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

Phase 2TerminatedNCT00914940

Fred Hutchinson Cancer Center41 enrolled

Overview

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.

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.

Interventions

Fludarabine PhosphateDRUG

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.

TacrolimusDRUG

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.

ThiotepaDRUG

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).

Total-Body Irradiation (TBI)RADIATION

TBI will be given as 165 cGy fractions twice per day x 4 days - total dose 1320cGy (days -10 to -7).

Magnetic Affinity Cell SortingOTHER

Device

Peripheral Blood Stem Cell TransplantationPROCEDURE

Patient will undergo a PBSC transplantation

Allogeneic Hematopoietic Stem Cell TransplantationPROCEDURE

Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation

T Cell-Depleted Hematopoietic Stem Cell TransplantationBIOLOGICAL

Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation

Eligibility

Sex: ALLMin age: 14 YearsMax age: 55 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: Up to 5 years post transplant

Secondary Outcomes

Transplant-related Mortality by Day 100

Number of participants who died due to transplant-related issues within the first 100 days of transplant

Time frame: 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.

Time frame: Up to 5 years post transplant

Number of Participants With Chronic GVHD

Chronic GVHD measured by meeting NIH criteria and treated with immune suppression

Time frame: Up to 5 years post transplant

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

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes