Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Condition: Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma; T-Cell Large Granular Lymphocyte Leukemia
MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic; Leukemia, Large Granular Lymphocytic
Intervention: Allogeneic Hematopoietic Stem Cell Transplantation; Cyclosporine; Fludarabine Phosphate; Laboratory Biomarker Analysis; Mycophenolate Mofetil; Peripheral Blood Stem Cell Transplantation; Pharmacological Study; Rituximab; Total-Body Irradiation
Intervention description: Undergo HSCT; Given PO; Given IV; Correlative studies; Given PO; Undergo HSCT; Correlative studies; Given IV; Undergo TBI
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Rituximab; Antineoplastic Agents, Immunological; Fludarabine; Fludarabine phosphate; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 66.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well fludarabine phosphate with radiation therapy and
      rituximab followed by donor stem cell infusions work in treating patients with high-risk
      chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with low side effects.
      Nonmyeloablative stem cell transplants use low doses of chemotherapy (fludarabine phosphate)
      and radiation to suppress the patient's immune system enough to prevent rejection of the
      donor's stem cells. Following infusion of donor stem cells, a mixture of the patient's and
      the donor's stem cells will exist and is called "mixed chimerism". Donor cells will attack
      the patient's leukemia. This is called the "graft-versus-leukemia" effect. Rituximab will be
      given 3 days before and three times after infusing stem cells to help in controlling CLL
      early after transplant till the "graft-versus-leukemia" takes control. Further, rituximab
      could augment the "graft-versus-leukemia" effect by activating donor immune cells and hence
      improve disease control. Sometimes the transplanted cells from a donor can also attack the
      body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may
      stop this from happening.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with a diagnosis of CLL (or SLL) or diagnosis of CLL that progresses to
             prolymphocytic leukemia (PLL)

          -  Patients with B-Cell CLL or PLL who:

               -  Failed to meet National Cancer Institute (NCI) Working Group criteria 2 for
                  complete or partial response after 2 cycles of therapy with regimen containing
                  fludarabine (or another nucleoside analog, e.g. cladribine [2-CDA], pentostatin)
                  or with disease relapse within 12 months after completing therapy with a
                  fludarabine (or another nucleoside analog) containing regimen

               -  Failed FCR or pentostatin/cyclophosphamide/rituximab (PCR) combination
                  chemotherapy at any time point

               -  Patients with novo or acquired "17p deletion" cytogenetic abnormality; patients
                  should have received induction treatment but could be transplanted in 1st CR

          -  Patients who have suitable human leukocyte antigen (HLA)-matched related or unrelated
             donors willing to receive filgrastim (G-CSF), undergo leukapheresis to collect
             peripheral blood mononuclear cell (PBMC), and to donate stem cells

          -  RELATED DONORS: When more than one potential donor exists, priority should be given to
             donors based on HLA identity > cytomegalovirus (CMV) seronegativity > ABO
             compatibility > sex matching

               -  Donor who is HLA phenotypically or genotypically identical at the allele level at
                  HLA-A, -B, -C, -DRB1, and -DQB1

               -  Must consent to G-CSF administration and leukapheresis;

               -  Must have adequate veins for leukapheresis or agree to placement of central
                  venous catheter (femoral, subclavian);

               -  Only G-CSF mobilized PBMC only will be permitted as a hematopoietic stem cell
                  (HSC) source on this protocol

          -  UNRELATED DONORS:

               -  Fred Hutchinson Cancer Research Center (FHCRC) matching allowed will be Grades
                  1.0 to 2.1; Unrelated donors who are prospectively:

               -  Matched for 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

          -  UNRELATED DONORS: 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; recommended procedure
             for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel
             reactive antibody screens to class I and 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

          -  UNRELATED DONORS: 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

          -  UNRELATED DONORS: Only G-CSF mobilized PBMC will be permitted as a HSC source on this
             protocol

        Exclusion Criteria:

          -  Infection with human immunodeficiency virus (HIV)

          -  Active diagnosis of central nervous system (CNS) involvement with CLL

          -  Patients unwilling to use contraceptive techniques before and for 12 months after HCT

          -  Pregnant women or females who are breastfeeding

          -  The addition of cytotoxic agents for 'cytoreduction' with the exception of tyrosine
             kinase inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low dose
             cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the
             initiation of conditioning

          -  Active bacterial or fungal infections unresponsive to medical therapy

          -  Performance status: Karnofsky score < 60 for adult patients

          -  Cardiac ejection fraction < 40%; ejection fraction is required if age > 50 years or
             there is a history of prior transplant, anthracycline exposure or history of cardiac
             disease; and poorly controlled hypertension despite multiple antihypertensives

          -  Diffusing capacity of the lung for carbon monoxide (DLCO) < 40%, total lung capacity
             (TLC) < 40%, forced expiratory volume in 1 second (FEV1) < 40% and/or requiring
             continuous supplementary oxygen, or severe deficits in pulmonary function testing as
             defined by pulmonary consultant service; and the FHCRC principal investigator (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,
             hepatic damage with bridging fibrosis, alcoholic hepatitis, esophageal varices, a
             history of bleeding esophageal varices or hepatic encephalopathy, uncorrectable
             hepatic synthetic dysfunction evidenced 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, or
             symptomatic biliary disease

          -  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

          -  DONOR: Age < 12 years

          -  DONOR: Identical twin

          -  DONOR: Pregnancy

          -  DONOR: Infection with HIV

          -  DONOR: Inability to achieve adequate venous access

          -  DONOR: Known allergy to filgrastim (G-CSF)

          -  DONOR: Current serious systemic illness