Fludarabine Phosphate, Low-Dose Total-Body Irradiation, and Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Older Patients With Chronic Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine if mixed hematopoietic chimerism can be safely established using a
non-myeloablative conditioning regimen in patients > 65 years of age with chronic myeloid
leukemia (CML) in chronic or accelerated phase who have human leukocyte antigen (HLA)
identical related donors.

II. To determine if mixed chimerism, established with non-myeloablative conditioning
regimens, can be converted to full donor hematopoietic chimerism by infusions of donor
lymphocytes (DLI), and thereby produce an immunologic cure of the malignancy.

OUTLINE:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to
-2 and undergo low-dose total-body irradiation (TBI) on day 0.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation
(PBSCT) on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) or IV BID or
thrice daily (TID) on days -3 to 56 with taper to day 77 or 180, and mycophenolate mofetil PO
or IV BID on days 0-27.

DLI: At least 2 weeks after completion of immunosuppression, patients with > 5% donor cluster
of differentiation (CD)3+ T cells and no evidence of graft-versus-host disease (GVHD) receive
donor lymphocytes IV over 30 minutes. Patients may receive up to 3 DLIs at increasing cell
doses in the absence of GVHD.

After completion of study treatment, patients are followed up periodically for 5 years.

Inclusion Criteria:

- Patients with Philadelphia chromosome positive (Ph+) CML in first and second chronic
and first accelerated phases

- Patients =< 65 years old who are at high risk of regimen related toxicity through
pre-existing chronic disease affecting liver, lungs, and/or heart, or others who wish
to be treated on this protocol, will be considered on a case-by-case basis;
transplants should be approved for these inclusion criteria by both the participating
institutions' patient review committees such as the Patient Care Conference (PCC) at
the Fred Hutchinson Cancer Research Center (FHCRC) and by the principal investigators
at the collaborating centers; patients =< 65 years of age who have received previous
high-dose transplantation do not require patient review committee approvals; all
children < 12 years must be discussed with the FHCRC principal investigator (PI)
(Brenda Sandmaier, MD 206-667-4961) prior to registration

- HLA genotypically identical related donor willing to undergo leukapheresis initially
for collection of peripheral blood stem cell (PBSC) and subsequently for collection of
peripheral blood mononuclear cell (PBMC)

- Patients treated with alpha interferon must have discontinued drug at least 1 month
prior to transplant

- DONOR: HLA genotypically identical family member (excluding identical twins)

- DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis

- DONOR: Donor must have adequate veins for leukapheresis or agree to placement of
central venous catheter (femoral, subclavian)

Exclusion Criteria:

- Patients who are human immunodeficiency virus positive (HIV+)

- GROUP 1: (PATIENTS AGED > 65 AND < 75 YEARS)

- Patients unwilling to use contraceptive techniques during and for 12 months following
treatment

- Presence of circulating leukemic blasts (in the peripheral blood) detected by standard
pathology for patients with CML

- Patients in an interferon induced complete or partial cytogenetic remission

- Organ dysfunction:

- Patients with renal failure are eligible, however patients with renal compromise
(Serum creatinine greater than 2.0) will likely have further compromise in renal
function and may require hemodialysis (which may be permanent) due to the need to
maintain adequate serum cyclosporine levels

- Cardiac ejection fraction < 40%; ejection fraction is required if the patient has
a history of anthracyclines or history of cardiac disease

- Diffusing capacity of the lung for carbon monoxide (DLCO) < 50% of predicted

- Liver function tests including total bilirubin, serum glutamic pyruvate
transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) > 2x the
upper limit of normal unless proven to be due to the malignancy

- Karnofsky score < 70

- Patients with poorly controlled hypertension

- GROUP 2 (PATIENTS AGED =< 65)

- Patients who are HIV+

- Presence of circulating leukemic blasts (in the peripheral blood) detected by standard
pathology for patients with CML

- Females who are pregnant

- Patients unwilling to use contraceptive techniques during and for 12 months following
treatment

- Patients in an interferon induced complete or partial cytogenetic remission

- Organ dysfunction:

- Patients with renal failure are eligible, however patients with renal compromise
(Serum creatinine greater than 2.0) will likely have further compromise in renal
function and may require hemodialysis (which may be permanent) due to the need to
maintain adequate serum cyclosporine levels

- Cardiac ejection fraction < 40% or a history of congestive heart failure;
ejection fraction is required if the patient has a history of anthracyclines or
history of cardiac disease

- Severe defects in pulmonary function testing as defined by the pulmonary
consultant (defects are currently categorized as mild, moderate and severe) or
receiving supplementary continuous oxygen; DLCO < 50% of predicted

- Liver function tests: total bilirubin > 2x the upper limit of normal, SGPT and
SGOT 4x the upper limit of normal

- Karnofsky score < 50

- Patients with poorly controlled hypertension

- DONOR: Age less than 12 years

- DONOR: Pregnancy

- DONOR: Infection with HIV

- DONOR: Inability to achieve adequate venous access

- DONOR: Known allergy to G-CSF

- DONOR: Current serious systemic illness