Fludarabine Phosphate and Total-Body Radiation Followed by Donor Peripheral Blood Stem Cell Transplant and Immunosuppression in Treating Patients With Hematologic Malignancies

Fred Hutchinson Cancer Center (FHCC)

Status: Completed

Conditions: Untreated Childhood Acute Lymphoblastic Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; Childhood Burkitt Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Splenic Marginal Zone Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Adult Acute Myeloid Leukemia in Remission; Recurrent Grade 3 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Childhood Myelodysplastic Syndromes; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Post-transplant Lymphoproliferative Disorder; Small Intestine Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Primary Systemic Amyloidosis; Chronic Myelomonocytic Leukemia; Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Waldenström Macroglobulinemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Recurrent Small Lymphocytic Lymphoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; Recurrent Grade 2 Follicular Lymphoma; Juvenile Myelomonocytic Leukemia; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Stage III Multiple Myeloma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Hepatosplenic T-cell Lymphoma; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Refractory Hairy Cell Leukemia; Recurrent Childhood Small Noncleaved Cell Lymphoma; Blastic Plasmacytoid Dendritic Cell Neoplasm; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder; Recurrent Adult Hodgkin Lymphoma; Untreated Adult Acute Myeloid Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Refractory Multiple Myeloma; Recurrent Childhood Acute Lymphoblastic Leukemia; Previously Treated Myelodysplastic Syndromes; Anaplastic Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Testicular Lymphoma; Recurrent Childhood Acute Myeloid Leukemia; Refractory Chronic Lymphocytic Leukemia; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Noncutaneous Extranodal Lymphoma; Intraocular Lymphoma; Adult Acute Myeloid Leukemia With Del(5q); Childhood Nasal Type Extranodal NK/T-cell Lymphoma; de Novo Myelodysplastic Syndromes; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Recurrent Adult Diffuse Large Cell Lymphoma; Adult Acute Lymphoblastic Leukemia in Remission; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Childhood Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Recurrent Childhood Lymphoblastic Lymphoma; Childhood Diffuse Large Cell Lymphoma; Mast Cell Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Adult Acute Myeloid Leukemia; Acute Undifferentiated Leukemia; Recurrent Adult T-cell Leukemia/Lymphoma; Peripheral T-cell Lymphoma; Stage II Multiple Myeloma

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

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00014235

1596.00 (Other Identifier)

P30CA015704 (U.S. NIH Grant/Contract)

NCI-2012-00671 (Registry Identifier)

Details and patient eligibility

About

This clinical trial studies fludarabine phosphate and total-body radiation followed by donor peripheral blood stem cell transplant and immunosuppression in treating patients with hematologic malignancies. Giving chemotherapy and total-body irradiation 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. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving total-body irradiation together with fludarabine phosphate, cyclosporine, and mycophenolate mofetil before transplant may stop this from happening.

Full description

PRIMARY OBJECTIVES:

I. To estimate the rate of grade III/IV graft-versus-host disease (GVHD) in patients treated with low-dose total body irradiation (TBI), fludarabine (fludarabine phosphate), PBSC infusion and immunosuppression with mycophenolate mofetil and a disease risk-based cyclosporine taper.

II. To estimate the risk of graft rejection, GVHD, disease response, non-relapse mortality and the incidence and severity of infectious complications using this treatment strategy.

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

ARM I (indolent disease):

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo TBI on day 0.

TRANSPLANTATION: Patients undergo donor peripheral blood stem cell transplantation (PBSCT) on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) or IV every 8-12 hours on days -3 to 56 with a taper to day 180 and mycophenolate mofetil PO BID or IV every 8-12 hours on days 0 to 27.

ARM II (aggressive disease):

CONDITIONING REGIMEN: Patients receive fludarabine phosphate and undergo TBI as in Arm I.

TRANSPLANTATION: Patients undergo donor PBSCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 70 and mycophenolate mofetil as in Arm I.

After completion of study treatment, patients are followed up for 5 years.

