Pilot and Feasibility Study of Reduced-Intensity Hematopoietic Stem Cell Transplant for MonoMAC
Condition: MDS; Immunodeficiency; GATA2
MeSH terms: Immunologic Deficiency Syndromes
Intervention: Cyclophosphamide (CTX, Cytoxan); Fludarabine(Fludara,Berlex Laboratories); Total Body Irradiation (TBI); Allogeneic Hematopoietic Stem Cell (HSC); Equine Anti-Thymocyte Globulin
Intervention description: 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)
Intervention MeSH terms: Cyclophosphamide; Fludarabine; Fludarabine phosphate; Antilymphocyte Serum
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 12 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: GATA2; Transplant; Immunodeficiency; Myelodysplasia; MonoMAC

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA RECIPIENT:

               1. Patient age of 12-60 years

               2. GATA2 Mutation Syndrome

                    1. Clinical history of at least two episodes of life-threatening infection with
                       opportunistic organisms, one of which is a MAC infection.

                    2. Mutation in the GATA2 gene performed by the CLIA certified laboratory of Dr.
                       Steven Holland of the NIAID Institute of the NIH.

               3. Available 10/10 HLA-matched related or 8/8 matched unrelated donor, or 4/6 (or
                  greater) matched UCB unit(s) with a total dose of greater than or equal to 3.5
                  times 10(7) TNC/kg.

               4. Patients may have evidence of MDS with one or more peripheral blood cytopenias
                  and greater than 5% blasts but less than 10% blasts in the bone marrow in the
                  absence of GCSF.

                  Patients previously treated for acute myelogenous leukemia are eligible if they
                  have less than or equal to 10% blasts in the bone marrow in the absence of G-CSF.

                  Subjects 12-17 years of age are required to have MDS with chromosomal
                  abnormalities in addition to mutation in the GATA2 gene for enrollment on this
                  protocol.

               5. Left ventricular ejection fraction > 50%, preferably by 2-D echo, or by MUGA, or
                  shortening fraction > 28% by ECHO, obtained within 28 days of enrollment.

               6. Pulmonary Function Tests: Adult patients: DLCO diffusion capacity and FEV1
                  greater than 10% of expected value obtained within 28 days of enrollment.
                  Pediatric patients: DLCO corrected for hemoglobin and alveolar volume greater
                  than or equal to 20% of predicted.

               7. Creatinine: Adult patients: less than or equal to 2.0 mg/dl and creatinine
                  clearance greater than or equal to 30 ml/min; Pediatric patients: age-adjusted
                  normal serum creatinine OR a creatinine clearance > 60 mL/min/1.73m(2).

               8. Serum total bilirubin less than 2.5 mg/dl; ALT and AST less than or equal to 5
                  times upper limit of normal .

               9. Adequate central venous access potential.

              10. Written informed consent/assent obtained from patient/parent or legal guardian.

              11. Life expectancy of at least 3 months but less than 24 months.

              12. Disease status: Patients are to be referred in remission for evaluation. Should a
                  patient have progressive disease or a donor not be available after enrollment,
                  the patient will be referred back to their primary hematologist-oncologist for
                  treatment. If this course of action is not in the best interest of the patient
                  according to the clinical judgment of the PI/LAI, then the patient may receive
                  standard treatment for the malignant disease under the current study. If under
                  either of these settings, it becomes apparent that the patient will not be able
                  to proceed to transplant, then he/she must come off study. Recipient-Subjects
                  receiving a standard therapy will be told about the therapy, associated risks,
                  benefits alternatives of the proposed therapy, and availability of receiving the
                  same treatment elsewhere, outside of a research protocol.

        EXCLUSION CRITERIA- RECIPIENT:

          1. HIV infection.

          2. Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For
             patients with a concomitant positive hepatitis B surface antigen, patients will
             require a hepatology consultation. The risk-benefit profile of transplant and
             hepatitis B will be discussed with the patient, and eligibility determined by the PI
             and the protocol chairperson.

          3. History of psychiatric disorder which may compromise compliance with transplant
             protocol, or which does not allow for appropriate informed consent.

          4. Active infection that is not responding to antimicrobial therapy.

          5. Active CNS involvement by malignancy (patients with known positive CSF cytology or
             parenchymal lesions visible by CT or MRI.

          6. Pregnant or lactating.

          7. Sexually active individuals capable of becoming pregnant who are unable or unwilling
             to use effective form(s) of contraception during time enrolled on study and for 1 year
             post-transplant. Effective forms of contraception include one or more of the
             following: intrauterine device (IUD), hormonal (birth control pills, injections, or
             implants), tubal ligation/hysterectomy, partners vasectomy, barrier methods, (condom,
             diaphragm, or cervical cap), or abstinence. The effects on breast-milk are also
             unknown and may be harmful to the infant; therefore, women should not breast feed
             during the interval from study entry to one year post-transplant. Males on the
             protocol must use an effective form of contraception at study entry, and for one year
             post-transplant. The effects of transplant, the radiation, and the medications used
             after transplant may be harmful to a fetus.

