Donor Stem Cell Transplant With No or Low-Intensity Chemotherapy Using Sirolimus and Treated Immune Cells to Treat Blood and Lymph Cancers
Condition: Lymphoma; Leukemia; Myeloproliferative Disorders; Multiple Myleoma; Myelodysplastic Syndrome
MeSH terms: Lymphoma; Leukemia; Preleukemia; Myelodysplastic Syndromes; Myeloproliferative Disorders; Syndrome
Intervention: Rituximab; Fludarabine; Etoposide; Doxorubicin; Vincristine; Cyclophosphamide; Peripheral blood stem cell (PBSC) transplantation; T cell donor lymphocyte infusion (DLI) with unmanipulated donor T cells; Prednisone; Allogeneic hematopoietic stem cell transplant (HSCT); Filgrastim; T-Rapa cell Donor Lymphocyte Infusion (DLI)
Intervention description: Rituximab: 375 mg/m(2)/day intravenous (IV), day 1 (for cluster of differentiation 20 (CD20+) patients).; Fludarabine: 30 mg/m(2)/day intravenous (IV), days -6 to -3.; Etoposide: 50 mg/m(2)/day continuous intravenous (CIV), days 1-4.; Doxorubicin:10 mg/m(2)/day continuous intravenous (CIV), days 1-4.; Vincristine: 0.4 mg/m(2)/day continuous intravenous (CIV), days 1-4.; Cyclophosphamide, 300 mg/m(2)/day intravenous (IV), days -6 to -3.; PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell.; The dose of the T cells will attempt to be held constant for each study recipient (target dose 2.5 x 10(7) T cells/kg; minimum dose will be 1 x 10(7) T cells/kg).; Prednisone: 60 mg/m(2)/day by mouth (PO), days 1-5.; Allogeneic Hematopoietic Stem Cell Transplant.; Filgrastim: 5 mcg/kg/day subcutaneous (SC), day 6 (require absolute neutrophil count (ANC) > 1000, two values; or ANC > 5000 cells/ul on one occasion).; The dose of T helper 2 (Th2) cells or unmanipulated donor T cells will attempt to be held constant for each study recipient (target dose 2.5 x 10(7) Th2/kg; minimum dose will be 1 x 10(7) Th2/kg).
Intervention MeSH terms: Prednisone; Cyclophosphamide; Rituximab; Doxorubicin; Fludarabine; Etoposide; Vincristine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 442.0
Sex: All
Minimum age: 11 Years
Maximum age: 90 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Leukemia; Lymphoma; Multiple Myeloma; Bone Marrow Transplantation; Immune Therapy

Summary:

      Background:

      Patients with cancers of the blood and immune system often benefit from transplants of stem
      cells from a genetically well-matched sibling. However, severe problems may follow these
      transplants because of the high-dose chemotherapy and radiation that accompany the procedure.
      Also, donated immune cells sometimes attack healthy tissues in a reaction called
      graft-versus-host disease (GVHD), damaging organs such as the liver, intestines and skin. To
      reduce toxicity of high-dose preparative chemotherapy, this study performs allogeneic
      transplant after low doses of chemotherapy. In an attempt to improve anti-tumor effects
      without increasing GVHD, this study uses donor immune cells (T helper 2 (Th2) cells) grown in
      the laboratory; some patients will receive standard donor immune cells (not grown in
      laboratory). All patients will receive immune modulating drugs sirolimus and cyclosporine to
      prevent GVHD.

      Objective:

      To determine the safety, treatment effects and rate of GVHD in patients receiving transplants
      that use low-intensity chemotherapy, sirolimus plus cyclosporine, and transplant booster with
      either Th2 cells or standard immune cells.

      Eligibility:

      Patients 16 to 75 years of age with acute or chronic leukemia, non-Hodgkin's lymphoma,
      Hodgkin's disease, multiple myeloma, or myelodysplastic syndrome.

      Patients must have a suitable genetically matched sibling donor and adequate kidney, heart
      and lung function.

      Design: The protocol has three treatment groups: cohort 1, Th2 booster at two weeks
      post-transplant; cohort 2, standard T cell booster at two weeks post-transplant; cohort 3,
      multiple infusion of Th2 cells.

      Condition: Hematologic Neoplasms, Myeloproliferative Disorders

      Intervention: Biological; therapeutic allogeneic lymphocytes

      Drug: Sirolimus

      Study Type: Interventional

      Study Design: Primary Purpose: Treatment

      Phase: Phase II
    

Eligibility criteria:

        -  INCLUSION CRITERIA: PATIENT RECIPIENT

               1. Patients with hematologic malignancies, myelodysplasia, or myeloproliferative
                  disorders, as summarized in the following table. The diagnosis must be
                  histologically confirmed by the Laboratory of Pathology of National Cancer
                  Institute (NCI) or Hackensack (There will be no central pathology review).

