Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations

Abstract Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndromes (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n=10), congenital amegakaryocytic thrombocytopenia (n=1), and dyskeratosis congenita (n=1). Exome sequencing revealed heterozygous mutations in SAMD9 (n=6) or SAMD9L (n=6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range: 1.2-12.8). Conditioning was myeloablative in 9 cases and reduced-intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS and morbid obesity failed to engraft and died from refractory acute myeloid leukemia (AML). The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome related comorbidities in MIRAGE cases. A patient with SAMD9L associated MDS, died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematological disorder and sustained peripheral blood donor chimerism. Ten out of 12 patients were alive with a median follow-up of 3.1 years (range: 0.1-14.7). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.