Tacrolimus and Mycophenolate Mofetil With or Without Sirolimus in Preventing Acute Graft-Versus-Host Disease in Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer
Condition: Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndrome; Refractory Chronic Lymphocytic Leukemia; Refractory Plasma Cell Myeloma; Waldenstrom Macroglobulinemia; Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Lymphoma; Childhood Myelodysplastic Syndrome; Stage II Contiguous Adult Burkitt Lymphoma; Stage II Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Contiguous Adult Diffuse Mixed Cell Lymphoma; Stage II Contiguous Adult Diffuse Small Cleaved Cell Lymphoma; Stage II Adult Contiguous Immunoblastic Lymphoma; Stage II Contiguous Adult Lymphoblastic Lymphoma; Stage II Grade 1 Contiguous Follicular Lymphoma; Stage II Grade 2 Contiguous Follicular Lymphoma; Stage II Grade 3 Contiguous Follicular Lymphoma; Stage II Contiguous Mantle Cell Lymphoma; Stage II Non-Contiguous Adult Burkitt Lymphoma; Stage II Non-Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Mixed Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Small Cleaved Cell Lymphoma; Stage II Adult Non-Contiguous Immunoblastic Lymphoma; Stage II Non-Contiguous Adult Lymphoblastic Lymphoma; Stage II Grade 1 Non-Contiguous Follicular Lymphoma; Stage II Grade 2 Non-Contiguous Follicular Lymphoma; Stage II Grade 3 Non-Contiguous Follicular Lymphoma; Stage II Non-Contiguous Mantle Cell Lymphoma; Stage II Small Lymphocytic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Burkitt Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Secondary Myelodysplastic Syndrome; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Immunoblastic Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Burkitt Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Burkitt Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Burkitt Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Burkitt Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma
MeSH terms: Burkitt Lymphoma; Lymphoma; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphoma, Follicular; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, Chronic, B-Cell; Hodgkin Disease; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma, Large B-Cell, Diffuse; Waldenstrom Macroglobulinemia; Lymphoma, Large-Cell, Anaplastic; Multiple Myeloma; Leukemia, Promyelocytic, Acute; Leukemia, Myeloid, Accelerated Phase; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Blast Crisis; Plasmablastic Lymphoma; Lymphoma, Large-Cell, Immunoblastic; Myelodysplastic Syndromes; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Syndrome; Recurrence
Intervention: Fludarabine Phosphate; Total-Body Irradiation; Peripheral Blood Stem Cell Transplantation; Allogeneic Hematopoietic Stem Cell Transplantation; Tacrolimus; Mycophenolate Mofetil; Sirolimus
Intervention description: Given IV; Undergo total-body irradiation; Undergo allogeneic peripheral blood stem cell transplantation; Undergo allogeneic peripheral blood stem cell transplantation; Given IV or PO; Given PO; Given PO
Intervention MeSH terms: Mycophenolic Acid; Sirolimus; Fludarabine; Fludarabine phosphate; Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 210.0
Sex: All
Healthy volunteers: No

Summary:

      This randomized phase II trial studies how well giving tacrolimus and mycophenolate mofetil
      (MMF) with or without sirolimus works in preventing acute graft-versus-host disease (GVHD) in
      patients undergoing donor stem cell transplant for hematologic cancer. Giving low doses of
      chemotherapy, such as fludarabine phosphate, and total-body-irradiation before a donor
      peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops
      the patient's immune system from rejecting the donor's stem cells. The donated stem cells may
      replace the patient's immune system 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 MMF and tacrolimus with or without
      sirolimus after transplant may stop this from happening.
    

Eligibility criteria:

        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 conventional 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 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 =< 50 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
             6674961] prior to registration)

          -  Ages =< 50 years of age with chronic lymphocytic leukemia (CLL); these patients do not
             require patient review committee approvals

          -  Ages =< 50 years of age with hematologic diseases treatable by allogeneic HCT who
             refuse a conventional HCT (Transplants must be approved for these inclusion criteria
             by both the participating institutions' patient review committee such as PCC at the
             FHCRC and by the principal investigators at the collaborating centers)

          -  The following diseases will be permitted although other diagnoses can be considered if
             approved by 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 hematopoietic stem cell transplant
                  (HSCT), not eligible for conventional myeloablative HSCT, or after failed
                  autologous HSCT

               -  Mantle Cell NHL may be treated in first complete response (CR) (Diagnostic lumbar
                  puncture [LP] required pretransplant)

               -  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
                       fludarabine phosphate (FLU) (or another nucleoside analog, e.g. Cladribine
                       [2-CDA], pentostatin) or experience disease relapse within 12 months after
                       completing therapy with a regimen containing FLU (or another nucleoside
                       analog);

                    -  Failed FLU-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

               -  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 will be accepted if they are beyond
                  chronic phase (CP)1 and if they have received previous myelosuppressive
                  chemotherapy or HCT and have < 5% marrow blasts at time of transplant

               -  Myelodysplasia (MDS)/Myeloproliferative Syndrome (MPS) patients must have
                  received previous myelosuppressive chemotherapy or HCT and 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 peripheral blood mononuclear cell (PBMC) only
             will be permitted as a 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)

          -  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, MDS, ALL or CML

          -  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

          -  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 age > 50 years or
             there is a history of anthracycline exposure or history of cardiac disease

          -  Diffusion capacity of 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 score < 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 3 must have rapamycin reduced according to the
             Standard Practice of 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 G-PBMC