Year: 2016
Type: article
Study design: Observational Study
Abstract: In 2009, mutations in the DOCK8 gene were identified as the cause of autosomal recessive Hyper-IgE syndrome, a combined immunodeficiency characterized by elevated IgE, respiratory infections, viral infections, eczema, severe food allergies and a high cancer risk. Cohort studies have shown that this disease has a dismal natural disease outcome with most patients dying prematurely, suggesting that early allogeneic HSCT should be the standard of care. A number of case reports have suggested that HSCT can cure all disease manifestations with the exception of food allergies, which can persist for years. We sought to investigate the results of HSCT for DOCK8 deficiency in a large international study and to analyze how variables such as donor, age at HSCT, year of HSCT or conditioning affected the outcome. Data were collected by retrospective chart review from centers participating in the cohort study by Aydin et al. Additional patients were identified via the PIDTC and EBMT-IEWP mailing lists. A total of 74 patients from 18 centers transplanted at a median age of 10 years (range: 2-27) between 1995 and 2015 could be included. Stem cell source was BM in 57, PBSC in 16 and one cord blood. After a median follow-up of 25 months (0-133), 61 of 74 patients are alive (82%). Acute GVHD grades 2-4 and grades 3-4 was observed in 25% and 11%; chronic GVHD of NIH scores 1, 2 and 3 in 4%, 3% and 3%, respectively. Causes of death were sepsis (n=4), GVHD (4), multi-organ failure (4) and undefined infection (1). Survival after HSCT from MSD/MFD (n=40) or MUD (27) or MMFD (6) was 88%, 84% and 67%, respectively. One UCB recipient died. There was a trend towards better survival in patients receiving treosulfan-based (n=15) versus myeloablative busulfan-based conditioning (n=27) or any other reduced intensity (n=32) regimen (100% vs 83% vs 76%, p=0.07 for treosulfan vs myeloablative busulfan), as well as for patients <8 (n=26) compared to those ≥8 years (n=48) at time of HSCT (96% vs 77%, p=0.06), and for HSCTs since 2010 (n=62) compared to those before (n=12; 88% vs 64%, p=0.06). Of 67 patients with chimerism data available at last follow-up, 64 (96%) had >80% donor T-cell chimerism. Two patients rejected their graft, both died during or after 2nd HSCT. Eczema improved in 74% (55/74), infections in 55% (41/74), mollusca in 45% (29/64), allergies improved in 50% (37/74) and pulmonary function tests improved in 36% (25/70) and remained unchanged in the remaining patients, albeit with a relatively short follow-up in some. HSCT is curative in a high proportion of DOCK8 deficient patients, confirming this approach as the treatment of choice. In this study HSCT at an early age from a matched donor using a treosulfan-based regimen resulted in the best survival rates. Longer-term observation will be needed to assess the response rate of all disease manifestations to HSCT.
Authors: Susanne Aydin, Alexandra F. Freeman, Helen Su, Dennis Hickstein, Sung-Yun Pai, Raif Geha, Talal Chatila, Rand K. Arnaout, Hamoud Al-Mousa, Hasan Al-Dhekri, Ellen D. Renner, Bernd H. Belohradsky, Gundula Notheis, Roland Aydin, Bobby H. Gaspar, Waleed Al-Herz, Andrew Gennery, Mary Slatter, Ayse Metin, Pamir Isik, Fatih Azik, Aydan Ikinciogullari, Sule Haskologlu, Figen Dogu, Ashish Kumar, Marianne Ifversen, Friedhelm Schuster, Wilhelm Woessmann, Robbert Bredius, Vincent Barlogis, Leena Kainulainen, Capucine Picard, Benedicte Neven, Evan Shereck, Ansgar Schulz, Gregor Dueckers, Joris Van Montfrans, Susanne Matthes-Martin, Sevgi Keles, Hans Ochs, Michael H. Albert
Institutions: Ludwig-Maximilians-Universität München, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Cancer Institute, Boston Children's Hospital, King Faisal Specialist Hospital & Research Centre, Technical University of Munich, University College London, Kuwait University, Newcastle University, Great North Children's Hospital, Ankara University, Cincinnati Children's Hospital Medical Center, Copenhagen University Hospital, Rigshospitalet, Justus-Liebig-Universität Gießen, Leiden University Medical Center, Aix-Marseille Université, Hôpital de la Timone, Turku University Hospital, Hôpital Necker-Enfants Malades, Inserm, Sorbonne Paris Cité, Assistance Publique – Hôpitaux de Paris, Institut des Maladies Génétiques Imagine, Université Paris Descartes, Oregon Health & Science University, University Hospital Ulm, Helios Klinikum Krefeld, University Medical Center Utrecht, St Anna Children's Hospital, Necmettin Erbakan University, Seattle Children's Hospital, University of Washington
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2375867648