Nonmyeloablative Allogeneic Stem Cell Transplantation From HLA-Matched Unrelated Donor for the Treatment of Hematologic Disorders

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Brief Title

Nonmyeloablative Allogeneic Stem Cell Transplantation From HLA-Matched Unrelated Donor for the Treatment of Hematologic Disorders

Official Title

Nonmyeloablative Allogeneic Stem Cell Transplantation From HLA-Matched Unrelated Donor for the Treatment of Hematologic Disorders

Brief Summary

      Allogeneic stem cell transplantation may provide long-term remissions for some patients with
      hematological malignancies. However, allogeneic transplantation is associated with a
      significant risk of potentially life threatening complications due to the effects of
      chemotherapy and radiation on the body and the risks of serious infection. In addition,
      patients may develop a condition called Graft versus host disease that arises from an
      inflammatory reaction of the donor cells against the recipient's normal tissues. The risk of
      graft versus host disease is somewhat increased in patients who are receiving a transplant
      from an unrelated donor.

      One approach to reduce the toxicity of allogeneic transplantation is a strategy call
      nonmyeloablative or "mini" transplants. In this approach, patients receive a lower dose of
      chemotherapy in an effort to limit treatment related side effects. Patients undergoing this
      kind of transplant remain at risk for graft versus host disease particularly if they receive
      a transplant from an unrelated donor. The purpose of this research study is to examine the
      ability of a drug called CAMPATH-1H to reduce the risk of graft versus host disease and make
      transplantation safer. CAMPATH-1H binds to and eliminates cells in the system such as T cells
      that can cause graft versus host disease (GvHD). As a result, earlier studies have shown that
      patients who receive CAMPATH-1H with an allogeneic transplant have a lower risk of GvHD. In
      the present study, we will examine the impact of treatment with CAMPATH-1H as part of an
      allogeneic transplant on the development of GvHD and infection. In addition, we will study
      the effects of CAMPATH-1H on the immune system by testing blood samples in the laboratory.
    

Detailed Description

      Allogeneic Transplantation and the Graft versus Disease Effect Over the past three decades,
      the transplantation of allogeneic marrow grafts has emerged as a uniquely effective therapy
      for patients with hematologic malignancies, marrow failure syndromes, and other lethal
      genetic and acquired diseases of hematopoiesis.1-9 Allogeneic transplantation potentially
      results in curative outcomes for patients with acute leukemia, chronic myelogenous leukemia,
      aplastic anemia, and lymphoid malignancies for whom standard therapies may not be effective.
      The anti-tumor effect mediated by allogeneic lymphocytes is an essential factor in
      eliminating residual disease post-transplant and preventing subsequent relapse.10-14 Numerous
      observations in patients undergoing allogeneic bone marrow transplant for hematological
      malignancies have convincingly demonstrated evidence of a graft-versus-disease (GVD) effect
      mediated by lymphocytes present in the donor graft. Supportive evidence for the importance of
      this phenomenon includes: 1) relapse rates of syngeneic BMT recipients are greater than in
      allogeneic recipients; 2) allogeneic BMT recipients who do not develop graft-versus-host
      disease (GVHD) have a significantly greater relapse rate than allogeneic BMT-recipients who
      do develop GVHD; 3) complete remissions have been observed in patients with relapsed disease
      after allogeneic BMT in association with flares of GVHD; 4) recipients of T-cell depleted
      BMT, a method of GVHD prophylaxis, relapse more frequently than recipients of non-T-cell
      depleted BMT; and 5) the use of an unrelated marrow graft in both non-T-cell depleted and
      T-cell depleted allogeneic BMT is associated with a reduced incidence of relapse.

