Donor Stem Cell Transplant in Treating Patients With Myeloid Cancer or Other Disease

OBJECTIVES:

Primary

- Determine the incidence of disease-free survival at 1 year in patients with acute or
chronic myeloid leukemias undergoing T-cell-depleted hematopoietic stem cell
transplantation from HLA-C mismatched, unrelated donors.

Secondary

- Determine the incidence of disease relapse at 1 year in patients treated with this
regimen.

- Determine the incidence and severity of acute graft-vs-host disease (GVHD) at 100 days
and chronic GVHD at 1 year in these patients.

- Determine the incidence of graft failure at day 100.

- Determine the transplant-related mortality of these patients at 1 year.

- Determine the overall survival of these patients at 1 year.

OUTLINE: This is a prospective, multicenter study. Patients are stratified according to
killer-cell immunoglobulin-like receptors (KIR) epitope mismatch (yes [experimental] vs no
[control]).

- Myeloablative preparative regimen: Patients undergo total body irradiation twice daily
on days -10 and -9 and receive thiotepa intravenously (IV) over 4 hours on days -8 and
-7, fludarabine phosphate IV over 30-60 minutes on days -7 to -3, and antithymocyte
globulin IV over 4-6 hours on days -5 to -2.

- Allogeneic peripheral blood stem cell (PBSC) transplantation: Patients undergo
filgrastim (G-CSF)-mobilized, T-cell-depleted, CD34+-selected allogeneic PBSC
transplantation on day 0.

After completion of study treatment, patients are followed periodically for at least 1 year.

Inclusion Criteria:

- Primary acute myeloid leukemia (AML)

- First complete remission (CR) with high risk features as defined by: failure to
achieve remission by day 21 after induction chemotherapy, or the presence of
chromosomal abnormalities involving any of the following: -5/de (5q), -7/del(7q),
inversion 3q, abnormalities of 11q23, 20q, 21q, del(9q), translocation 6;9,
translocation 9;22, abnormalities of 17p, or complex karyotype with > or = 3
abnormalities. Complete remission is defined as < 5% blasts in the marrow.

- Second CR or subsequent in remission

- Refractory or relapsed disease with absolute peripheral blood blasts < 2000/mcL

- Secondary AML in remission or relapse

- Chronic myelogenous leukemia (CML) in accelerated or blast phase

- Accelerated phase is defined by any one of the following:

- Blasts 10% to 19% of peripheral blood white cells or bone marrow cells

- Peripheral blood basophils at least 20%

- Persistent thrombocytopenia (<100 x 10^9/L) unrelated to therapy, or
persistent thrombocytosis (>1000 x 10^9/L) unresponsive to therapy

- Increasing spleen size and increasing white blood cell (WBC) count
unresponsive to therapy

- Cytogenetic evidence of clonal evolution (i.e., the appearance of an
additional genetic abnormality that was not present in the initial specimen
at the time of diagnosis of chronic phase CML)

- Resistance to tyrosine kinase inhibitors (imatinib or other) defined as no
complete cytogenetic response even if the above criteria are not met.

- Blast phase is defined by either of the following:

- Blasts 20% or more of peripheral blood white cells or bone marrow cells

- Extramedullary blast proliferation

- Large foci or clusters of blasts in bone marrow biopsy

- Primary myelodysplastic syndrome (MDS) with an IPSS score >1

- Secondary MDS with any international prostate symptom score (IPSS)

- Age ≤60 years

- Co-Morbidity score 0-2

- At least 35 days following start of preceding leukemia induction therapy

Exclusion Criteria:

- Patients for whom a suitable HLA genotypically identical sibling or fully matched
HLA-A, -B, -C, and -DRB1 unrelated donor is available.

- Patients greater than 60 years of age.

- Hypersensitivity to thymoglobulin.

- Symptomatic uncontrolled coronary artery disease or congestive heart failure.

- Hepatic disease with transaminases or bilirubin > 2 times upper limit of normal (ULN)
except for isolated hyperbilirubinemia attributed to Gilbert's syndrome.

- Severe hypoxemia with room air - Partial Pressure of Oxygen in Arterial Blood - (PAO2)
< 70, supplemental oxygen-dependence, or carbon monoxide diffusing capacity (DLCO) <
50% predicted.

- Impaired renal function with creatinine > 2 times upper limit of normal (ULN) or
creatinine clearance measured by 24-hour urine collection < 50% normal for age,
gender, and weight.

- Patients with central nervous system (CNS) involvement with disease refractory to
intrathecal chemotherapy.

- Patients who are human immunodeficiency virus (HIV) seropositive.

- Patients who are pregnant or breast-feeding.

- Patients with active infections that are untreated, or failing to respond to
appropriate therapy.

- Karnofsky performance status < 50%.

- Prior allogeneic or autologous bone marrow, peripheral blood stem cell, or umbilical
cord blood transplant.

- Inability to provide informed consent.

- Co-morbidity score >2

- Less than 35 days from start of previous leukemia induction therapy