          8. Presence of active malignancy in another organ system other than the hematopoietic

          9. No available 10/10 HLA-matched related or 8/8 matched unrelated donor, or 4/6 (or
             greater) matched UCB unit(s) with a total dose of greater than or equal to 3.5 times
             10(7) TNC/kg.

         10. Lack of mutation in GATA2 as demonstrated by the CLIA certified laboratory of Dr.
             Steven Holland in the NIAID.

        INCLUSION CRITERIA- MATCHED RELATED DONOR:

          1. Related donor matched at HLA-A, B, C, DR, and DQ loci by high resolution typing (10/10
             antigen/allele match) are acceptable donors.

          2. Matched related donors for pediatric recipients must be 18 years of age or older. If
             more than one matched related donor is available, we will select the oldest donor to
             further decrease the risk of potential disease transmission.

          3. Ability to give informed consent.

          4. Age 18-60 years.

          5. No history of life-threatening opportunistic infection.

          6. Adequate venous access for peripheral apheresis, or consent to use a temporary central
             venous catheter for apheresis.

          7. Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C
             antibody negative. This is to prevent the possible transmission of these infections to
             the recipient.

          8. A donor who is lactating must be willing and able to interrupt breast-feeding or
             substitute formula feeding for her infant during the period of filgrastim
             administration and for two days following the final dose. Filgrastim may be secreted
             in human milk, although its bioavailability from this source is not known. Limited
             clinical data suggest that short-term administration of filgrastim or sargramostim to
             neonates is not associated with adverse outcomes.

        INCLUSION CRITERIA- MATCHED UNRELATED DONOR:

          1. Unrelated donor matched at 10/10 or 9/10 HLA-A, B, C, DRB1, and DQB1 loci by high
             resolution typing.

          2. Matched unrelated donors for pediatric recipients must be 18 years of age or older.

          3. The evaluation of donors shall be in accordance with existing NMDP Standard Policies
             and Procedures. General donor inclusion criteria specified in the NMDP Standard.

        EXCLUSION CRITERIA- MATCHED RELATED DONOR:

          1. Age less than 18 years.

          2. HIV infection.

          3. Chronic active hepatitis B. Donor may be hepatitis core antibody positive.

          4. History of psychiatric disorder which in the opinion of the PI may compromise
             compliance with transplant protocol, or which does not allow to be appropriately
             informed.

          5. History of hypertension that is not controlled by medication, stroke, or severe heart
             disease. Individuals with symptomatic angina will be considered to have severe heart
             disease and will not be eligible to be a donor.

          6. Other medical contraindications to stem cell donation (i.e. severe atherosclerosis,
             autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular
             accident).

          7. History of prior malignancy. However, cancer survivors who have undergone potentially
             curative therapy may be considered for stem cell donation on a case-by-case basis. The
             risk/benefit of the transplant and the possibility of transmitting viable tumor cells
             at the time of transplantation will be discussed with the patient.

          8. Donors must not be pregnant. Pregnancy is an absolute contraindication under this
             protocol. The effects of cytokine administration on a fetus are unknown. Donors of
             childbearing potential must use an effective method of contraception. Effective forms
             of contraception include one or more of the following: intrauterine device (IUD),
             hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy,
             partner s vasectomy, barrier methods, (condom, diaphragm, or cervical cap), or
             abstinence.

          9. Thrombocytopenia (platelets less than 150,000 per micro l) at baseline evaluation.

         10. Donors receiving experimental therapy or investigational agents.

         11. Sensitivity to filgrastim or to E. coli-derived recombinant protein products.

         12. History of autoimmune disorders, with the exception of thyroid disorders.

         13. History of documented deep vein thrombosis or pulmonary embolism.

        EXCLUSION CRITERIA- MATCHED UNRELATED DONOR:

        Failure to qualify as an NMDP donor

        INCLUSION CRITERIA- UMBILICAL CORD BLOOD UNIT-HLA TYPING AND DOSE

          1. At least an HLA UCB 4/6 match (Class I-A, B by low resolution, and Class II-DR by high
             resolution) to recipient. The following algorithm will be applied to determine if
             patient will receive single or double umbilical cord graft:

          2. For Single UCB SCT:

               -  If 6/6 match the unit must have > 3 x 10(7) nucleated cells /kg of recipient body
                  weight.

               -  If 5/6 match the unit must have > 4 x 10(7) nucleated cells /kg of recipient body
                  weight.

