Pilot and Feasibility Study of Reduced-Intensity Hematopoietic Stem Cell Transplant for MonoMAC
Condition: MDS; Immunodeficiency; GATA2
MeSH terms: Immunologic Deficiency Syndromes
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

        -  Stem cells are immature blood cells that grow in the bone marrow and produce all of the
           cells needed for normal blood and immunity. Stem cells can be taken from one person
           (donor) and given to another person (recipient) through allogeneic stem cell
           transplantation. Donor stem cells can then replace the recipients stem cells in the bone
           marrow, restoring normal blood production and immunity. Most allogeneic transplants now
           use stem cells collected from the donors blood in a process called peripheral blood stem
           cell transplantation.

        -  Monocytopenia and mycobacterial infection (MonoMAC) is an immunodeficiency disease that
           is characterized by a lack of monocytes, a type of white blood cell, and an increased
           risk of developing mycobacteria infections that may cause tuberculosis.

        -  Allogeneic stem cell transplantation has been used successfully to treat many kinds of
           immune diseases and cancers that develop in blood or immune system cells. Researchers
           have been studying a particular kind of stem cell transplantation that uses lower than
           usual doses of chemotherapy and particular combinations of drugs to improve the results
           of the procedure for patients with blood-related cancers and pre-cancerous conditions.

      Objectives:

        -  To determine the safety and efficacy of reduced-intensity hematopoietic stem cell
           transplants (a particular stem cell transplantation procedure) for treating MonoMAC.

      Eligibility:

        -  Patients 18-60 years of age who have MonoMAC and who have been matched with a suitable
           stem cell donor.

      Design:

        -  Donors and recipients will undergo separate procedures as part of this protocol.

        -  Donors:

        -  National Institutes of Health researchers will take the donor s medical history, perform
           a physical exam, take blood samples, and explain the procedure. Tests will be performed
           to check the donors heart, lung, kidney, and liver function.

        -  Donors will receive injections of a drug called filgrastim (G-CSF), which causes stem
           cells to travel from bone marrow into blood. The G-CSF shots will be given for 5 to 7
           days before the collection procedure.

        -  Donors will undergo apheresis to collect white blood cells and stem cells directly from
           the blood, which can be done as an outpatient procedure. Researchers may consider the
           alternative of directly collecting bone marrow from the donor, which will require an
           overnight hospital stay.

        -  Recipients:

        -  Recipients will receive 3 days of pre-transplant chemotherapy and radiation therapy to
           prepare for the transplant. For 4 days before the transplant, recipients will receive
           the chemotherapy drug fludarabine, followed by a single dose of radiation therapy, and
           will also receive the drugs tacrolimus and sirolimus to prevent the donor cells from
           attacking the recipient s normal tissues.

        -  Recipients will then receive the transplant of donor stem cells and will continue to
           receive tacrolimus and sirolimus for 3 months after the transplant to prevent the donor
           cells from attacking the recipient s normal tissues. Recipients will be discharged from
           the hospital once their condition is stable.

        -  Recipients will visit the NCI clinic regularly for the first 5 months after the
           transplant, and then less often for at least 5 years. Recipients may receive additional
           donor immune cells (donor lymphocyte infusion) after the transplant if the study doctors
           believe they are needed.
    

Detailed description: 
      BACKGROUND:

      Mutations in GATA binding protein 2 (GATA2) lead to an immunodeficiency disease that
      transforms into myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). This
      syndrome, previously known as MonoMAC, has 4 clinical features: 1) infections with
      Mycobacterium Avium Complex (MAC) and other opportunistic infections as a teenager or young
      adult, 2) a peripheral blood leukocyte flow cytometry profile with T-lymphocytes, but a
      severe deficiency of monocytes, B-lymphocytes, and Natural Killer (NK) cells, 3) the
      propensity to progress to MDS/AML, and 4) mutations in the gene GATA2. In this pilot study we
      propose to evaluate the efficacy and safety of a reduced intensity allogeneic hematopoietic
      stem cell transplantation (HSCT) regimen for patients with mutations in GATA2. We are
      particularly interested in determining whether allogeneic HSCT using this regimen
      reconstitutes normal hematopoiesis in patients with mutations in GATA2.

      OBJECTIVES:

      Primary Objective:

        -  To determine efficacy, namely whether reduced-intensity allogeneic HSCT results in
           engraftment and restores normal hematopoiesis by day +100 in patients with mutations in
           GATA2.

        -  To determine the safety of this HSCT regimen in patients with mutations in GATA2,
           including transplant related toxicity, the incidence of acute and chronic graft-versus
           host disease, immune reconstitution, overall survival, and disease-free survival

      ELIGIBILITY:

      Eligibility includes patients 12-60 years old with mutations in GATA2 who have a life
      expectancy of > 3 months but < 24 months, and who have a 10/10 matched related donor, a 10/10
      or 9/10 matched unrelated donor (HLA -A, -B, -C, DRB1, DQB1 by high resolution typing
      identified through the National Marrow Donor Program), a 4/6 (or greater human leukocyte
      antigens (HLA -A), -B, DRB1) matched unrelated umbilical cord donor, or a haploidentical
      donor. Patients with GATA2 mutations who are 12-17 years of age are required to have MDS with
      chromosomal abnormalities to be eligible for this protocol.

      DESIGN:

        -  Patients with mutations in GATA2 with a 10/10 matched related or 10/10 matched unrelated
           donor, will receive a reduced-intensity pre-transplant conditioning regimen consisting
           of fludarabine 30 mg/m(2)/day on days -4, -3, and -2, 200 centigray (cGy) total body
           irradiation (TBI) on day -1, and HSCT on day 0. Patients with mutations in GATA2 and a
           9/10 matched unrelated donor will receive a reduced-intensity pre-transplant
           conditioning regimen consisting of fludarabine 30 mg/m(2)/day on days -4, -3, and -2,
           300cGy total body irradiation (TBI) on day -1, and HSCT on day 0. Patients with
           mutations in GATA2 with umbilical cord blood units will receive a reduced-intensity
           conditioning regimen with cyclophosphamide 50 mg/kg on day -6, fludarabine 40 mg/m(2) on
           days -6 to -2, equine anti-thymocyte globulin (ATG) 30 mg/kg intravenous (IV) on days
           -6, -5 and -4, 200 cGy TBI on day -1, and HSCT on day 0. Patients with a haploidentical
           donor will receive a reduced intensity-conditioning regimen with cyclophosphamide 14.5
           mg/kg on days -6 and -5, fludarabine 30 mg/m(2) on 4days -6 to -2, and 200 cGy TBI on
           day -1. Donor bone marrow cells will be infused on day 0.

        -  Post-transplant immunosuppression for graft-versus-host-disease prophylaxis will consist
           of sirolimus (Rapamycin) and tacrolimus until day +180, provided that there is no
           evidence of graft-versus-host disease. Post-transplant immunosuppression for graft
           versus-host-disease prophylaxis for recipients of haploidentical donors will consist of
           cyclophosphamide 50 mg/kg on days +3 and +4, along with sirolimus from day +5 to day
           180, and tacrolimus from day +5 to day 180, providing that there is no graft-versus-host
           disease (GVHD).
    

Intervention name(s): Cyclophosphamide (CTX, Cytoxan); Fludarabine(Fludara,Berlex Laboratories); Total Body Irradiation (TBI); Allogeneic Hematopoietic Stem Cell (HSC); Equine Anti-Thymocyte Globulin
Intervention type(s): Drug; Drug; Procedure; Procedure; Drug
Intervention description(s): 14.5 mg/kg intravenous (IV) (in the vein) infusion over 30 minutes once daily on days -6 and -5 (weight based dosing) or 50 mg/kg IV infusion over 2 hours on day -6 (weight based dosing) or 50/kg IV once daily x 2 doses on days +3 and +4; 40 mg/m2 IV (in the vein) over 30 minutes (in the vein) once daily on Days -6, -5, -4, and -3 or 30 mg/m(2) IV over 30 minutes (in the vein) once daily on Days -6, -5, -4, -3, and -2; 200 centigray (cGy) on Day -1 or 300 cGy on Day -1 (for 9/10 URD and Haplo patients); stem cell transplant; 30mg/kg IV (in the vein) once daily x 3 days on Days -6, -5, -4 (3 doses total)
Other intervention name(s): Cytoxan; Fludara; TBI; ATG
Intervention MeSH terms: Cyclophosphamide; Fludarabine; Fludarabine phosphate; Antilymphocyte Serum
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: GATA2; Transplant; Immunodeficiency; Myelodysplasia; MonoMAC