Clinical Trials /

Specialized Blood Cell Transplants for Cancers of the Blood and Bone Marrow

NCT00003838

Description:

The are a variety of cancerous diseases of the blood and bone marrow that can be potentially cured by bone marrow transplantation (BMT). Diseases like leukemia, lymphoma, and multiple myeloma are among the conditions that can be treated with BMT. Some patients with these diseases can be treated with medical chemotherapy alone. However, patients who relapse following chemotherapy are usually not curable with additional chemotherapy treatments. The only option known to provide a potential cure if this occurs is BMT. Allogenic transplants are cells collected from relatives of the patient. The transplant requires additional high intensity chemotherapy and radiation in order to destroy cancerous cells. In the process, many normal bone marrow cells are also destroyed. This is the reason for transplanting stem cells. The stem cells help to build new functioning bone marrow, red cells, white cells, and platelets. In addition, the immune cells from the donor are implanted into the recipient s body and help to fight off infection and kill remaining cancerous cells. Unfortunately, the powerful doses of chemotherapy and radiation therapy associated with allogenic BMT have toxic side effects and often make BMTs too dangerous to attempt in many patients. In order to reduce the complications of BMT, and make it a safer available option for patients with cancers of the blood and bone marrow, researchers have developed a new approach to the BMT. In this study researchers plan to use stem cells collected from the blood stream of patient s relatives rather than from the bone marrow (blood progenitor/stem cell transplant). In addition, researchers plan to use low doses of chemotherapy and no radiation therapy to reduce side effects. The majority of the cancer killing effect will be the responsibility of the stem cell transplant rather than the chemotherapy.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • Chronic Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Follicular Lymphoma
  • Mantle Cell Lymphoma
  • Multiple Myeloma
  • Non-Hodgkin Lymphoma
  • Refractory Anemia with Excess Blasts
  • Small Lymphocytic Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Specialized Blood Cell Transplants for Cancers of the Blood and Bone Marrow
  • Official Title: Non-Myeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Hematologic Malignancies in High Risk Patients and in Patients With Debilitating Hematologic Diseases

Clinical Trial IDs

  • ORG STUDY ID: 990050
  • SECONDARY ID: 99-H-0050
  • NCT ID: NCT00003838
  • NCT ALIAS: NCT00001875

Conditions

  • Myeloproliferative Disorders
  • Acute Myelogenous Leukemia
  • Chronic Myelogenous Leukemia
  • Myelodysplastic Syndrome

Purpose

The are a variety of cancerous diseases of the blood and bone marrow that can be potentially cured by bone marrow transplantation (BMT). Diseases like leukemia, lymphoma, and multiple myeloma are among the conditions that can be treated with BMT. Some patients with these diseases can be treated with medical chemotherapy alone. However, patients who relapse following chemotherapy are usually not curable with additional chemotherapy treatments. The only option known to provide a potential cure if this occurs is BMT. Allogenic transplants are cells collected from relatives of the patient. The transplant requires additional high intensity chemotherapy and radiation in order to destroy cancerous cells. In the process, many normal bone marrow cells are also destroyed. This is the reason for transplanting stem cells. The stem cells help to build new functioning bone marrow, red cells, white cells, and platelets. In addition, the immune cells from the donor are implanted into the recipient s body and help to fight off infection and kill remaining cancerous cells. Unfortunately, the powerful doses of chemotherapy and radiation therapy associated with allogenic BMT have toxic side effects and often make BMTs too dangerous to attempt in many patients. In order to reduce the complications of BMT, and make it a safer available option for patients with cancers of the blood and bone marrow, researchers have developed a new approach to the BMT. In this study researchers plan to use stem cells collected from the blood stream of patient s relatives rather than from the bone marrow (blood progenitor/stem cell transplant). In addition, researchers plan to use low doses of chemotherapy and no radiation therapy to reduce side effects. The majority of the cancer killing effect will be the responsibility of the stem cell transplant rather than the chemotherapy.

Detailed Description

      Patients with malignant and non-malignant hematologic diseases including severe aplastic
      anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS),
      acute and chronic leukemias, Hodgkin's and non-Hodgkin's lymphoma and multiple myeloma (MM)
      can now be cured by allogeneic bone marrow transplantation (BMT). This curative effect has
      been ascribed to the use of high dose chemo-radiotherapy and the anti-tumor or anti-bone
      marrow effect of the allograft. Dose intensification of conditioning regimens in attempts to
      reduce disease recurrence has been largely unsuccessful because of increased toxicity and
      mortality. Indeed, most evidence now points to donor-derived T-cells as being the principal
      modality leading to the complete eradication of both malignant and non-malignant host
      hematopoietic cells.

      The assumption that successful allogeneic BMT relies on the myeloablative effect of intensive
      but hazardous chemo-radiotherapy has largely restricted this therapeutic modality to patients
      with malignant or life-threatening hematologic disorders under the age of 55 years.
      Treatment-related mortality increases substantially with age, prior intensive treatment with
      chemo-radiotherapy, worsening performance status, and co-morbid medical conditions. An
      unacceptable risk of death from conventional BMT renders many patients ineligible for what
      may otherwise be curative therapy.

