allogeneic hematopoietic stem cell transplant for gata2 mutations

Conditions: GATA2; Immunodeficiency; MDS

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.

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.

Eligibility criteria:
* eligibility criteria: inclusion criteria- recipient 1. patient age of 8-70 years. 2. 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. 3. 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. 4. availability of a 10/10 or 9/10 or 8/10 hla-matched related or unrelated donor, or a haploidentical related donor. 5. 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. 6. 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. 7. left ventricular ejection fraction \> 40%, preferably by 2-d echocardiogram obtained within 90 days prior to initiation of conditioning therapy. 8. creatinine: adult patients: \ = 30 ml/min; pediatric patients (\ 30 ml/min/1.73m\^2. 9. serum conjugated bilirubin \< 2.5 mg/dl; serum alt and ast \<= 5 times upper limit of normal. 10. pulmonary function tests: fev1 and dlco \>30% 11. 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. 12. 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. 13. 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. exclusion criteria- recipient 1. 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 2. 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. 3. history of allergic reactions attributed to compounds of similar chemical or biological composition to agents (steroids, cyclophosphamide, busulfan) used in the study 4. 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. 5. history of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent. 6. active infection refractory to antimicrobial therapy. 7. active cns involvement by malignancy (patients with known positive csf cytology or parenchymal lesions visible by prior ct or mri). 8. pregnant or lactating. 9. 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. 10. 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. 11. no available 10/10 or 9/10 or 8/10 hla-matched related or unrelated donor, or haploidentical related donor.

Keywords: allogeneic donors peripheral blood stem cell immunodeficiency myelodysplasia haploidentical