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

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine which of 3 GVHD prophylaxis regimens results in reduction of acute grades II-IV GVHD to =< 40%. SECONDARY OBJECTIVES: I. Reduce the incidence of non-relapse mortality from infections and GVHD before day 200 to =< 15%. II. Reduce the utilization of high-dose corticosteroids compared to protocols 1463, 1641, and 1668. III. Compare survival and progression-free survival to that achieved under protocols 1463, 1641, and 1668. OUTLINE: CONDITIONING: All patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -4 to -2 and undergo total-body irradiation on day 0. TRANSPLANTATION: All patients undergo allogeneic peripheral blood stem cell transplantation on day 0. IMMUNOSUPPRESSION: Patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive tacrolimus IV or orally (PO) every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD. ARM II: Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD. ARM III: Patients receive tacrolimus and MMF as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80. After completion of study treatment, patients are followed up at 6 months and then every year thereafter.

Official Title
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A Randomized Phase II Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute GVHD After Unrelated Donor G-CSF Mobilized Peripheral Blood Mononuclear Cell (G-PBMC) Transplantation Using Nonmyeloablative Conditioning for Patients With Hematologic Malignancies A Multi-Center Trial

Conditions
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Childhood Burkitt Lymphoma, 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 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

Intervention / Treatment
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* Drug: Fludarabine Phosphate
* Radiation: Total-Body Irradiation
* Procedure: Peripheral Blood Stem Cell Transplantation
* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil
* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (MMF and tacrolimus)<br>Patients receive tacrolimus IV or PO every 12 hours on days -3 to 180 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-96 with taper beginning on day 40 in the absence of GVHD. | Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Radiation: Total-Body Irradiation<br>* Undergo total-body irradiation<br>* Other names: Whole-Body Irradiation;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo allogeneic peripheral blood stem cell transplantation<br>* Other names: Peripheral Stem Cell Transplantation;Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic peripheral blood stem cell transplantation<br>* Other names: HSCT;Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: FK 506;Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;|
| Experimental: Arm II (MMF and tacrolimus alternate schedule)<br>Patients receive tacrolimus IV or PO every 12 hours on days -3 to 150 with taper beginning on day 100 in the absence of GVHD. Patients also receive MMF PO every 8 hours on days 0-29 and then every 12 hours on days 30-180 with taper beginning on day 150 in the absence of GVHD. | Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Radiation: Total-Body Irradiation<br>* Undergo total-body irradiation<br>* Other names: Whole-Body Irradiation;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo allogeneic peripheral blood stem cell transplantation<br>* Other names: Peripheral Stem Cell Transplantation;Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic peripheral blood stem cell transplantation<br>* Other names: HSCT;Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: FK 506;Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;|
| Experimental: Arm III (MMF, tacrolimus, and sirolimus)<br>Patients receive tacrolimus and MMF as in arm II. Patients also receive sirolimus PO once daily on days -3 to 80. | Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Radiation: Total-Body Irradiation<br>* Undergo total-body irradiation<br>* Other names: Whole-Body Irradiation;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo allogeneic peripheral blood stem cell transplantation<br>* Other names: Peripheral Stem Cell Transplantation;Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic peripheral blood stem cell transplantation<br>* Other names: HSCT;Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: FK 506;Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Drug: Sirolimus<br>* Given PO<br>* Other names: WY-090217;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grades II-IV Acute GVHD | Number of patients with grades II-IV acute GVHD aGVHD Stages Skin: a maculopapular eruption involving < 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma w/ bullous formation and often w/ desquamation Liver: bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL bilirubin > 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients w/ visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death | 150 days after transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Non-Relapse Mortalities | Percentage of NRM as estimated by cumulative incidence methods with competing risks. Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref) Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198 | 200 days after transplant | 
| Number of Participants Utilizing High-Dose Corticosteroids | Number of patients utilizing high-dose corticosteroids (as a surrogate marker for reduction of acute GVHD), estimated by cumulative incidence methods. Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref) Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198 | 150 days after transplant | 
| Number of Participants Surviving Overall | Number of patients surviving, estimated by cumulative incidence methods Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref) Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198 | 1 Year post-transplant | 
| Number of Participants Surviving Without Progression | Number of patients with progression-free survival, estimated by cumulative incidence methods Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring (ref) Here is the reference. Gooley TA, Leisenring W, Crowley J, Storer BE: Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 18:695-706, 1999. PMID 10204198 | 2 Years post-transplant |