Evaluating the Safety of G-CSF Mobilization in Individuals With Beta Thalassemia Major
Condition: Beta-Thalassemia
MeSH terms: Thalassemia; beta-Thalassemia
Study type: Interventional

Summary: 
      Beta thalassemia major is a serious genetic disease of the blood. Treatments are limited, and
      although a bone marrow transplant from a compatible donor can be curative, only a limited
      percentage of individuals with this disease have a matched donor available. A long-term goal
      of study researchers is to develop a gene transfer process as a method of curing beta
      thalassemia major. Gene transfer involves obtaining blood stem cells from an individual,
      adding a normal globin gene to the stem cells, and putting the cells back into the
      individual.

      Before gene transfer methods can be attempted in individuals with beta thalassemia major, a
      safe method of obtaining blood stem cells needs to be developed. The purpose of this study is
      to investigate the safety and feasibility of collecting peripheral blood stem cells (PBSC)
      from individuals with beta thalassemia major. Research participants will be given G-CSF
      (filgrastim) for several days to increase the number of stem cells in the blood, a process
      called "mobilization." After mobilization, participants will undergo a procedure called
      apheresis to remove the white blood cells. Researchers in the laboratory will purify the stem
      cells from the mixture and test methods of putting a normal globin gene into the stem cells.
      Half of the participants will receive hydroxyurea (HU) prior to G-CSF mobilization. HU is
      used in splenectomized patients to attempt to reduce the risk of clotting during
      mobilization. In non-splenectomized patients, HU is given in an attempt to decrease the size
      of the spleen.
    

Detailed description: 
      Primary Objective: To determine the safety of PBSC mobilization with G-CSF, with or without
      HU pretreatment in adults with beta thalassemia major.

      Secondary Objective: To determine the number of CD34+ stem/progenitor cells that are
      mobilized under these conditions, as well as the ability of these cells to be transduced with
      a recombinant lentivirus vector for beta-globin and engraft immunodeficient mice.

      Study Design: The ability of G-CSF to safely and effectively mobilize PBSC in adults with
      beta thalassemia major will be assessed in 12 splenectomized and 12 non-splenectomized
      patients. Of the 12 splenectomized patients, 6 will be treated with HU and G-CSF, and 6 will
      be treated only with G-CSF. Likewise, of the 12 non-splenectomized patients, 6 will be
      treated with HU and G-CSF, and 6 will be treated only with G-CSF. G-CSF mobilized
      participants will undergo leukapheresis on 2 consecutive days, with a target yield of 2
      million CD34+ cells per kg of body weight. Safety will be assessed by monitoring for
      study-related toxicity. Efficacy will be assessed by measuring the total number of CD34+
      cells, the ability of these cells to be transduced with a recombinant lentivirus vector for
      beta-globin, and the ability of these cells to engraft immunodeficient mice.

      Population: Adults with beta thalassemia major.

      Sample size: A total of 24 subjects will be enrolled: 12 splenectomized participants and 12
      non-splenectomized participants.

      End Points: This is a pilot study and no specific hypotheses are being tested. However, the
      study will allow for qualitative comparisons if outcomes between the various arms are
      markedly different. For example, the study will provide qualitative data on the safety and
      feasibility of utilizing HU and G-CSF to mobilize stem cells in individuals with beta
      thalassemia major. The study will be completed upon full enrollment, or when stopping
      criteria are met within specific study arms.
    

Intervention name(s): Hydroxyurea
Intervention type(s): Drug
Intervention description(s): Hydroxyurea: Subjects will be treated for one month with hydroxyurea at a starting dose of 10 mg/kg orally (closest approximation to 500 mg capsule, alternate day dosing, e.g. 500 alternating with 1000 to achieve 750 mg average daily dose), once daily, with a gradual dose escalation up to 20 mg/kg (in non-splenectomized patients) and up to 25 mg/kg (in splenectomized patients).
G-CSF: G-CSF will be administered subcutaneously. In general, G-CSF will be administered at 10μg/kg/day (5μg/kg on a twice a day schedule) for at least 4-5 days before leukapheresis and for 1-2 additional days during collections. For the splenectomized patients who are not receiving HU pretreatment, and for the splenectomized patients who receive HU pretreatment who have greater than or equal to 12,000 WBCs before G-CSF, G-CSF will start at a lower dose (for example, 1.5 or 2.5 µg/kg); the next doses will be adjusted by the Principal Investigator based on the observed degree of leukocytosis.
Other intervention name(s): hydrea
Intervention MeSH terms: Hydroxyurea
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Beta Thalassemia Major; Hematopoietic Stem Cell Mobilization; Gene Transfer Techniques