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Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Mutations

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ClinicalTrials.gov Identifier: NCT01861106
Recruitment Status : Recruiting
First Posted : May 23, 2013
Last Update Posted : May 21, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

- GATA2 deficiency is a disease caused by mutations in the GATA2 gene. It can cause different types of leukemia and other diseases. Researchers want to see if a stem cell transplant can be used to treat this condition. A stem cell transplant will give stem cells from a matching donor (related or unrelated) to a recipient. It will allow the donor stem cells to produce healthy bone marrow and blood cells that will attack the recipient s cancer cells.

Objectives:

- To see if stem cell transplants are successful at treating GATA2 mutations and related conditions.

Eligibility:

  • Recipients who are between 8 and 70 years of age and have GATA2 deficiency, or the clinical syndrome MonoMac.
  • Donors who are between 6 and 70 years of age and are matched with the recipients.
  • Have a 10/10 or 9/10 HLA-matched related or unrelated donor, or a haploidentical related donor.

Design:

  • All participants will be screened with a physical exam and medical history. Blood samples will be collected. Recipients will have imaging studies and other tests.
  • Donor participants will provide stem cells for the treatment. In some cases, Filgrastim injections will allow these cells to be collected from the blood. Bone marrow donations will be used as stem cells source.
  • Recipients will have chemotherapy or radiation to prepare for the transplant. On the day of the transplant, they will receive the donated stem cells.
  • Recipients will stay in the hospital until their condition is stable after transplant.
  • Frequent blood tests and scans will be required for the first 6 months after the transplant, followed by less frequent visits over time.

Condition or disease Intervention/treatment Phase
GATA2 Immunodeficiency MDS Procedure: Allogeneic HSC Drug: Busulfan Test dose Drug: Fludarabine(Fludara, Berlex Laboratories) Drug: Busulfan (Busulfex) Drug: Cyclophosphamide(CTX, Cytoxan) Procedure: Total Body Irradiation (TBI) Drug: Mycophenolatemofetil (MMF) Drug: Tacrolimus Phase 2

Detailed Description:

Background:

Genetic and sporadic mutations on one allele of the GATA2 gene lead to a syndrome termed MonoMAC. MonoMAC is 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), and 4) mutations on one allele of GATA2 in most patients. We propose to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) using different conditioning regimens from different donor sources in reconstituting normal hematopoiesis and reversing the disease phenotype in patients with mutations in GATA2, or the clinical syndrome of MonoMAC.

Objectives: Primary:

-To determine whether allogeneic hematopoietic stem cell transplant (HSCT) approach reconstitutes normal hematopoiesis and reverses the disease phenotype by one year posttransplant in patients with mutations in GATA2 or the clinical syndrome of MonoMAC.

Eligibility:

  • Recipients ages 8-70 years old with mutations in GATA2 or the clinical syndrome of MonoMAC. MDS or clinical history of at least one life-threatening infection.
  • Have a 10/10 or a 9/10 HLA-matched related or unrelated donor (HLA -A, -B, -C, DRB1, DQB1 by high resolution typing identified through the National Marrow Donor Program), or a haploidentical related donor.

Design: Two Arms

  • Patients with mutations in GATA2, or the clinical syndrome of MonoMAC, with a 10/10 (or 9/10 matched if the mismatch is at DQ) HLA-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 day s -6, -5, -4, and -3, busulfan based on pharmacokinetic levels from test dose (3.2 mg/kg IV will be the default dose) once daily on days -6, -5, -4, and -3, and HSCT on day 0.
  • Patients with mutations in GATA2, or the clinical syndrome of MonoMAC, with a 9/10 HLA-matched related or unrelated (except if the mismatch is at DQ), or with a haploidentical related donor, will receive a pre-transplant conditioning regimen consisting of cyclophosphamide 14.5 mg/kg IV once daily for 2 days on days -6 and -5, busulfan based on pharmacokinetic levels from test dose ( 3.2 mg/kg IV will be the default dose) once daily on days -4, -3, (if poor or very poor risk clonal cytogenetic abnormalities are present, then three days of busulfan IV once daily on days -4, -3, and -2 will be given), fludarabine 30 mg/m2 IV once daily for 5 days on days -6 to -2, 200 cGy TBI on day -1, and HSCT on day 0.
  • Post-transplant immunosuppression for GVHD prophylaxis for recipients of all groups will consist of cyclophosphamide 50 mg/kg IV once daily for 2 days on day s +3 and +4, along with mycophenolate mofetil from day +5 to approximately day +35 and tacrolimus from day +5 to approximately day +180. If there is no evidence of graft-versus- host disease, tacrolimus will be stopped or tapered at approximately day +180.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Allogeneic Hematopoietic Stem Cell Transplant for Patients With Mutations in GATA2 or the MonoMAC Syndrome
Actual Study Start Date : July 24, 2013
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Arm A
10/10 HLA Matched Related Donor or Unrelated DonorTransplant.
Procedure: Allogeneic HSC
Stem cell transplant

Drug: Busulfan Test dose
0.8 mg/kg IV infusion over 2 hours one time dose administered 5 to 14 days prior to start of preparative regimen (Days -11 to -20)

Drug: Fludarabine(Fludara, Berlex Laboratories)
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 /m2 IV over 30 minutes (in the vein) once daily on Days -6, -5, -4, -3, and -2

Drug: Busulfan (Busulfex)
3.2 mg/kg IV (in the vein) over 2 hours once daily on Days -6, -5, -4 and -3 (weight based dosing)

Drug: Mycophenolatemofetil (MMF)
15mg/kg IV over 2 hours BID starting on day +5 will continue until day +35 (+/- 2 days)

Drug: Tacrolimus
0.02mg/kg IV continuous infusion over 24 hours starting on day +5 until day +180

Active Comparator: Group B
9/10 HLA Matched Related Donor or Unrelated Donor Transplant
Procedure: Allogeneic HSC
Stem cell transplant

Drug: Busulfan Test dose
0.8 mg/kg IV infusion over 2 hours one time dose administered 5 to 14 days prior to start of preparative regimen (Days -11 to -20)

Drug: Fludarabine(Fludara, Berlex Laboratories)
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 /m2 IV over 30 minutes (in the vein) once daily on Days -6, -5, -4, -3, and -2

Drug: Busulfan (Busulfex)
3.2 mg/kg IV (in the vein) over 2 hours once daily on Days -6, -5, -4 and -3 (weight based dosing)

Drug: Mycophenolatemofetil (MMF)
15mg/kg IV over 2 hours BID starting on day +5 will continue until day +35 (+/- 2 days)

Drug: Tacrolimus
0.02mg/kg IV continuous infusion over 24 hours starting on day +5 until day +180

Active Comparator: Group C
Haploidentical Related Donor Transplant
Procedure: Allogeneic HSC
Stem cell transplant

Drug: Busulfan Test dose
0.8 mg/kg IV infusion over 2 hours one time dose administered 5 to 14 days prior to start of preparative regimen (Days -11 to -20)

Drug: Fludarabine(Fludara, Berlex Laboratories)
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 /m2 IV over 30 minutes (in the vein) once daily on Days -6, -5, -4, -3, and -2

Drug: Busulfan (Busulfex)
3.2 mg/kg IV (in the vein) over 2 hours once daily on Days -6, -5, -4 and -3 (weight based dosing)

Drug: Cyclophosphamide(CTX, Cytoxan)
14.5 mg/kg 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

Procedure: Total Body Irradiation (TBI)
200 cGy Transplant Day -1

No Intervention: Group E
Donor



Primary Outcome Measures :
  1. To determine whether allogeneic HSCT approach results in engraftment and restores normal hematopoiesis and reverses the disease phenotype by one year in patients with mutations GATA2. [ Time Frame: 1 year after completing ASCT ]
    Determination that engraftment has occurred, normal hematopoiesis has been restored and the clinical phenotype after allogeneic HSCT has been reversed


Secondary Outcome Measures :
  1. To determine the safety [ Time Frame: 3 years ]
    To determine the safety

  2. To characterize the immune reconstitution inflammatory syndrome (IRIS) [ Time Frame: Days 30, 100, 6 months, and one year post-transplant ]
    To characterize the immune reconstitution inflammatory syndrome (IRIS)

  3. To determine the incidence of grade III-IV acute GVHD [ Time Frame: 100 days ]
    To determine the incidence of grade III-IV acute GVHD

  4. Overall survival, and disease-free survival. [ Time Frame: 3 years ]
    Overall survival, and disease-free survival.

  5. To characterize the immune reconstitution in 10/10 matched related and unrelated donor transplant recipients and haploidentical related donor transplants who receive GVHD prophylaxis [ Time Frame: Days 30, 100, 6 months, 12months post-transplant ]
    To characterize the immune reconstitution in 10/10 matched related and unrelated donor transplant recipients and haploidentical related donor transplants who receive GVHD prophylaxis

  6. To determine the incidence of chronic graft-versus-host disease [ Time Frame: 1-2 years ]
    To determine the incidence of chronic graft-versus-host disease



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • ELIGIBILITY CRITERIA:

INCLUSION CRITERIA- Recipient

  1. Patient age of 8-70 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, Intermediate-2 or High.
  4. Availability of a 10/10 or 9/10 HLA-matched related or unrelated donor, 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 - The majority of patients with MDS will have less than 5% blasts.
  6. Left ventricular ejection fraction > 40%, preferably by 2-D echocardiogram obtained within 90 days prior to enrollment.
  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 ( <18 years old): creatinine <1.5 mg/dL and a creatinine clearance , using the

    Schwartz Formula, > 30 mL/min/1.73m(2).

  8. Serum conjugated bilirubin < 2.5 mg/dl; serum ALT and AST less than or equal to 5 times upper limit of normal.
  9. Ability of subject or Legally Authorized Representative (LAR) (if the patient is deemed by the treating physician to be cognitively impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable) to understand and the willingness to sign a written informed consent document indicating that they are aware of the investigational nature of this study or written informed consent obtained from parent or legal guardian if subject is a minor.
  10. 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 or hematological disorder 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 and alternatives of the proposed therapy, and availability of receiving the same treatment elsewhere, outside of a research protocol.
  11. As therapeutic agents used in this trial may be harmful to a fetus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least one-year post-allo HSCT. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in the study, she should inform her treating physician immediately.
  12. All transplant patients remain in the NIH hospital or, if discharged, stay close to the NIH for a minimum of 100 days after transplant or longer, if there are complications. An adult caregiver must be with the patient at all times from discharge to day 100.

EXCLUSION CRITERIA- Recipient

  1. Patients who are receiving any other investigational agents with the exception of virus- specific cytotoxic T-cells for the treatment of viral infection/reactivation prior to allo HSCT
  2. HIV-positive patients are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  3. History of allergic reactions attributed to compounds of similar chemical or biological composition to agents (steroids, cyclophosphamide, busulfan) used in the study
  4. 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.
  5. History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.
  6. Active infection refractory to antimicrobial therapy.
  7. Active CNS involvement by malignancy (patients with known positive CSF cytology or parenchymal lesions visible by CT or MRI).
  8. Pregnant or lactating.
  9. 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, 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.
  10. Presence of active malignancy in another organ system other than the hematopoietic, except when driven by viruses in which case the immune reconstitution after transplant may control the malignancy. This includes solid tumors not in remission.
  11. No available 10/10 or 9/10 HLA-matched related, unrelated donor, or haploidentical related donor.

INCLUSION CRITERIA-Related Donor

  1. Age 6-70 years
  2. Related donor deemed suitable and eligible, and willing to donate per clinical evaluations who are additionally willing to donate blood, urine, and marrow specimens for research. Related donors will be evaluated in accordance with existing Standard Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all related donors, but is not required for clinical donation.
  3. 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 high resolution typing.
  2. The evaluation of donors shall be in accordance with existing NMDP Standard Policies and Procedures. General donor inclusion criteria specified in the NMDP Standards.

EXCLUSION CRITERIA-Related Donor

  1. 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.
  2. History of other medical conditions that in the opinion of PI constitute a contraindication to donation.
  3. 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.
  4. 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.
  5. 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01861106


Contacts
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Contact: Dennis D Hickstein, M.D. (240) 760-6169 hicksted@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Dennis D Hickstein, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01861106    
Other Study ID Numbers: 130132
13-C-0132
First Posted: May 23, 2013    Key Record Dates
Last Update Posted: May 21, 2020
Last Verified: March 18, 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Allogeneic Donors
Peripheral Blood Stem Cell
Immunodeficiency
Myelodysplasia
Haploidentical
Additional relevant MeSH terms:
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Immunologic Deficiency Syndromes
Immune System Diseases
Mycophenolic Acid
Cyclophosphamide
Busulfan
Fludarabine
Fludarabine phosphate
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Calcineurin Inhibitors
Enzyme Inhibitors
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents