Allogeneic Hematopoietic Stem Cell Transplant for Patients With Mutations in GATA2 or the MonoMAC Syndrome
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 144
- 试验地点
- 1
- 主要终点
- To determine whether allogeneic HSCT approach results in engraftment and restores normal hematopoiesis by one year in patients with mutations GATA2.
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Years 至 70 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •ELIGIBILITY CRITERIA:
- •INCLUSION CRITERIA- Recipient
- •Patient age of 6-70 years.
- •Mutation in the GATA2 gene, or evidence of loss of expression of one allele of GATA2, by cDNA analysis performed by a CLIA certified laboratory, or the clinical syndrome of MonoMAC.
- •Clinical history of at least one serious or disfiguring infection and/or GATA2 bone marrow immunodeficiency disorder with lose 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.
- •Availability of a 10/10 or 9/10 or 8/10 HLA-matched related or unrelated donor, or a haploidentical related donor.
- •Patients may have evidence of MDS with one or more peripheral blood cytopenias and greater than 5% blasts but must have less than 10% blasts in the bone marrow in the absence of filgrastim in order to proceed directly to transplant. The majority of patients with MDS will have less than 5% blasts.
- •Disease status: Patients are to be referred in remission for evaluation. Should a patient have progressive disease with >10% blasts on screening/baseline bone marrow biopsy, the patient may receive standard treatment under the current study prior to proceeding with transplant. Once the patient has <10% blasts, they may proceed to transplant. The patient may also be referred back to their primary hematologist or oncologist for treatment. If this course of action is not in the best interest of the patient according to the clinical judgment of the PI/LAI, then the patient may receive standard treatment for the malignant disease or hematological disorder under the current study. If under either of these settings, it becomes apparent that the participant will not be able to proceed to transplant, then he/she must come off study. Recipient-Subjects receiving a standard therapy will be told about the therapy, associated risks, benefits and alternatives of the proposed therapy, and availability of receiving the same treatment elsewhere, outside of a research protocol.
- •Left ventricular ejection fraction > 40%, preferably by 2-D echocardiogram obtained within 90 days prior to initiation of conditioning therapy.
- •Creatinine: Adult patients: <= 2.0 mg/dl and creatinine clearance >= 30 ml/min; Pediatric patients (<18 years old): creatinine <1.5 mg/dL and a creatinine clearance, using the Schwartz Formula, > 30 mL/min/1.73m^
- •Serum conjugated bilirubin < 2.5 mg/dl; serum ALT and AST <= 5 times upper limit of normal.
- •Pulmonary function tests: FEV1 and DLCO >30% Note: For children who are unable to cooperate for PFTs, the criterion is: No evidence of dyspnea at rest, no exercise intolerance, and no requirement for supplemental oxygen therapy
- •Ability of patient or Legally Authorized Representative (LAR) (if the patient is deemed by the treating physician to be cognitively impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable) to understand and the willingness to sign a written informed consent document indicating that they are aware of the investigational nature of this study or written informed consent obtained from parent or legal guardian if subject is a minor.
- •As therapeutic agents used in this trial may be harmful to a fetus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least one-year post-allo HSCT. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in the study, she should inform her treating physician immediately.
- •All transplant patients remain in the NIH hospital or, if discharged, stay close to the NIH for a minimum of 100 days after transplant or longer, if there are complications. An adult caregiver must be with the patient at all times from discharge to day 100.
排除标准
- •Recipient
- •Patients who are receiving any other investigational agents with the exception of virus- specific cytotoxic T-cells for the treatment of viral infection/reactivation prior to allo HSCT
- •HIV-positive patients are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
- •History of allergic reactions attributed to compounds of similar chemical or biological composition to agents (steroids, cyclophosphamide, busulfan) used in the study
- •Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For patients with a concomitant positive hepatitis B surface antigen, patients will require a hepatology consultation. The risk-benefit profile of transplant and hepatitis B will be discussed with the patient, and eligibility determined by the PI or Lead Associate Investigator.
- •History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.
- •Active infection refractory to antimicrobial therapy. Exceptions may be made per PI discretion for patients with disseminated mycobacterial infections if the potential benefit of HSCT is thought to outweigh the risks.
- •Active CNS involvement by malignancy (patients with known positive CSF cytology or parenchymal lesions visible by prior CT or MRI).