               2. Chronic Lymphocytic Leukemia - Disease Status: a) Relapse post-fludarabine, b)
                  Non-Complete Response (CR) after salvage regimen.

                  Hodgkin's and Non-Hodgkin's Lymphoma (all types, including Mantle Cell Lymphoma)
                  - Disease Status: a) Primary treatment failure, b) Relapse after autologous stem
                  cell transplant (SCT), c) Non-CR after salvage regimen

                  Special Cases of High-Risk Lymphoma, including but not limited to : (1) plasma
                  dendritic cell type, 2) Hepato-splenic T cell type, 3) gamma delta pinniculitic T
                  cell type, 4) Muco-cutaneous natural killer (NK) cell type and 5) stage III-IV
                  nasal NK cell type- Disease Status: a) Primary treatment failure, b) Relapse
                  after autologous, c) Non-CR after salvage regimen, d) In first CR or any later CR

                  Chronic Epstein Barr Virus (EBV)-associated lymphoproliferative disease a) At any
                  point after diagnosis, including up-front therapy

                  Multiple Myeloma - Disease Status: a) Primary treatment failure, b) Relapse after
                  autologous stem cell transplant (SCT), c) Non-CR after salvage regimen.

                  Acute Myelogenous Leukemia - Disease Status: a) CR number 1 and high-risk
                  [excludes t(8;21), t(15;17), or inv(16)], b) CR number 2 or greater).

                  Acute Lymphocytic Leukemia - Disease Status: a) CR number 1 plus high-risk
                  [t(9;22) or bcr-abl(+); t(4;11), 1(1;19), t(8;14)], b) In CR number2 or greater.

                  Myelodysplastic Syndrome - Disease Status: a) Refractory Anemia with Excess
                  Blasts (RAEB), b) Refractory Anemia with Excess Blasts in Transformation (RAEB-T)
                  (requires marrow and blood blasts less than 10% after induction chemotherapy).

                  Myeloproliferative disorders - Disease Status: a) Idiopathic myelofibrosis, b)
                  Polycythemia vera, c) Essential thrombocytosis, d) Chronic myelomonocytic
                  leukemia.

                  Chronic Myelogenous Leukemia (CML) - Disease Status: a) Chronic phase CML,
                  refractory to imatinib treatment b) Accelerated phase CML. b) Accelerated phase
                  CML

                  Patients with myeloproliferative disorders must be end-stage, which is primarily
                  defined as disease severity refractory to splenectomy.

               3. Patient age of 16 to 75 years.

               4. Consenting first degree relative matched at 6/6 HLA antigens (A, B, and DR).

               5. Patient or legal guardian must be able to give informed consent.

               6. All previous intravenous therapy administered outside of the National Institutes
                  of Health (NIH) Clinical Center must be completed at least 2 weeks prior to study
                  entry, with recovery to less than or equal to non-hematologic grade 2 toxicity of
                  previous therapy.

               7. Eastern Cooperative Oncology Group (ECOG) performance status equal to 0 or 1.

               8. Life expectancy of at least 3 months.

               9. Patients with acute leukemia must have chemotherapy sensitive disease, as defined
                  by at least a 50% reduction in circulating absolute blast count due to the most
                  proximal regimen.

              10. Left ventricular ejection fraction greater than or equal to 45%, preferably by
                  2-dimension (2-D) echo, or by multi-gated acquisition scan (MUGA). However,
                  patients with left ventricular ejection fraction (LVEF) of between 35% and 44%
                  may also be eligible provided that such patients are cleared by a Cardiology
                  Consultation that must include a cardiac stress test.

              11. Corrected diffusing capacity or transfer of the lung for carbon monoxide (DLCO)
                  greater than 50% of expected value.

              12. Creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than
                  or equal to 50 ml/min.

              13. Serum total bilirubin less than 2.5 mg/dl; serum alanine aminotransferase (ALT)
                  and aspartate aminotransferase (AST) equal 2.5 times upper limit of normal.
                  Values above these levels may be accepted, at the discretion of the principal
                  investigator (PI) or study chairman, if such elevations are thought to be due to
                  liver involvement by malignancy or graft versus host disease (GVHD).

