Haploidentical Transplant for People With Chronic Granulomatous Disease (CGD) Using Alemtuzumab, Busulfan and TBI With Post-Transplant Cyclophosphamide

• INCLUSION CRITERIA:

• Must have sufficient complications from underlying disease to warrant undergoingtransplantation. (History of one or more life threatening infections and/or anongoing infection not responsive to current medical therapy and/or ongoinginflammation along with an oxidase level within quartile 1 or 2.

• Patients will be reviewed at a multidisciplinary meeting for assessment of therisk/benefit ratio of transplant for the patient to determine suitability for thishigh risk treatment. This multidisciplinary meeting is a combined NCI/NIAIDbimonthly meeting comprised of investigators from multiple branches of the NC andNIAID to review patients with immunodeficiencies being considered for varioustransplant protocols.

• Patients who are deemed to have colitis in the severe category (severe colitis) asdefined below in the Subject Exclusion Criteria, who are at high risk for GvHD, willbe included in enrollment to the protocol after 10 patients have completed theprotocol regimen successfully. Patients among the first 10 may have colitis that isnot deemed in the severe category. The success of the regimen will be determined asengraftment with a maximum GvHD of grade 2 (See the exclusion criteria for patientswith severe colitis).

• Patients who are 4 65 years of age.

• HLA mismatched related (more than 1 mismatch) donor graft available.

• Ability to comprehend and willingness to sign the informed consent or have aparent/guardian consent if the donor is a minor; assent being obtained from minorsas appropriate.

• Must be HIV negative.

• Must be able to stay within one hour s travel of the NIH for the first 3 monthsafter transplantation and have a family member or other designated companion to staywith during the post-transplant period.

• Must provide a durable power of attorney for health care decisions to an appropriateadult relative or guardian in accordance with NIH Form-200 NIH Durable Power ofAttorney for Health Care Decision Making."

• Where appropriate, subjects must agree to use contraception for 3 monthspost-transplant.

NOTE: Alemtuzumab (IV formulation) is no longer distributed commercially. In order to receive product, the physician must contact the program for the patient. If the subject is not willing to consent to submit their info (address, date of birth and gender) to the program such that we can obtain the drug, then we cannot proceed with conditioning therefore no transplant will occur on this protocol.

Participation of Women:

Contraception: The effects of the combination of conditioning medications (alemtuzumab, busulfan, cyclophosphamide and mycophenolate mofetil) and total body irradiation on the developing human fetus are unknown. For this reason, men and women of childbearing potential 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 transplant. Females of childbearing-age must have a negative pregnancy test result prior to receiving any chemotherapy or conditioning agents. During the course of the study, if a woman becomes pregnant or suspects she is pregnant, she should inform the study staff and her primary care physician immediately.

Participation of Children:

Children greater than or equal to 4 years of age may participate in this study.

EXCLUSION CRITERIA:

• The subject cannot have a 9/10 or 10/10 HLA matched related or unrelated donor.

• Eastern Cooperative Oncology Group (ECOG) or equivalent performance status greaterthan or equal to 3

• Patients with inflammatory bowel disease deemed in the severe category (severecolitis), because they are at higher risk for GvHD, will be excluded from theprotocol until there are 10 patients without severe colitis that have successfullycompleted a regimen, as determined by engraftment and acute GvHD of a maximum ofgrade 2. Severity of colitis will be determined in consultation with agastroenterologist specialist. However, severe colitis will be evaluated within 4months of transplant and defined as any of the following (where this screening maybe performed on a natural history or screening protocol):

• The consultant gastroenterologist clinically determines that the patient hassevere colitis.

• Patient adult CDAI score is in the 350-450 range and Pediatric CDAI score isgreater than 30 within the month before initiation of conditioning Crohn sDisease Activity Index (CDAI) for transplant.

• The patient has been requiring 1 mg/kg/day or more of prednisone or equivalentsteroid for control of colitis within 1 month of the CDAI scoring used todetermine eligibility.

• The patient requires continuing treatment with a biologic that consists ofanti-TNF alpha (e.g. infliximab, Humira, certolizumab and others of thisfamily), anti-interleukin 12 (e.g. Ustekinumab) or anti-integrin (e.g.Vedolizumab) for control of colitis within 2 months of the CDAI scoring used todetermine eligibility.

• If the patient had a colonoscopy within 6 months of transplant which revealedfindings of a simplified endoscopic score of Crohn s Disease (SES-CD) greaterthan 15.

• Left ventricular ejection fraction < 40%.

• Transaminases > 5x upper limit of normal.

• Psychiatric disorder or mental deficiency severe enough as to make compliance withthe HSCT treatment unlikely, and/or making regulatorily and legally effectiveinformed consent impossible. This will include adult patients that are unable toconsent.

• Major anticipated illness or organ failure incompatible with survival from AlloPBSCtransplant.

• Pregnant or lactating.

• HIV positive.

• Participants older than 65 are excluded. It is known from standard transplantationthat these participants have a higher risk of morbidity and mortality related totransplantation. Given the investigational nature of this protocol, the risk benefitratio is not warranted to include these participants at this time.

• Participants who are not willing to submit their information as part of thealemtuzumab (Campath ) Distribution Program application or participants whom theDistribution Program committee has determined are not qualified to receivealemtuzumab.

• Any condition or circumstance, which the Principal Investigator (PI) feels, wouldcreate difficulty in maintaining compliance with the requirements of this protocol.

• Any active infectious disease, whether CGD-related or not, that is deemed to beincompatible with successful tolerance to the rigors of transplantation.

• C-reactive protein of greater than 100 Units within 6 weeks of anticipatedtransplant.

• Any history of seizures, controlled or otherwise, if unrelated to an infectiouscause.

• Any history of any neurologic disorders or family history of such, unrelated toinfection.

• Brain CT or MRI findings suggestive of neurologic disorders other than infection.