Tacrolimus and Mycophenolate Mofetil in Preventing Graft-Versus-Host Disease in Patients Who Have Undergone Total-Body Irradiation With or Without Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant for Hematologic Cancer

Fred Hutchinson Cancer Center (FHCC)

Status and phase: Completed; Phase 2

Conditions: Stage I Childhood Anaplastic Large Cell Lymphoma; Stage III Mantle Cell Lymphoma; Polycythemia Vera; Stage IV Marginal Zone Lymphoma; Stage IB Mycosis Fungoides/Sezary Syndrome; Cutaneous B-cell Non-Hodgkin Lymphoma; Childhood Burkitt Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Childhood Myelodysplastic Syndromes; Stage III Grade 3 Follicular Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Post-transplant Lymphoproliferative Disorder; Small Intestine Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Stage I Multiple Myeloma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Childhood Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Waldenström Macroglobulinemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage IVA Mycosis Fungoides/Sezary Syndrome; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Stage III Adult Burkitt Lymphoma; Stage II Childhood Large Cell Lymphoma; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Stage III Multiple Myeloma; Stage III Marginal Zone Lymphoma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Hepatosplenic T-cell Lymphoma; Refractory Hairy Cell Leukemia; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Untreated Adult Acute Myeloid Leukemia; Stage I Grade 2 Follicular Lymphoma; Refractory Multiple Myeloma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Stage II Childhood Anaplastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage I Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Stage IIIA Mycosis Fungoides/Sezary Syndrome; Noncutaneous Extranodal Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Childhood Lymphoblastic Lymphoma; Stage IVB Mycosis Fungoides/Sezary Syndrome; Stage IV Adult Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage I Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Acute Myeloid Leukemia; Peripheral T-cell Lymphoma; Stage II Multiple Myeloma; Untreated Childhood Acute Lymphoblastic Leukemia; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage I Marginal Zone Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Splenic Marginal Zone Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Adult Acute Myeloid Leukemia in Remission; Stage I Small Lymphocytic Lymphoma; Stage I Childhood Large Cell Lymphoma; Contiguous Stage II Adult Burkitt Lymphoma; Stage IA Mycosis Fungoides/Sezary Syndrome; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Stage III Chronic Lymphocytic Leukemia; Essential Thrombocythemia; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Small Lymphocytic Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Stage I Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Accelerated Phase Chronic Myelogenous Leukemia; Nodal Marginal Zone B-cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Noncontiguous Stage II Adult Burkitt Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Stage I Grade 3 Follicular Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage IIIB Mycosis Fungoides/Sezary Syndrome; Stage III Grade 2 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Stage IIB Mycosis Fungoides/Sezary Syndrome; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Stage I Chronic Lymphocytic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Previously Treated Myelodysplastic Syndromes; Anaplastic Large Cell Lymphoma; Relapsing Chronic Myelogenous Leukemia; Recurrent Adult Diffuse Mixed Cell Lymphoma; Testicular Lymphoma; Refractory Chronic Lymphocytic Leukemia; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Prolymphocytic Leukemia; Intraocular Lymphoma; Adult Acute Myeloid Leukemia With Del(5q); Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Stage III Childhood Large Cell Lymphoma; de Novo Myelodysplastic Syndromes; Contiguous Stage II Small Lymphocytic Lymphoma; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Recurrent Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Adult Acute Lymphoblastic Leukemia in Remission; Stage III Childhood Anaplastic Large Cell Lymphoma; Childhood Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Stage IV Childhood Large Cell Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Stage IV Mantle Cell Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Primary Myelofibrosis; Recurrent Childhood Large Cell Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage IIA Mycosis Fungoides/Sezary Syndrome; Recurrent Adult T-cell Leukemia/Lymphoma; Stage IV Grade 1 Follicular Lymphoma

Treatments: Other: laboratory biomarker analysis; Drug: fludarabine phosphate; Drug: mycophenolate mofetil; Procedure: peripheral blood stem cell transplantation; Radiation: total-body irradiation; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Drug: tacrolimus

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00089011

P01CA078902 (U.S. NIH Grant/Contract)

P30CA015704 (U.S. NIH Grant/Contract)

1898.00 (Other Identifier)

NCI-2010-00267 (Registry Identifier)

Details and patient eligibility

About

This phase II trial studies how well tacrolimus and mycophenolate mofetil works in preventing graft-versus-host disease in patients who have undergone total-body irradiation (TBI) with or without fludarabine phosphate followed by donor peripheral blood stem cell transplant for hematologic cancer. Giving low doses of chemotherapy, such as fludarabine phosphate, and TBI 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 tacrolimus and mycophenolate mofetil after the transplant may stop this from happening.

Full description

PRIMARY OBJECTIVES:

I. To estimate the incidence of grade III/IV graft-versus-host disease (GVHD) after conditioning with 200 centigray (cGy) TBI alone or Fludarabine (fludarabine phosphate)/200 cGy TBI followed by tacrolimus (Tac)/mycophenolate mofetil (MMF) immunosuppression in patients with hematologic malignancies.

II. To estimate the incidence of chronic extensive GVHD.

SECONDARY OBJECTIVES:

I. To estimate the incidences of graft rejection.

II. To estimate overall survival 1-year after conditioning.

III. To evaluate the incidences of grades II-IV acute GVHD.

IV. To evaluate the rates of disease progression and/or relapse-related mortality.

V. To estimate the rate and duration of steroid use for the treatment of chronic GVHD.

OUTLINE: Patients are assigned to 1 of 2 treatment arms.

ARM I (nonmyeloablative conditioning with fludarabine phosphate and TBI): Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo TBI on day 0.

ARM II (nonmyeloablative conditioning with TBI): Patients undergo TBI on day 0.

