Flu,Alemtuzumab,and TBI Followed By Donor Stem Cell Chronic Phase CML

OBJECTIVES:

- Determine the treatment-related mortality in patients with imatinib mesylate-resistant
chronic phase chronic myelogenous leukemia treated with nonmyeloablative conditioning
comprising fludarabine, alemtuzumab, and total-body irradiation followed by
T-cell-depleted allogeneic stem cell transplantation and post-transplantation allogeneic
T-cell infusion.

- Determine if donor engraftment can be safely established using partial T-cell depletion
with additional T-cell infusions in these patients.

OUTLINE: Patients receive alemtuzumab IV over 5-6 hours on day -8 and fludarabine IV on days
-4 to -2. Patients undergo total-body irradiation followed by T-cell-depleted (CD34+
selected) allogeneic stem cell transplantation on day 0. Patients receive allogeneic T-cell
infusion on days 30 and 60. Patients also receive cyclosporine twice daily beginning on day
-3 and continuing until day 100 followed by a taper until day 177.

PROJECTED ACCRUAL: Not specified.

Inclusion criteria:

- Patients aged 4-75 with chronic myelogenous leukemia (CML) treatable by allogeneic
hematopoietic stem cell transplant.

- Patients with cytogenetically confirmed chronic phase CML.

o Hematologic parameters for chronic phase are: i) Percentage of blasts in peripheral
blood or marrow < 15% ii) Percentage of blasts + promyelocytes in the peripheral blood
or bone marrow < 30% iii) Percentage of basophils in blood or marrow <20% iv) Platelet
count > 100 x 109/l

- Patients must have demonstrated refractoriness/resistance to STI571 defined as
follows:

i) Hematologically resistant- failure to achieve a complete hematologic remission
(CHR) despite 3 months of STI571 therapy.

ii) Hematologically refractory - a rising WBC count > 20 x 109/l confirmed by two samples
taken two weeks apart in a patient with a previous CHR despite concurrent treatment with
STI571 iii) Cytogenetically resistant - bone marrow cytogenetics showing > 65% Philadelphia
chromosome positivity (Ph+) after 6 months of STI571 based therapy.

iv) Cytogenetically refractory - An increase in the number of Philadelphia chromosome
positive (Ph+) bone marrow cells by at least 30%, or an increase to > 65%, confirmed by
samples at least 1 month apart following a previous STI571 induced cytogenetic response,
while continuing STI571 therapy.

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

- Patients with a human leukocyte antigen (HLA) matched sibling donor at the HLA-A, B,
and DR loci.

- Patients with an unrelated hematopoietic stem cell donor must be matched using high
resolution typing for class II human leukocyte antigen (HLA-DR beta-1, 3, 4, 5 and DQ
beta-1) and matched with intermediate to high resolution molecular typing at class I
human leukocyte antigen (HLA-A, B, and C) loci.

- Patients with accelerated or blast crisis of CML who have returned to chronic phase as
described above are eligible.

- Written informed, voluntary consent.

Exclusion criteria:

- Patients who have received another investigational drug within 30 days.

- Fertile men unwilling to use contraceptive techniques during and for 24 months
following treatment.

- Females who are pregnant or fertile women unwilling to use contraceptive techniques
for two months prior to entering the study and for 24 months following treatment.

- Patients with active bacterial or fungal infections unresponsive to medical therapy.

- Patients with organ dysfunction including cardiac ejection fraction of less than 35%
or pulmonary status with a diffusing capacity of the lung for carbon monoxide(DLCO) of
less than 40% and/or receiving supplemental oxygen.

- Liver Function Abnormalities: patients will be excluded if they are found to have
fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension,
alcoholic hepatitis, varices, history of bleeding varices, hepatic encephalopathy or
chronic viral hepatitis where the total serum bilirubin is greater than 3 mg per
deciliter with symptomatic biliary disease.

- Patients with a history of non-compliance to medical regimens or who are considered
potentially unreliable.

- Patients with a history of any prior bone marrow or peripheral blood stem cell
transplantation.

- Patients with any other serious, uncontrolled, concomitant medical condition

- HIV positive patients

Eligibility criteria for donors:

Inclusion Criteria for Donors:

- Sibling donors are permitted if matched at class I human leukocyte antigen (HLA-A, B),
and class II human leukocyte antigen (DR) loci.

- Unrelated donors must be matched for class II human leukocyte antigen(HLA-DR
beta-1,2,3,4,5) and class II human leukocyte antigen (DQ beta-1) with high resolution
typing and with intermediate resolution molecular typing at class I human leukocyte
antigen(HLA-A, B, and C) loci.

- Donors must be eligible to serve as a peripheral stem cell allograft donor. Bone
marrow donors will not be permitted on this protocol.

- Donors must be >18 and < 75 years of age.

Exclusions Criteria for Donors:

- Volunteer donors who wish to serve as bone marrow donors only and refuse exogenous
cytokines.

- Donors who are Human immunodeficiency virus (HIV+), Human T-lymphotropic virus
(HTLV-1+), or hepatitis Bs Ag+..

- Donors with medical conditions that would result in increased risk for Granulocyte
colony-stimulating factor (G-CSF) mobilization and harvest of peripheral blood stem
cells (PBSC) including renal insufficiency with Cr > 2.0, idiopathic splenomegaly,
underlying coagulopathy, uncontrolled coronary artery disease, and major surgery
within 28 days.