) screens to class I and class II antigens are recommended before HCT. If PRA >10%, then flow cytometric or B- and T-cell cytotoxic crossmatches must be obtained. The donor is excluded if any crossmatch is positive.
- •For patients with a Class I allele mismatch, flow cytometric or B- and T-cell cytotoxic crossmatches must be performed regardless of PRA results. A positive anti-donor cytotoxic crossmatch is an absolute exclusion.
- •Vector homozygosity: Donors are excluded if the patient is homozygous in the graft rejection vector against the donor's mismatched HLA class I allele
- •DONOR: Donors donating outside of the United States of America (USA)
研究组 & 干预措施
Treatment (CD34-selected graft with CD45RA-depleted PBSC)
Patients receive cyclophosphamide IV, over 1-2 hours on days -6 and -5, fludarabine IV , over 30 minutes on days -6 to -2 and total body irradiation for 1 treatment on day -1 or 0. Patients receive CD34+ enriched peripheral blood stem cells and CD45RA+ depleted cells IV on day 0. Patients undergo bone marrow aspiration/biopsy, echocardiography, and blood sample collection throughout the study.
干预措施: Allogeneic CD34+-enriched and CD45RA-depleted PBSCs (Biological)
Treatment (CD34-selected graft with CD45RA-depleted PBSC)
Patients receive cyclophosphamide IV, over 1-2 hours on days -6 and -5, fludarabine IV , over 30 minutes on days -6 to -2 and total body irradiation for 1 treatment on day -1 or 0. Patients receive CD34+ enriched peripheral blood stem cells and CD45RA+ depleted cells IV on day 0. Patients undergo bone marrow aspiration/biopsy, echocardiography, and blood sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Treatment (CD34-selected graft with CD45RA-depleted PBSC)
Patients receive cyclophosphamide IV, over 1-2 hours on days -6 and -5, fludarabine IV , over 30 minutes on days -6 to -2 and total body irradiation for 1 treatment on day -1 or 0. Patients receive CD34+ enriched peripheral blood stem cells and CD45RA+ depleted cells IV on day 0. Patients undergo bone marrow aspiration/biopsy, echocardiography, and blood sample collection throughout the study.
干预措施: Bone Marrow Aspiration (Procedure)
Treatment (CD34-selected graft with CD45RA-depleted PBSC)
Patients receive cyclophosphamide IV, over 1-2 hours on days -6 and -5, fludarabine IV , over 30 minutes on days -6 to -2 and total body irradiation for 1 treatment on day -1 or 0. Patients receive CD34+ enriched peripheral blood stem cells and CD45RA+ depleted cells IV on day 0. Patients undergo bone marrow aspiration/biopsy, echocardiography, and blood sample collection throughout the study.
干预措施: Bone Marrow Biopsy (Procedure)
Treatment (CD34-selected graft with CD45RA-depleted PBSC)
Patients receive cyclophosphamide IV, over 1-2 hours on days -6 and -5, fludarabine IV , over 30 minutes on days -6 to -2 and total body irradiation for 1 treatment on day -1 or 0. Patients receive CD34+ enriched peripheral blood stem cells and CD45RA+ depleted cells IV on day 0. Patients undergo bone marrow aspiration/biopsy, echocardiography, and blood sample collection throughout the study.
干预措施: Total-Body Irradiation (Radiation)
Treatment (CD34-selected graft with CD45RA-depleted PBSC)
Patients receive cyclophosphamide IV, over 1-2 hours on days -6 and -5, fludarabine IV , over 30 minutes on days -6 to -2 and total body irradiation for 1 treatment on day -1 or 0. Patients receive CD34+ enriched peripheral blood stem cells and CD45RA+ depleted cells IV on day 0. Patients undergo bone marrow aspiration/biopsy, echocardiography, and blood sample collection throughout the study.
干预措施: Fludarabine (Drug)
Treatment (CD34-selected graft with CD45RA-depleted PBSC)
Patients receive cyclophosphamide IV, over 1-2 hours on days -6 and -5, fludarabine IV , over 30 minutes on days -6 to -2 and total body irradiation for 1 treatment on day -1 or 0. Patients receive CD34+ enriched peripheral blood stem cells and CD45RA+ depleted cells IV on day 0. Patients undergo bone marrow aspiration/biopsy, echocardiography, and blood sample collection throughout the study.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Graft versus host disease (GVHD) relapse-free survival
时间窗: At 1 year
Defined as duration between date of transplant and documentation of the date of first occurrence of: relapse, grade III-IV acute GVHD, chronic GVHD, or death due to any cause. Will be estimated using the method of Kaplan Meier. Ninety percent confidence intervals (to be consistent with 1-sided 5% testing) around proportions at milestone time points (e.g. 1-year) will be calculated using the log-log transformation.
次要结局
- Overall survival(At day 365 and 730 days post transplant)
- Time to relapse(At 1 year post transplant)
- Treatment related mortality(At day 100 and 365 days post transplant)
- Graft rejection or graft failure rate(Two years post transplant)
- Incidence of acute GVHD(At day 100, 180 and 365 post transplant)
- Incidence of chronic GVHD(At day 365 and 730 post transplant)