Outcome of Haematopoietic Stem Cell Transplantation in Dyskeratosis Congenita
Multi-centre clinical research collaborations are essential to advancing our understanding of complex haematological conditions, particularly those which are relatively rare in nature. One such condition is dyskeratosis congenita, a genetic multisystem disorder with frequent involvement of the bone marrow. Dyskeratosis congenita can also present concomitantly with pulmonary fibrosis, liver abnormalities, neurological, gastrointestinal, ocular impairment and cancer predisposition. The causative mechanism of the disease is abnormal telomere shortening due to a defect in one of the genes encoding for the telomerase-shelterin complex. Haematopoietic stem cell transplantation (HSCT) is the only definitive cure to restore haematopoiesis in dyskeratosis congenita, even though it cannot correct other organ dysfunctions.
A team of international investigators supported by researchers from Our Lady’s Children’s Hospital Crumlin, examined the outcome of HSCT in the largest cohort of DC (n = 94) patients ever studied and who had received allogeneic HSCT between 1979 and 2015. The retrospective, multi-centre study showed that overall survival (OS) and event-free survival (EFS) at 3 years after HSCT were 66% and 62%, respectively. Multivariate analysis showed better outcomes in patients aged less than 20 years and in patients transplanted from a matched, rather than a mismatched, donor. OS and EFS curves tended to decline over time.
Early lethal events were infections, whereas organ damage and secondary malignancies appeared afterwards, even a decade after HSCT. A non-myeloablative conditioning regimen appeared to be most advisable. Organ impairment present before HSCT seemed to favour the development of chronic graft-versus-host disease and T-B immune deficiency appeared to enhance pulmonary fibrosis. According to the present data, HSCT in DC is indicated in cases of progressive marrow failure, whereas in patients with pre-existing organ (particularly lung) damage, this should be carefully evaluated as it may increase the risk of graft-versus-host disease and worsen survival.
The investigators conclude that HSCT might be an option in subjects affected by dyskeratosis congenita and bone marrow failure, but it is associated with a high risk of early and late mortality due to infections, organ damage and secondary malignancies. They believe that the indication for HSCT in dyskeratosis congenita patients with bone marrow failure need to be established on an individual basis after thorough evaluation of lung and non-haematological organ damage.
Fioredda F, Iacobelli S, Korthof ET, Knol C, van Biezen A, Bresters D, Veys P, Yoshimi A, Fagioli F, Mats B, Zecca M, Faraci M, Miano M, Arcuri L, Maschan M, O'Brien T, Diaz MA, Sevilla J, Smith O, Peffault de Latour R, de la Fuente J, Or R, Van Lint MT, Tolar J, Aljurf M, Fisher A, Skorobogatova EV, Diaz de Heredia C, Risitano A, Dalle JH, Sedláček P, Ghavamzadeh A, Dufour C.
Br J Haematol. 2018 Jul 9. doi: 10.1111/bjh.15495. PMID: 29984823