High Dose Peripheral Blood Stem Cell Transplantation With Post Transplant Cyclophosphamide for Patients With Chronic Granulomatous Disease

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 participants 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 on
the overall quality of life significantly, and lead to significant morbidity, such as renal
failure and deafness. CGD patients have auto

inflammation 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
most commonly uses a human leukocyte antigen (HLA)-matched related sibling as the donor
(allogeneic stem sell 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
appear to be at a significantly increased risk of severe engraftment syndrome and/or GvHD,
based on our results to date and will be therefore be excluded from this protocol.

GvHD is a result of the graft recognizing host antigens as foreign, typically in the presence
of inflammation, and results in a type of iatrogenic autoimmune disease. For participants
with non-malignant diseases, the aim of the transplant is solely to replace the defective or
deficient cell population. Furthermore, as a graft versus tumor effect is not required,
regimens designed to establish tolerance induction and/or stable mixed chimerism may be
preferable for cure in this participant population; therefore, alternate transplant
strategies can and should be used to further suppress the development of any GvHD effects.

In a prior protocol we observed low rates of GvHD, using a nonmyeloablative conditioning
regimen but had significant rates of graft failure and/or loss. To improve upon our results
we therefore propose to increase the target cell dose to be infused and use post transplant
cyclophosphamide to mitigate the increased risk of GvHD.

For the patients with an HLA matched sibling donor (Group 1-Sibling Related) we propose using
a busulfan-based, nonmyeloablative conditioning regimen combined with Alemtuzumab
(Campath-1H, Campath ) an immunosuppressive monoclonal antibody currently approved by the
U.S. Food and Drug Administration (FDA) as a single treatment for patients with B-cell
chronic lymphocytic leukemia; however, for this protocol we are using it for its mechanism of
action as an immunosuppressive agent. For GvHD prophylaxis we will use post-transplant
cyclophosphamide (Cytoxan ) and sirolimus (Rapamune ).

For patients with only a MUD (Group 2-MUD) we will use a similar conditioning regimen, with a
few modifications including the addition of total body irradiation (TBI) to enhance immune
suppression (but with lower dose of busulfan),due to the increased risk of graft rejection
with HLA-matched but unrelated cells, along with the posttransplant cyclophosphamide. We will
compare the results obtained here to our previous clinical trial which did not use post
transplant Cytoxan and where the cell dose infused was lower than the targeted dose of 10
million CD34+ hematopoietic stem cells/kg body weight in this study, but did use the same
conditioning regimen.

- INCLUSION CRITERIA:

- Must have confirmed Chronic Granulomatous Disease.

- 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 or have a Quartile 1 and/or 2
residual oxidase production level.

- Ages 4 years - 65 years

- HLA-matched family donor graft or an HLA matched unrelated peripheral blood stem cell
(PBSC) graft (10/10 or 9/10 mismatch) available

- Must be HIV negative

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

- Must provide a durable power of attorney for health care decisions to an appropriate
adult relative or guardian in accordance to NIH -200 NIH Durable Power of Attorney for
Health Care Decision Making .

- If of child-bearing potential, must agree to consistently use contraception from one
month prior to, and throughout, study participation, and for 3 months post-study.
Acceptable forms of contraception are:

- Contraceptive pills or patch, Norplant , Depo-Provera , 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.

EXCLUSION CRITERIA:

- Eastern Cooperative Oncology Group (ECOG) or equivalent performance status greater
than or equal to 3 (See Supportive Care guidelines, available at
http://intranet.cc.nih.gov/bmt/clinicalcare)

- Left ventricular ejection fraction < 40%

- Transaminases > 5x upper limit of normal based on the participant 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 making regulatorily and legally effective informed
consent impossible

- Major anticipated illness or organ failure incompatible with survival from AlloPBSC
transplant

- Pregnant or lactating

- HIV positive

- Uncontrolled seizure disorder

- Individuals older than 65 are excluded. It is known from standard transplantation that
these participants 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 participants at this time.

- Any condition or circumstance which 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) Distribution Program application or participants whom the Distribution
Program committee has determined are not qualified to receive alemtuzumab.

- Patients with a CRP greater than 100 mg/L within 30 days of anticipated transplant.