All patients then undergo allogeneic peripheral blood stem cell transplantation on day 0 and receive tacrolimus orally (PO) every 12 hours on days -3 to 180, with taper on day 56, or tacrolimus IV if unable to tolerate PO; and mycophenolate mofetil PO every 12 hours on days 0-27 or mycophenolate mofetil IV if unable to tolerate PO.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 2 years and then annually for 3 years.

Enrollment: 150 patients

Sex: All

Ages: Under 74 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Patient must be not eligible for conventional allogeneic hematopoietic cell transplantation (HCT) and must have disease expected to be stable for at least 100 days without chemotherapy; patients with hematologic malignancies treatable with HCT or with a B cell malignancy except those curable with autologous transplant will be included; patients not eligible for active disease specific protocols may be enrolled in this protocol; patients will include the following
• Diffuse large B cell non-Hodgkin lymphoma (NHL) and other aggressive lymphomas - not eligible for conventional myeloablative HCT or after autologous HCT
• Low grade NHL- with < 6 months duration of complete response (CR) between courses of conventional therapy
• Mantle cell NHL- may be treated in first CR
• Chronic lymphocytic leukemia (CLL) - must have either 1) 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. 2-chlorodeoxyadenosine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog); 2) failed FLU-cyclophosphamide (CY)-Rituximab (FCR) combination chemotherapy at any time point; or 3) have "17p deletion" cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in 1st CR; 4) patients with a diagnosis of CLL (or small lymphocytic lymphoma) or a diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or PLL
• Hodgkin lymphoma (HL) - must have received and failed frontline therapy; patients must have failed or were not eligible for autologous transplant
• Multiple myeloma (MM) - following a planned autologous transplant or equivalent high-dose therapy without a graft, or following a failed prior autograft
• Acute myeloid leukemia (AML) - must have < 5% marrow blasts at the time of transplant
• Acute lymphoblastic leukemia (ALL) - must have < 5% marrow blasts at the time of transplant
• Chronic myelogenous leukemia (CML) - patients will be accepted beyond first chronic phase (CP1) if they have received previous myelosuppressive chemotherapy or HCT, and have < 5% marrow blasts at time of transplant
• Myelodysplastic syndromes/myeloproliferative disorders (MDS/MPD) - 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
• Myelosuppressive chemotherapy must be discontinued three weeks prior to conditioning with the exception of hydroxyurea or imatinib
• Patients < 12 years old must be approved by both the participating institutions' patient review committee such as the Patient Care Conference (PCC) at the Fred Hutchinson Cancer Research Center (FHCRC) and the FHCRC principal investigator
• Patient who refused to be treated on a conventional HCT protocol; for this inclusion criterion, transplants must be approved by both the participating institution's patient review committee such as the Patient Care Conference (PCC) at the FHCRC and the FHCRC principal investigators
• Patients with human leukocyte antigen (HLA)-matched related donors
• Patients with renal failure are eligible; however, patients with renal compromise (serum creatinine > 2.0) will likely have further compromise in renal function and may require hemodialysis (which may be permanent) due to the need to maintain adequate serum tacrolimus levels
• DONOR: Related donor who is HLA genotypically identical at least at one haplotype and may be phenotypically or genotypically identical at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1
• DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis
• DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian)

Exclusion criteria

• Eligible for a high priority curative autologous transplant
• Patient with rapidly progressive, aggressive NHL unless in minimal disease state
• Patients with chronic myelomonocytic leukemia (CMML)
• Life expectancy severely limited by diseases other than malignancy
• Any current 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
• Fertile men or women unwilling to use contraceptives during and for up to 12 months post treatment
• Female patients who are pregnant or breastfeeding
• Human immunodeficiency virus (HIV)-positive patients
• Patients with active non-hematologic malignancies (except non-melanoma skin cancers); this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
• Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
• Fungal pneumonia with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month
• Karnofsky score < 50 for adult patients
• Lansky-Play performance score < 50 for pediatric patients
• Symptomatic coronary artery disease or ejection fraction < 35% or other cardiac failure requiring therapy (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
• Poorly controlled hypertension
• Diffusing capacity of the lung for carbon monoxide (DLCO) < 30%, total lung capacity (TLC) < 30%, forced expiratory volume in one second (FEV1) < 30% and/or receiving supplementary continuous oxygen; the FHCRC principal investigator (PI) of the study must approve enrollment of all patients with pulmonary nodules
• Liver function abnormalities: 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 or bridging fibrosis, 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, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease
• Patients with active bacterial or fungal infections unresponsive to medical therapy
• DONOR: Age less than 12 years
• DONOR: Identical twin
• DONOR: Pregnancy
• DONOR: Infection with HIV
• DONOR: Known allergy to filgrastim (G-CSF)
• DONOR: Current serious systemic illness that would result in increased risk for G-CSF mobilization and harvest of peripheral blood stem cells (PBSC)

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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150 participants in 2 patient groups

Arm I (nonmyeloablative conditioning with fludarabine and TBI)

Experimental group

Description:

Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.

Treatment:

Other: laboratory biomarker analysis

Radiation: total-body irradiation

Drug: fludarabine phosphate

Arm II (nonmyeloablative conditioning with TBI)

Experimental group

Description:

Patients undergo TBI on day 0. All patients then undergo allogeneic peripheral blood stem cell transplantation on day 0 and receive tacrolimus PO every 12 hours on days -3 to 180, with taper on day 56, or tacrolimus IV if unable to tolerate PO; and mycophenolate mofetil PO every 12 hours on days 0-27 or mycophenolate mofetil IV if unable to tolerate PO.

Treatment:

Drug: tacrolimus

Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation

Other: laboratory biomarker analysis

Radiation: total-body irradiation

Procedure: peripheral blood stem cell transplantation

Drug: mycophenolate mofetil