Background:
Chronic granulomatous disease (CGD) affects the immune system. People with CGD are more likely to get infections. Drugs can help control infections, but these treatments can cause side effects including kidney failure and deafness. Stem cell transplants can cure CGD, but these don t always work.
Objective:
To find out if a different drug treatment can improve the success rates of stem cell transplants in people with CGD.
Eligibility:
People aged 4-65 years with CGD.
Design:
Participants will undergo screening. They will have a physical exam. They will have blood and urine tests and tests of their heart function and breathing. They will have imaging scans. They will have a bone marrow biopsy; a needle will be inserted into their hip to draw a sample of tissue from the bone.
A tube called a catheter will be placed into a vein in the participant s chest. This catheter will remain in place for the transplant and recovery period. Blood for tests can be drawn from the catheter, and medications and the stem cells can be administered through it.
Participants will be in the hospital for either 10 or 21 days to receive 3 or 4 drugs before the transplant. They will get 2 doses of total body radiation on the same day.
Participants will receive donor stem cells through the catheter. They will remain in the hospital for 6 weeks afterward.
Participants will visit the clinic 2 to 3 times per week for 3 months after discharge.
Follow-up visits will continue for 5 years.
Must have the ability to comprehend and a willingness to sign the informed consent. For pediatric patients, must have a parent/guardian who can sign consent if the donor is a minor; assent will be obtained from minors as appropriate.
Must have confirmed diagnosis of CGD.
Must have sufficient complications from underlying disease to warrant undergoing transplantation (either a history of or ongoing inflammation/CGD-related autoimmunity OR a CGD-related infection while on prophylaxis) OR have a Quartile 1 or 2 residual oxidase production level.
Ages 4 years-65 years.
Ejection fraction of less than 30% by echocardiography.
Forced expiratory volume (FEV1%) of less than 35% and/or an adjusted diffusing capacity of lung of carbon monoxide (adj DLCO) of less than 30%.
Transaminases >5x upper limit of normal based on the individual s clinical situation and at the discretion of the investigator.
Psychiatric disorder or mental deficiency severe enough as to make compliance with the HSCT treatment unlikely, and/or to make regulatorily and legally effective informed consent impossible.
Parallel
Sirolimus
DrugPost transplant drug - Immunosuppressant to prevent donor peripheral blood stem cell rejection and graft versus host disease. This is a well studied drug, and is not under an IND.
Cyclophosphamide
DrugPost transplant drug - cyclophosphamide give to prevent graft versus host disease. This is a well studied drug and s not under an IND.
Alemtuzumab
DrugTransplant Conditioning Drug - Monoclonal antibody that targets recipient and donor T-cells to prevent graft versus host disease. Not an IND. This is a well-studied drug, and is not under an IND.
Busulfan
DrugTransplant Conditioning Drug - Chemotherapy to create space in the patient's bone marrow so that the donor peripheral blood stem cells can repopulate in the patient's bone marrow. This is a well studied drug, and is not under IND.
Pheripheral blood stem cells
Biological/VaccineDonor peripheral blood stem cells either matched unrelated donors or matched related relative to replace the patient's immune cells with functional immune cells. The peripheral blood stem cells are not regulated by the FDA.
Emapalumab-Izsg
DrugTransplant conditioning drug for High Risk Group only - An interferon gamma blocking antibody used to prevent inflammation/engraftment syndrome post HSC transplant.
Tociluzumab
DrugTransplant Conditioning Drug - An interleukin-6 (IL-6) receptor antagonist used to decrease Chronic Granulomatous Disease (CGD) inflammation during the HSC transplant process.
Total Body Irradiation
DrugTransplant Conditioning - Total Body Irradiation (300 cGy in fractionated doses) to create space n the subject's bone marrow so that the donor peripheral blood stem cells can repopulate in the subject's bone marrow.
Overall Survival
Alive at 1 years post-transplant.
To assess the infection rates in the setting of Alemtuzumab (Campath-1H) and post-transplant cyclophosphamide with the addition of an Il-6 antagonist and TNF inhibitor.
Any documented viral, bacterial, fungal, or parasitic infection.
To assess kinetics of engraftment
Measurement of chimerism, lymphocyte phenotype (TBNK/SCID/TVB), and cytokine analysis laboratory values and research cytokine, alemtuzumab, and CXCL9 levels
Improve eligibility for allogeneic transplantation.
Subject eligible to enroll in the protocol.
Engraftment without GvHD
As defined by a \>10-20% myeloid engraftment of donor neutrophils. Will be assess as event-free survival (EFS)
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