Background: People with GATA-binding factor 2 (GATA2) deficiency have a mutation on the GATA2 gene. This gene affects immune function. People with this disease are prone to serious infections; in time, they may develop blood cancers. A hematopoietic stem cell (HSC) transplant can cure GATA2 deficiency, but using stem cells donated by other people can cause serious side effects. Objective: To test a new drug (Briquilimab) to see if it can make HSC transplants safer. Eligibility: People aged 6 to 70 years who have GATA2 deficiency. Design: Participants will be screened. They will have a physical exam, with blood and urine tests. They will have tests of their heart and lung function. They may have a bone marrow biopsy: Their hip will be numbed; a large needle will be inserted to draw out tissue from inside the pelvis. Participants will have a central venous catheter placed in a vein of the neck or chest. This will be used to draw blood and administer drugs. Briquilimab will be given through the catheter about 11 days before the transplant. This is part of conditioning: preparing the body to receive the new stem cells. Conditioning also includes other medications and total body irradiation. Donor stem cells will be administered through the catheter. Participants will receive other approved drugs to help prevent side effects. Participants will stay in the hospital from the beginning of the conditioning until several weeks after the transplant. They will remain in the local area for 100 days after discharge; they will come to the clinic at least once a week during this time. Follow-up visits will continue for 3 years....
Background: * GATA-binding factor 2 (GATA2) deficiency, an immunodeficiency and bone marrow failure disorder due to inherited or sporadic mutations in or loss of one allele of the GATA2 gene, is characterized by: 1) nontuberculous mycobacteria (NTM) 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). * Allogeneic hematopoietic cell transplantation (HCT) appears to be curative, and interim results from protocol #13-C-0132, NCT01861106, demonstrated a 2-year event-free survival rate of 83% for 59 participants with GATA2 deficiency who underwent HCT with a busulfan-based conditioning regimen. * However, traditional HCT approaches using alkylating agents such as busulfan continue to place recipients at risk for potentially life-threatening, transplant-related toxicities as well as late effects such as infertility and secondary malignancy. * Briquilimab is a humanized, glycosylated immunoglobulin G1 (IgG1) monoclonal antibody that targets CD117 (human c-Kit) present on endogenous hematopoietic stem cells (HSC). Briquilimab has been shown in pre-clinical and early clinical studies to safely deplete human and non-human primate HSC with minimal toxicity. Primary Objective: -To determine whether allogeneic hematopoietic cell transplantation with Briquilimab-based conditioning results in sustained donor engraftment by 100 days post-transplant in participants with GATA2 deficiency Eligibility: * Recipients aged 6-70 years old with pathogenic germline mutations in GATA2 and clinical manifestations consistent with a diagnosis of GATA2 deficiency * Have an 8/8 Human leukocyte antigen (HLA)-matched related or unrelated donor or a 7/8 HLA-matched unrelated donor or haploidentical related donor * Have "early stage" GATA2 deficiency defined as a hypocellular for age bone marrow with less than 5% blasts and normal or favorable cytogenetics (defined as "good" or "very good" cytogenetics risk groups plus trisomy 8) Design: * All participants with GATA2 deficiency will receive a pre-transplant conditioning regimen consisting of Briquilimab administered as a single intravenous (IV) infusion on day -11 (range day -13 to -10) with pharmacokinetics, followed by fludarabine or fludarabine/cyclophosphamide IV infusions (3 or 5 days depending on the donor) and 200 cGy total body irradiation (TBI) on day -1. HCT will be infused on day 0. * Participants with an 8/8 human leukocyte antigen (HLA)-matched related or unrelated donor assigned to Arm A will receive a fludarabine for three days on days -4, -3, and -2. * Participants with a 7/8 HLA-matched unrelated donor or a haploidentical related donor assigned to Arm B will receive a fludarabine for five days on days -6, -5, -4, -3, and -2, cyclophosphamide for 2 days on days -6 and -5 * Post-transplant immunosuppression for Graft Versus Host Disease (GVHD) prophylaxis for recipients of Arms A and B will consist of cyclophosphamide for 2 days on days +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 GVHD, tacrolimus will be stopped or tapered at approximately day +180
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
13
15 mg/kg intravenous (IV) three times per day starting on day +5 until approximately day +30 (+/- 2 days)
0.02 mg/kg intravenous (IV) daily starting on day +5
50 mg/kg intravenous (IV) daily on days +3 and +4
200 centigray (cGy) on day -1
Stem cell transplant on day 0
Single 0.6 mg/kg intravenous (IV) infusion administered between days -13 and day -10
14.5 mg/kg intravenous (IV) daily on days -6 and -5; for 7/8 Unrelated or Haploidentical Donor, prior to transplant.
30 mg/m\^2 intravenous (IV) over 30 minutes daily. For 8/8 Matched Related or Unrelated Donor, fludarabine dose will be on days -4, -3, and -2. For 7/8 Unrelated or Haploidentical Donor, fludarabine dose will be on days -6, -5, -4, -3, and -2.
Screening ≤90 days.
Screening ≤90 days.
Screening ≤90 days.
Screening ≤90 days.
Screening ≤90 days.
