This phase II trial is for patients with acute lymphocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome or chronic myeloid leukemia who have been referred for a peripheral blood stem cell transplantation to treat their cancer. In these transplants, chemotherapy and total-body radiotherapy ('conditioning') are used to kill residual leukemia cells and the patient's normal blood cells, especially immune cells that could reject the donor cells. Following the chemo/radiotherapy, blood stem cells from the donor are infused. These stem cells will grow and eventually replace the patient's original blood system, including red cells that carry oxygen to our tissues, platelets that stop bleeding from damaged vessels, and multiple types of immune-system white blood cells that fight infections. Mature donor immune cells, especially a type of immune cell called T lymphocytes (or T cells) are transferred along with these blood-forming stem cells. T cells are a major part of the curative power of transplantation because they can attack leukemia cells that have survived the chemo/radiation therapy and also help to fight infections after transplantation. However, donor T cells can also attack a patient's healthy tissues in an often-dangerous condition known as Graft-Versus-Host-Disease (GVHD). Drugs that suppress immune cells are used to decrease the severity of GVHD; however, they are incompletely effective and prolonged immunosuppression used to prevent and treat GVHD significantly increases the risk of serious infections. Removing all donor T cells from the transplant graft can prevent GVHD, but doing so also profoundly delays infection-fighting immune reconstitution and eliminates the possibility that donor immune cells will kill residual leukemia cells. Work in animal models found that depleting a type of T cell, called naïve T cells or T cells that have never responded to an infection, can diminish GVHD while at least in part preserving some of the benefits of donor T cells including resistance to infection and the ability to kill leukemia cells. This clinical trial studies how well the selective removal of naïve T cells works in preventing GVHD after peripheral blood stem cell transplants. This study will include patients conditioned with high or medium intensity chemo/radiotherapy who can receive donor grafts from related or unrelated donors.
OUTLINE: Patients are assigned to 1 of 4 treatment arms. CONDITIONING: ARMS A AND C (high-intensity myeloablative conditioning): Patients undergo total body irradiation twice daily (BID) on days -10 to -7. Patients also receive thiotepa intravenously (IV) over 4 hours on days -6 and -5 and fludarabine phosphate IV over 30 minutes on days -6 to -2. ARMS B AND D (lower-intensity myeloablative conditioning): Patients receive cyclophosphamide IV over 1 hour on day -6, fludarabine phosphate IV over 30 minutes on days -6 to -2, and thiotepa IV over 4 hours on days -5 and -4. Patients also undergo total body irradiation once daily (QD) on days -2 and -1. TRANSPLANT: In all arms, patients undergo allogeneic HSCT with granulocyte colony-stimulating factor (GCSF)-mobilized CD34-enriched PBSC and CD45RA-depleted cells on day 0. GVHD PROPHYLAXIS: ARMS A AND C: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or orally (PO) (BID if given PO) for 50 days with taper in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11. ARMS B AND D: Beginning day -1, patients receive tacrolimus IV over 22-24 hours or PO (BID if given PO) for 50 days and mycophenolate mofetil IV and PO every 8 hours on days -3 to approximately day 30, with or without taper at the discretion of the treating physician. Mycophenolate mofetil should be continued or resumed after day 30 if donor chimerism is low, after discussion with the principal investigator. After completion of study treatment, patients are followed up at 80-100 days, 360 days, and then yearly for up to 5 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
84
Undergo allogeneic HSCT
Given IV
Given IV
Correlative studies
Given IV
Given IV and PO
Undergo PBSCT with GCSF-mobilized CD34-enriched PBSC
Undergo PBSCT with CD45RA-depleted cells
Given IV or PO
Given IV
Undergo TBI
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Occurrence of chronic graft-versus-host disease (GHVD), defined operationally as the occurrence of compatible symptoms meeting National Institutes of Health criteria and requiring systemic pharmacological immunosuppression
Match related donor (MRD)-high intensity (Arm A), MRD-lower intensity (Arm B), match unrelated donor (MUD)-high intensity (Arm C) and MUD-lower intensity (Arm D) cohorts will be analyzed separately.
Time frame: Up to 5 years
Use of additional immune suppressive agents other than first line therapy (prednisone and tacrolimus/cyclosporine)
Time frame: Up to 5 years
Time to completion of prednisone
Time frame: Up to 5 years
Time to completion of all immunosuppression
Time frame: Up to 5 years
Requirement of immunosuppression after transplant
Time frame: At 2 years after transplant
Presence of acute graft-versus-host disease (GVHD) grades II-IV
Defined operationally as the occurrence of compatible symptoms or signs in the skin, gastrointestinal tract, or liver.
Time frame: Up to day 100
Requirement for secondary systemic therapy for acute graft-versus-host disease (GVHD) management
Time frame: Up to day 100
Graft failure
Defined operationally as failure to reach an absolute neutrophil count (ANC) of \> 500/ul for 3 consecutive days by day 28 or irreversible decrease in ANC to \< 100 after an established donor graft.
Time frame: Up to day 28
Time to absolute neutrophil count (ANC) of > 500/uL on the first of three consecutive days
Time frame: Up to 5 years
Time to absolute neutrophil count (ANC) of > 1,000/uL on the first of three consecutive test results
Time frame: Up to 5 years
Time to platelet count > 20,000/uL for 3 days without transfusion
Time frame: Up to 5 years
Time to platelet count > 50,000/uL for 3 days without transfusion
Time frame: Up to 5 years
Chimerism analysis
Will be analyzed from peripheral blood or marrow.
Time frame: Up to 360 days
Relapse
Defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology.
Time frame: Up to 5 years
Transplant related mortality
Defined as mortality in any patient for whom there has not been a diagnosis of relapse.
Time frame: Up to 5 years
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