NCT01861106

Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Mutations

Allogeneic Hematopoietic Stem Cell Transplant for Patients With Mutations in GATA2 or the MonoMAC Syndrome

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 144 (estimated)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 6 Years – 70 Years
• Healthy volunteers: Not accepted

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 6 and 70 years of age and have GATA2 deficiency. 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. * 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....

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 participants. 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 participants 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 participants with mutations in GATA2 or the clinical syndrome of MonoMAC. Eligibility: * Recipients ages 6-70 years old with mutations in GATA2 or the clinical syndrome of MonoMAC. Clinical history of at least one serious or disfiguring infection and GATA2 bone marrow immunodeficiency disorder with loss of one or more immune populations in the bone marrow including monocytes, Natural Killer (NK) cells, and B-lymphocytes, with or without additional cytopenias involving the red blood cell, neutrophil, or platelet compartment. * Have a 10/10 or a 9/10 or an 8/10 HLA-matched related or unrelated donor (HLA -A, -B, -C, DRB1, DQB1 by high resolution typing) or a haploidentical related donor; unrelated donors are identified through the National Marrow Donor Program. Design: Two Arms * Participants 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 days -6, -5, -4, and -3, busulfan based on pharmacokinetic levels from test dose or real time pharmacokinetics (PKs) (3.2 mg/kg IV will be the default dose) once daily on days -6, -5, -4, and -3, and HSCT on day 0. * Participants with mutations in GATA2, or the clinical syndrome of MonoMAC, with a 9/10 or an 8/10 HLA-matched related or unrelated donor (if the mismatch is not 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 or real time PKs ( 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 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 graft-versus- host disease, tacrolimus will be stopped or tapered at approximately day +180.

Conditions

• GATA2
• Immunodeficiency
• MDS

Interventions

Type	Name	Description
PROCEDURE	Allogeneic HSCT	Stem cell transplant
DRUG	Busulfan Test dose	0.8 mg/kg IV infusion over 3 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 3 hours once daily on Days -6, -5, -4 and -3 (weight based dosing). If in Arm B and if poor or very poor risk clonal chromosomal abnormalities, busulfan will also be given on day -2.
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). For post-transplant, 50/kg IV once daily x2 doses on days +3 and +4
PROCEDURE	Total Body Irradiation (TBI)	200 cGy on Day -1
DRUG	Mycophenolate mofetil (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
BIOLOGICAL	Equine Anti-Thymocyte Globulin	(Deleted this intervention per amendment I): 30mg/kg IV (in the vein)once daily x 3 days on Days -6, -5, -4 (3 doses total)

Timeline

• Start date: 2013-07-24
• Primary completion: 2027-12-31
• Completion: 2028-12-31
• First posted: 2013-05-23
• Last updated: 2026-04-16

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study