Reduced-Intensity Busulfan and Fludarabine With or Without Antithymocyte Globulin Followed by Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Other Disease
Condition: Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes
MeSH terms: Lymphoma; Leukemia; Multiple Myeloma; Neoplasms, Plasma Cell; Preleukemia; Plasmacytoma; Myelodysplastic Syndromes; Myeloproliferative Disorders; Syndrome
Intervention: anti-thymocyte globulin; sargramostim; therapeutic allogeneic lymphocytes; busulfan; fludarabine phosphate; methotrexate; tacrolimus; nonmyeloablative allogeneic hematopoietic stem cell transplantation; peripheral blood stem cell transplantation
Intervention description: 0.5 mg/kg on day -3, 2.5 mg/kg on day -2 (groups 2, 3 and 4) and 3 mg/kg on day -1 (group 4 only); GM-CSF 500 ug everyday (QD) subcutaneously will be given to recipients who remain with an Absolute neutrophil count (ANC) < 1000/microliter (uL) past day 20; A minimum total cluster of differentiation 34 (CD34)+ cell dose of 3 x 10^6 cells/kg and a maximum 8 x 10^6 cells/kg will be infused on day 0; 6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5; fludarabine 30 mg/m^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3; Methotrexate 5 mg/m^2 per day on days +1, +3 and +6; Suggested starting dose is 0.03 mg/kg po bid starting on Day -1; Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0; Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0
Intervention MeSH terms: Methotrexate; Fludarabine phosphate; Fludarabine; Busulfan; Tacrolimus; Antilymphocyte Serum; Sargramostim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 71.0
Sex: All
Minimum age: 10 Years
Healthy volunteers: No
Keywords: adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); prolymphocytic leukemia; accelerated phase chronic myelogenous leukemia; adult acute lymphoblastic leukemia in remission; adult acute myeloid leukemia in remission; blastic phase chronic myelogenous leukemia; childhood acute lymphoblastic leukemia in remission; childhood acute myeloid leukemia in remission; childhood chronic myelogenous leukemia; chronic phase chronic myelogenous leukemia; de novo myelodysplastic syndromes; extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue; nodal marginal zone B-cell lymphoma; noncontiguous stage II adult Burkitt lymphoma; noncontiguous stage II adult diffuse large cell lymphoma; noncontiguous stage II adult diffuse mixed cell lymphoma; noncontiguous stage II adult diffuse small cleaved cell lymphoma; noncontiguous stage II adult immunoblastic large cell lymphoma; noncontiguous stage II adult lymphoblastic lymphoma; noncontiguous stage II grade 1 follicular lymphoma; noncontiguous stage II grade 2 follicular lymphoma; noncontiguous stage II grade 3 follicular lymphoma; noncontiguous stage II mantle cell lymphoma; noncontiguous stage II marginal zone lymphoma; noncontiguous stage II small lymphocytic lymphoma; previously treated myelodysplastic syndromes; recurrent adult acute lymphoblastic leukemia; recurrent adult Burkitt lymphoma; recurrent adult Hodgkin lymphoma; recurrent adult diffuse large cell lymphoma; recurrent adult diffuse mixed cell lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult lymphoblastic lymphoma; recurrent adult acute myeloid leukemia; recurrent childhood acute myeloid leukemia; recurrent/refractory childhood Hodgkin lymphoma; recurrent childhood acute lymphoblastic leukemia; recurrent childhood large cell lymphoma; recurrent childhood lymphoblastic lymphoma; recurrent childhood small noncleaved cell lymphoma; recurrent cutaneous T-cell non-Hodgkin 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 mycosis fungoides/Sezary syndrome; recurrent small lymphocytic lymphoma; refractory chronic lymphocytic leukemia; refractory multiple myeloma; relapsing chronic myelogenous leukemia; secondary acute myeloid leukemia; secondary myelodysplastic syndromes; splenic marginal zone lymphoma; stage I multiple myeloma; stage II multiple myeloma; stage III adult Burkitt lymphoma; stage III adult Hodgkin 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 large cell lymphoma; stage III adult lymphoblastic lymphoma; stage III chronic lymphocytic leukemia; 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 multiple myeloma; stage III small lymphocytic lymphoma; stage IV adult Burkitt lymphoma; stage IV adult Hodgkin 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 large cell lymphoma; stage IV adult lymphoblastic lymphoma; stage IV chronic lymphocytic leukemia; 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; primary myelofibrosis; Waldenstrom macroglobulinemia; adult nasal type extranodal natural killer (NK)/T-cell lymphoma; recurrent adult grade III lymphomatoid granulomatosis; childhood myelodysplastic syndromes

Summary:

      RATIONALE: Giving low doses of chemotherapy, such as busulfan and fludarabine, before a donor
      stem cell transplant helps stop the growth of cancer and abnormal cells. It also helps stop
      the patient's immune system from rejecting the donor's stem cells. The donated stem cells may
      replace the patient's immune cells and help destroy any remaining cancer or abnormal cells
      (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an
      immune response against the body's normal cells. Immunosuppressive therapy may improve bone
      marrow function and may be an effective treatment for hematologic cancer or other disease.

