Mycophenolate Mofetil and Cyclosporine in Reducing Graft-Versus-Host Disease in Patients With Hematologic Malignancies or Metastatic Kidney Cancer Undergoing Donor Stem Cell Transplant

PRIMARY OBJECTIVES:

I. To determine whether the incidence of life-threatening GVHD can be reduced after unrelated
donor peripheral blood mononuclear cell (PBMC) hematopoietic cell transplantation (HCT) using
nonmyeloablative conditioning with earlier discontinuation of cyclosporine (CSP) and extended
administration of mycophenolate mofetil (MMF) in patients with hematologic malignancies and
metastatic renal cell carcinoma.

SECONDARY OBJECTIVES:

I. To compare the incidence of acute and chronic GVHD to protocols 1463 and 1641.

II. To compare the utilization of corticosteroids to protocols 1463 and 1641.

III. To compare survival to that achieved under protocol 1463 and 1641.

OUTLINE:

CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on
days -4 to -2, and undergo total-body irradiation (TBI) on day 0.

TRANSPLANTATION: Patients undergo allogeneic PBMC transplant on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to
80 with taper to day 150 and mycophenolate mofetil PO or IV thrice daily (TID) on days 0-30,
BID on days 31-150, and then taper to day 180. Treatment continues in the absence of
unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 24 months and
then yearly for 5 years.

Inclusion Criteria:

- Ages > 50 years with hematologic malignancies treatable by unrelated HCT

- Ages =< 50 years of age with hematologic diseases treatable by allogeneic HCT who
through pre-existing medical conditions or prior therapy are considered to be at high
risk for regimen related toxicity associated with a conventional transplant (> 40%
risk of transplant-related mortality [TRM]) or those patients who refuse a
conventional HCT; transplants must be approved for these inclusion criteria by both
the participating institution's patient review committee such as the Patient Care
Conference (PCC at the Fred Hutchinson Cancer Research Center [FHCRC]) and by the
principal investigator at the collaborating center; patients =< 50 years of age who
have received previous high-dose transplantation do not require patient review
committee approval; all children < 12 years must be discussed with the FHCRC primary
investigator (PI) prior to registration

- Patients with metastatic renal cell carcinoma with the histologic subtypes of clear
cell, papillary and medullary may be accepted regardless of age

- The following diseases will be permitted although other diagnoses can be considered if
approved by PCC or the participating institution's patient review committees and the
principal investigator:

- Aggressive non-Hodgkin lymphomas (NHLs) and other histologies such as diffuse
large B cell NHL-not eligible for autologous hematopoietic stem cell transplant
(HSCT), not eligible for conventional myeloablative HSCT, or after failed
autologous HSCT

- Low grade NHL- with < 6 month duration of complete remission (CR) between courses
of conventional therapy

- Mantle cell NHL-may be treated in first CR

- Chronic lymphocytic leukemia (CLL)- Must be refractory to fludarabine; patients
who fail to have a complete or partial response after therapy with a regimen
containing fludarabine (or another nucleoside analog, e.g. 2-cladribine [CDA],
pentostatin) or experience disease relapse within 12 months after completing
therapy with a regimen containing fludarabine (or another nucleoside analog)

- Hodgkin disease (HD)- must have received and failed frontline therapy

- Multiple myeloma (MM)- must have received prior chemotherapy; consolidation of
chemotherapy by autografting prior to nonmyeloablative HCT is permitted

- Acute myeloid leukemia (AML)- must have < 5% marrow blasts at the time of
transplant.

- Acute lymphocytic leukemia (ALL)- must have < 5% marrow blasts at the time of
transplant

- Chronic myelogenous leukemia (CML)- Patients will be accepted in chronic phase or
accelerated phase; patients who have received prior autografts after high dose
therapy or have undergone intensive chemotherapy with filgrastim
(G-CSF)-mobilized peripheral blood mononuclear cells (G-PBMC) autologous or
conventional HCT for advanced CML may be enrolled provided they are in CR or CP
and have < 5% marrow blasts at time of transplant

- Myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD)- Only patients
with MDS/refractory anemia (RA) or MDS/refractory anemia with ringed sideroblasts
(RARS) will be eligible for this protocol; additionally patients with
myeloproliferative syndromes (MPS) will be eligible; those patients with MDS or
MPS with > 5% marrow blasts (including those with transformation to AML) must
receive cytotoxic chemotherapy and achieve < 5% marrow blasts at time of
transplant

- Renal cell carcinoma- Must have evidence of disease not amenable to surgical cure
or history of or active metastatic disease by radiological and histologic
criteria

- DONOR: FHCRC matching allowed will be grade 1.0 to 2.1: Unrelated donors who are
prospectively:

- Matched for human leukocyte antigen (HLA)-A, B, C, major histocompatibility
complex, class II, DR beta 1 (DRB1) and major histocompatibility complex, class
II, DQ beta 1 (DQB1) by high resolution typing;

- Only a single allele disparity will be allowed for HLA-A, B, or C as defined by
high resolution typing

- DONOR: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion

- DONOR: Patient and donor pairs homozygous at a mismatched allele in the graft
rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and
the donor is A*0201, and this type of mismatch is not allowed

- DONOR: G-PBMC only will be permitted as a HSC source on this protocol

Exclusion Criteria:

- Patients with rapidly progressive intermediate or high grade NHL

- Renal cell carcinoma patients

- With expected survival of less than 6 months

- Disease resulting in severely limited performance status (< 70%)

- Any vertebral instability

- History of brain metastases

- Central nervous system (CNS) involvement with disease refractory to intrathecal
chemotherapy

- Fertile men or women unwilling to use contraceptive techniques during and for 12
months following treatment

- Females who are pregnant

- Patients with non-hematological tumors except renal cell carcinoma

- Fungal infections with radiological progression after receipt of amphotericin B or
active triazole for greater than 1 month

- Cardiac ejection fraction < 35%; ejection fraction is required if there is a history
of anthracycline exposure or history of cardiac disease

- Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% and/or receiving
supplementary continuous oxygen

- The FHCRC PI of the study must approve of enrollment of all patients with pulmonary
nodules

- Patients with clinical or laboratory evidence of liver disease would be evaluated for
the cause of liver disease, its clinical severity in terms of liver function, and the
degree of portal hypertension; patients will be excluded if they are found to have
fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension,
alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices,
hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by
prolongation of the prothrombin time, ascites related to portal hypertension, bridging
fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral
hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease

- Karnofsky scores < 60 (except renal cell carcinoma [RCC])

- Patients with > grade II hypertension by Common Toxicity Criteria (CTC)

- Human immunodeficiency virus (HIV) positive patients

- The addition of cytotoxic agents for "cytoreduction" with the exception of hydroxyurea
and imatinib mesylate will not be allowed within two weeks of the initiation of
conditioning

- DONOR: Marrow donors

- DONOR: Donors who are HIV-positive and/or, medical conditions that would result in
increased risk for G-CSF mobilization and harvest of G-PBMC