Enrollment: 160 estimated patients

Sex: All

Ages: Under 74 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Patients with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) or multiple myeloma who are not eligible for a curative autologous transplantation or who have received a prior autologous transplantation; patients with NHL or CLL must have failed prior therapy with an alkylating agent and/or fludarabine, or be at high risk of relapse; patients with multiple myeloma must have stage II or III disease and received prior chemotherapy

• Patients < 50 years of age with NHL, Hodgkin's disease (HD), CLL or multiple myeloma at high risk of regimen related toxicity through prior autologous transplant or through pre-existing medical conditions

• Patients < 75 years of age with other malignant diseases treatable by allogeneic bone marrow transplant (BMT) whom through pre-existing chronic disease affecting kidneys, liver, lungs, and heart are considered to be at high risk for regimen related toxicity using standard high dose regimens; the following diseases are the likely candidates

  • Myelodysplastic syndromes
  • Myeloproliferative syndromes
  • Acute Leukemia with < 10% blasts
  • Amyloidosis
  • Hodgkin's disease

• The Fred Hutchinson Cancer Research Center (FHCRC) Patient Care Conference (PCC) may approve patients with other malignancies or patients declining standard allografts for transplant following presentation and approval; centers outside the FHCRC that have a PCC or equivalent should obtain their Institutional approval; if there is not a comparable group at the Institution, please contact the FHCRC Principal Investigator for FHCRC approval through PCC

• DONOR: Human leukocyte antigen (HLA) genotypically or phenotypically identical related donor

• 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
• Patients with rapidly progressive aggressive NHL unless in minimal disease state
• Any current central nervous system (CNS) involvement with disease
• Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
• Females who are pregnant
• Patients who are human immunodeficiency virus (HIV) positive
• Cardiac ejection fraction < 40%; ejection fraction is required if the patient has a history of anthracyclines or history of cardiac disease
• Receiving supplementary continuous oxygen
• Diffusing capacity of the lung for carbon monoxide (DLCO) < 30%
• Total lung capacity (TLC) < 30%
• Forced expiratory volume in one second (FEV1) < 30%
• Total bilirubin > 2x the upper limit of normal
• Serum glutamate pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) 4x the upper limit of normal
• Karnofsky score < 50
• Patients with poorly controlled hypertension who are unable to have blood pressure kept below 150/90 on standard medication
• Patients with renal failure are eligible, however patients with renal compromise (serum creatinine greater than 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 cyclosporine levels
• The addition of cytotoxic agents for "cytoreduction" with the exception of hydroxyurea and imatinib mesylate will not be allowed within two weeks of the initiation of conditioning
• DONOR: Identical twin
• DONOR: Age less than 12 years
• DONOR: Pregnancy
• DONOR: Infection with HIV
• DONOR: Inability to achieve adequate venous access
• DONOR: Known allergy to G-CSF
• DONOR: Current serious systemic illness

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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160 participants in 2 patient groups

Arm I (indolent disease)

Experimental group

Description:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 180 and mycophenolate mofetil PO BID or IV every 8-12 hours on days 0 to 27.

Treatment:

Other: laboratory biomarker analysis

Radiation: total-body irradiation

Procedure: allogeneic hematopoietic stem cell transplantation

Procedure: peripheral blood stem cell transplantation

Drug: cyclosporine

Drug: fludarabine phosphate

Drug: mycophenolate mofetil

Arm II (aggressive disease)

Experimental group

Description:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate and undergo TBI as in Arm I. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV every 8-12 hours on days -3 to 56 with a taper to day 70 and mycophenolate mofetil as in Arm I.

Treatment:

Other: laboratory biomarker analysis

Radiation: total-body irradiation

Procedure: allogeneic hematopoietic stem cell transplantation

Procedure: peripheral blood stem cell transplantation

Drug: cyclosporine

Drug: fludarabine phosphate

Drug: mycophenolate mofetil