- •Pregnant or lactating.
- •The effects on breast-milk are unknown and may be harmful to the infant; therefore, women should not breast feed during the interval from study entry to one year post-transplant.
- •Presence of active malignancy in another organ system other than the hematopoietic, except when driven by viruses in which case the immune reconstitution after transplant may control the malignancy. This includes solid tumors not in remission.
研究组 & 干预措施
Arm D (Deleted this arm per amendment I)
Umbilical Cord Blood Transplant
干预措施: Total Body Irradiation (TBI) (Procedure)
Arm C (combined with Arm B per Amendment N)
Haploidentical Related Donor Transplant
干预措施: Allogeneic HSCT (Procedure)
Arm C (combined with Arm B per Amendment N)
Haploidentical Related Donor Transplant
干预措施: Busulfan (Busulfex) (Drug)
Arm D (Deleted this arm per amendment I)
Umbilical Cord Blood Transplant
干预措施: Allogeneic HSCT (Procedure)
Arm B
9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant
干预措施: Mycophenolate mofetil (MMF) (Drug)
Arm C (combined with Arm B per Amendment N)
Haploidentical Related Donor Transplant
干预措施: Total Body Irradiation (TBI) (Procedure)
Arm D (Deleted this arm per amendment I)
Umbilical Cord Blood Transplant
干预措施: Fludarabine (Fludara, Berlex Laboratories) (Drug)
Arm E (Deleted this arm per amendment O)
Donor
Arm B
9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant
干预措施: Fludarabine (Fludara, Berlex Laboratories) (Drug)
Arm C (combined with Arm B per Amendment N)
Haploidentical Related Donor Transplant
干预措施: Cyclophosphamide (CTX, Cytoxan) (Drug)
Arm B
9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant
干预措施: Busulfan (Busulfex) (Drug)
Arm C (combined with Arm B per Amendment N)
Haploidentical Related Donor Transplant
干预措施: Busulfan Test dose (Drug)
Arm B
9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant
干预措施: Busulfan Test dose (Drug)
Arm A
10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant
干预措施: Tacrolimus (Drug)
Arm B
9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant
干预措施: Tacrolimus (Drug)
Arm C (combined with Arm B per Amendment N)
Haploidentical Related Donor Transplant
干预措施: Tacrolimus (Drug)
Arm D (Deleted this arm per amendment I)
Umbilical Cord Blood Transplant
干预措施: Equine Anti-Thymocyte Globulin (Biological)
Arm B
9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant
干预措施: Allogeneic HSCT (Procedure)
Arm A
10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant
干预措施: Allogeneic HSCT (Procedure)
Arm B
9/10 or 8/10 HLA Match Related Donor or Unrelated Donor or Haploidentical Donor Transplant
干预措施: Cyclophosphamide (CTX, Cytoxan) (Drug)
Arm D (Deleted this arm per amendment I)
Umbilical Cord Blood Transplant
干预措施: Cyclophosphamide (CTX, Cytoxan) (Drug)
Arm C (combined with Arm B per Amendment N)
Haploidentical Related Donor Transplant
干预措施: Fludarabine (Fludara, Berlex Laboratories) (Drug)
Arm A
10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant
干预措施: Busulfan Test dose (Drug)
Arm A
10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant
干预措施: Busulfan (Busulfex) (Drug)
Arm A
10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant
干预措施: Mycophenolate mofetil (MMF) (Drug)
Arm A
10/10 HLA Matched Related Donor or Unrelated Donor or 9/10 HLA with DQ mismatch Transplant
干预措施: Fludarabine (Fludara, Berlex Laboratories) (Drug)
结局指标
主要结局
To determine whether allogeneic HSCT approach results in engraftment and restores normal hematopoiesis by one year in patients with mutations GATA2.
时间窗: 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
次要结局
- To determine the incidence of chronic graft-versus-host disease(1 year and 2 years post-transplant)
- Overall survival, and disease-free survival.(5 years post-transplant)
- To determine the safety of allogeneic HSCT for patients with mutations in GATA2(3 years)
- To determine the incidence of grade III-IV acute GVHD(100 days)
- 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)
- To characterize the immune reconstitution inflammatory syndrome (IRIS)(Days 30, 100, 6 months, and one year post-transplant)
- Overall survival, and disease-free survival.(3 years post-transplant)