Hematopoietic stem cell transplantation rescues the hematological, immunological and vascular phenotype in DADA2

Deficiency of adenosine deaminase 2 (DADA2) is caused by biallelic deleterious mutations in CECR1 DADA2 results in variable autoinflammation and vasculopathy (recurrent fevers, livedo reticularis, polyarteritis nodosa, lacunar ischemic strokes and intracranial hemorrhages), immunodeficiency and bone marrow failure. TNF-α blockade is the treatment of choice for the autoinflammation and vascular manifestations. Hematopoietic stem cell transplantation (HSCT) represents a potential definitive treatment. We present a cohort of 14 patients from 6 countries who received HSCT for DADA2. Indication for HSCT was bone marrow dysfunction or immunodeficiency. Six of 14 patients had vasculitis pre-HSCT. The median age at HSCT was 7.5 years. Conditioning regimens were myeloablative (9), and reduced intensity (5). Donors were HLA-matched sibling (n=1), HLA-matched unrelated (n=9), HLA-mismatched unrelated (n=3), and HLA haploidentical sibling (n=1). All patients are alive and well with no new vascular events and resolution of hematological and immunological phenotype at a median follow-up of 18mo (range 5mo to 13yr). Plasma ADA2 enzyme activity normalized in those tested post-HSCT (7/7), as early as D+14 (myeloid engraftment). Post-HSCT hematological autoimmunity (cytopenias) was reported in 4 patients, acute graft versus host disease (GvHD) grade 1 in 2, grade 2 in 3 and grade 3-4 in 1, and moderate chronic GvHD in 1 patient. In conclusion, in 14 patients, HSCT was an effective and definitive treatment for DADA2.