TINF2 Mutations Are Associated with Poor Outcome Post Hematopoietic Stem Cell Transplantation for Dyskeratosis Congenita

Background. Dyskeratosis congenita (DC) is a telomere biology disorder with a high risk of bone marrow failure, cancer, pulmonary and liver disease. Mutation in multiple telomere related genes including DKC1, TINF2, RTEL1, TERC, TERT, WRAP53, CTC1, NOP10, NHP2 and TPP1 have been reported. Patients with mutations in several DC genes (e.g. heterozygous TINF2, hemizygous DKC1 and biallelic RTEL1 mutations) typically tend to have a particularly serious disease with severe bone marrow failure (SBMF) at a young age, non-hematological manifestations and very short telomeres. Currently, allogeneic hematopoietic stem cell transplantation (HSCT) is the only available curative treatment for bone marrow failure and leukemia in DC patients. Relatively few case series of patients with DC undergoing HSCT have been reported, which generally suggested a poor outcome. The present study aimed to characterize the outcome of HSCT in a Canadian cohort of patients with DC and determine potential relationships between outcome and genotype.

Methods. The Canadian Inherited Marrow Failure Registry (CIMFR) is a multicenter registry that includes tertiary centers that care for IBMFS patients across all Canadian provinces. Patients with DC who had been enrolled in CIMFR and underwent HSCT between January 2001 and December 2019 were included. Data were extracted from the CIMFR database.

Results. Among 35 patients with DC enrolled in the CIMFR, 11 underwent HSCT. Seven patients were male. Median age at presentation, diagnosis and HSCT was 2.1 years (range: 0 to 9.13s), 5.5 years (range: 1.94 to 35.25), and 7.0 years (range; 0.5-37), respectively. The diagnosis of 3 patients was made after HSCT. Median follow up time from HSCT was 5.89 years (range; 0.2-14.0 years). Among transplanted patients, five had TINF2 mutations, two had RTEL1 mutations, and one patient had DKC1 mutation. Eight patients underwent HSCT for severe bone marrow failure, and three patients for single or multilneage cytopenia. All patients had normal bone marrow karyotype before HSCT.

All patients had a full matched donor; two were related and nine were unrelated. Ten patients received reduced-intensity conditioning, and one received myeloablative conditioning.

Two patients experienced engraftment failure and underwent a second HSCT. Five years and ten years overall survival after HSCT were 90.9% (95% CI 73.9-100%) and 80% (95% CI 27.2- 97.5%), respectively; however, complications and deaths started appearing thereafter, mainly in patients with TINF2 mutation. All five patients with TINF2 mutation died, and other patients were alive. The causes of death were: 1) pulmonary fibrosis (N=2), 2) gastrointestinal bleeding (N=2), and 3) EBV infection (N=1). Two patients were diagnosed with pulmonary fibrosis after 8 and 11 years from HSCT and died 13.7 and 14 years post-transplant. Two patients had gastrointestinal bleeding after 3.9 years and 4.8 years from HSCT and died 6.6 and 5.7 years post-transplant. Of the patients with GI bleeding, both had hepatic fibrosis and one had pulmonary fibrosis.

Summary: In this series, most patients with DC had resolution of the bone marrow failure and relatively good quality of life in the first few years post HSCT. However, longer outcome in the patients with TINF2 mutation was dismal because of DC-related complications, especially pulmonary fibrosis and gastrointestinal bleeding. Effective therapies to prevent these complications are critically needed. Additional reports about HSCT outcome of patients with DC are necessary to characterize HSCT in patients with other genetic groups and to replicate the above results in TINF2 patients.