Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease (CGD) With an Alemtuzumab, Busulfan and TBI-based Conditioning Regimen Combined With Cytokine (IL-6, +/- IFN-gamma) Antagonists

Chronic Granulomatous Disease (CGD) is an inherited disorder resulting from a failure to produce nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, necessary for protection against a number of infectious organisms. Patients are subject to recurrent infections and inflammatory complications. The current management of these patients is limited to close surveillance for infections, administration of prophylactic antimicrobials, and rapid and aggressive treatment of suspected and documented infections with broad-spectrum antibiotics. Although often effective, these treatments can require long hospitalizations, impacting the overall quality of life significantly and leading to significant morbidity, such as renal failure and deafness. CGD patients have autoinflammation that may manifest as inflammatory bowel disease, hypoxic lung inflammation, and/or liver nodular regenerative hyperplasia with venopathy as examples.

Currently the only available cure for these disorders is bone marrow transplantation, which preferentially uses a human leukocyte antigen (HLA)-matched related sibling as the donor (allogeneic stem cell transplantation). However, as only 30% of participants in the general

population have an HLA-matched related sibling, allogeneic related transplantation is often not an option, resulting in the need for matched unrelated donor (MUD) transplantation. The National Marrow Donor Program (NMDP) serves as both a national registry of volunteers who are willing to donate progenitor cells to eligible recipients as well as a repository of cord blood products. Despite continued improvement in the use of transplantation schemas - including the development of nonmyeloablative regimens - there remain significant morbidity and mortality associated with transplantation, in particular graft versus host disease (GvHD) and graft rejection.

CGD with severe autoinflammation manifested as C-reactive protein (CRP) >= 100 milligrams per milliliter (mg/mL) has been a significant risk factor for mortality due to severe engraftment syndrome, and thus patients with elevated CRPs have not been eligible for prior transplant protocols.

In addition, despite improving engraftment rates, there continues to be mixed chimerism and late graft loss in CGD participants despite a variety of conditioning regimens being used at various centers.

In our most recent protocol, we have continued to have a low incidence of graft versus host disease and improved engraftment, but still could see improvement in graft stability. Thus, in order to improve outcomes with participants with elevated CRPs as well as improve overall engraftment, we are building on our prior regimens by targeting the inflammatory cytokines that appear to be involved in graft failure and engraftment syndrome.

Participants with a CRP of less than 100 mg/mL will be pretreated with a dose of tocilizumab, an anti-IL6 monoclonal antibody. Participants with a CRP of greater than 100 mg/mL will be pretreated with 2 doses of tocilizumab as well as an inhibitor of interferon-gamma in order to decrease the inflammation that has been seen in these participants with engraftment. Otherwise, the conditioning regimen will be similar to maintain the low rates of GvHD that we have seen to date.

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all the following criteria:

• 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.
• HLA-matched family donor graft or an HLA-matched unrelated PBSC graft (10/10 or 9/10 mismatch) available.
• Must be human immunodeficiency virus (HIV) negative.
• When discharged from the hospital the participant must be able to stay within 1 hour s travel of the NIH for the first 3 months after transplantation.
• Must have a family member or other designated care provider to assist with care during the post-transplant period when the patient is in the outpatient setting.
• Must provide a durable power of attorney for health care decisions to an appropriate adult relative or guardian in accordance with NIH 200 'NIH Durable Power of Attorney for Health Care Decision Making.'
• Females of child-bearing potential must agree to consistently use one form of contraception from 1 month prior to study entry and for at least 1 year post transplant. Male participants must agree to consistently use contraception for 1 year post transplant. Acceptable forms of contraception are:

• Contraceptive pills or patch, Norplant [Registered], Depo-Provera [Registered], or other FDA-approved contraceptive method.
• Male partner has previously undergone a vasectomy.
• Male participants will be advised to consistently use contraception throughout study participation and for 3 months post-transplant.
• Stated willingness to comply with all study procedures and is available for protocol visits for the duration of the study when possible.
• Patients who have a CRP of greater than 100 but otherwise meet inclusion criteria will be enrolled on the high-risk arm.

• CRP will be assessed no more than 7 weeks and no less than 6 weeks prior to anticipated transplant to determine on which arm the patient will be treated.

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• 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.
• Major anticipated illness or organ failure incompatible with survival from allogeneic peripheral blood stem cell (AlloPBSC) transplant.
• Pregnant or lactating.
• Uncontrolled seizure disorder per principal investigator (PI) discretion.
• Individuals older than 65 years are excluded. It is known from standard transplantation that these individuals have a higher risk of morbidity and mortality related to transplantation. Given the investigational nature of this protocol, the risk-benefit ratio is not warranted to include these individuals at this time.
• Active TB infection.
• Any condition or circumstance that the PI feels would create difficulty in maintaining compliance with the requirements of this protocol.
• Individuals who are not willing to submit their information as part of the alemtuzumab (Campath [Registered]) Distribution Program application or participants whom the Distribution Program committee has determined are not qualified to receive alemtuzumab.

NOTE: Alemtuzumab (Campath-1H) (intravenous [IV] formulation) is no longer distributed commercially. To receive product, the physician must contact the program for the patient. If the patient is not willing to consent to submit their info (demographics, contact information, and rationale for use) to the program such that we can obtain the drug, then we cannot proceed with conditioning; therefore no transplant will occur on this protocol. http://www.campath.com/