              14. Adequate central venous access potential.

              15. Potential patients referred for the study may not be eligible for the
                  experimental protocol therapy due to reasons such as uncertainty about donor
                  human leukocyte antigen (HLA) typing or need to control malignant disease,
                  infection, or metabolic abnormality such as hypercalcemia on a emergent basis.
                  Should a referred patient present to us in such a scenario, the patient will be
                  referred back to their primary hematologist-oncologist for treatment. However, if
                  referral back to the referring physician is not in the best interest of the
                  patient according to the clinical judgement of the principal investigator (PI),
                  then the patient may receive standard treatment for the malignant disease or
                  complicating conditions (infection, metabolic problems under the current study.
                  In other cases, a patient may have reasonable control of malignancy but does not
                  meet the cluster of differentiation 4 (CD4) cell cut-off of 50 cells per
                  microliter required for cohort 3 therapy; in such cases, standard care
                  chemotherapy regimens may be administered for the specific goal of reducing the
                  CD4 count (that is, immune depleting regimens such as the pentostatin plus
                  cyclophosphamide combination, administered similar to the manner that we have
                  developed on protocol 08-C- 0088). If it becomes apparent that the patient will
                  not be able to proceed to experimental therapy, then he/she must come off study.
                  Recipient-Subjects receiving a standard therapy, and availability of receiving
                  the same treatment elsewhere, outside of a research protocol. Because such
                  standard care therapy is not experimental, it is not necessary to complete the
                  eligibility criteria prior to receiving such standard care; however, prior to
                  initiation of the experimental therapy, the patient must meet each of the
                  eligibility criteria detailed above. Attempts will be made to standardize such
                  pretransplant chemotherapy (by administration of etoposide, prednisolone,
                  oncovin, cyclophosphamide, hydroxydaunorubicin, fludarabine, rituximab (EPOCH-FR)
                  chemotherapy, which is detailed later in this protocol); however, other regimens
                  using approved agents will be allowed if such regimens are thought to be in the
                  best interest of the patient.

        INCLUSION CRITERIA: DONOR

          1. First-degree relative with genotypic identity at 6/6 HLA loci (HLA- A, B, and DR).

          2. Age 11 to 90 years and able to give consent or assent. For donors < 18 years old, the
             legal guardian must be able to provide informed consent.

          3. Adequate venous access for peripheral apheresis, or consent to use a temporary central
             venous catheter for apheresis.

          4. Donors must be human immunodeficiency virus (HIV) negative.

          5. Donors with a history of hepatitis B or hepatitis C infection may be eligible.
             However, eligibility determination of such patients will require a hepatology
             consultation. The risk/benefit of the transplant and the possibility of transmitting
             hepatitis will be discussed with the patient and eligibility will then be determined
             by the principal investigator and lead associate investigator (LAI).

          6. Lactating donors must substitute formula feeding for her infant during period of
             filgrastim administration (to prevent any filgrastim effect on infant).

        EXCLUSION CRITERIA: PATIENT

          1. Active infection that is not responding to antimicrobial therapy.

          2. Active central nervous system (CNS) involvement by malignancy.

          3. HIV infection (treatment may result in progression of HIV and other viral infections).

          4. Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For
             patients with concomitant positive hepatitis B surface antigen, patient will require a
             hepatology consultation. The risk/benefit profile of transplant and hepatitis B will
             be discussed with the patient and eligibility determined by the principal investigator
             and Lead Associate Investigator.

          5. Hepatitis C infection. Patient may have hepatitis C infection. However, each patient
             will require a hepatology consultation. The risk/benefit profile of transplant and
             hepatitis C will be discussed with the patient and eligibility determined by the
             principal investigator and Lead Associate Investigator.

          6. Pregnant or lactating. Patients of childbearing potential must use an effective method
             of contraception. The effects of the chemotherapy, the subsequent transplant and the
             medications used after the transplant are highly likely to be harmful to a fetus. The
             effects upon breast milk are also unknown and may be harmful to the infant.

          7. History of psychiatric disorder which may compromise compliance with transplant
             protocol, or which does not allow for appropriate informed consent.

        EXCLUSION CRITERIA: DONOR

          1. History of psychiatric disorder which may compromise compliance with transplant
             protocol, or which does not allow for appropriate informed consent.

          2. History of hypertension that is not controlled by medication, stroke, autoimmune
             disease, or severe heart disease (donors with symptomatic angina will be excluded).
             Donors with a history of coronary artery bypass grafting or angioplasty who are
             symptom free will receive a cardiology evaluation and be considered on a case-by-case
             basis.

          3. History of prior malignancy. However, cancer survivors who have undergone potentially
             curative therapy may be considered for stem cell donation on a case-by-case basis. In
             addition, donors with localized cancer such as prostate cancer that are on a
             watch-and-wait management due to the low-risk of disease progression may also be
             considered for stem cell donation on a case-by-case basis. The risk/benefit of the
             transplant and the possibility of transmitting viable tumor cells at the time of
             transplantation will be discussed with the patient.

          4. Donors must not be pregnant (unknown effect of filgrastim on fetus). Donors of
             childbearing potential must use an effective method of contraception.

          5. Anemia (Hemoglobin (Hb) less than 11 gm/dl) or thrombocytopenia (platelets less than
             100,000 per microliter). However, potential donors with Hb levels less than 11 gm/dl
             that is due to iron deficiency will be eligible as long as the donor is initiated on
             iron replacement therapy and the case is individually approved by National Institutes
             of Health (NIH) or Hackensack Blood Bank.