      Several in vitro studies have demonstrated the existence of donor-derived CD4 and CD8
      positive lymphocytes with specific reactivity for the patient s leukemia. These cells provide
      a potent graft-versus-leukemia (GVL) effect. This GVL effect is best seen in patients with
      CML relapsing after BMT, where a single infusion of donor lymphocytes has been shown to
      induce complete remission. In addition to the potent anti-leukemia effect of these cells,
      there is now strong evidence that donor T-cells are capable of completely eradicating
      residual host hematopoietic cells in a non-myeloablative transplant setting
      (graft-versus-marrow) leading to successful and complete donor hematopoietic engraftment.

      Non-myeloablative allogenic peripheral blood stem cell transplants are currently being
      investigated in phase I/II trials assessing engraftment efficacy and toxicity at a number of
      transplant centers. Preliminary data, including our own experience with greater than 150
      patients undergoing this type of procedure, have shown a high rate of complete donor
      engraftment with a low toxicity profile. Two recent studies investigating non-myeloablative
      allo-transplantation in standard risk patients revealed an extremely low rate of
      transplant-related complications and mortality.

      The decreased risk of transplant-related complications associated with non-myeloablative
      transplants expands the eligibility of transplant candidates as well as opens the possibility
      to evaluate non-myeloablative regimens in patients at high risk for complications with
      standard transplantation. Besides hematologic malignancies, allogeneic BMT has been shown to
      be curative in a number of debilitating hematologic diseases which may behave in a relatively
      indolent fashion, such as paroxysmal nocturnal hemoglobinuria (PNH) and refractory anemia
      (RA) or refractory anemia with ringed sideroblasts (RARS). However, the 30% risk of
      treatment-related mortality (TRM) with standard myeloablative allotransplantation usually
      precludes these patients from potentially curative therapy, because of concerns about
      shortening life in patients with these disorders. In this protocol we investigate
      non-myeloablative allogeneic peripheral blood stem cell (PBSC) transplantation in two groups
      of subjects where standard allogeneic transplantation is considered to have unacceptable
      toxicity.

      Group A: Subjects with hematologic malignancies with factors putting them at high risk for
      transplant related complications and mortality, including prior intensive chemo-radiotherapy
      and co-morbid diseases.

      Group B: Subjects with hematologic diseases (both clonal and non-clonal) associated with
      reasonable longevity not currently considered for allogeneic BMT because of prohibitive
      procedural mortality with conventional BMT (enrollment closed October 2010).

      In this protocol, eligible subjects are treated with an allogeneic PBSC transplant from an
      HLA identical or single HLA antigen-mismatched family donor, using an intensive
      immunosuppressive regimen without myeloablation in an attempt to decrease the transplant
      related toxicities while preserving the anti-malignancy and/or anti-host marrow effect of the
      graft. The low intensity non-myeloablative conditioning regimen should provide adequate
      immunosuppression to allow stem cell and lymphocyte engraftment. T-cell replete,
      donor-derived, granulocyte colony stimulating factor (G-CSF)-mobilized PBSCs will be used to
      establish hematopoietic and lymphoid reconstitution. We will add back lymphocytes in
      recipients with less than 100% donor T-cell chimerism in an attempt to prevent graft
      rejection and enhance a graft-versus-malignancy effect.

      The primary endpoint of this study is transplant related mortality (200 day survival). Other
      end points include engraftment, degree of donor-host chimerism, incidence of acute and
      chronic graft versus host disease (GVHD), transplant related morbidity as well as
      disease-free and overall survival.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalSubjects will receive a non-myeloablative preparative regimen of cyclophosphamide 60mg/kg/d x 2 days, and fludarabine 25mg /m2 intravenously (IV) over 30 minutes daily x 5 days followed by a PBPC graft targeted to deliver >5x10^6 CD34+ cells/kg

    Eligibility Criteria

            -  INCLUSION CRITERIA - Recipients:
    
            Group A: Subjects at high risk for transplant related complications and mortality as
            defined below:
    
            Ages 10 to 75 (both inclusive) with a history of one of the following:
    
              -  Treatment with dose intensive chemotherapy and/or radiotherapy
    
              -  Previous history of allo/auto transplant
    
              -  History of multiple myeloma or extramedullary plasmacytoma
    
              -  Chronic disease or co-morbid medical condition including subjects with symptoms or
                 signs of significant pulmonary disease, hepatic disease, kidney disease, cardiac
                 disease or disease of other organ systems which would result in increased risk of
                 morbidity or death from a standard myeloablative transplant.
    
            Diseases to be included:
    
              -  CML chronic phase
    
              -  Acute lymphoblastic leukemia (ALL), all subjects in complete or partial remission.
    
              -  AML: AML in first complete or partial remission Exceptions: AML with good risk
                 karyotypes: AML M3 t(15:17), AML M4Eo (inv. 16), AML t(8;21). All AML in second or
                 subsequent complete remission.
    
              -  MDS: refractory anemia with excess blasts (RAEB), or chronic myelomonocyte leukemia
                 (CMML).
    