Baseline ≤28 days.
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Percentage of Evaluable Participants With GATA-binding Factor 2 (GATA2) Deficiency With Sustained Donor Engraftment by 100 Days Post-transplant Reported Along With a Two-sided 90% Confidence Interval
To determine whether allogeneic hematopoietic cell transplantation with Briquilimab-based conditioning results in sustained donor engraftment by 100 days post-transplant, the percentage of evaluable participants with GATA2 deficiency will be reported along with a two-sided 90% confidence interval. Sustained donor engraftment is defined as neutrophil recovery with ANC ≥ 500/mm\^3 for 3 consecutive days associated with \>90% myeloid and \>10% cluster of differentiation 3 (CD3+) T cell donor chimerism by 100 days post-transplant.
Time frame: 100 days
Percentage of Evaluable Participants With GATA-binding Factor 2 (GATA2) Deficiency With Sustained Donor Engraftment by 100 Days Post-transplant Reported Along With a Two-sided 95% Confidence Interval
To determine whether allogeneic hematopoietic cell transplantation with Briquilimab-based conditioning results in sustained donor engraftment by 100 days post-transplant, the percentage of evaluable participants with GATA2 deficiency will be reported along with a two-sided 95% confidence interval. Sustained donor engraftment is defined as neutrophil recovery with ANC ≥ 500/mm\^3 for 3 consecutive days associated with \>90% myeloid and \>10% cluster of differentiation 3 (CD3+) T cell donor chimerism by 100 days post-transplant and restoration of normal hematopoiesis by one-year post-transplant.
Time frame: 100 days
Percentage of Evaluated Participants With GATA-binding Factor 2 (GATA2) Deficiency Who Received Allogeneic Hematopoietic Cell Transplantation With Briquilimab-based Conditioning That Results in Restoration of Normal Hematopoiesis by 1-year Post-transplant
To determine whether allogeneic hematopoietic cell transplantation with Briquilimab-based conditioning results in restoration of normal hematopoiesis by one-year post-transplant in participants with GATA2 deficiency the percentage of evaluated participants will be reported along with a 95% two-sided confidence interval. Restoration of normal hematopoiesis is defined as normalization of peripheral blood counts hemoglobin (Hb) \>8 g/dL, platelet count \> 100,000/µ/L and absolute neutrophil count (ANC)\>1,500/µ/L).
Time frame: 1-year
Number of Participants With GATA2 Deficiency Conditioned With Briquilimab With Transplant-related Toxicity Reported by Type and Grade of Adverse Event by Arm
By Arm, the participants with transplant-related toxicity will be reported by type and grade of event. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is serious. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Time frame: 3 years
3-year Overall Survival (OS)
OS is defined as time from treatment start date until death from any cause, last follow up or date last known alive. OS was determined by using the Kaplan-Meier method and is reported along with the median value and the 95% confidence interval.
Time frame: 3 years
3-year Event-free Survival (EFS)
EFS is defined as death, receipt of a second transplant, or graft failure. EFS was determined using the Kaplan-Meier method and is reported along with the median value and the 95% confidence interval. Primary graft failure is defined as the lack of donor-derived neutrophil engraftment by day +60 after transplant. Secondary graft failure is defined as initial donor-derived neutrophil engraftment followed by the subsequent loss of donor chimerism to \< 10% donor whole blood or myeloid peripheral blood chimerism.
Time frame: 3 years
Percentage of Participants With Secondary Graft Failure Within 3 Years After Transplant
Percentage of participants with secondary graft failure at 3 years is reported separately by cohort along with 95% two-sided confidence interval. Secondary graft failure is defined as initial donor-derived neutrophil engraftment followed by the subsequent loss of donor chimerism to \< 10% donor whole blood or myeloid peripheral blood chimerism within 3 years after transplant.
Time frame: 3 years
Incidence of Grades III-IV Acute and Moderate to Severe Chronic Graft Versus Host Disease (GVHD)
Incidence of grades III-IV acute and moderate to severe chronic graft versus host disease within 3 years after transplant will be reported separately by cohort using simple estimates along with 95% two-sided confidence intervals. In addition, cumulative incidence curves along with 95% two-sided confidence interval. Acute GVHD staging and grading will be assessed according to the 1994 Consensus Conference on Acute GVHD Grading criteria. Grade III liver (bilirubin) stage 2-3 or stage 2.4 gut (stool output per day). Grade IV is stage 4 (skin) or stage 4 liver (bilirubin). Chronic GVHD diagnosis and staging will be assessed according to the 2014 Chronic GVHD Consensus Project. Diagnostic signs and symptoms of chronic GVHD are those that establish the diagnosis of chronic GVHD without need for further testing or evidence of other organ involvement.
Time frame: Day 100 (Acute GVHD) and 1-, 2-, and 3-year post-transplant (Chronic GVHD)
Cumulative Incidence of Transplant-related Mortality Reported Along With a 95% Two-sided Confidence Interval
Cumulative incidence curves accounting for the competing risk of transplant-related mortality will be constructed by cohort, with the values reported at day 100, one, and two years, along with a 95% two-sided confidence interval.
Time frame: Day 100, 1 year and 2 years
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