      The most direct evidence for the role of allogeneic lymphocytes in mediating an antitumor
      effect has been that patients who experience relapse following allogeneic transplantation may
      be successfully treated by the infusion of donor leukocytes.15-22 Summarizing the European
      experience, Kolb et al reported that the over 80% of patients with CML who relapse into the
      chronic phase following transplant may achieve a second complete remission after the infusion
      of donor leukocytes infusion in treating relapsed CML following transplant. Complete
      remissions with the use of DLI for the treatment of relapsed acute leukemias, chronic
      lymphocytic leukemia, myelodysplastic syndromes, multiple myeloma, and polycythemia vera,
      although lower than those seen in CML, have been well demonstrated by several groups.
      Additionally, a potent graft versus disease effect associated with allogeneic transplantation
      and donor leukocyte infusion has been observed in patients with non-Hodgkin's lymphoma and
      multiple myeloma.23-25 Thus, allogeneic transplantation offers a uniquely effective approach
      to eradicating hematological malignancy in which myeloablative therapy results in profound
      tumor cytoreduction and donor lymphocytes subsequently eliminate minimal residual disease via
      immunological mechanisms.

      Limitations in the Application of Allogeneic Transplantation The use of allogeneic BMT has
      been limited by the significant treatment related morbidity and mortality associated with
      this procedure. Patients often experience significant organ dysfunction as a result of
      regimen related toxicity. Moderate to severe graft versus host disease occurs in
      approximately 40% of patients undergoing matched sibling conventional transplants and
      increases in incidence in older patients and those receiving unrelated or mismatched
      grafts.26-28 Opportunistic infections due to immune dysfunction remains a major source of
      morbidity and mortality particularly in older patients. The application of allogeneic
      transplantation is therefore restricted to younger patients with normal underlying organ
      function. Because the median age of many hematological malignancies may exceed 60 years of
      age, a majority of patients with these disorders are not considered candidates for this
      procedure.

      The difficulty in applying allogeneic transplantation in patients with hematological
      malignancies is particularly highlighted in patients with lymphoid malignancies such as
      multiple myeloma, chronic lymphocytic leukemia and low-grade lymphoma. These disorders are
      incurable with standard dose chemotherapy but may follow a relatively indolent course for
      several years before patients develop progressive chemoresistant disease. Allogeneic
      transplantation has been associated with long-term disease free survival in these settings
      but is associated with a high incidence of upfront transplant related mortality. Strategies
      to limit transplant related toxicity are essential to translate the decreased incidence of
      relapse into an improvement in overall survival in this patient population.

      Nonmyeloablative Allogeneic Transplantation One approach to limit the toxicity of allogeneic
      transplantation has been the use of nonmyeloablative regimens preceding the infusion of
      allogeneic cells.29-33 With this strategy, patients receive immunosuppressive therapy that
      allows for the engraftment of donor cells without the immediate eradication of patient
      hematopoiesis. The primary mechanism by which the underlying disease is eradicated is not
      through chemotherapy-mediated cytoreduction, but rather through the donor lymphocyte mediated
      graft versus tumor effect. As a result, patients experience far less regimen related
      toxicity. Therefore, the adoption of this strategy may allow for the use of allogeneic
      transplantation in disease settings and patient populations for which it had not been readily
      applicable in the past.

      Over the past several years, the use nonmyeloablative transplant has rapidly expanded.
      Several reduced intensity conditioning regimens have been developed including fludarabine and
      cyclophosphamide; fludarabine and melphalan; fludarabine, anti-thymocyte globulin and low
      dose busulfan; and fludarabine and low dose TBI. Investigators have demonstrated the
      feasibility of this treatment approach with the majority of patients demonstrating donor
      engraftment, decreased regimen related toxicity, and graft mediated regression of disease. In
      some studies, patients demonstrate a period of mixed donor/host chimerism in which the
      infusion of donor lymphocytes is associated with achievement of complete donor chimerism.

