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

Fred Hutchinson Cancer Center (FHCC)

Status and phase

Terminated

Phase 2

Conditions

Graft Versus Host Disease

Leukemia

Myelodysplastic Syndromes

Treatments

Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation

Drug: Tacrolimus

Procedure: Peripheral Blood Stem Cell Transplantation

Drug: Thiotepa

Drug: Fludarabine Phosphate

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Other: Magnetic Affinity Cell Sorting

Radiation: Total-Body Irradiation (TBI)

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00914940

2222.00

RG2810004 (Other Identifier)

CDR0000644201 (Registry Identifier)

0903004832 (Other Identifier)

IR-6907 (Other Identifier)

P30CA015704 (U.S. NIH Grant/Contract)

NCI-2010-00713 (Registry Identifier)

P01CA018029 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

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.

Enrollment

41 patients

Sex

All

Ages

14 to 55 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

41 participants in 1 patient group

Arm 1

Experimental group

Description:

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.

Treatment: