Pilot and Feasibility Study of Reduced-Intensity Hematopoietic Stem Cell Transplant for MonoMAC

Phase 2

Completed

Conditions: MDS
Immunodeficiency
GATA2

Interventions: Drug: Cyclophosphamide (CTX, Cytoxan)
Drug: Fludarabine(Fludara,Berlex Laboratories)
Procedure: Total Body Irradiation (TBI)
Procedure: Allogeneic Hematopoietic Stem Cell (HSC)
Drug: Equine Anti-Thymocyte Globulin

Registration Number: NCT00923364

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

* Stem cells are immature blood cells that grow in the bone marrow and produce all of the cells needed for normal blood and immunity. Stem cells can be taken from one person (donor) and given to another person (recipient) through allogeneic stem cell transplantation. Donor stem cells can then replace the recipients stem cells in the bone marrow, restoring normal blood production and immunity. Most allogeneic transplants now use stem cells collected from the donors blood in a process called peripheral blood stem cell transplantation.

* Monocytopenia and mycobacterial infection (MonoMAC) is an immunodeficiency disease that is characterized by a lack of monocytes, a type of white blood cell, and an increased risk of developing mycobacteria infections that may cause tuberculosis.

* Allogeneic stem cell transplantation has been used successfully to treat many kinds of immune diseases and cancers that develop in blood or immune system cells. Researchers have been studying a particular kind of stem cell transplantation that uses lower than usual doses of chemotherapy and particular combinations of drugs to improve the results of the procedure for patients with blood-related cancers and pre-cancerous conditions.

Objectives:

* To determine the safety and efficacy of reduced-intensity hematopoietic stem cell transplants (a particular stem cell transplantation procedure) for treating MonoMAC.

Eligibility:

* Patients 18-60 years of age who have MonoMAC and who have been matched with a suitable stem cell donor.

Design:

* Donors and recipients will undergo separate procedures as part of this protocol.

* Donors:

* National Institutes of Health researchers will take the donor s medical history, perform a physical exam, take blood samples, and explain the procedure. Tests will be performed to check the donors heart, lung, kidney, and liver function.

* Donors will receive injections of a drug called filgrastim (G-CSF), which causes stem cells to travel from bone marrow into blood. The G-CSF shots will be given for 5 to 7 days before the collection procedure.

* Donors will undergo apheresis to collect white blood cells and stem cells directly from the blood, which can be done as an outpatient procedure. Researchers may consider the alternative of directly collecting bone marrow from the donor, which will require an overnight hospital stay.

* Recipients:

* Recipients will receive 3 days of pre-transplant chemotherapy and radiation therapy to prepare for the transplant. For 4 days before the transplant, recipients will receive the chemotherapy drug fludarabine, followed by a single dose of radiation therapy, and will also receive the drugs tacrolimus and sirolimus to prevent the donor cells from attacking the recipient s normal tissues.

* Recipients will then receive the transplant of donor stem cells and will continue to receive tacrolimus and sirolimus for 3 months after the transplant to prevent the donor cells from attacking the recipient s normal tissues. Recipients will be discharged from the hospital once their condition is stable.

* Recipients will visit the NCI clinic regularly for the first 5 months after the transplant, and then less often for at least 5 years. Recipients may receive additional donor immune cells (donor lymphocyte infusion) after the transplant if the study doctors believe they are needed.

Detailed Description: BACKGROUND:

Mutations in GATA binding protein 2 (GATA2) lead to an immunodeficiency disease that transforms into myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). This syndrome, previously known as MonoMAC, has 4 clinical features: 1) infections with Mycobacterium Avium Complex (MAC) and other opportunistic infections as a teenager or young adult, 2) a peripheral blood leukocyte flow cytometry profile with T-lymphocytes, but a severe deficiency of monocytes, B-lymphocytes, and Natural Killer (NK) cells, 3) the propensity to progress to MDS/AML, and 4) mutations in the gene GATA2. In this pilot study we propose to evaluate the efficacy and safety of a reduced intensity allogeneic hematopoietic stem cell transplantation (HSCT) regimen for patients with mutations in GATA2. We are particularly interested in determining whether allogeneic HSCT using this regimen reconstitutes normal hematopoiesis in patients with mutations in GATA2.

OBJECTIVES:

Primary Objective:

* To determine efficacy, namely whether reduced-intensity allogeneic HSCT results in engraftment and restores normal hematopoiesis by day +100 in patients with mutations in GATA2.

* To determine the safety of this HSCT regimen in patients with mutations in GATA2, including transplant related toxicity, the incidence of acute and chronic graft-versus host disease, immune reconstitution, overall survival, and disease-free survival

ELIGIBILITY:

Eligibility includes patients 12-60 years old with mutations in GATA2 who have a life expectancy of \> 3 months but \< 24 months, and who have a 10/10 matched related donor, a 10/10 or 9/10 matched unrelated donor (HLA -A, -B, -C, DRB1, DQB1 by high resolution typing identified through the National Marrow Donor Program), a 4/6 (or greater human leukocyte antigens (HLA -A), -B, DRB1) matched unrelated umbilical cord donor, or a haploidentical donor. Patients with GATA2 mutations who are 12-17 years of age are required to have MDS with chromosomal abnormalities to be eligible for this protocol.

