Donor Stem Cell Transplantation for Congenital Immunodeficiencies
Condition: Inherited Immune Deficiencies
MeSH terms: Immunologic Deficiency Syndromes
Study type: Interventional
Phase: Early Phase 1

Summary: 
      This study uses transplantation to treat patients with problems in their immune system. The
      immune system cells come from the bone marrow where they grow from special cells called stem
      cells. Giving patients stem cells from someone else may help to cure many patients with
      certain immune diseases. This is called 'bone marrow transplantation'. This procedure can
      have side effects that are life-threatening. To try to make transplantation safer we are
      using lower doses of the medications used in preparing the patient for the transplant.

      'Conditioning' treatments are given to patients to create space in their bone marrow. This
      lets the cells of the donor go into the bone marrow and produce normal immune cells. This
      study will use lower doses of a drug called busulfan and lower doses of radiation than what
      are currently being used in other kinds of bone marrow transplantation for other diseases.

      Another problem that can occur with bone marrow transplantation is 'graft-versus-host
      disease'. This happens when the cells of the donor attacks different parts of the patient s
      body. This study will use a medicine called sirolimus instead of the usual medicine,
      cyclosporine, to prevent graft-versus-host disease.

      To go onto this study, you must have:

        1. A severe immune deficiency, such as chronic granulomatous disease or leukocyte adhesion
           deficiency.

        2. Have problems from the disease that call for stem cell transplantation.

        3. You must also be between the ages of 2 and 40 years.

      Two groups of patients are included in this study:

        1. Patients who have a brother or sister that have stem cells that match the patient. This
           is known as an allogeneic matched sibling transplant.

        2. Patients who do not have a matched sibling donor but have a donor that matches in the
           National Marrow Donor Program. This is know as matched unrelated donor transplantation.

      Patients will have the following procedures:

        -  To create space in the bone marrow, patients are given two drugs, Campath-1H and
           busulfan. To prevent the body from getting rid of the donated cells, patients are given
           sirolimus. On the day before the BMT, patients in the matched unrelated donor group also
           receive a low-dose of whole-body radiation. This will further improve the chances that
           the patients body will accept the donor cells.

        -  Patients will get the donor stem cells through an intravenous (IV) line that goes into a
           vein in their body. The cells make their way to the bone marrow space and slowly refill
           the marrow over the next several weeks. Patients will usually stay in the hospital for
           30 days after the transplant.

        -  For the first 3 months after the transplant, patients are watched closely. The patients
           will have frequent visits to the clinic. During these visits the patient will have a
           physical examination and blood tests. The doctor and nurse will also check any symptoms
           the patient may have. At day 100 after the transplant a sample of bone marrow is taken.

        -  Patients will continue to be followed periodically for at least 5 years after the
           transplant.
    

Detailed description: 
      This is an open-label pilot study of HLA-matched allogenic and matched unrelated donor (MUD)
      hematopoietic stem cell (HSC) transplant (also referred to as peripheral blood stem cell
      (PBSC) or bone marrow transplant (BMT)) for patients with X-linked severe combined immune
      deficiency (XSCID). XSCID is caused by mutations in the IL2RG gene encoding the interleukin
      receptor signaling gamma chain [gamma c]). The study population are older children (greater
      than or equal to 2 years of age) and adults (less than or equal to 40 years of age) who are
      experiencing deteriorating and/or dysfunctional immunity and any of a constellation of severe
      or chronic medical problems warranting transplantation. The study is designed to evaluate
      whether the use of uniquely designed transplant conditioning and graft-versus-host disease
      (GvHD) prevention regimens achieve sufficient engraftment of donor hematopoietic stem cells
      (HSCs) to facilitate robust restoration of cellular immunity (T cell/NK cell number and
      function) including thymic function, and humoral immunity (B cell number and function) while
      at the same time enhancing tolerance of the donor graft in a fashion that reduces the
      occurrence of GvHD but not at significantly enhancing the risk of post-transplant virus
      infection. One target population are XSCID patients who received matched sibling or
      haploidentical lymphocyte-depleted transplants as infants with little or no myeloid
      conditioning, resulting in variable restoration of T cell immunity, but little or no
      restoration of NK or B cell immunity. Another target population are XSCID patients with
      partial production or function of gamma c or XSCID patients with clonal somatic reversion of
      the mutation in the IL2RG gene, who have less severe immune deficiency in childhood. A subset
      of patients from all of these target XSCID populations may experience progressive
      deterioration of immune function leading to acute and chronic medical problems that warrant
      consideration of allogeneic or MUD transplant to restore immunity.

      The conditioning and GvHD prevention regimens for this HSC transplant protocol are designed
      to use mobilized peripheral blood stem cells (PBSC) or bone marrow (BM) (if mobilization is
      not possible) from either an HLA-matched related sibling donor (alloPBSC) as first choice or
      from an HLA matched unrelated donor (MUD) for those without an appropriate HLA-matched
      related sibling donor. If there is no appropriately matched sibling donor nor MUD adult donor
      available, then an appropriately matched cord blood from the cord blood registries may be
      used for small children XSCID recipients. For the alloPBSC (or alloBM) transplantation
      (referred to as Group 1), we propose using a busulfan-based, nonmyeloablative conditioning
      regimen combined with horse Anti-human Thymocyte Globulin (h-ATG) immune suppression
      conditioning plus post-transplant sirolimus for tolerance inducing immunosuppressant to
      prevent GvHD. For the MUD or unrelated cord blood transplantation (referred to as Group 2),
      we will use a similar conditioning regimen, with a few modifications that include addition of
      total body irradiation with shielding and reduction in busulfan dosing, changes designed to
      address the increased risk of graft rejection with HLA-matched but unrelated donor HSC.
    

Intervention name(s): Campath 1H; Busulfan; Horse Anti-human Thymocyte Globulin (h-ATG); Total Body Irradiation (TBI); Sirolimus or equivalent based on response
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Conditioning with Campath 1 mg/kg total dose given intravenously over 5 days; Busulfan 5-10 mg/kg total dose given intravenously over 2 days based on patient underlining immune deficiency disorder; Conditioning with h-ATG 40 mg/kg total dose over 4 days given intravenously; TBI 200 - 300 centigray (cGy) in two fractions at day -2 or same day depending on patient underlining immune deficiency disorder; post Transplantation immunosuppressants
Other intervention name(s): alemtuzumab; Busulfex® (IV formulation); ATG; TBI; Rapamune®/rapamycin
Intervention MeSH terms: Sirolimus; Busulfan; Alemtuzumab
Allocation: Non-Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: MUD Transplant; Transplant; AlloPBSC; HLA Matched Transplant; BMT; Congenital Immunodeficiency; Bone Marrow Transplant