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

  • End date
    Dec 31, 2032
  • participants needed
  • sponsor
    National Institute of Allergy and Infectious Diseases (NIAID)
Updated on 4 October 2022



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.


To find out if a different drug treatment can improve the success rates of stem cell transplants in people with CGD.


People aged 4-65 years with CGD.


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.


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 schemasincluding 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.

Condition Chronic Granulomatous Disease
Treatment cyclophosphamide, busulfan, Total body irradiation, Sirolimus, alemtuzumab, Tociluzumab, Pheripheral blood stem cells, Emapalumab-Izsg
Clinical Study IdentifierNCT05463133
SponsorNational Institute of Allergy and Infectious Diseases (NIAID)
Last Modified on4 October 2022


Yes No Not Sure

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
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
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