      Although regimen related toxicity is decreased following reduced intensive conditioning
      regimens, graft versus host disease and opportunistic infections remain a significant source
      of morbidity and mortality following nonmyeloablative allogeneic transplantation. The impact
      of nonmyeloablative transplantation on immunological reconstitution has not been fully
      defined. Persistence of host antigen presenting cells in the post-transplant period may
      increase the incidence of GVHD due to the presentation of alloantigens to donor T cells. In
      contrast, residual host cellular immunity may provide enhanced protection against infectious
      pathogens and allow for more rapid education of donor lymphocytes. Of note, CMV infections
      remain common in this population but present later in the post-transplant period
      characteristically following the attainment of full donor chimerism.34

      Nonmyeloablative Allogeneic Transplantation in Conjunction with CAMPATH Therapy One approach
      to reduce the incidence of GVHD following nonmyeloablative transplantation is the addition of
      CAMPATH to the preparative regimen to deplete T cells from both the recipient and the
      incoming graft.35 CAMPATH-1H (Alemtuzumab) is a recombinant DNA-derived humanized monoclonal
      antibody directed against the cell surface glycoprotein, CD52; produced in mammalian cell
      (Chinese hamster ovary) suspension.36-39 Campath-1H is indicated for the treatment of B-cell
      chronic lymphocytic leukemia in patients who have been treated with alkylating agents and
      have failed fludarabine therapy. Campath-1H has been used in patients with autoimmune
      neutropenia, non-Hodgkin's lymphoma, rheumatoid arthritis, and vasculitis. It has also been
      used to prevent graft-versus-host disease in patients receiving stem cell transplantation.
      GVHD prophylaxis was with cyclosporin A alone.

      Mackinnon et al investigated a nonmyeloablative conditioning regimen in 47 patients with
      hematological malignancies receiving allogeneic bone marrow stem cells from matched,
      unrelated donors.40 The majority of patients had high-risk features, including having failed
      a prior transplantation (29 individuals). Twenty of the transplants were mismatched for HLA
      class I and/or class II alleles. They added CAMPATH-1H to a preparative regimen of
      fludarabine and melphalan and administered either GCSF mobilized peripheral blood stems or
      unmanipulated bone marrow from matched unrelated donors. Primary graft failure occurred in
      only 2 of 44 evaluable patients (4.5%). Chimerism studies in 34 patients indicated that the
      majority (85.3%) attained initial full donor chimerism. Only 3 patients developed grade III
      to IV acute GVHD, and no patients have yet developed chronic extensive GVHD. The estimated
      probability of nonrelapse mortality at day 100 was 14.9% (95% confidence interval [CI],
      4.7%-25.1%). With a median follow-up of 344 days (range, 79-830), overall and
      progression-free survivals at 1 year were 75.5% (95% CI, 62.8%-88.2%) and 61.5% (95% CI,
      46.1%-76.8%), respectively. It was subsequently reported that a significant subset of
      patients demonstrated evidence of CMV reactivation.41 However, the presence of CMV did not
      negatively impact survival. While the investigators noted a need for longer follow-up of this
      cohort, they felt that this preparative regimen incorporating in vivo CAMPATH-1H was
      associated with durable engraftment and minimal treatment related toxicity.

      Immune Reconstitution Following Allogeneic Transplantation Allogeneic transplantation is
      associated with a period of immune dysfunction that characteristically persists for at least
      1 year post-transplant.42,43 Immune recovery is dependent on the reconstitution of elements
      of humoral and cellular immunity and their reeducation in the transplant recipient. It is
      particularly delayed in recipients of an unrelated or T cell depleted graft. The
      post-transplant period is characterized by decreased levels of helper T cells, an associated
      inversion of the C4:CD8 ratio, and the blunting of T cell responses to mitogenic stimuli and
      recall antigens.44-46 Humoral immune dysfunction is associated with the loss of protective
      antibody levels to bacterial and viral pathogens, decreased levels of circulating
      immunoglobulins particularly of the IgG2 subtype, and the reduced complexity in the pattern
      of the immunoglobulin gene rearrangement.47,48

