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1857 Genotypic and Phenotypic Spectrum of Dyskeratosis Congenita: Results from the Canadian Inherited Marrow Failure Registry

Program: Oral and Poster Abstracts
Session: 508. Bone Marrow Failure: Poster II
Hematology Disease Topics & Pathways:
Diseases, Bone Marrow Failure
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Mohammed Al Nuaimi, MD, BSc, FRCPC1*, Evelyn Elias, MSc1*, Albert Catala, MD, PhD1*, Bozana Zlateska, MD, MSc2*, Yeon Jung Lim, MD3*, Robert J Klaassen, MD, FRCPC4, Geoff D.E. Cuvelier, MD5, Conrad Fernandez, FRCPC, MD, BSc6, Meera Rayar7*, MacGregor Steele, MD, FRCPC8, Sharon Abish, MD9, Yves D. Pastore, MD10, Vicky R. Breakey, BSc, MEd, FRCPC11, Soumitra Tole, MD, MSc12, Josee Brossard, MD13*, Roona Sinha, MD14, Mariana Silva, MD, FRCPC15, Lisa Goodyear, MD, FRCPC16*, Jeffrey H. Lipton, MD, PhD17, Bruno Michon, MD, FRCPC18*, Catherine Corriveau-Bourque, MD19, Lillian Sung, MD, PhD20, Yigal Dror, MD, FRCPC1 and Michaela Cada, MD, FRCPC, FAAP, MPH1

1Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada
2Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
3Program in Genetics and Genome Biology, Research Institute, Hospital for Sick Children, Toronto, Canada
4Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
5Pediatric Blood and Marrow Transplant, Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada
6Pediatric Hematology/Oncology, IWK Health Center, Halifax, NS, Canada
7British Columbia Children’s Hospital, Vancouver, Canada
8Cumming School of Medicine, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada
9Pediatric Hematology Oncology, Montreal Children's Hospital, Montreal, QC, Canada
10CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada
11McMaster Children's Hospital, Hamilton, ON, Canada
12Children's Hospital, London Health Sciences Centre, London, ON, Canada
13Centre hospitalier universitaire, Sherbrooke, QC, Canada
14Jim Pattison Children’s Hospital, Saskatoon, SK, Canada
15Kingston General Hospital, Queen’s University, Kingston, ON, Canada
16Janeway Child Health Centre, St. John's, Canada
17Hans Messner Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
18Division of Hematology-Oncology, Centre Hospitalier de l'Universite Laval (CHUL), Quebec, QC, Canada
19Division of Pediatric Hematology, Oncology and BMT, University of Alberta, Stollery Children's Hospital, Edmonton, AB, Canada
20Division of Hematology/Oncology, Department of Pediatrics, Hospital for Sick Children, Toronto, Canada

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome caused by mutations in one of 13 telomere-related genes, resulting in disruption of normal telomere maintenance; however, about 30% of patients do not have a molecular diagnosis. DC patients are at increased risk for severe bone marrow failure (SBMF), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumours. Life expectancy is compromised by SBMF, malignancy, pulmonary and liver fibrosis, and GI bleeding.

Among patients with DC in Canada, aims were to: (1) characterize the genetic profile of DC in Canada, (2) define the spectrum of clinical features of DC, (3) determine the incidence and age when SBMF, MDS, AML or solid tumours develop, (4) identify factors that are associated with higher mortality risk, and (5) describe the causes of death.

Data of patients enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR) and meeting diagnostic criteria for DC between January 1, 2001 and March 1, 2018 were included. The CIMFR is a multicentre registry that captures data on patients with inherited marrow failure syndromes from pediatric tertiary referral centres across all Canadian provinces. We investigated several continuous (e.g. age at diagnosis of SBMF/MDS/AML) and categorical (e.g. mutated gene) variables that are associated with specific outcomes, namely overall survival and development of SBMF. Cox proportional hazard models were used to assess risk of death based on age at diagnosis and presence of SBMF. Kaplan–Meier curves were used to assess overall survival.

As of March 1st, 2018, 35 patients with DC were enrolled. The mean age of diagnosis was 10.94 years (0-39.9). The underlying genotypes were: DKC1 (7), TERT (6), TINF2 (5), RTEL1 (3), PARN (2), TERC (2) but remained undetermined in the others (10). Twenty-seven patients were classified as classical DC, 7 had Hoyeraal-Hreidarsson syndrome and 1 patient had Coats plus syndrome. Eight patients (23%) developed SBMF. The mean age of SBMF was 4.22 years (1-8.66). No statistical difference was found between genotypes and progression to SBMF (P=0.1). Modelling death as a function of time varying SBMF status using a cox proportional hazard regression model showed that the presence of SBMF in DC patients was predictive of higher mortality rate (P= 0.009, hazard ratio 5.7, CI 1.54-21.5). None of the patients developed malignancy during childhood (0-18 years). One adult patient developed skin cancer. Eleven patients (31%) received a hematopoietic stem cell transplant (HSCT). The mean age of HSCT was 9.5 years (0.5-37). Ten (29%) patients died, five of whom were recipients of HSCT. Mean age of death was 12.98 years (2-24.6).
Extra-hematological complications included gastrointestinal bleeding (50%), pulmonary fibrosis (40%), overwhelming infection (40%), liver fibrosis (20%), cardiomyopathy (10%), hemolytic uremic syndrome (HUS) (10%) and thrombotic microangiopathy (TMA) (10%). Most patients had more than one organ dysfunction.

Analysis of survival showed that all patients with TINF2 mutations have died (at median age of 10.8 years, range 2.5-23.25) whereas none died in the TERT group. Patients diagnosed at younger age had lower overall survival compared to patients diagnosed at older ages (P= 0.03, HR: 0.72, CI: 0.57-0.90). All deaths were due to organ dysfunction related to DC. Fifty percent of the patients had concurrent SBMF at the time of death.

In this analysis, we characterised the genetic and phenotypic spectrum of DC patients registered in the CIMFR. We found a high mortality rate mainly related to organ dysfunction and SBMF, and described the impact of genotype, earlier age at diagnosis and presence of SBMF in predicting survival. We found that malignancy is an uncommon complication in the pediatric age group.

Disclosures: Klaassen: Amgen Inc: Consultancy; TranQoL and KIT: Other: creater and owner of Kids ITP tool and TranQoL; Octapharma AG: Speakers Bureau; Baxalta: Speakers Bureau; Biogen Canada Limited: Speakers Bureau; Novo Nordisk Canada Inc: Consultancy; Hoffman-LaRoche Ltd: Consultancy; Agios Pharmaceuticals Inc: Consultancy; Shire Pharma Canada Inc: Consultancy. Pastore: Pfizer: Honoraria. Lipton: BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

*signifies non-member of ASH