Haploidentical HSCT: more curative options for patients with CGD Free

In this issue of Blood, Riller et al¹ describe encouraging outcomes after haploidentical allogeneic hematopoietic cell transplantation (haplo-HSCT) for 64 patients with chronic granulomatous disease (CGD). The authors present what is to date the largest published cohort of patients with CGD treated with haplo-HSCT and discuss the increasing therapeutic choices for patients with CGD.

We live and work in exciting times. Arguably, this is very true for patients with CGD.

CGD is an inherited multisystem immunodeficiency characterized by life-threatening infections, immune dysregulation, and granulomatous inflammation. It is caused by genetic mutations encoding proteins involved in the formation of the nicotinamide adenine dinucleotide phosphate oxidase complex, responsible for the generation of reactive oxygen species in phagocytes. It can be inherited in both an X-linked or an autosomal recessive manner. Characteristic clinical features include growth failure, bacterial skin infections, deep-seated abscesses, fungal pneumonia, lymphadenitis, inflammatory lung disease, and colitis.² 

When first described 75 years ago, life expectancy among those with CGD was significantly shortened, with most patients dying in childhood. When HSCT was first attempted in the late 1970s and early 1980s, the observed engraftment rates were poor and transplant-related mortality very high. Therefore, children with CGD were managed conservatively, mainly with antimicrobial prophylaxis.

Over the subsequent years, developments in HSCT have dramatically improved transplant outcomes for many diseases, including CGD. Five years ago, Chiesa et al³ described excellent outcomes after allogeneic HSCT for the largest CGD cohort to date (712 pediatric and adult patients), with 3-year overall survival (OS) and event-free survival (EFS) of 85.7% and 75.8%, respectively, for the whole cohort. However, EFS for patients treated with 1 Ag or >1 Ag mismatched unrelated donor transplant(s) were significantly worse at 66% and 62.3%, compared with 85.3% following matched family donor transplants. Events contributing to poorer outcomes included graft failure. Overall, these encouraging results from such a large study triggered a growing enthusiasm to transplant patients when fully matched family and unrelated donors were available.

Simultaneously, advances in gene therapy offered potential curative alternatives for patients in the United States and Europe with access to clinical trials and without an appropriately matched donor. In 2020, Kohn et al reported the initial outcomes for 9 patients with X-linked CGD who were treated with lentiviral gene–modified autologous stem cells after busulfan conditioning as part of a phase 1/2 clinical trial.⁴ That study confirmed proof of concept, achieving stable engraftment of gene-modified stem cells, improvement of neutrophil function, and resolution of clinical features, particularly infectious complications.

There is currently a phase 1/2 study open using lentiviral vector gene therapy for autosomal recessive CGD (www.ClinicalTrials.gov) and, this year, 2 further phase 1 (first time in humans, to our knowledge) studies will test prime editing for autosomal recessive p47 CGD (open and recruiting) and in vivo gene editing for X-CGD (will open).

So, why all the fuss about a relatively small (n = 64) study on haplo-HSCT for CGD? One of the most pressing questions in the field is how best to manage CGD patients without fully matched family or unrelated donors. Until now, the choices have been conservative management, gene therapy (as part of a clinical trial), or a mismatched unrelated donor HSCT.

Riller et al, on behalf of the EBMT-IEWP, have described an impressive 3-year OS and EFS of 75.9% and 70.2%, respectively, after haplo-HSCT. They compared the most commonly used modes of T-cell depletion in haplo-HSCT: in vitro T-cell receptor-αβ/CD19 depletion of the graft and in vivo depletion with posttransplant cyclophosphamide, and observed no differences in OS, EFS, or graft failure. Notably, the observed EFS was superior to that for mismatched unrelated donor transplants in the study by Chiesa et al,³ although center numbers were fewer and the median age at transplant (5.8 years) lower in this study, with all patients <15 years of age at HSCT.

Engraftment remains a challenge when transplanting patients with inborn errors of immunity associated with significant inflammation or immune dysregulation. Throwing a haploidentical donor “into the mix” increases this challenge. In this study, rates of primary graft failure were 20.6% (compared with 13% in the Chiesa et al³ study), which is encouraging when considering the “hard-to-engraft” inflammatory stem cell niche milieu in CGD.

Riller et al have demonstrated that, for CGD, using a haploidentical donor is an acceptable alternative to using mismatched unrelated donors.

For patients lacking fully matched donors wishing to pursue a potentially curative treatment option, yet without access to gene therapy clinical trials, there is now the choice of haplo-HSCT.

Conflict-of-interest disclosure: E.C.M. declares no competing financial interests.