Lineage-Specific Chimerism and Outcome After Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency

Abstract

Bi-allelic variants in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency, characterized by recurrent sinopulmonary and skin infections, food allergies, eczema, eosinophilia, and elevated IgE. Long-term outcome is poor given susceptibility to infections, malignancy, and vascular complications. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option and has shown promising outcome. The impact of mixed chimerism on long-term outcome is unclear. We reasoned that reversal of disease phenotype would depend on cell lineage-specific chimerism. DOCK8 variants were confirmed by Sanger and/or exome sequencing and immunoblot and/or intracellular flow cytometry. Donor chimerism was analyzed by XY-fluorescence in situ hybridization or quantitative short tandem repeat PCR. Outcome was assessed by laboratory tests, lymphocyte subsets, intracellular DOCK8 protein flow cytometry, T-cell proliferation analysis, and multiparameter immunoblot allergy screening. We report on nine patients, four of whom with mixed chimerism, with a median follow-up of 78 months after transplantation. Overall, we report successful transplantation with improvement of susceptibility to infections and allergies, and resolution of eczema in all patients. Immunological outcome in patients with mixed chimerism suggests a selective advantage for wild-type donor T-cells but lower donor B-cell chimerism possibly results in a tendency to hypogammaglobulinemia. No increased infectious and allergic complications were associated with mixed chimerism. Aware of the relatively small cohort size, we could not demonstrate a consistent detrimental effect of mixed chimerism on clinical outcomes. We nevertheless advocate aiming for complete donor chimerism in treating DOCK8 deficiency, but recommend reduced toxicity conditioning.

Reduced toxicity conditioning and a high CD34+ cell dose can achieve full donor chimerism in DOCK8 deficiency

“… 7 Raedler et al published a cohort of 9 patients, 4 of whom had mixed chimerism. 2 Of note, they used a reduced intensity conditioning in all but 1 patient, with a median CD34 + cell dose of 5.6 million cells/kg (range 2.4-14.1 million cells/kg). Peripheral blood stem cells were used as a stem cell source in 2 patients, and bone marrow was used in the remaining 7 patients.…”

“…However, DOCK8-deficient patients with mixed chimerism continue to require long-term immunoglobulin infusion. 2 Therefore, a recent study of lineage-specific chimerism in patients with DOCK8 deficiency advocated aiming for complete donor chimerism with reduced intensity conditioning. 2 Reduced intensity conditioning increases the likelihood of mixed chimerism, whereas myeloablative conditioning in children with immunodeficiencies increases the risk of transplant-related mortality.…”

“… 2 Therefore, a recent study of lineage-specific chimerism in patients with DOCK8 deficiency advocated aiming for complete donor chimerism with reduced intensity conditioning. 2 Reduced intensity conditioning increases the likelihood of mixed chimerism, whereas myeloablative conditioning in children with immunodeficiencies increases the risk of transplant-related mortality. 3 To strike a balance between conditioning toxicity and chimerism, we adopted a strategy of reduced toxicity conditioning and high CD34 + cell dose.…”

Emerging spectrum of DOCK8 deficiency in children and challenges associated with providing treatment: experience from a tertiary referral centre in India

“…Recent data has con rmed the role of HSCT in DOCK8 de ciency, with resolution of eczema and mollusca earlier than food allergies [28]. Maintaining complete chimerism with reduced toxicity conditioning has been shown to improve outcomes [29]. Haploidentical HSCT with post-transplant cyclophosphamide has also been shown to have an emerging role in these children [30].…”