Total-Body Irradiation With or Without Fludarabine Phosphate Followed By Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer
Condition: Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia in Remission; Aggressive Non-Hodgkin Lymphoma; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Diffuse Large B-Cell Lymphoma; Hematopoietic and Lymphoid Cell Neoplasm; Indolent Non-Hodgkin Lymphoma; Mantle Cell Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm; Plasma Cell Myeloma; Refractory Chronic Lymphocytic Leukemia; Refractory Hodgkin Lymphoma; Waldenstrom Macroglobulinemia
MeSH terms: Lymphoma; Leukemia; Neoplasms; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Lymphoma, Mantle-Cell; Lymphoma, Large B-Cell, Diffuse; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Waldenstrom Macroglobulinemia; Leukemia, Myeloid, Chronic-Phase; Multiple Myeloma; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases
Intervention: Total-Body Irradiation; Fludarabine Phosphate; Mycophenolate Mofetil; Cyclosporine; Peripheral Blood Stem Cell Transplantation
Intervention description: Undergo TBI; Given IV; Given PO; Given PO; Undergo transplantation
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Fludarabine; Fludarabine phosphate; Cyclosporins
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 87.0
Sex: All
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      This randomized phase III trial is studying total-body irradiation (TBI) and fludarabine
      phosphate to see how it works compared with TBI alone followed by donor stem cell transplant
      in treating patients with hematologic cancer. Giving low doses of chemotherapy, such as
      fludarabine phosphate, and radiation therapy before a donor 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 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 cyclosporine and mycophenolate mofetil after transplant may stop this from
      happening. It is not yet known whether TBI followed by donor stem cell transplant is more
      effective with or without fludarabine phosphate in treating hematologic cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients 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

          -  An autograft immediately prior (less than 6 months) to nonmyeloablative HCT (tandem
             approach) is not permitted

          -  Patients with hematologic malignancies treatable with HCT or with a B cell malignancy
             except those curable with autologous transplant will be included

          -  Aggressive non-Hodgkin lymphomas (NHLs) and other histologies such as diffuse large B
             cell NHL: patients are eligible IF they are not eligible for autologous hematopoietic
             stem cell transplantation (HSCT), not eligible for conventional myeloablative HSCT, or
             have failed an autologous HSCT

          -  Low grade NHL with < 6 month duration of complete remission (CR) between courses of
             conventional therapy

          -  Mantle cell NHL; may be treated in first CR

          -  Chronic lymphocytic leukemia (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-cyclophosphamide [CY]-rituximab (FCR) combination chemotherapy at any
                  time point

               -  Have "17p deletion" cytogenetic abnormality; patients should have received
                  induction chemotherapy but could be transplanted in 1st CR

               -  Or patients with a diagnosis of CLL (or small lymphocytic lymphoma) or 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): must have chemosensitive disease after failed autografting (an
             autografting immediately prior [within 6 months] to nonmyeloablative HCT [tandem
             approach] is not permitted)

          -  Acute myeloid leukemia (AML): must have < 5% marrow blasts at the time of transplant
             and be beyond first CR

          -  Acute lymphocytic leukemia (ALL): must have < 5% marrow blasts at the time of
             transplant and be beyond first CR

          -  Chronic myelogenous leukemia (CML): patients will be accepted in chronic phase (CP)
             beyond CP1 if they have received previous myelosuppressive chemotherapy or HCT, < 5%
             marrow blasts at time of transplant

          -  Myelodysplastic syndromes (MDS)/myeloproliferative disorders (MPD): must have received
             previous myelosuppressive chemotherapy or HCT, < 5% marrow blasts at time of
             transplant

          -  Waldenstroms Macroglobulinemia: must have failed 2 courses of therapy

          -  Patients will not be allowed to receive myelosuppressive chemotherapy for three weeks
             prior to conditioning

          -  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

          -  Patients 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 investigator

          -  Patients with human leukocyte antigen (HLA)-matched related donors

          -  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)

          -  DONOR: For females of child bearing age, serum pregnancy qualitative (PGSTAT) within
             72 hours prior to initial dose of filgrastim (G-CSF); results must be available prior
             to filgrastim

        Exclusion Criteria:

          -  Eligible for a high priority curative autologous transplant

          -  Patients with rapidly progressive, aggressive NHL unless in minimal disease state

          -  Patients with chronic myelomonocytic leukemia

          -  Presence of circulating leukemic blasts (in the peripheral blood) detected by standard
             pathology for patients with AML, ALL or CML

          -  Life expectancy severely limited by diseases other than malignancy

          -  Any current central nervous system (CNS) involvement with disease refractory to
             intrathecal chemotherapy

          -  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-hematological malignancies (except localized non-melanoma
             skin malignancies)

          -  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

          -  Fungal infections with radiological progression after receipt of amphotericin
             formulation or mold-active azoles for greater than 1 month

          -  Patients with active bacterial or fungal infections unresponsive to medical therapy

          -  Karnofsky score < 50 for adult patients

          -  Lansky-Play performance score < 50 for pediatric patients

          -  The addition of cytotoxic agents for "cytoreduction" with the exception of tyrosine
             kinase inhibitors (imatinib mesylate), cytokine therapy, hydroxyurea, low dose
             cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the
             initiation of conditioning

          -  Patients with the following organ dysfunction:

               -  Symptomatic coronary artery disease or ejection fraction < 35% or other cardiac
                  failure requiring therapy (required for patients with history of cardiac disease
                  or anthracycline use); ejection fraction is required if age > 50 years or there
                  is a history of anthracycline exposure or history of cardiac disease

               -  Poorly controlled hypertension on multiple antihypertensives

               -  Pulmonary: diffusion capacity of 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 study principal investigator
                  (PI) 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, bridging fibrosis, 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,
                  bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis
                  with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease

          -  DONOR: Age less than 12 years

          -  DONOR: Identical twin

          -  DONOR: Pregnancy

          -  DONOR: Infection with HIV

          -  DONOR: Known allergy to filgrastim

          -  DONOR: Current serious systemic illness that would result in increased risk for
             filgrastim mobilization and harvest of PBSC