      PURPOSE: This clinical trial is studying the side effects and how well giving busulfan and
      fludarabine with or without antithymocyte globulin followed by donor stem cell transplant
      works in treating patients with hematologic cancer or other disease.
    

Eligibility criteria:

        DISEASE CHARACTERISTICS:

          -  Histologically confirmed diagnosis of 1 of the following:

               -  Chronic lymphocytic leukemia (CLL), meeting the following criteria:

                    -  Absolute lymphocyte count > 5,000/mm³

                    -  Lymphocytes must appear morphologically mature with < 55% prolymphocytes

                    -  Lymphocyte phenotype with expression of CD19 and cluster of differentiation
                       5 (CD5)

               -  Prolymphocytic leukemia (PLL), meeting the following criteria:

                    -  Absolute lymphocyte count > 5,000/mm³

                    -  More than 55% prolymphocytes

                    -  Morphologically diagnosed

               -  Chronic myelogenous leukemia (CML), meeting the following criteria:

                    -  Diagnosis of CML or similar myeloproliferative disorders based on t(9;22) or
                       related t(9;12) cytogenetic abnormalities AND characterized by elevated
                       white blood cell (WBC) counts in peripheral blood or bone marrow

                    -  In first chronic phase CML and a candidate for treatment with reduced-dose
                       busulfan

                    -  Patients with other cytogenetic abnormalities, such as t(9;12), that are
                       associated with an aggressive clinical course are eligible

               -  Non-Hodgkin's lymphoma (NHL), meeting the following criteria:

                    -  Any World Health Organization (WHO) class histologic subtype allowed

                    -  Core biopsies are acceptable provided they contain adequate tissue for
                       primary diagnosis and immunophenotyping

                    -  Bone marrow biopsies as sole means of diagnosis are not allowed for
                       follicular lymphoma

               -  Hodgkin's lymphoma, meeting the following criteria:

                    -  Any WHO class histologic subtype allowed

                    -  Core biopsies are acceptable provided they contain adequate tissue for
                       primary diagnosis and immunophenotyping

               -  Multiple myeloma, meeting the following criteria:

                    -  Active disease requiring treatment (Durie-Salmon stages I, II, or III)

               -  Acute myeloid leukemia with documented control, defined as < 10% bone marrow
                  blasts and no circulating blasts

               -  Acute lymphoblastic leukemia, meeting the following criteria:

                    -  In early first relapse or beyond OR in first complete remission and has 1 of
                       the following high-risk features:

                         -  t(9;22) or t(4;11)

                         -  WBC count > 30,000/mm³ at presentation

                         -  Non-T-cell phenotype

                         -  More than 30 years of age

               -  Agnogenic myeloid metaplasia/myelofibrosis

                    -  Patients who are transfusion dependent or who have evolving myelodysplastic
                       or leukemic features or high-risk cytogenetic abnormalities are eligible

               -  Myelodysplastic syndromes (MDS) as defined by WHO criteria

          -  Meets 1 of the following criteria:

               -  Over 55 years of age

               -  Ineligible for busulfan-based therapy based on diminished organ function or poor
                  performance status

               -  Indolent and chemotherapy-responsive CLL, low-grade NHL, small lymphocytic
                  lymphoma, or PLL

          -  Patients who have undergone prior autologous stem cell transplantation are
             preferentially enrolled on clinical trial CALGB-100002, if available and patient is
             eligible

          -  HLA-matched or mismatched related donor or HLA-matched unrelated donor available

               -  HLA-identical sibling (6/6 or 9/10) (minimal serologic typing required for class
                  I [A, B]; molecular typing required for class II (DRB1))

               -  9/10 matched unrelated donor (MUD) (molecular analysis at HLA A, B, C, DRB1, and
                  DQB1 by high resolution typing required)

               -  5/6 MUD (molecular analysis at HLA A, B, and DRB1 required)

               -  No syngeneic donors

        PATIENT CHARACTERISTICS:

          -  Creatinine clearance ≥ 40 mL/min

          -  Bilirubin ≤ 3 times upper limit of normal (ULN)

          -  aspartate aminotransferase (AST) ≤ 3 times ULN

          -  Diffusing capacity of the lungs for carbon monoxide (DLCO) > 40% with no symptomatic
             pulmonary disease

          -  Left ventricular ejection fraction (LVEF) ≥ 30% by multigated acquisition scan (MUGA)

          -  No uncontrolled diabetes mellitus or active serious infection

          -  No known hypersensitivity to Escherichia coli-derived products

          -  No HIV infection

          -  Not pregnant or nursing

          -  Negative pregnancy test

          -  Fertile patients must use effective contraception

        PRIOR CONCURRENT THERAPY:

          -  See Disease Characteristics

          -  More than 4 weeks since prior chemotherapy, radiotherapy (except prophylactic cranial
             x-ray therapy), or surgery