Allogeneic Transplantation for P40 CGD Is Curative of Inflammatory Disease
Authors: Kang Elizabeth M. , Wright Nicola A. , Nicholls Katherine , Hilligoss Dianne , Kelly Corin , Kuhns Douglas B. , Malech Harry L. 
Published: October 2019

Abstract
Chronic Granulomatous Disease is an inherited immunodeficiency resulting from a defect in one of 5 proteins necessary for the production of NADPH oxidase, an important component in managing infections by neutrophils. The most common form of the disease is X-linked due to mutations in the GP91 protein. Patients with CGD are thus prone to various infections from specific bacteria and/or fungi, but generally have normal viral responses. They are also prone to inflammatory diseases, including sarcoid, lupus, and colitis. Allogeneic hematopoieitic transplantation has been shown to be curative and will arrest or even reverse some of the inflammatory problems and is now more commonly used in patients with a history of inflammation or recurrent infections.
In 2009, a new form of CGD was described resulting from a mutation in the P40 protein and to date only 2 patients have been described with this form of CGD. Unlike the other subtypes, these patients did not present with infection but in fact with severe colitis, making their diagnosis much more difficult. The role of P40 versus the other components of the NADPH oxidase does not necessarily explain this particular presentation as opposed to infection susceptibility; however assays such as DHR to test oxidase production can be misleading (both patients demonstrated only a partial reduction of oxidase production by DHR assay with normal sequencing for standard CGD subtypes) and may need to be performed specifically for a P40 dysfunction. We now report on the results of allogeneic transplant for two patients with P40 CGD.
The first patient was referred to the National Institutes of Health (NIH) at the age of 9. His initial presentation was at an early age with diarrhea and perirectal abscesses. Notably, on his first EGD and colonoscopy he had evidence of granulomatous disease. He was eventually referred to a second institution for further testing and determined to have compound heterozygous mutations in the NCF4 genes with a frameshift mutation resulting in a premature stop codon in one allele and a missense mutation in the other. (Blood 114: 3309-3315, 2009) He had had a diverting ileostomy done at his referring institution as a result of his refractory colitis and was still requiring immunosuppression for his disease at the time of referral for transplant. He had no matched sibling donors and therefore underwent transplant using a 9 out of 10 matched unrelated donor.
The second patient was a 17 year old male diagnosed at the age of 15, again with colitis and significant perirectal disease, with treatment including Interferon gamma, high dose corticosteroids, topical anti-inflammatories, azathioprine, and long-term antibiotics. His diagnosis of P40 CGD was made at the NIH where sequencing confirmed a compound heterozygous mutation of NCF4 with frameshift mutations in Exon 3 and Exon 9. His unaffected sister was a full match and was his donor.
Both patients received busulfan (5mg/kg and 10mg/kg respectively) and Campath as part of their conditioning regimen with 300cGY of TBI also given for the MUD transplant. Sirolimus was used as the sole GvHD prophylaxis.
The products were unmanipulated peripheral blood stem cell grafts (doses 8x10e6 and 10.4 x 10e6 CD34/kg respectively) and both patients had full myeloid engraftment by Day 30.
The first patient had some grade 1 GvHD of the skin and GI tract initially, but is now more than 3 years post transplant and is considering revision to reconnect his ostomy with no evidence of GvHD, chronic or otherwise. The second patient is also doing well more than 1 year out, with no evidence of GvHD and has had complete resolution of his colitis off of his immunosuppression.
Thus, allogeneic transplant with either a matched related or unrelated donor appears to be curative in patients with this rare form of CGD, leading to complete resolution of their inflammatory complications.

Disclosures
No relevant conflicts of interest to declare.