What's the purpose of this trial?
Background:
People with 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 (JSP191) 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.
JSP191 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....
This trial is currently open and accepting patients.
What will happen during the trial?
You may be able to join this trial if you:
The following criteria is a partial list of reasons why patients may be
eligible to participate in this clinical trial. Further evaluation with a medical professional is
required.
* INCLUSION CRITERIA:
* Age \>= 6 and \<= 70 years old
* Germline mutation in the GATA2 gene, predicted to be deleterious or previously reported in GATA2 deficiency as determined by targeted GATA2 sequencing performed at the NIH
* Clinical manifestation(s) consistent with a diagnosis of GATA2 deficiency, including any of the following (Note: only one clinical manifestation is required):
* History of severe, disfiguring, and/or recurrent infections
* Low monocyte (\< 190 cells/microL), B cell (\< 61 cells/microL) and/or NK cell (\< 126 cells/microL) counts
* Myelodysplastic syndrome by World Health Organization (WHO) criteria
* Early stage GATA2 deficiency defined as a hypocellular for age bone marrow with less than 5% blasts and normal cytogenetics or favorable cytogenetics (defined as good or very good cytogenetics risk groups plus trisomy 8)
* Availability of an 8/8 HLA-matched related or unrelated donor, a 7/8 HLA-matched unrelated donor or a haploidentical related donor
* Lansky (for participants \< 16 years of age) or Karnofsky (for participants \>=16 years of age) performance status of \>= 40%
* Left ventricular ejection fraction \> 40%, preferably by 2-D echocardiogram (echo) obtained within 90 days prior to treatment initiation
* Participants must have adequate organ function as defined below:
* Total bilirubin \<=2.5 x upper limit of normal (ULN)
* Alanine transaminase (ALT) and aspartate aminotransferase (AST) \<= 5 x ULN
* Creatinine:
Adult participants: \<=2.0 mg/dl and creatinine clearance \>= 30 ml/min.
Pediatric participants (\<18 years old): creatinine \<1.5 mg/dL and a creatinine clearance using the Schwartz Formula \> 30 mL/min/1.73m\^2
* Pulmonary function tests (PFT)s: FEV1 and adjusted DLCO \>30%. Children who are unable to cooperate for PFTs due to age are still eligible if no evidence of dyspnea at rest and no need for supplemental oxygen
* Women of childbearing potential (WOCBP) and men must agree to use highly effective contraception (hormonal, intrauterine device (IUD), abstinence, tubal ligation, partner has had the previous vasectomy) at the study entry, for the duration of study treatment, and for at least one-year post-allogeneic HCT or 4 months after completion of chemotherapy preparative administration if HCT is not performed
* Breastfeeding participants must be willing to discontinue breastfeeding
* Willingness to remain in the NIH hospital or, if discharged, stay close to the NIH (60 minutes drive), for a minimum of 100 days after transplant or longer if there are complications. The participants must commit to having an adult caregiver with them during the first 100 days after transplant in case of discharging from the hospital before 100 days verified by social worker
* Participants with hepatitis B virus (HBV) or hepatitis C virus (HCV) antibody-positive testing are allowed if HBV DNA \<100 IU/m or HCV RNA level is undetectable. Additionally, transplantation must be approved by a hepatology consult for these participants
* Participants or parents/guardians must be able to understand and willing to sign a written informed consent document
EXCLUSION CRITERIA:
* Participants with a Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) score \>8
* Participants who have received any investigational agents within 4 weeks before treatment initiation with the exception of virus-specific T cells for the treatment of viral infection/reactivation prior to allogeneic HCT
* Participants with a history of hematologic malignancy (e.g., AML, CMML). Note: participants with MDS are included
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents (fludarabine, cyclophosphamide, tacrolimus, mycophenolate mofetil, granulocyte-colony stimulating factor (G-CSF)) used in the study
* Presence of active malignancy. Note: participants with malignancy driven by viruses (e.g., human papillomavirus (HPV) or HPV or Epstein-Barr virus (EBV)) are allowed as the immune reconstitution after transplant may control the malignancy and participants with MDS are allowed
* Human immunodeficiency virus (HIV)-infected participants
* Pregnancy (confirmed with Beta-HCG serum or urine pregnancy test performed in WOCBP at screening)
* Uncontrolled intercurrent illness or social situations (as determined by social work consult) that would limit compliance with study requirements
Additional Trial Information
Phase 2
Enrollment: 32 patients (estimated)
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