Depletion of CD45RA Positive Naive T Cells for the Prevention of Graft Versus Host Disease in Older Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia or Myelodysplastic Syndrome

OUTLINE:

Patients receive cyclophosphamide intravenously (IV), over 1-2 hours on days -6 and -5, fludarabine IV, over 30 minutes on days -6 to -2 and total body irradiation for 1 treatment on day -1 or 0. Patients receive CD34+ enriched peripheral blood stem cells and CD45RA+ depleted cells IV on day 0. Patients undergo bone marrow aspiration/biopsy, echocardiography, and blood sample collection throughout the study.

After completion of study treatment, patients are followed up at day 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, then weekly until 1 completion of year 1 as well as at day 180 and 270, at 1.5 and 2 years and then periodically until 5 years post day 0.

Inclusion criteria

• PARTICIPANT: Age > 60 years
• PARTICIPANT: Diagnosis of acute leukemia or myelodysplastic syndrome (MDS):

• Acute lymphocytic leukemia (ALL) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
• Acute myeloid leukemia (AML) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
• Other acute leukemia or related neoplasm (including but not limited to 'mixed phenotype' 'biphenotypic', 'acute undifferentiated' or 'ambiguous lineage' acute leukemia, blastic plasmacytoid dendritic cell neoplasm, lymphoblastic lymphoma, Burkitt leukemia/lymphoma, mast cell leukemia, chronic myeloid leukemia [CML] with blast crisis or other chronic myeloproliferative neoplasm) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
• Myelodysplastic syndrome (MDS) with a history of excess blasts (≥ approximately 5% in marrow blasts by morphology) and a history of receiving cytoreductive therapy (including but not limited to BCL-2 inhibitors or cytotoxic chemotherapy) within the past 3 months
• PARTICIPANT: Karnofsky performance status (KPS) ≥ 60% at pre-HCT evaluation
• PARTICIPANT: Ability to provide informed consent
• PARTICIPANT: Prior autologous or allogeneic HCT is permitted
• DONOR: Human leukocyte antigen (HLA) matching: HLA-identical related donors or unrelated donors matched for HLA-A, -B, -C, - DRB1, and -DQB1 by high-resolution deoxyribonucleic acid (DNA) typing. A single allele-level mismatch at HLA class I is permitted
• DONOR: Stem cell source: Donors must be able to undergo peripheral blood stem cell (PBSC) collection. Only G-CSF-mobilized PBSC are permitted as the hematopoietic stem cell (HSC) source on this protocol

Exclusion criteria

• PARTICIPANT: Circulating blasts:

• Acute leukemia: circulating abnormal blasts detectable by standard pathology.
• MDS: > 5% circulating abnormal blasts by standard pathology
• PARTICIPANT: Patients with promyelocytic leukemia (APL)
• PARTICIPANT: Patients with active extramedullary disease are excluded. History of extramedullary disease is allowed if only minimal residual disease is present prior to HCT
• PARTICIPANT: Ejection fraction < 35% (or shortening fraction < 26% if ejection fraction [EF] unavailable)
• PARTICIPANT: Cardiac insufficiency requiring treatment or symptomatic coronary artery disease
• PARTICIPANT: Patients with shortening fraction < 26% may enroll if approved by a cardiologist
• PARTICIPANT: Carbon monoxide diffusing capability (DLCO) < 40%, total lung capacity (TLC) < 40%, forced expiratory volume in 1 second (FEV1) < 40%, and/or requiring continuous supplemental oxygen
• PARTICIPANT: If pulmonary function tests (PFTs) cannot be obtained: any patient with room air oxygen saturation < 89% during a 6-minute walk test (6MWT) will be excluded
• PARTICIPANT: Serum creatinine must be within institutional normal limits
• PARTICIPANT: If serum creatinine > upper limit of normal, a 24-hour creatinine clearance will be performed; patients are excluded if < 50 mL/min/1.73 m^2
• PARTICIPANT: Exclude patients with any of the following:

• Fulminant liver failure.
• Cirrhosis with evidence of portal hypertension.
• Alcoholic hepatitis.
• Esophageal varices or history of variceal bleeding.
• Hepatic encephalopathy.
• Uncorrectable synthetic dysfunction (prolonged prothrombin time).
• Ascites due to portal hypertension.
• Bridging fibrosis.
• Bacterial or fungal liver abscess.
• Biliary obstruction.
• Chronic viral hepatitis with total bilirubin >3 mg/dL.
• Symptomatic biliary disease
• PARTICIPANT: Active infectious disease requiring deferral of conditioning (per Infectious disease consult). Upper respiratory tract infection is not considered to represent an uncontrolled infection in this context
• PARTICIPANT: Fungal infection with radiologic progression despite appropriate antifungal therapy
• PARTICIPANT: Viral infection risk: HIV-1, HIV-2, human T-lymphotropic virus (HTLV) 1 or HTLV2 positivity or active infectious hepatitis
• PARTICIPANT: Patients with active central nervous system (CNS) leukemia at the time of treatment are excluded. A history of CNS leukemia is allowed if CNS disease has resolved prior to treatment initiation
• PARTICIPANT: Weight > 110kg
• PARTICIPANT: Other malignancies:

• Active non-hematologic malignancies (except non-melanoma skin cancers).
• Non-hematologic malignancy in remission but with > 20% risk of recurrence within 5 years.
• Exclusion does not apply to indolent non-hematologic malignancies not requiring therapy
• PARTICIPANT: Patients with a life expectancy < 12 months from co-existing disease other than the leukemia or MDS
• PARTICIPANT: Hypersensitivity to cyclophosphamide, fludarabine, tacrolimus or mycophenolate mofetil (MMF)
• PARTICIPANT: Inability to provide informed consent
• PARTICIPANT: Alternative treatment: Patients who are suitable for and willing to receive a standard high intensity (myeloablative) preparative regimen
• DONOR: Stem cell source restriction: Donors (or centers) that can exclusively provide bone marrow harvests
• DONOR: Medical contraindications: HIV-1, HIV-2, HTLV-1, HTLV-2 seropositive or with active hepatitis B or hepatitis C virus infection
• DONOR: Preexisting immunoreactivity:

• Determined per institutional standard practices.
• For patients with a 10/10 HLA allele-level match, panel reactive antibody (PRA) screens to class I and class II antigens are recommended before HCT. If PRA >10%, then flow cytometric or B- and T-cell cytotoxic crossmatches must be obtained. The donor is excluded if any crossmatch is positive.
• For patients with a Class I allele mismatch, flow cytometric or B- and T-cell cytotoxic crossmatches must be performed regardless of PRA results. A positive anti-donor cytotoxic crossmatch is an absolute exclusion.
• Vector homozygosity: Donors are excluded if the patient is homozygous in the graft rejection vector against the donor's mismatched HLA class I allele
• DONOR: Donors donating outside of the United States of America (USA)