      Dendritic Cells and Immune Reconstitution The nature of the recovery of antigen presenting
      cells such as dendritic cells are likely to play an essential role in the reconstitution of
      posttransplant immunity and host/donor tolerance. Dendritic cells (DC) form a complex network
      of antigen presenting cells that play a vital role in the induction of primary immunity as
      well as the modulation of tolerance.49.50 DC are the most potent antigen presenting cells and
      are uniquely able to induce primary immune responses against novel antigens through the rich
      expression of costimulatory and adhesion molecules. DC generated from nonmyeloid lineages or
      in an immature state may mediate immune tolerance and direct T cell responses towards a TH2
      phenotype. Distinct DC populations have been identified in the peripheral blood that are
      differentiated by the presence of myeloid (CD11c) or plasmacytoid (CD123) markers.51,52 DC2
      (plasmacytoid) cells are characterized by expression of type 2 cytokines and thus initiate a
      Th2 response, whereas DC1 (myeloid) cells initiate Th1 cytokine response. DC isolated from
      patients with malignancy demonstrate functional deficiencies that potentially contribute to
      lack of tumor recognition by host immunity. Little is known about DC engraftment or
      phenotypic and functional characteristics after allogeneic transplantation. The interactions
      of DC with effector populations is likely to be unique following nonmyeloablative
      conditioning given the presence of mixed donor/recipient chimerism that may characterize the
      post-transplant period.

      In a murine model, Shlomchik et al demonstrated that persistence of host antigen presenting
      cells post-transplant was associated with the development of GVHD.53 In this model, host DC
      capable of presenting minor histocompatibility antigens to infused donor T-cells potentially
      initiate T-cell activation and an associated Th-1 cytokine cascade implicated in the
      pathogenesis of aGVHD. The relative levels of DC1/DC2 subsets in the hematopoietic graft
      strongly correlate with the incidence of graft versus host disease and incidence of relapse.
      G-CSF mediated stem mobilization is associated with increased levels of DC2 populations.54 In
      an animal model, the infusion of splenocytes and bone marrow from donors treated with G-CSF
      was associated with emergence of a DC2 phenotype, and thus, tolerance.55 In one study of
      patients undergoing allogeneic transplantation, the presence of increased numbers of DC2
      cells in the hematopoietic graft was associated with a decrease in GVHD, and increase in
      relapse and poorer outcomes.56 The impact of DC chimerism, patterns of reconstitution, and
      presence of DC1 and DC2 populations following nonmyeloablative allogeneic transplantation has
      not been well studied. Recent studies have demonstrated that CD52 is expressed by some DC
      populations and suggest that CAMPATH therapy may impact antigen presentation by depletion of
      DC populations from the host.57-59 Depletion of host derived DC may decrease in the incidence
      of GVHD, while presence of donor DC is likely essential for the reconstitution of cellular
      immunity.

      In the proposed study, we intend to examine the application of a CAMPATH based preparative
      regimen in patients with hematological malignancies undergoing nonmyeloablative allogeneic
      stem cell transplantation from an unrelated donor. The study will involve patients who would
      otherwise not be candidates for a conventional myeloablative conditioning regimen because of
      age or organ dysfunction and who do not have HLA-matched sibling donors. It will also include
      patients suffering from lymphoid malignancies such as low-grade lymphoma, CLL, and multiple
      myeloma that have experienced unacceptably high transplant related mortality with
      conventional allogeneic transplantation. Inclusion of both myeloid and lymphoid hematological
      malignancies in the study cohort will optimize accrual and will not limit the ability to the
      ability to pursue the study goals. Patterns of engraftment, graft versus host disease, immune
      reconstitution, and donor/host chimerism are primarily determined by the preparative regimen
      and transplant strategy and should not differ considerably within the patient cohort.

      For the conditioning regimen, we have chosen an intermediate dose of cyclophosphamide and
      fludarabine in an attempt to minimize the incidence of graft rejection without increasing the
      frequency of treatment related morbidity and mortality. Based on the work of MacKinnon et al,
      we will add CAMPATH-1H to the preparative regimen to further decrease the incidence of GVHD
      and promote donor stem cell engraftment. Following this regimen circulating levels CAMPATH
      are present for several weeks post-transplant and may excessively deplete donor T cells as
      well as eliminate DC populations from the donor graft. In an effort to improve
      post-transplant immune reconstitution and limit risks of infection and relapse, we have
      chosen a lower dose of CAMPATH and will follow levels at serial time points post-transplant.

