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Allogeneic Hematopoietic Stem Cell Transplant for Patients With Mutations in GATA2


Phase 2
6 Years
70 Years
Open (Enrolling)
Both
GATA2, Immunodeficiency, MDS

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Trial Information

Allogeneic Hematopoietic Stem Cell Transplant for Patients With Mutations in GATA2


Background:

Genetic and sporadic mutations on one allele of the GATA2 gene lead to a syndrome
characterized by: 1) infections with Mycobacterium Avium Complex (MAC) and other
opportunistic infections, 2) deficiency of monocytes, B-lymphocytes, and Natural Killer (NK)
cells in the peripheral blood, and 3) progression to myelodysplastic syndrome (MDS), chronic
myelomonocytic leukemia (CMML), and acute myelogenous leukemia (AML). We propose to evaluate
the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) using
different conditioning regimens for donor sources in reconstituting normal hematopoiesis in
patients with mutations in GATA2.

Objectives:

To determine the efficacy of this allogeneic HSCT approach in reconstituting normal
hematopoiesis by day +100 in patients with mutations in GATA2.

To determine the safety of this allogeneic HSCT approach in patients with GATA2 mutations,
including transplant related toxicity, the incidence of acute and chronic graftversus- host
disease, immune reconstitution, overall and disease-free survival.

Eligibility:

Recipients ages 10-70 years old with mutations in GATA2, or the clinical syndrome of
MonoMAC.Clinical history of at least one life-threatening infection

Have a 10/10 or a 9/10 matched related or unrelated donor (HLA -A, -B, -C, DRB1, DQB1 by
high resolution typing identified through the National Marrow Donor Program), 4/6 (or
greater HLA -A, -B, DRB1) matched unrelated umbilical cord units, or a haploidentical
related donor.

Design:

Patients with mutations in GATA2 with a 10/10 or 9/10 matched related or unrelated donor
will receive a pre-transplant conditioning regimen consisting of fludarabine 40 mg/m2 IV
once daily for 4 days on days -6, -5, -4, and -3, busulfan 3.2 mg/kg IV once daily on days
-6, -5, -4, and -3, and HSCT on day 0.

Patients with mutations in GATA2 with umbilical cord blood donors will receive pretransplant
conditioning with cyclophosphamide 50 mg/kg IV on day -6, fludarabine 40 mg/m2 IV once daily
for 5 days on days -6 to -2, equine (horse) antithymocyte globulin (HATG) 30 mg/kg IV once
daily x 3 days on days -6, -5 and -4, 200 cGy TBI on day -1, and HSCT on day 0.

Post-transplant immunosuppression for graft-versus-host-disease (GVHD) prophylaxis for
recipients of matched related and unrelated donor transplants, and umbilical cord blood
transplant will consist of methotrexate 5 mg/m2 IV on days +1, +3, +6, and +11 and
tacrolimus from day -3 until day +180. If there is no evidence of graft-versus-host disease,
and patients have achieved full donor chimerism, Tacrolimus will be tapered off after day
+180.

Patients with a haploidentical related donor will receive pre-transplant conditioning with
cyclophosphamide 14.5 mg/kg IV once daily for 2 days on days -6 and -5, fludarabine 30 mg/m2
IV once daily for 5 days on days -6 to -2, and 200 cGy TBI on day -1, and HSCT on day 0.

Post-transplant immunosuppression for GVHD prophylaxis for recipients of haploidentical
donors will consist of cyclophosphamide 50 mg/kg IV once daily for 2 days 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 GVHD.

Inclusion Criteria


- ELIGIBILITY CRITERIA:

INCLUSION CRITERIA- Recipient

1. Patient age of 10-70 years.

2. Mutation in the GATA2 gene, or evidence of loss of expression of one allele of GATA2,
by cDNA analysis performed by a CLIA certified laboratory, or the clinical syndrome
of MonoMAC

3. Clinical history of at least one life-threatening infection and/or MDS with
International Prognostic Scoring System (IPSS) category of Intermediate-1 or High.

4. 10/10 or 9/10 HLA-matched related or unrelated donor, 4/6 (or greater) matched
umbilical cord blood (UCB) unit(s) with a total dose of greater than or equal to 3.5
times 10(7) TNC/kg, or a haploidentical related donor.

5. 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
filgrastim.

6. Left ventricular ejection fraction > 40%, preferably by 2-D echo obtained within 28
days of enrollment

7. Pulmonary Function Tests: FEV1 > 10% of expected value obtained within 28 days of
enrollment.

8. 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( < 18 years old) creatinine <
1.5 mg/dL and a creatinine clearance > 30 mL/min/1.73m(2).

