Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD
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|ClinicalTrials.gov Identifier: NCT00914940|
Recruitment Status : Terminated (Did not reach one of the primary endpoints of decreased total acute GVHD)
First Posted : June 5, 2009
Results First Posted : August 20, 2020
Last Update Posted : August 20, 2020
RATIONALE: Allogeneic hematopoietic stem cell transplant (HSCT) is a treatment that can cure acute leukemia and myelodysplasia. After giving the patient chemotherapy and total body irradiation to stop the growth of cancer and remove the patient's diseased bone marrow, healthy stem cells from a donor are infused into the patient to replace the patient's bone marrow and make red and white blood cells and platelets. Unfortunately HSCT is often complicated by 'graft versus host disease' (GVHD) in which the transplanted cells from a donor can make an immune response against the body's normal cells and cause tissue damage and severe symptoms. Removing a subset of the donor T cells, called 'naive T cells', before transplant may reduce the frequency and intensity of GVHD.
PURPOSE: This phase II trial will determine whether the removal of the naive T cells from donor cells can decrease the rate and severity of graft-vs-host disease while preserving specific immunity against infections in patients with acute leukemia or advanced myelodysplastic syndromes.
|Condition or disease||Intervention/treatment||Phase|
|Graft Versus Host Disease Leukemia Myelodysplastic Syndromes||Drug: Fludarabine Phosphate Drug: Tacrolimus Drug: Thiotepa Radiation: Total-Body Irradiation (TBI) Other: Magnetic Affinity Cell Sorting Procedure: Peripheral Blood Stem Cell Transplantation Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation||Phase 2|
- Estimate the probability of grades II-IV acute graft-vs-host disease (GVHD) in patients with acute leukemia or advanced myelodysplastic syndromes treated with CD45RA+ T-cell-depleted allogeneic peripheral blood stem cell transplantation and compare this to relevant historical experience.
- Estimate the probability of graft failure in these patients.
- Evaluate immune reconstitution and pathogen-specific T-cell reconstitution in these patients.
- Estimate the probability of transplant-related mortality by day 100 in these patients.
- Estimate the probability of relapse in these patients.
- Estimate the probability and severity of chronic GVHD in these patients.
OUTLINE: This is a multicenter study.
- Myeloablative conditioning regimen: Patients undergo total body irradiation twice daily for 4 days (Days -10 to -7) Patients also receive thiotepa IV over 4 hours for 2 days (Days -6 and -5) and fludarabine phosphate IV over 30 minutes for 5 days (Days -6 to -2.)
- Transplantation: Patients receive a CD34+ enriched allogeneic peripheral blood stem cell (PBSC) product followed by a CD45RA+ T-cell-depleted allogeneic PBSC product on day 0.
Graft-vs-host disease (GVHD) prophylaxis: Patients will receive Tacrolimus as per cohort 1. If the rate of grade II-IV acute GVHD in the first 35 patients is significantly reduced (compared to historical controls), subsequent patients are enrolled in cohort 2.
- Cohort 1: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 50, followed by a standard taper in the absence of grade II-IV acute GVHD.
- Cohort 2: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 30, followed by a rapid taper in the absence of grade II-IV acute GVHD.
Patients are followed actively for at least 1 year post transplant.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||41 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Multi-center Phase II Study of Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD|
|Actual Study Start Date :||December 17, 2009|
|Actual Primary Completion Date :||December 1, 2019|
|Actual Study Completion Date :||May 26, 2020|
Experimental: Arm 1
CONDITIONING: Patients undergo total-body irradiation twice daily on days -10 to -7. Patients also receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine IV over 30 minutes on days -6 to -2. TRANSPLANTATION: Patients undergo infusion of CD34+ enriched allogeneic peripheral blood stem cells (PBSC) followed by CD45RA+ T-cell-depleted allogeneic PBSC on day 0.
GRAFT-VS-HOST DISEASE PROPHYLAXIS: Cohort A: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 50 followed by standard taper in the absence of grade II-IV acute GVHD. Cohort B: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 30 followed by rapid taper in the absence of grade II-IV acute GVHD.
Drug: Fludarabine Phosphate
Fludarabine will be administered in a dose of 25 mg/m2/day IV over approximately 30 minutes for 5 consecutive days (day -6 to -2). The total dose of fludarabine will be 125 mg/m2.
Tacrolimus will be administered beginning on day -1 at a dose of 0.03 mg/kg/day by continuous IV infusion.
For the first cohort of 35 patients, if there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus should then be tapered at the rate of approximately 5% of the day 50 dose each week for liquid, and 20% of the day 50 dose per month for capsules.
In the second cohort of 25 patients if there is no evidence of grade II GVHD on or prior to day 30, tacrolimus should then be tapered at the rate of approximately 8% of the day 30 dose each week for liquid, and 33% of the day 30 dose per month for capsules.
Thiotepa will be administered in a dose of 5 mg/kg/day (adjusted body weight) IV over approximately 4 hours for 2 consecutive days (day -6 and day -5).
Radiation: Total-Body Irradiation (TBI)
TBI will be given as 165 cGy fractions twice per day x 4 days - total dose 1320cGy (days -10 to -7).
Other Name: TBI
Other: Magnetic Affinity Cell Sorting
Other Name: Magnetic-Activated Cell Sorter (CliniMACS, Miltenyi)
Procedure: Peripheral Blood Stem Cell Transplantation
Patient will undergo a PBSC transplantation
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation
Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation
Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation
- Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD [ Time Frame: Within 360 days of transplant ]Number of participants with aGVHD and severity of aGVHD within the first 360 days post-transplant as graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Acute GVHD is graded by standard criteria, and all suspected cases of acute GVHD will be confirmed histologically by biopsy of an affected organ. The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract. Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening.
- Number of Participants Who Did Not Engraft After Receiving a CD45RA+ T Cell Depleted PBSC Transplant [ Time Frame: Up to 5 years post transplant ]Graft failure is defined as either a failure to reach an ANC of >500/uL for 3 consecutive days by day 28 post-transplant, or an irreversible decrease in ANC <100 after an established donor graft, unless there is a reasonable explanation such as a viral infection or drug effect that may be responsible for a reversible decrease in ANC.
- Transplant-related Mortality by Day 100 [ Time Frame: Transplant to day 100 ]Number of participants who died due to transplant-related issues within the first 100 days of transplant
- Number of Participants Who Have Relapsed Within 5 Years of CD45RA+ T Cell Depleted PBSC Transplant [ Time Frame: Up to 5 years post transplant ]Relapse is defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology. Testing for recurrent malignancy in the blood and bone marrow performed by monitoring the CBC and bone marrow at Day 28, 58, 80, 360, and as needed for suspected relapse.
- Number of Participants With Chronic GVHD [ Time Frame: Up to 5 years post transplant ]Chronic GVHD measured by meeting NIH criteria and treated with immune suppression
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00914940
|United States, Connecticut|
|Yale University School of Medicine/Yale New Haven Hospital|
|New Haven, Connecticut, United States, 06520|
|United States, Washington|
|Fred Hutchinson Cancer Research Center|
|Seattle, Washington, United States, 98109-1024|
|Principal Investigator:||Marie Bleakley, MD||Fred Hutchinson Cancer Research Center|
|Principal Investigator:||Warren Shlomchik, MD||Yale University School of Medicine/Yale New Haven Hospital|