Dyskeratosis Congenita: Evaluation of Immune Status and Hematopoietic Stem Cell Transplantation. A Literature and EBMT Data Base Survey of 75 Patients,

Abstract 4144

Dyskeratosis congenita (DC) is a rare inherited disease characterized by mucocutaneous abnormalities, progressive hematopoietic bone marrow failure as well as a predisposition to pulmonary fibrosis and malignancies. Unknown is if the lymphocytic lineage is affected as well. DC is a disease of defective telomere maintenance; the known mutations are located in the telomere biology genes DKC1, TERC, TERT, TINF2, NHP2 and NOP10 with X-linked, autosomal dominant and recessive inheritance patterns. Allogeneic stem cell transplantation (SCT) is the only potential curative treatment for bone marrow failure in patients with classical DC; however available data on SCT is scarce. Our objectives in this retrospective literature and database study on classical DC were to evaluate immune status at diagnosis, transplant procedures performed, engraftment, complications and survival.

Data from all accessible English, French, German and Dutch articles of PubMed, UptoDate, EMBASE and Cochrane presenting classical DC patients with SCT were collected in a DC specific database. Corresponding authors were asked for additional data and for registration at the European Blood and Marrow Transplantation group (EBMT) database to prevent double inclusion. Forty-seven patients were found this way. From the EBMT Working Parties Inborn Errors and Severe Aplastic Anemia data bases we included 28 patients. In total 75 patients with DC who underwent 83 SCTs (8 patients were grafted twice) were included.

Immune status at diagnosis could be studied in 26 patients, comparing data to age-matched controls. One or more decreased lymphocyte subset counts (CD3, CD4, CD8, NK or B cells) were found in 9/13 evaluable patients (69%) while IgG, IgM and IgA values were normal in 16/22 evaluable patients (73%).

For the whole group, data on gene mutations were only available for 6 patients; data on 13 cases are pending. Median age at SCT was 11.1 (1.0–28.8) years. Most donors were matched siblings, matched unrelated or mismatched unrelated (n=32, 20, and 10, resp.). Stem cell source was BM in 56, PB in 7 and CB in 9 cases (unknown, 3). Conditioning was myeloablative in 30, reduced intensity (RIC) in 32 and unknown in 13 cases without difference in engraftment and chimaerism but with a tendency towards less TRM and better survival in RIC. Acute graft-versus-host-disease (GvHD) grade II-IV was seen in 13/54 evaluable cases, chronic GvHD in 13/50 evaluable cases. Cyclosporine monotherapy was associated with an OR of 5.5 (CI 1.073–28.198) for chronic GvHD when compared to cyclosporine combination therapy. Alive at last follow-up were 34/75 patients; causes of death in 11/26 evaluable patients were transplant related in 6/11 and DC related in 5/11. Probability of survival was 66% at 5 years and 28% at 10 years post SCT. Pulmonary fibrosis was diagnosed in 6/75 cases; malignancies in 3/41 evaluable cases.

This is the largest study ever conducted on immune status and SCT in DC suggesting an immune defect inherent to DC and a superiority for reduced intensity conditioning. DC related complications are the main cause of death later than 5 years after SCT, underlining the need for prolonged follow-up after SCT.

At this moment we are adding data of another 8 patients from the Eastern Mediterranean Bone Marrow Transplant group. Continuing international collaboration is vital to understand the immune defect which could be primary related to the genotype or secondary to general attrition of rapidly dividing cells with inefficient telomere maintenance, and find ways to improve transplant procedures in this rare disease, classical DC.