9. Serum conjugated bilirubin < 2.5 mg/dl; serum ALT and AST less than or equal to 5
times upper limit of normal

10. ECOG score of 0, 1, or 2 for patients 16 years of age and greater. Lansky scale of 50
or greater if less than 16 years of age.

11. Adequate central venous access potential.

12. Written informed consent/assent obtained from patient/parent or legal guardian.

13. Disease status: Patients are to be referred in remission for evaluation. Should a
patient have progressive disease, or a donor becomes not 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
or Lead Associate Investigator.

3. History of psychiatric disorder which may compromise compliance with transplant
protocol, or which does not allow for appropriate informed consent.

4. Active infection refractory 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 posttransplant. 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. 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 or 9/10 HLA-matched related or unrelated donor, 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, or haploidentical related donor.

INCLUSION CRITERIA- Matched Related Donor

1. Related donor matched at 9/10 or 10/10 HLA-A, B, C, DR, and DQ loci by high
resolution typing.

2. Ability to give informed consent

3. Age 6-70 years

4. No history of life-threatening opportunistic infection

5. Adequate venous access for peripheral apheresis, or consent to use a temporary
central venous catheter for apheresis.

6. 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.

7. 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.

8. No mutation in GATA2, or in the case where the mutation in GATA2 has not been
identified, but the recipient has the clinical syndrome of MonoMAC, the donor is
required to have no clinical evidence of MonoMAC .

INCLUSIN 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 Standards
(19th Edition, Section 12.4).

INCLUSION CRITERIA- Haploidentical Related Donor

1. A haploidentical donor is a related 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 (allelelevel) 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 6 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, CMV, etc. to
select the donor

2. Age 6-70 years

3. No history of life-threatening opportunistic infection

4. 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.

5. Haploidentical donors will undergo marrow harvest with general anesthesia. Subjects
will undergo anesthesia consultation prior to enrollment. CD34 plus fraction will be
determined.

6. No mutation in GATA2, or in the case where the mutation in GATA2 has not been
identified, but the recipient has the clinical syndrome of MonoMAC, the donor is
required to have no clinical evidence of MonoMAC

EXCLUSION CRITERIA- Matched Related Donor

1. Age less than6 years or greater than 70 years.

2. History of psychiatric disorder which in the opinion of the PI may compromise
compliance with transplant protocol, or does not allow for appropriate informed
consent.

3. History of other medical conditions that in the opinion of PI constitute a
contraindication to donation.

4. 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.
Risk/benefit of the transplant and the possibility of transmitting viable tumor cells
at the time of transplantation will be discussed with the patient.

5. 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.

6. Mutation in GATA2, or evidence of loss of expression of one allele of GATA2 by cDNA
analysis performed by a CLIA certified laboratory, or in the case where the mutation
in GATA2 has not been identified, but the recipient has the clinical syndrome of
MonoMAC, the donor is excluded if he or she has the clinical syndrome of MonoMAC.

EXCLUSION CRITERIA- Matched Unrelated Donor

a) Failure to qualify as an NMDP donor as described in Section 12.4.

EXCLUSION CRITERIA- Haploidentical Related Donor

1. Age less than 6 years or greater than 70.

2. 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

3. History of other medical conditions that in the opinion of PI constitute a
contraindication to donation.

4. 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.

5. 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.

6. Mutation in GATA2, or evidence of loss of expression of one allele of GATA2 by Cdna
analysis performed by a CLIA certified laboratory, or in the case where the mutation
in GATA2 has not been identified, but the recipient has the clinical syndrome of
MonoMAC, the donor is required to have no clinical history of MonoMAC

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 times 10(7) TNC/kg of
recipient body weight.

- The minimum combined dose of both units must be at least 3.5 times 10(7) TNC/kg
of recipient body weight.

- The smaller of the two units (UCB2) will have a minimum of 1.5 times 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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine whether allogeneic HSCT approach results in engraftment and restores normal hematopoiesis by day + 100 in patients with mutations GATA2.

Outcome Time Frame:

3 years

Safety Issue:

No

Principal Investigator

Dennis D Hickstein, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

130132

NCT ID:

NCT01861106

Start Date:

April 2013

Completion Date:

April 2018

Related Keywords:

  • GATA2
  • Immunodeficiency
  • MDS
  • Allogeneic Donors
  • Peripheral Blood Stem Cell
  • Immunodeficiency
  • Myelodysplasia
  • Haploidentical
  • Immunologic Deficiency Syndromes

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892