Donor CD8+ Memory T-Cells for the Treatment of Myelodysplastic Syndrome, Acute Leukemia, or Chronic Myelogenous Leukemia

Status: closed to accrual

This phase II trial studies the effect of donor CD8+ memory T-cells in treating patients with myelodysplastic syndrome, acute leukemia, or chronic myelogenous leukemia. Transplants may cure cancer through two ways. 1) The chemotherapy and radiation therapy received as part of a transplant is a high dose and may eliminate cancer cells, and 2) The donor cells themselves once growing in the body after transplant may eliminate cancer cells: the process by which the donor cells eliminate cancer cells is called “graft versus leukemia/myelodysplastic syndrome” (GVL). Once the donor immune cells are growing in the body, they too may recognize the body as foreign and “attack” the normal body tissue in a process called graft-versus-host-disease (GvHD). One standard method to eliminate GvHD is to select only the donor ‘stem cells’ (called ‘CD34+ stem cells’) in the graft and remove all donor immune cells. This strategy effectively eliminates the risks of GvHD and reduces the complications of a transplant. Yet removing all the donor immune cells from the donor graft may be associated with increased infections and a higher risk of the cancer returning after the transplant because of limited GVL. Many transplant centers use a CD34+ stem cell graft (depleted of immune cells) to reduce GvHD and rely on the intensity of the transplant chemotherapy and radiation therapy to eradicate all the cancer cells. This study will investigate if adding back a part of the donor immune cells, called CD8+ memory T-cells, to the CD34+ stem cell graft will allow for beneficial GVL effects yet without the harmful GvHD effects.

Inclusion Criteria

RECIPIENT INCLUSION CRITERIA
Acute leukemia, in morphologic complete remission; OR myelodysplasia with < 10% blasts in the marrow, and no circulating blasts that contain Auer rods; OR chronic myelogenous leukemia (CML) with any one of the following high-risk features: * Chronic phase CML yet with additional karyotypic features at diagnosis that are beyond the reciprocal translocation (9;22)(q34;q11) known as Philadelphia (Ph) chromosome * Resistant CML, defined as: ** A failure of therapy to achieve a complete cytogenetic response within 12 months of diagnosis ** A failure of therapy to maintain a > 3 log-fold reduction in molecular response once beyond 12 months of treatment ** Any new leukemia associated chromosomal/sequence abnormality detected by conventional cytogenetics; fluorescence in situ hybridization (FISH); molecular or next generation sequencing ** Enlarging spleen size despite ongoing treatment * Accelerated phase CML, defined as: ** 10% to 19% blasts in the blood and/or bone marrow ** > 20% basophils in the peripheral blood ** Any new leukemia-associated chromosomal/sequence abnormality detected by conventional cytogenetics; FISH; molecular or next generation sequencing * Blast crises CML, defined as: ** > 20% marrow or blood blasts
Subjects with chronic myelomonocytic leukemia (CMML) must have a white blood cell (WBC) count =< 10,000 cells/uL and < 10% blasts in the marrow (within 70 days of beginning conditioning therapy)
Planned myeloablative conditioning regimen at Stanford University Medical Center
Karnofsky or Lansky performance score >= 70%
Must have an HLA matched donor as follows: donor must be an 8/8 match for HLA-A, -B and -C at intermediate (or higher) resolution, and -DRB1 at high resolution using deoxyribonucleic acid (DNA)-based typing. The donors must be willing to receive granulocyte colony-stimulating factor (G-CSF) followed by collection of cells by apheresis, and must meet the program’s criteria for donation
Ejection fraction at rest >= 40% (within 70 days of beginning conditioning therapy)
Serum creatinine value of < 1.5 mg/dL, or an estimated creatinine clearance greater than 50 mL/minute (using the Stanford calculator for estimated glomerular filtration rate [eGFR] available in EPIC) (within 70 days of beginning conditioning therapy)
Diffusing capacity of the lungs for carbon monoxide (DLCO) >= 50% (adjusted for hemoglobin [Hgb]) (within 70 days of beginning conditioning therapy)
Forced vital capacity (FVC) >= 50% (within 70 days of beginning conditioning therapy)
Forced expiratory volume (FEV1) >= 50% (within 70 days of beginning conditioning therapy)
Total bilirubin < 2 times the upper limit of normal (ULN) (unless the elevated bilirubin is attributed to Gilbert’s syndrome) (within 70 days of beginning conditioning therapy)
Alanine aminotransferase (ALT) < 2.5 x ULN (within 70 days of beginning conditioning therapy)
Aspartate aminotransferase (AST) < 2.5 x ULN (within 70 days of beginning conditioning therapy)
Signed informed consent
DONOR INCLUSION CRITERIA
HLA-matched donor (matching at 8/8 antigens or alleles including HLA-A, -B, -C, and -DRB1)
State of general good health
Completed a donor evaluation with history, medical examination and standard blood tests within 60 days of starting the hematopoietic cell collection procedure. In order to fairly represent the interests of the donor, the donor evaluation and consent will be performed by a study team member other than the recipient’s attending physician
Hepatitis A, B and C, human immunodeficiency virus (HIV) 1 and 2, human T-cell leukemia virus (HTLV), varicella zoster virus (VZV), EBV, herpes simplex virus (HSV), West Nile virus, syphilis treponema, T cruzi (Chagas), CMV, and the MPX nucleic acid testing (NAT) individual donor testing (IDT) (HIV/HCV/HBV) will be tested as per national standard of care guidelines for transplant donors. Donors who are HIV positive will be excluded. Donors who are positive by serology for hepatitis B or C are eligible as long as polymerase chain reaction (PCR) for ribonucleic acid (RNA)/DNA is negative
White blood cell count > 3.5 x 10^9/L
Platelets > 150 x 10^9/L
Hematocrit > 35%
Capable of undergoing leukapheresis
Able to understand and sign informed consent