              -  Myeloproliferative diseases associated with either cytopenia or uncontrolled
                 proliferation.
    
              -  CLL or small lymphocytic lymphoma (SLL) with bulky or progressive disease despite
                 prior treatment with chemotherapy which includes purine analogs.
    
              -  NHL
    
            A) Intermediate or high grade relapsed or progressive despite treatment with standard
            therapy ineligible for autologous PBSC transplant.
    
            B) NHL intermediate or high grade relapsing despite prior autologous transplant.
    
            C) Low grade follicular or small lymphocytic lymphoma (1) high risk patients who have
            relapsed following conventional chemotherapy, (2) relapsed following autologous marrow or
            PBSC transplant, or (3) chemo resistant disease.
    
            D) Mantle cell lymphoma
    
            E) NHL intermediate or high grade with concurrent BCL2 and MYC translocations who are at
            high risk for relapsed and who have low survival with conventional chemotherapy.
    
              -  HD, relapsed after prior autologous transplant or after 2 or more combination
                 chemotherapy regimens and ineligible for autologous PBSC transplant.
    
              -  EBV driven lymphoproliferative disorders progressing despite standard therapies.
    
              -  MM: MM subjects must be between the ages of 8 and 65 (both inclusive)
    
              -  Mycosis fungoides, which has been shown to be amenable to allogeneic stem cell
                 transplants.
    
            Group B: (Closed to enrollment Oct 2010) Subjects with hematologic diseases associated with
            reasonable longevity, shown to be curable by allogeneic BMT but where concern for a high
            procedural mortality with conventional BMT may delay or prevent such treatment.
    
            Ages 8 to 80 (both inclusive) with a history of one of the following
    
              -  PNH associated with either life-threatening thrombosis, cytopenia, transfusion
                 dependence or recurrent and debilitating hemolytic crisis.
    
              -  Aplastic anemia or PRCA (acquired or congenital) in subjects associated with
                 transfusion dependence and/or neutropenia who are not candidates for or who have
                 failed immunosuppressive therapy
    
              -  RA or RARS MDS subjects who have associated transfusion dependence and/or neutropenia.
    
            Ability to comprehend the investigational nature of the study and provide informed consent.
            The procedure will be explained to subjects age 8-17 years with formal consent being
            obtained from parents or legal guardian.
    
            Availability of HLA identical or single HLA locus mismatched family donor
    
            INCLUSION CRITERIA - Donor:
    
            HLA identical or single HLA mismatched family donor
    
            Age greater than or equal to 2 up to 80 years old
    
            Weight greater than or equal to 18 kg
    
            Ability of donor or guardian of donor to comprehend the investigational nature of the study
            and provide informed consent.
    
            EXCLUSION CRITERIA - Recipient - any of the following:
    
            Pregnant or lactating
    
            Group A: age less than 10 or greater than 75 (multiple myeloma age less than 8 or greater
            than 65);
    
            Group B: Age less than 8 or greater than 80 years.
    
            ECOG performance status of 3 or more (See NIH Bone and Marrow Consortium Supportive Care
            Guidelines for Allogeneic Hematopoietic Stem Cell Transplant Recipients -
            http://intranet.cc.nih.gov/bmt/_pdf/ECOG_Karnofsky_Lansky_Scales.pdf)
    
            Psychiatric disorder or mental deficiency severe as to make compliance with the BMT
            treatment unlikely and making informed consent impossible
    
            Major anticipated illness or organ failure incompatible with survival from PBSC transplant
    
            Diffusion capacity of carbon monoxide (DLCO) less than 40% predicted.
    
            Left ventricular ejection fraction: less than 30%.
    
            Serum creatinine greater than 2.5 mg/dl or creatinine clearance less than 50 cc/min by 24
            hr urine collection
    
            Serum bilirubin greater than 4 mg/dl, transaminases greater than 5x upper limit of normal,
    
            Other malignant diseases liable to relapse or progress within 5 years.
    
            EXCLUSION CRITERIA - Donor - any of the following:
    
            Pregnant or lactating
    
            Donor unfit to receive G-CSF and undergo apheresis (uncontrolled hypertension, history of
            congestive heart failure or unstable angina, thrombocytopenia)
    
            HIV positive donor. Donors who are positive for hepatitis B (HBV), hepatitis C (HCV) or
            human T-cell lymphotropic virus (HTLV I/II) will be used at the discretion of the
            investigator following counseling and approval from the recipient
          
    Maximum Eligible Age:80 Years
    Minimum Eligible Age:2 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Transplant related mortality at 200 days.
    Time Frame:200 days
    Safety Issue:
    Description:Transplant related mortality at 200 days.

    Secondary Outcome Measures

    Measure:To determine the incidence and severity of acute and chronic graft-versus-host disease (GVHD).
    Time Frame:Study End
    Safety Issue:
    Description:

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Active, not recruiting
    Lead Sponsor:National Heart, Lung, and Blood Institute (NHLBI)

    Trial Keywords

    • Graft vs. Host Disease
    • Peripheral Blood Stem Cells
    • Non-Myeloablative Bone Marrow Transplantation
    • Engraftment
    • Graft-Versus-Leukemia

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