Background:
* 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 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 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
