Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD

Study Overview
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Brief Summary
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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.

Detailed Description
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OBJECTIVES: Primary 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. Secondary 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.

Official Title
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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

Conditions
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Graft Versus Host Disease, Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of 1 of the following: Acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) in first or subsequent remission ALL or AML in relapse or primary refractory ALL or AML with a circulating blast count ≤ 10,000/mm^3 Refractory anemia with excess blasts (RAEB) (RAEB-1 or RAEB-2) if the patient has received induction chemotherapy within the past 60 days Appropriate candidate for allogeneic hematopoietic stem cell transplantation (HSCT) No CNS involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiotherapy PATIENT CHARACTERISTICS: Age 14-55 Creatinine < 1.5 mg/dL Cardiac ejection fraction > 45% DLCO corrected > 60% of predicted Total bilirubin < 2 times upper limit of normal (ULN) (unless attributed to Gilbert syndrome) AST and ALT < 2 times ULN Not pregnant or nursing Fertile patients must use effective contraception during and for 12 months after transplantation HIV negative No co-existing disease (other than leukemia or RAEB) that would limit life expectancy to < 3 months No uncontrolled infection that, in the opinion of the consulting infectious disease physician, would contraindicate myeloablative HSCT No other medical condition that would contraindicate HSCT No known hypersensitivity to tacrolimus PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior HSCT No concurrent participation in other experimental studies for the prevention of graft-vs-host disease DONOR CHARACTERISTICS: Genotypic or phenotypic HLA-identical related donor Able to donate peripheral blood stem cells Age > 14 years Applicable to male patients only: No female donors who have previously given birth to a male child or have had a pregnancy beyond the first trimester miscarriage or termination of pregnancy or nursing No donors who have received blood transfusions No CD45 Mutation with aberrant CD45RA isoform expression

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>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<br>* 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.<br>* Other names: Fludara;Drug: Tacrolimus<br>* 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.<br>* Other names: Protopic;Drug: Thiotepa<br>* 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).<br>* Other names: TSPA;Radiation: Total-Body Irradiation (TBI)<br>* TBI will be given as 165 cGy fractions twice per day x 4 days - total dose 1320cGy (days -10 to -7).<br>* Other names: TBI;Other: Magnetic Affinity Cell Sorting<br>* Device<br>* Other names: Magnetic-Activated Cell Sorter (CliniMACS, Miltenyi);Procedure: Peripheral Blood Stem Cell Transplantation<br>* Patient will undergo a PBSC transplantation<br>* Other names: Peripheral Blood Stem Cell;Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation<br>Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation<br>* Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD | 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. | Within 360 days of transplant | 
| Number of Participants Who Did Not Engraft After Receiving a CD45RA+ T Cell Depleted PBSC 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. | Up to 5 years post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transplant-related Mortality by Day 100 | Number of participants who died due to transplant-related issues within the first 100 days of transplant | Transplant to day 100 | 
| Number of Participants Who Have Relapsed Within 5 Years of CD45RA+ T Cell Depleted PBSC 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. | Up to 5 years post transplant | 
| Number of Participants With Chronic GVHD | Chronic GVHD measured by meeting NIH criteria and treated with immune suppression | Up to 5 years post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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graft versus host disease, adult acute lymphoblastic leukemia in remission, recurrent adult acute lymphoblastic leukemia, childhood acute lymphoblastic leukemia in remission, recurrent childhood acute lymphoblastic leukemia, adult acute myeloid leukemia in remission, recurrent adult acute myeloid leukemia, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), childhood acute myeloid leukemia in remission, recurrent childhood acute myeloid leukemia, childhood myelodysplastic syndromes, previously treated myelodysplastic syndromes, refractory anemia with excess blasts, de novo myelodysplastic syndromes, secondary myelodysplastic syndromes