Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Mutations
- Conditions
- GATA2ImmunodeficiencyMDS
- Interventions
- Procedure: Allogeneic HSCTBiological: Equine Anti-Thymocyte GlobulinProcedure: Total Body Irradiation (TBI)
- Registration Number
- NCT01861106
- Lead Sponsor
- 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.
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 8-70 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 immuneodeficiency 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 144
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B Busulfan Test dose 9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant Arm B Fludarabine (Fludara, Berlex Laboratories) 9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant Arm A Busulfan (Busulfex) 10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant Arm B Mycophenolate mofetil (MMF) 9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant Arm C (combined with Arm B per Amendment N) Fludarabine (Fludara, Berlex Laboratories) Haploidentical Related Donor Transplant Arm D (Deleted this arm per amendment I) Fludarabine (Fludara, Berlex Laboratories) Umbilical Cord Blood Transplant Arm B Busulfan (Busulfex) 9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant Arm C (combined with Arm B per Amendment N) Busulfan (Busulfex) Haploidentical Related Donor Transplant Arm B Cyclophosphamide (CTX, Cytoxan) 9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant Arm D (Deleted this arm per amendment I) Cyclophosphamide (CTX, Cytoxan) Umbilical Cord Blood Transplant Arm A Mycophenolate mofetil (MMF) 10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant Arm A Allogeneic HSCT 10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant Arm A Busulfan Test dose 10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant Arm A Fludarabine (Fludara, Berlex Laboratories) 10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant Arm A Tacrolimus 10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant Arm B Allogeneic HSCT 9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant Arm C (combined with Arm B per Amendment N) Allogeneic HSCT Haploidentical Related Donor Transplant Arm C (combined with Arm B per Amendment N) Total Body Irradiation (TBI) Haploidentical Related Donor Transplant Arm C (combined with Arm B per Amendment N) Tacrolimus Haploidentical Related Donor Transplant Arm D (Deleted this arm per amendment I) Total Body Irradiation (TBI) Umbilical Cord Blood Transplant Arm B Tacrolimus 9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant Arm C (combined with Arm B per Amendment N) Busulfan Test dose Haploidentical Related Donor Transplant Arm C (combined with Arm B per Amendment N) Cyclophosphamide (CTX, Cytoxan) Haploidentical Related Donor Transplant Arm D (Deleted this arm per amendment I) Allogeneic HSCT Umbilical Cord Blood Transplant Arm D (Deleted this arm per amendment I) Equine Anti-Thymocyte Globulin Umbilical Cord Blood Transplant
- Primary Outcome Measures
Name Time Method To determine whether allogeneic HSCT approach results in engraftment and restores normal hematopoiesis by one year in patients with mutations GATA2. 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
Name Time Method To determine the incidence of grade III-IV acute GVHD 100 days fractions will be reported using simple estimates along with 95% two-sided confidence intervals
To determine the incidence of chronic graft-versus-host disease 1 year and 2 years post-transplant Fractions of patients with transplant related toxicity as well as the fractions with aGVHD and cGVHD will be reported along with 95% confidence intervals.
Overall survival, and disease-free survival. 5 years post-transplant determined using the Kaplan-Meier method for all evaluable patients beginning at their date of transplant, along with the median value and the 95% confidence interval at the median
To determine the safety of allogeneic HSCT for patients with mutations in GATA2 3 years Fractions of patients with transplant related toxicity will be reported along with 95% confidence intervals
To characterize the immune reconstitution in 10/10 matched related and unrelated donor transplant recipients and haploidentical related donor transplants who receive GVHD prophylaxis Days 30, 100, 6 months, and one year post-transplant Fractions will be compared using Fisher's exact test.
To characterize the immune reconstitution inflammatory syndrome (IRIS) Days 30, 100, 6 months, and one year post-transplant fraction of patients who experience a reversal of the described immunologic abnormalities will be reported along with a 95% two-sided confidence interval. Fractions will be compared using Fisher's exact test.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States