Exclusion Criteria

RECIPIENT EXCLUSION CRITERIA
Prior autologous or allogeneic hematopoietic stem cell transplant
Prior malignancies, except resected non-melanoma or treated cervical carcinoma in situ. Cancer treated with curative intent >= 5 years previously is allowed. Cancer treated with curative intent < 5 years previously will not be allowed unless approved by the protocol officer or one of the protocol chairs
Active central nervous system (CNS) involvement by malignant cells
Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
Requirement for supplemental oxygen
Uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment
History of uncontrolled autoimmune disease or on active treatment (defined as > 5 mg prednisone daily)
Seropositive for HIV-1 or -2
Seropositive for HTLV-I or -II
Active hepatitis B or C viral replication by PCR
Documented allergy to iron dextran or murine proteins
Pregnant (positive serum or urine beta human chorionic gonadotropin [BHCG]) or breastfeeding
Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use an effective form of birth control or abstinence for one year after transplantation
Unable to comply with the treatment protocol, including appropriate supportive care, follow-up and research tests
Planned to receive post-transplant maintenance therapy except for FLT3 inhibitors or BCR-ABL tyrosine kinase inhibitors (TKIs)
DONOR EXCLUSION CRITERIA
Psychological traits or psychological or medical conditions which make them unlikely to tolerate the procedure
Pregnant or lactating female

PRIMARY OBJECTIVE:

I. To determine the rate of graft-versus-host-disease (GvHD)-free, relapse-free survival (GRFS) at one year following CD34-selected allogeneic hematopoietic cell transplantation using myeloablative conditioning combined with an infusion of phenotypic CD8+ memory T-cells from human leukocyte antigen (HLA)-matched donors for subjects with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or chronic myelogenous leukemia (CML).

SECONDARY OBJECTIVE:

I. To determine the rate of graft rejection, acute and chronic GvHD, non relapse mortality, relapse, overall survival, and disease-free survival.

EXPLORATORY OBJECTIVE:

I. To determine in some donor recipient pairs the expansion and migration of Epstein-Barr virus (EBV) and cytomegalovirus (CMV)-reactive CD8+ memory T-cells and correlation with EBV and CMV reactivation.

OUTLINE:

Patients undergo total body irradiation (TBI) or non-TBI conditioning per standard of care.

TBI CONDITIONING: Patients undergo hyperfractionated TBI on days -10 to -7 and receive thiotepa intravenously (IV) over 4 hours on days -6 and -5 and fludarabine IV over 30 minutes once daily (QD) on days -6 to -2.

NON-TBI CONDITIONING: Patients receive busulfan IV over 2 hours once every 6 hours (Q6H) on days -9 to -7, melphalan IV over 30 minutes QD on days -6 to -5, and fludarabine IV over 30 minutes QD on days -6 to -2.

After completion of myeloablative conditioning, patients undergo stem cell transplant and receive CD8+ memory T-cells IV on day 0.

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Donor CD8+ Memory T-Cells for the Treatment of Myelodysplastic Syndrome, Acute Leukemia, or Chronic Myelogenous Leukemia

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