Ultra-Low Dose IL-2 Therapy as GVHD Prophylaxis in Haploidentical Allogeneic Stem Cell Transplantation
Condition: Acute Lymphoblastic Leukemia (ALL); Acute Myelogenous Leukemia (AML); Chronic Lymphocytic Leukemia (CLL); Chronic Myelogenous Leukemia (CML); MDS
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - Stem cell transplantation from a partially matched donor can lead to graft-versus-host
      disease (GVHD). Researchers want to learn how to improve these transplantations.

      Objective:

      - To see if very low doses of Interleukin-2 after a partially matched transplantation prevent
      GVHD.

      Eligibility:

        -  Recipients: age 18 65, with certain bone marrow or lymphatic system diseases and an
           available family member with partial tissue match.

        -  Donors: age 18 80.

      Design:

        -  Recipients will be screened with medical history, physical exam, and many tests
           including blood and tissue tying.

        -  Donors will be screened with medical history, physical exam, blood tests and tissue
           typing.

        -  Recipients will stay in the hospital 3 6 weeks.

        -  All participants will have apheresis. Blood is drawn from one arm, run through a machine
           that collects white blood cells, then returned into the other arm.

        -  Recipients will have:

        -  Intravenous (IV) line placed under the skin and into a neck vein, to stay throughout
           transplant and recovery. They may also have a catheter inserted for collecting immune
           cells.

        -  Bone marrow sample taken by needle. They will have 3 more after transplant.

        -  Donors will have:

        -  Filgrastim injected once daily for 5 6 days.

        -  Stem and immune cells collected by another apheresis.

        -  Recipients will get:

        -  Eight 30-minute doses of radiation, sitting at a machine.

        -  Donor immune cells by IV, 6 days before the transplant day.

        -  Chemotherapy drugs by IV.

      <TAB><TAB>- Donor stem cells by IV on transplant day.

        -  After transplant, recipients will give self-injections of very low doses of
           Interleukin-2 once daily for about 12 weeks.

        -  Before and after transplant, recipients will get medicine to suppress the immune system
           and antibiotics to prevent infections

        -  Recipients must stay near NIH for 3 6 months after transplant.

        -  All recipients and donors will have 3 years of follow-up.
    

Detailed description: 
      Although allogeneic stem cell transplantation (allo-SCT) is a curative option for many
      hematologic malignancies, not all have a suitable donor. Haploidentical peripheral blood stem
      cell transplantation (haplo-SCT) has the advantage of immediate availability, higher stem
      cell dose, and feasibility of repeated cell collections for generating lymphocyte infusions
      to treat or prevent relapse or infection. However, haplo-SCT incurs a risk of bidirectional
      rejection with either severe graft versus host disease (GVHD) or graft rejection by the
      recipient. Therefore it is important to develop novel strategies to optimize the outcome of
      haplo-SCT. Designing a haplo-SCT that incorporates the concepts of modulating the immune
      system and allowing the opportunity for graft manipulation and/or adoptive immunotherapy may
      improve the treatment outcome. To achieve this, we are first interested in studying the
      immune modulatory effect of ultra-low dose Interleukin 2 (ULD IL-2) as GVHD prophylaxis.

      This is an investigator initiated pilot study to determine the safety and feasibility of ULD
      IL-2 as GVHD prophylaxis in haploidentical allogeneic stem cell transplantation for patients
      with hematologic malignancies. Because GVHD has previously been associated with low numbers
      of circulating CD4+ CD25+FOXP3+ regulatory T cells (T(regs)), research efforts in increasing
      T(regs) either ex-vivo with adoptive transfer of T(regs) or in vivo using immunomodulatory
      agents such as IL-2, have shown promise in reducing incidences of GVHD.

      The primary objective of this study is to evaluate safety and feasibility. Secondary
      objectives are to determine the incidences of acute and chronic GVHD, engraftment, overall
      survival, transplant related mortality, and relapse.

      We will adopt the 2 step haplo-SCT method developed by Grosso et. al1 to study our method of
      GVHD prophylaxis. This 2 step approach, in which the lymphoid and myeloid portions of the
      graft are given in two separate steps in order to control and optimize T-cell, has already
      been published as a feasible and safe platform for haplo SCT for patients with hematologic
      malignancies and has been adopted by the Jefferson University Hospital (PA, USA), where they
      continue to treat patients under this protocol. As an additional GVHD prophylaxis, we will
      use sirolimus, an previously established GVHD prophylaxis which may work with ULD IL-2
      synergistically to increase T(regs) .

      The haploidentical donor will be mobilized by G-CSF and undergo one apheresis to collect
      lymphocytes and CD34+ stem cell product after Miltenyi CD34+ selection. The products will be
      cryopreserved until the time of transplantation. Recipients will receive a myeloablative
      conditioning regimen of fludarabine and total body irradiation (TBI) on days -10 to -6. After
      the last fraction of TBI, a donor lymphocyte infusion (DLI) product (2 times 10(8) CD3+/kg)
      will be given. Cyclophosphamide will be given on days -3 and -2, followed by CD 34+ selected
      donor stem cell product infused on day 0. Sirolimus will be initiated on day -1 until day+60.
      ULD-IL2 (100,000 IU/m2) will give subcutaneously daily for 12 weeks starting day +1.

      This study will evaluate 14 recipients (ages greater than or equal to 18 - less than or equal
      to 75; planned accrual up to 20 recipient in event of replacement) with hematologic
      malignancies meeting indication for transplant but who do not have matched related or
      unrelated donor available. Safety will be monitored continuously with a stopping rule for
      toxicity based on the treatment-related serious adverse event rate (TRSAE). Safety monitoring
      will continue until at least 114 days after transplantation, and recipients experiencing
      adverse events will be monitored until toxicity resolution or stabilization. Stopping rule is
      defined as nonrelapse mortality and steroid refractory GVHD during the period of safety
      monitoring for ULD IL-2. Recipients will be followed for up to 1 year to evaluate the
      incidences of acute and chronic GVHD, engraftment, overall survival, transplant related
      mortality, and relapse.
    

Intervention name(s): CliniMACS CD34 selection system; ULD IL-2
Intervention type(s): Device; Biological
Intervention description(s): Stem cells will be selected with the CliniMACS system before transplant.; sterile, white to off-white, preservative-free, lyophilized powder suitable for IV infusion upon reconstitution and dilution
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Acute Lymphoblastic Leukemia (ALL); MDS; Chronic Myelogenous Leukemia (CML); Chronic Lymphocytic Leukemia (CLL); Acute Myelogenous Leukemia (AML)