Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 2; pp. 704 - 717.e5
• Main Authors: Leiding, Jennifer W., Okada, Satoshi, Hagin, David, Abinun, Mario, Shcherbina, Anna, Balashov, Dmitry N., Kim, Vy H.D., Ovadia, Adi, Guthery, Stephen L., Pulsipher, Michael, Lilic, Desa, Devlin, Lisa A., Christie, Sharon, Depner, Mark, Fuchs, Sebastian, van Royen-Kerkhof, Annet, Lindemans, Caroline, Petrovic, Aleksandra, Sullivan, Kathleen E., Bunin, Nancy, Kilic, Sara Sebnem, Arpaci, Fikret, Calle-Martin, Oscar de la, Martinez-Martinez, Laura, Aldave, Juan Carlos, Kobayashi, Masao, Ohkawa, Teppei, Imai, Kohsuke, Iguchi, Akihiro, Roifman, Chaim M., Gennery, Andrew R., Slatter, Mary, Ochs, Hans D., Morio, Tomohiro, Torgerson, Troy R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2018; Elsevier Limited
• Subjects: Allografts; Autoimmune diseases; Autoimmunity; Bacterial infections; Bone marrow; chronic mucocutaneous candidiasis; Cloning; Cytokines; Deoxyribonucleic acid; Disease-Free Survival; DNA; Female; gain of function; Gain of Function Mutation; Genetic Predisposition to Disease; Genotype & phenotype; Graft rejection; Graft versus host disease; Graft vs Host Disease - genetics; Graft vs Host Disease - immunology; Graft vs Host Disease - mortality; Graft-versus-host reaction; Grafts; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; hemophagocytic lymphohistiocytosis; Histiocytosis; Human subjects; Humans; Immunodeficiency; Infections; Janus kinase; Kinases; Lymphocytosis; Male; Mutagenesis; Mutation; Patients; Phosphorylation; Plasmids; Retrospective Studies; Risk Factors; signal transducer and activator of transcription; Stat1 protein; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - immunology; Stem cell transplantation; Stem cells; Survival analysis; Survival Rate; Transcription; Transplants & implants; HLH; hemophagocytic lymphohistiocytosis; MMUD; chronic mucocutaneous candidiasis; signal transducer and activator of transcription; EFS; CMC; Janus kinase; HSCT; MUD; WT; Hematopoietic stem cell transplantation; CID; GOF; graft rejection; OS; KREC; PBSC; RIC; STAT; JAK; UCB; gain of function; GAS; IPEX; TREC; NK; graft-versus-host disease; MRD
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.03.049

Gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life-threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established. We sought to aggregate the worldwide experience of HSCT in patients with GOF-STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft-versus-host disease, and transplant-related complications. Data were collected from an international cohort of 15 patients with GOF-STAT1 mutations who had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation. Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event-free survival was poor (10% by 100 days). A subset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes. Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.