               -  If 4/6 match the unit must have > 5 x 10(7) nucleated cells/kg of recipient body
                  weight. Recipient body weight will be determined as per standard guidelines.

          3. If no single UCB with the above characteristics is available, a double UCB will be
             considered. Units will be selected with the following criteria:

               -  Both units will be at least 4/6 match (Class I-A, B by low resolution, Class
                  II-DR by high resolution) to recipient, and should be at least a 4/6 match (Class
                  I-A, B by low resolution, Class II-DR by high resolution) to each other.

               -  At least one UCB will have a minimum cell dose of 2.0 X 10(7) TNC/kg of recipient
                  body weight.

               -  The minimum combined dose of both units must be at least 3.5 x 10(7) TNC/kg of
                  recipient body weight.

               -  The smaller of the two units (UCB2) will have a minimum of 1.5 X 10(7) TNC/kg of
                  recipient body weight.

               -  The TNC of non-RBC reduced units will be dose corrected by -25% to allow for cell
                  loss while washing the unit.

        INCLUSION CRITERIA- HAPLOIDENTICAL RELATED DONOR:

          -  A haploidentical donor that shares one haplotype in common with the recipient such
             that HLA compatibility will be a minimum of 5 out of 10 HLA loci matched. The HLA loci
             to be tested will be HLA A, B, Cw, DRB1, and DQB1. A minimum number of mismatches is
             desirable; however if several options are available the selection of a donor will be
             based on the loci where the mismatch occurs and the relative importance of its
             potential immunological function. Donor-recipient pairs will initially be typed
             molecularly to provide a low resolution typing (antigen-level) to aid in the selection
             of the potential donor. Upon review of the familial inheritance pattern, a qualified
             HLA staff member will review haplotype inheritance. High resolution (allele-level)
             typing will be performed. Final selection of a donor will be in consultation with NCI
             physicians and qualified HLA personnel. Haploidentical related donors for pediatric
             recipients must be 15 years of age or older. If more than one haploidentical related
             donor is available, we will evaluate each donor individually according to overall
             health, ABO matching, cytomegalovirus (CMV), etc. to select the donor

          -  Age 15-60 years

          -  No history of life-threatening opportunistic infection

          -  Adequate venous access for peripheral apheresis, or consent to use a temporary central
             venous catheter for apheresis.

          -  Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C
             antibody negative. This is to prevent the possible transmission of these infections to
             the recipient.

          -  Haploidentical donors will undergo marrow harvest with general anesthesia. Subjects
             will undergo anesthesia consultation, and meet criteria for eligibility/enrollment.
             CD34+ fraction will be determined.

          -  Subjects will also undergo the Donor Health History Screen to determine donor
             eligibility using standard DTM criteria in the Dowling Apheresis Clinic by skilled
             staff in the Blood Services Section for adult patients and age-appropriate questioning
             when indicated for pediatric subjects.

          -  Subjects will undergo follow-up history and physical examination within 1 week of
             donation.

        EXCLUSION CRITERIA- HAPLOIDENTICAL DONOR:

          -  Age less than 15 years.

          -  HIV infection

          -  Chronic active hepatitis B. Donor may be hepatitis core antibody positive.

          -  History of psychiatric disorder which in the opinion of the PI may compromise
             compliance with transplant protocol, or which does not allow for appropriate informed

          -  History of hypertension that is not controlled by medication, stroke, or severe heart
             disease. Individuals with symptomatic angina will be considered to have severe heart
             disease and will not be eligible to be a donor.

          -  Other medical contraindications to stem cell donation (i.e. severe atherosclerosis,
             autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular
             accident)

          -  History of prior malignancy. However, cancer survivors who have undergone potentially
             curative therapy may be considered for stem cell donation on a case-by-case basis. The
             risk/benefit of the transplant and the possibility of transmitting viable tumor cells
             at the time of transplantation will be discussed with the patient.

          -  Donors must not be pregnant. Pregnancy is an absolute contraindication under this
             protocol. The effects of cytokine administration on a fetus are unknown. Donors of
             childbearing potential must use an effective method of contraception. Effective forms
             of contraception include one or more of the following: intrauterine device (IUD),
             hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy,
             partners vasectomy, barrier methods, (condom, diaphragm, or cervical cap), or
             abstinence.

          -  Thrombocytopenia (platelets less than 150,000 per microliter) at baseline evaluation.

          -  Donors receiving experimental therapy or investigational agents.

          -  Sensitivity to filgrastim or to E. coli-derived recombinant protein products.

          -  History of autoimmune disorders, with the exception of thyroid disorders

          -  History of documented deep vein thrombosis or pulmonary embolism

          -  Mutation in GATA2