DESIGN:

* Patients with mutations in GATA2 with a 10/10 matched related or 10/10 matched unrelated donor, will receive a reduced-intensity pre-transplant conditioning regimen consisting of fludarabine 30 mg/m(2)/day on days -4, -3, and -2, 200 centigray (cGy) total body irradiation (TBI) on day -1, and HSCT on day 0. Patients with mutations in GATA2 and a 9/10 matched unrelated donor will receive a reduced-intensity pre-transplant conditioning regimen consisting of fludarabine 30 mg/m(2)/day on days -4, -3, and -2, 300cGy total body irradiation (TBI) on day -1, and HSCT on day 0. Patients with mutations in GATA2 with umbilical cord blood units will receive a reduced-intensity conditioning regimen with cyclophosphamide 50 mg/kg on day -6, fludarabine 40 mg/m(2) on days -6 to -2, equine anti-thymocyte globulin (ATG) 30 mg/kg intravenous (IV) on days -6, -5 and -4, 200 cGy TBI on day -1, and HSCT on day 0. Patients with a haploidentical donor will receive a reduced intensity-conditioning regimen with cyclophosphamide 14.5 mg/kg on days -6 and -5, fludarabine 30 mg/m(2) on 4days -6 to -2, and 200 cGy TBI on day -1. Donor bone marrow cells will be infused on day 0.

* Post-transplant immunosuppression for graft-versus-host-disease prophylaxis will consist of sirolimus (Rapamycin) and tacrolimus until day +180, provided that there is no evidence of graft-versus-host disease. Post-transplant immunosuppression for graft versus-host-disease prophylaxis for recipients of haploidentical donors will consist of cyclophosphamide 50 mg/kg on days +3 and +4, along with sirolimus from day +5 to day 180, and tacrolimus from day +5 to day 180, providing that there is no graft-versus-host disease (GVHD).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 19

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Recipients and Healthy Related Donors	Equine Anti-Thymocyte Globulin	Hematopoietic Stem Cell Transplant for MonoMAC: 10/10 Human Leukocyte Antigen (HLA) Matched Related Donor (MRD) or Unrelated Donor (URD) Transplant. 9/10 HLA Matched Related Donor or Unrelated Donor Transplant. Haploidentical Related Donor Transplant. Umbilical Cord Blood Transplant.
Recipients and Healthy Related Donors	Total Body Irradiation (TBI)	Hematopoietic Stem Cell Transplant for MonoMAC: 10/10 Human Leukocyte Antigen (HLA) Matched Related Donor (MRD) or Unrelated Donor (URD) Transplant. 9/10 HLA Matched Related Donor or Unrelated Donor Transplant. Haploidentical Related Donor Transplant. Umbilical Cord Blood Transplant.
Recipients and Healthy Related Donors	Allogeneic Hematopoietic Stem Cell (HSC)	Hematopoietic Stem Cell Transplant for MonoMAC: 10/10 Human Leukocyte Antigen (HLA) Matched Related Donor (MRD) or Unrelated Donor (URD) Transplant. 9/10 HLA Matched Related Donor or Unrelated Donor Transplant. Haploidentical Related Donor Transplant. Umbilical Cord Blood Transplant.
Recipients and Healthy Related Donors	Cyclophosphamide (CTX, Cytoxan)	Hematopoietic Stem Cell Transplant for MonoMAC: 10/10 Human Leukocyte Antigen (HLA) Matched Related Donor (MRD) or Unrelated Donor (URD) Transplant. 9/10 HLA Matched Related Donor or Unrelated Donor Transplant. Haploidentical Related Donor Transplant. Umbilical Cord Blood Transplant.
Recipients and Healthy Related Donors	Fludarabine(Fludara,Berlex Laboratories)	Hematopoietic Stem Cell Transplant for MonoMAC: 10/10 Human Leukocyte Antigen (HLA) Matched Related Donor (MRD) or Unrelated Donor (URD) Transplant. 9/10 HLA Matched Related Donor or Unrelated Donor Transplant. Haploidentical Related Donor Transplant. Umbilical Cord Blood Transplant.

Primary Outcome Measures

Name	Time	Method
Days to Neutrophil Engraftment	30 days	Neutrophil engraftment is defined as a neutrophil count of \>0.5 x 10(9) cells/L for 3 consecutive days.
Days to Platelet Engraftment	30 days	Platelet engraftment is defined as a platelet count of \>20 x 10(9) cells/L for 7 consecutive days without requiring a platelet transfusion.

Secondary Outcome Measures

Name	Time	Method
Percentage of Donor Cells at Last Follow Up in Patients With Mutations GATA Binding Protein 2 (GATA2)	2 years	Engraftment of donor cells was assessed using polymorphisms in regions known to contain short tandem repeats. Peripheral blood cluster of differentiation 14 (CD14+), cluster of differentiation 3 (CD3-)/cluster of differentiation 56 (CD56+), cluster of differentiation 19 (CD19+), and CD3+ subsets were isolated by flow cytometry and chimerism was assessed.
Incidence of Acute and Chronic Graft-versus-host Disease (GVHD)	2 years	Acute GVHD is assessed according to the 1994 Consensus Conference Grading Criteria. Chronic GVHD is assessed by the 2005 Chronic GVHD Consensus Project. GVHD can affect performance status and attack multiple organ systems such as the skin, liver, gut, mouth, eyes, joints, lung, etc. that can lead to a rash, diarrhea, metabolic changes, infection and/or death. The clinical grading of acute GVHD is grade 0 (none) to 4 (severe). Chronic GVHD is a delayed form of GVHD that may occur after day 100 post transplant.
Overall Survival	2 years	Overall survival is defined as date of on-study to date of death from any cause or last follow up.
Number of Participants With Disease Free Survival	2 years	Number of participants with documented evidence of disease progression following start of treatment.
Number of Participants With Serious and Non-serious Adverse Events	Date treatment consent signed to date off study, approximately, 91 months	Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events v3.0. A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.