      The principal endpoints of the trial will include defining: 1) the treatment related toxicity
      profile and post-transplant hematopoietic recovery 2) the incidence and severity of CMV
      infection and acute and chronic GVHD 3) the phenotypic and functional characteristics of DC
      and T cell populations post-transplant; and 4) the patterns of donor/host chimerism in DC and
      T cell populations and its correlation with GVHD. As a secondary endpoint, 1 and 2 year DFS
      and OS will be determined.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Primary objective of study is to determine the safety of non-myeloablative allogenic stem cell transplantation from matched unrelated donors in patients with hematologic malignancies with a focus on the incidence of treatment-related mortality.

Secondary Outcome

 Secondary clinical endpoints includes; incidence of graft failure or rejection; incidence and severity of acute and chronic GVHD; tumor response, and long-term overall and disease-free survival.

Condition

AML

Intervention

Cyclophosphamide; Fludarabine; Cyclosporin; CAMPATH-1H (Alemtuzumab); GM-CSF


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

25

Start Date

December 2002

Completion Date

January 2007

Primary Completion Date

January 2007

Eligibility Criteria

        Inclusion Criteria:

          -  Age less than 65 years. There is no lower age limit. Patients 65 years and older will
             be accrued on a case-by-case basis to this protocol, after discussion and approval by
             the principal investigator. The acceptance to this protocol for such patients would be
             based on the absence of coexisting medical problems, which would seriously compromise
             the patient's ability to tolerate the known morbidity and risks of bone marrow
             transplantation.

          -  Patients must have a 5/6 or 6/6 HLA matched, unrelated donor of bone marrow stem
             cells.

          -  Each patient must be willing to participate as a research subject and must sign an
             informed consent form after having been advised as to the nature and risk of the study
             prior to entering the protocol. Parents or legal guardians of patients who are minors
             will sign the informed consent form after being advised of the nature and risks of the
             study. Attending physicians in the Bone Marrow Transplant Service will enroll patients
             to this study and will obtain written consents.

        Eligibility Criteria - Donor

          -  5/6 or 6/6 HLA matched with the recipient as determined by molecular testing. Donors
             will be identified through the National Marrow Donor Program for unrelated donors.

          -  Donor selection will be performed as outlined in the donor selection SOP's. In
             patients who have more than one potential donor preference will be given to donors who
             have no evidence of CMV exposure (if the recipient is CMV-), those who are younger and
             those who are male. Selection of an unrelated donor from the NMDP registry will
             proceed according to the donor selection SOP. Molecular testing of HLA-A, B, and DR
             alleles will identify potential donors and the American Red Cross HLA lab will confirm
             all typing. Donor selection will be coordinated with transplant physician and the HLA
             laboratory director. Preference will be given to donors who are 6/6 molecular matches,
             those who are CMV- (if the recipient is CMV-), those who are younger, and males.

        Exclusion Criteria:

          -  Active CNS leukemia involvement.

          -  Female patients who are pregnant or breast feeding

          -  Karnofsky performance status < 70%, (appendix 1).

          -  Left ventricular ejection fraction of < 40%.

          -  Serum creatinine > 1.5 X normal

          -  Patients seropositive for HIV; HTLV -1, or with evidence of chronic active hepatitis
             as demonstrated by detection of hepatitis surface antigen in the serum

          -  Patients with serologic evidence of hepatitis B or C exposure will undergo liver
             biopsy to assess for presence of active hepatitis or fibrosis and quantification of
             risk of proceeding with transplant

          -  Patients not providing informed consent.

          -  Patients with known hypersensitivity to E. Coli derived products.

          -  SGOT and SGPT > 2.5 x ULN, unless thought to be disease related

          -  Total bilirubin > 2.0 mg/dl, with direct bilirubin > 0.5 mg/dl
      

Gender

All

Ages

N/A - 65 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

David F McDermott, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00533923

Organization ID

2002P000219


Responsible Party

Principal Investigator

Study Sponsor

Beth Israel Deaconess Medical Center

Collaborators

 Bayer

Study Sponsor

David F McDermott, MD, Principal Investigator, Beth Israel Deaconess Medical Center


Verification Date

July 2016