Donor Stem Cell Transplant in Treating Patients With Relapsed Hematologic Malignancies or Secondary Myelodysplasia Previously Treated With High-Dose Chemotherapy and Autologous Stem Cell Transplant

OBJECTIVES:

Primary

- To demonstrate the efficacy of performing reduced-intensity conditioning allogeneic
hematopoietic cell transplantation in patients with relapsed hematologic malignancies
or secondary myelodysplasia after completion of prior high-dose chemotherapy and
autologous hematopoietic stem cell transplantation.

- To compare the strategy of this regimen with the strategy used in CALGB-100002.

Secondary

- To describe the response rate at 6 and 12 months in patients treated with this regimen.

- To describe the time-to-progression in patients treated with this regimen.

- To determine the ability to use pharmacokinetic-directed busulfan to achieve AUC within
20% of target AUC in > 80% of patients.

- To determine percent of donor chimerism in T-cell, myeloid and B-cell populations
achieved with this regimen compared with CALGB-100002.

- To determine the risk of acute and chronic graft-versus-host disease and other
toxicities of this regimen in these patients.

- To describe the overall survival and disease-free survival of patients treated on this
regimen.

- To determine the rate of viral, bacterial, and fungal opportunistic infections
occurring in the first year after transplantation compared with CALGB-100002.

OUTLINE: This is a multicenter study.

- Preparative Regimen:

- Busulfan test dose: Patients receive busulfan IV over 45 minutes once during days
-14 and -9.

- Busulfan treatment dose: Patients receive fludarabine phosphate IV over 30 minutes
on days -7 to -3 and busulfan IV over 3 hours on days -6 to -3.

- Graft-vs-Host Disease (GVHD) Prophylaxis:

- HLA-identical donor: Patients receive antithymocyte globulin IV over 6-10 hours on
days -6 to -5; oral tacrolimus twice daily on days -2 to 90 followed by a taper*
as tolerated until day 150 or 180; and methotrexate IV on days 1, 3, and 6.

NOTE: * Tacrolimus may be tapered on days 60-90 if donor chimerism of CD3+ cells is < 50% at
day 60 or patient has progressive disease.

- Matched-unrelated donor: Patients receive antithymocyte globulin, tacrolimus, and
methotrexate as in HLA-identical donor regimen. Patients also receive oral
mycophenolate mofetil twice daily on days 0 to 60.

- Allogeneic Stem Cell Transplantation: Patients undergo allogeneic peripheral blood
stem cell transplantation on days 0 and 1. Patients then receive filgrastim
subcutaneously daily beginning on day 7 and continuing until blood counts recover.

- Donor Lymphocyte Infusion (DLI): After day 180 (or day 210 for patients without an
HLA-identical donor), patients with stable or progressive disease and no active
GVHD may receive up to 3 DLIs every 8 weeks.

Blood samples are collected at baseline and then periodically during study therapy for
pharmacokinetic studies.

After completion of study therapy, patients are followed up every 3 months for 2 years and
then every 6 months for up to 5½ years.

DISEASE CHARACTERISTICS:

- Histologically confirmed hematologic malignancies:

- Chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL)

- Absolute lymphocytosis of > 5,000/μL

- Lymphocytes must appear morphologically mature with < 55% prolymphocytes
(CLL)

- Patients with > 55% prolymphocytes are considered as having PLL

- Lymphocyte phenotype with expression of CD20, CD19, and CD5 (CLL)

- Non-Hodgkin lymphoma

- Any WHO classification of histologic subtype

- Core biopsies acceptable for primary diagnosis and immunophenotyping

- Bone marrow biopsies as sole means of diagnosis not allowed for follicular
lymphoma

- Hodgkin lymphoma

- Any WHO classification of histologic subtype

- Core biopsies acceptable for primary diagnosis and immunophenotyping

- Bone marrow biopsy is required

- Multiple myeloma

- Patients must have active disease requiring treatment (Durie-Salmon stage
I-III)

- Acute myeloid leukemia

- Must have < 10% bone marrow blasts and no circulating blasts

- Myelodysplastic syndrome (MDS)

- MDS as define by WHO criteria

- Must have < 10% marrow blasts

- Relapsed or progressive disease or myelodysplasia ≥ 6 months after prior high-dose
chemotherapy with autologous hematopoietic cell support

- Prior syngeneic transplantation allowed

- Healthy donor meeting one of the following criteria:

- HLA-identical sibling (6/6)

- Serologic typing for class I (A, B) and molecular typing for class II
(DRB1) required

- 8/8 matched-unrelated donor

- Molecular identity at HLA A, B, C, and DRB1 by high-resolution typing
required

- No syngeneic donors

PATIENT CHARACTERISTICS:

- Creatinine clearance ≥ 40 mL/min

- Total bilirubin ≤ 2 mg/dL

- AST ≤ 3 times upper limit of normal

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- DLCO ≥ 40% with no symptomatic pulmonary disease

- LVEF ≥ 30% by MUGA or ECHO

- No uncontrolled diabetes mellitus or active serious infection

- No known hypersensitivity to E.coli-derived products

- No HIV infection

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- At least 4 weeks should elapse between prior standard cytotoxic chemotherapy,
radiation therapy, or surgery and the planned start of the preparative regimen on day
-7