PRIMARY OBJECTIVES:
I. To compare the effectiveness of 2 GVHD prophylaxis regimens in preventing acute grades
II-IV GVHD.
SECONDARY OBJECTIVES:
I. Compare non-relapse mortality in the 2 arms.
II. Compare survival and progression-free survivals in the 2 arms.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
All patients receive FLU intravenously (IV) over 30 minutes on days -4 to -2 followed by 2-3
Gy TBI on day 0.
ARM 0: Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day
150 and and sirolimus PO once daily (QD) on days -3 to 150 with taper to day 180. Arm removed
as of 14-Sep-2011
ARM I: Patients receive CSP orally (PO) twice daily (BID) on days -3 to 96 with taper to day
150 and MMF PO three times daily (TID) on days 0-29 and then BID on days 30-150 with taper to
day 180.
ARM II: Patients receive CSP as in Arm I and sirolimus PO once daily (QD) on days -3 to 150
with taper to day 180. Patients also receive MMF PO TID on days 0-29 and then BID on days
30-40. MMF will then be discontinued without taper unless GVHD or disease relapse/progression
occurs.
TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 following the TBI.
After completion of study treatment, patients are followed up periodically.
Inclusion Criteria:
- Ages > 50 years with hematologic malignancies treatable by unrelated hematopoietic
cell transplant (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 high dose transplant (> 40% risk
of transplant related mortality [TRM]); this criterion can include patients with a
HCT-comorbidity index (CI) score of >= 1; transplants should be approved for these
inclusion criteria by the principal investigators at the collaborating centers and at
the Fred Hutchinson Cancer Research Center (FHCRC); all children < 12 years must be
discussed with the FHCRC principal investigator (PI) prior to registration
- Ages =< 50 years of age with chronic lymphocytic leukemia (CLL)
- Ages =< 50 years of age with hematologic diseases treatable by allogeneic HCT who
refuse a high-dose HCT; transplants must be approved for these inclusion criteria by
the principal investigators at the collaborating centers and at FHCRC
- The following diseases will be permitted although other diagnoses can be considered if
approved by Patient Care Conference (PCC) or the participating institutions' patient
review committees and the principal investigators
- Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as diffuse
large B cell NHL: not eligible for autologous HCT, not eligible for high-dose
allogeneic HCT, or after failed autologous HCT
- Mantle cell NHL: may be treated in first complete remission (CR); (diagnostic
lumbar puncture [LP] required pre-transplant)
- Low grade NHL: with < 6 month duration of CR between courses of conventional
therapy
- CLL: must have either:
- Failed to meet National Cancer Institute (NCI) Working Group criteria for
complete or partial response after therapy with a regimen containing FLU (or
another nucleoside analog, e.g. 2-Chlorodeoxyadenosine [2-CDA], pentostatin)
or experience disease relapse within 12 months after completing therapy with
a regimen containing FLU (or another nucleoside analog);
- Failed FLU-cyclophosphamide (CY)-Rituximab (FCR) combination chemotherapy at
any time point; or
- Have "17p deletion" cytogenetic abnormality; patients should have received
induction chemotherapy but could be transplanted in 1st CR; or
- Patients with a diagnosis of CLL (or small lymphocytic lymphoma) or
diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell
CLL or PLL
- Hodgkin lymphoma: must have received and failed frontline therapy
- Multiple myeloma: 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 myeloid leukemia (CML): patients in 1st chronic phase (CP1) must have
failed or be intolerant of tyrosine-kinase inhibitors (TKI); patients beyond CP1
will be accepted if they have < 5% marrow blasts at time of transplant
- Myelodysplasia (MDS)/myeloproliferative syndrome (MPS): patients must have < 5%
marrow blasts at time of transplant
- Waldenstrom's macroglobulinemia: must have failed 2 courses of therapy
- DONOR: FHCRC matching allowed will be grades 1.0 to 2.1: Unrelated donors who are
prospectively:
- Matched for human leukocyte antigen (HLA)-A, B, C, DRB1 and 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: Donors are excluded when preexisting immunoreactivity is identified that would
jeopardize donor hematopoietic cell engraftment; this determination is based on the
standard practice of the individual institution; the recommended procedure for
patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel
reactive antibody (PRA) screens to class I and class II antigens for all patients
before HCT; if the PRA shows > 10% activity, then flow cytometric or B and T cell
cytotoxic cross matches should be obtained; the donor should be excluded if any of the
cytotoxic cross match assays are positive; for those patients with an HLA class I
allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be
obtained regardless of the PRA results; 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*0102, and this type of mismatch is not allowed
- DONOR: Only filgrastim (G-CSF) mobilized PBSC only will be permitted as a
hematopoietic stem cell (HSC) source on this protocol
Exclusion Criteria:
- Patients with rapidly progressive intermediate or high grade NHL
- Patients with a diagnosis of chronic myelomonocytic leukemia (CMML)
- Patients with refractory anemia with excess blasts (RAEB) who have not received
myelosuppressive chemotherapy i.e. induction chemotherapy
- Central nervous system (CNS) involvement with disease refractory to intrathecal
chemotherapy
- Presence of circulating leukemic blasts (in the peripheral blood) detected by standard
pathology for patients with AML, ALL or CML
- Presence of >= 5% circulating leukemic blasts (in the peripheral blood) detected by
standard pathology for patients with MDS/MPS
- Fertile men or women unwilling to use contraceptive techniques during and for 12
months following treatment
- Females who are pregnant or breast-feeding
- Patients with active non-hematological malignancies (except non-melanoma skin cancers)
or those with non-hematological malignancies (except non-melanoma skin cancers) who
have been rendered with no evidence of disease, but have a greater than 20% chance of
having disease recurrence within 5 years; this exclusion does not apply to patients
with non-hematologic malignancies that do not require therapy
- Fungal infections with radiological progression after receipt of amphotericin B or
active triazole for greater than 1 month
- Cardiac ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening
fraction of < 26%); ejection fraction is required if age > 50 years or there is a
history of anthracycline exposure or history of cardiac disease; patients with a
shortening fraction < 26% may be enrolled if approved by a cardiologist
- Diffusing capacity of the lung for carbon monoxide (DLCO) < 40%, total lung capacity
(TLC) < 40%, forced expiratory volume in one second (FEV1) < 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, or symptomatic biliary disease
- Karnofsky scores < 60 or Lansky Score < 50
- Patient has poorly controlled hypertension and on multiple antihypertensives
- Human immunodeficiency virus (HIV) positive patients
- Active bacterial or fungal infections unresponsive to medical therapy
- All patients receiving antifungal therapy voriconazole, posaconazole, or fluconazole
and who are then randomized to ARM 2 must have sirolimus reduced according to the
Standard Practice Antifungal Therapy Guidelines
- The addition of cytotoxic agents for "cytoreduction" with the exception of tyrosine
kinase inhibitors (such as imatinib), cytokine therapy, hydroxyurea, low dose
cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of the
initiation of conditioning
- DONOR: Donor (or centers) who will exclusively donate marrow
- DONOR: Donors who are HIV-positive and/or, medical conditions that would result in
increased risk for G-CSF mobilization and harvest of PBSC
