RATIONALE: Giving low doses of chemotherapy, monoclonal antibodies, and radiation therapy
before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells.
It may also stop the patient's immune system from rejecting the donor's stem cells. The
donated stem cells may replace the patient's immune cells and help destroy any remaining
cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can
also make an immune response against the body's normal cells. Giving tacrolimus, sirolimus,
and antithymocyte globulin before and after transplant may stop this from happening.
PURPOSE: This phase II trial is studying the side effects of giving sirolimus together with
tacrolimus and antithymocyte globulin and to see how well it works in preventing
graft-versus-host disease in patients with hematologic cancer who are undergoing donor stem
- To determine the incidence and severity of acute graft-versus-host disease (GVHD) after
HLA-matched or -mismatched unrelated donor peripheral blood stem cell transplantation
(PBSCT) in patients with hematologic malignancies treated with immunosuppressive
therapy comprising sirolimus, tacrolimus, and anti-thymocyte globulin as GVHD
- To determine the safety of this regimen in these patients at 6 months after PBSCT.
- To determine the time to engraftment (i.e., platelet and absolute neutrophil recovery)
in patients treated with this regimen.
- To determine the length of hospital stay of these patients within 100 days after PBSCT.
- To determine the incidence of infections, including CMV and EBV reactivation and
post-transplant lymphoproliferative disorders, in patients treated with this regimen.
- To determine the incidence of thrombotic microangiopathy and veno-occlusive disease in
patients treated with this regimen.
- To determine the incidence of chronic GVHD in patients treated with this regimen.
- To determine the overall and disease-free survival of these patients at 2 years after
- To determine the Karnofsky performance status of these patients at baseline and at
various time points after PBSCT.
- To conduct immunocorrelative studies prior to and at various time points after PBSCT.
- Conditioning regimen: Patients receive 1 of 6 conditioning regimens between days -9 and
-3, based on diagnosis and the treating physician's preference regarding regimen
- Regimen I: Patients receive fludarabine phosphate IV and busulfan IV.
- Regimen II: Patients undergo total body irradiation (TBI) twice daily for 8
fractions and receive etoposide IV.
- Regimen III: Patients undergo TBI once or twice daily for 11 fractions and receive
- Regimen IV: Patients undergo TBI and receive fludarabine phosphate IV and busulfan
- Regimen V: Patients receive carmustine IV, etoposide IV, cytarabine IV, and
melphalan IV. Some patients also receive rituximab IV.
- Regimen VI: Patients receive fludarabine phosphate IV and melphalan IV. Some
patients also undergo TBI.
- Allogeneic peripheral blood stem cell transplantation: Patients undergo filgrastim
(G-CSF)-mobilized allogeneic peripheral blood stem cell transplantation on day 0.
- Graft-versus-host disease prophylaxis (GVHD): Patients receive tacrolimus IV
continuously over 24 hours or orally and sirolimus orally beginning on day -3 and
continuing until day 30 or day 90, followed by a taper in the absence of GVHD. Patients
also receive anti-thymocyte globulin IV over 4-8 hours on days -3 to -1.
Blood samples are obtained at baseline and periodically during study for correlative
biomarker studies. Samples are analyzed by T-cell immunophenotyping, absolute subset number
quantification, and multi-parameter flow cytometry for evaluation of immune reconstitution,
T-cell differentiation status, NK-cell recovery, allo-reactivity of donor T-cells after
transplantation, and regulatory T-cell reconstitution.
After completion of study therapy, patients are followed periodically for up to 2 years.
- Diagnosis of a hematological malignancy, including any of the following:
- Non-Hodgkin lymphoma in complete remission (CR) or partial remission (PR)
- Hodgkin lymphoma in CR or PR
- Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) meeting
either of the following criteria:
- In CR
- Not in CR and meets the following criteria:
- Bone marrow blast < 20% within 4 weeks of transplantation
- Peripheral blood absolute blast count < 500 per microliter on the day
of initiating conditioning therapy
- Myelodysplastic syndromes, treated or untreated
- Chronic myeloid leukemia in chronic phase or accelerated phase
- Multiple myeloma in CR or PR
- Chronic lymphocytic leukemia in second or greater CR or PR
- Myelofibrosis or other myeloproliferative disorders meeting the following
- Bone marrow blasts < 20% within 4 weeks of transplantation
- Peripheral blood absolute blast count < 500 per microliter on the day of
initiating conditioning therapy
- Patients with ascites not allowed
- No prior bone marrow or ex vivo engineered or processed graft (i.e., CD34+
enrichment, T-cell depletion, etc)
- Scheduled to undergo peripheral blood stem cell transplantation from a suitable
HLA-matched or -mismatched unrelated donor, as determined by treating physician
- High resolution molecular HLA typing is required for HLA class I and II
- No more than one antigen or allele mismatch
- No documented uncontrolled CNS disease
- ECOG performance status (PS) 0-2
- Karnofsky PS 60-100%
- Creatinine clearance > 50 mL/min
- Bilirubin < 3 times upper limit of normal (ULN)
- ALT and AST < 3 times ULN
- LVEF > 50%
- FVC, FEV_1, or DLCO > 50% predicted
- Patients on home oxygen not allowed
- Able to cooperate with oral medication intake
- HIV negative
- No active hepatitis B or hepatitis C
- No known contraindication to sirolimus, tacrolimus, or anti-thymocyte globulin
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics