Allogeneic hematopoietic cell transplantation in dyskeratosis congenita: Short and long- term outcome of 183 consecutive patients transplanted at EBMT centers

Abstract Introduction Dyskeratosis congenita (DKC) is a rare telomere disorder causing multi-organ dysfunction and bone marrow failure, with allogeneic hematopoietic cell transplantation (HCT) being the only curative option for hematologic complications. We previously reported 3- and 5-years overall survival (OS) rates of 66% and 59% in patients (pts) transplanted before 2016 (Fioredda et al., 2018). This study assesses outcomes in pts transplanted between 2016 and 2023 (new cohort) and compares long-term results with those of the pre-2016 cohort (old cohort). Methods This retrospective study was conducted by the Severe Aplastic Anemia Working Party (SAAWP) of the EBMT. Data were extracted from the EBMT registry, identifying pts diagnosed with DKC who underwent HCT. The following outcomes were analyzed in the new cohort: engraftment, graft failure (GF), acute and chronic graft versus host disease (GVHD), OS, event-free survival (EFS, defined as the absence of primary/secondary GF, relapse, second transplant, or death) and GVHD/relapse-free survival (GRFS; defined as survival without grade III–IV acute GVHD, extensive chronic GVHD, GF or lack of engraftment, relapse, or death). Causes of death were specifically investigated in both cohorts. Descriptive statistics were used for data analysis. Results Eighty-five DKC pts (63.5% males) underwent HCT between 2016 and 2023 in 55 EBMT centers. Median age at HCT was 11.7 (IQR, 5.9-21) years. Median time from diagnosis to HCT was 17.1 (7.6-38) months. Almost all pts (71.6%) had HCT- comorbidity index risk of 0 at HCT. Median follow-up was 1.7 (1.1-2.1) years. Pts were transplanted either from an HLA-matched sibling (17.6%), matched related donor (2.4%), mismatched related donor (14.1%), matched unrelated donor (36.5%), and mismatched-unrelated donor (18.8%). Number of mismatches was unknown in 10.6% of unrelated donor transplants. Graft sources included bone marrow (BM) in 51.8%, peripheral blood (PB) in 40%, cord blood in 5.9%, combination of BM and PB in 2.4%. Fludarabine-Cyclophosphamide (Flu-Cy) was the most used conditioning regimen (70.4%). GVHD prophylaxis was based on serotherapy (anti-thymocyte globulin 44.2%, alemtuzumab 41.6%), calcineurin inhibitors (5.2%), and post-transplant Cy (9.1%). HCT characteristics were not significantly different between the old and the new cohort, except for the time (in months) from diagnosis to transplant [22.1 (8.5–70.7) vs. 17.1 (7.6–38), p = 0.007], GVHD prophylaxis (increased use of alemtuzumab in the new cohort, p = 0.048), and conditioning regimen (greater use of Flu-based regimens in the new cohort, p = 0.002). Neutrophil recovery by day 28 and day 42 occurred in 67% and 82% of pts, respectively, with a median of 19 (95% CI 18-24) days post HCT, whereas platelet recovery by day 60 was achieved in 66% of pts, with a median of 26 (95% CI 21-39) days post HCT. Day 100 cumulative incidence of grade II-IV acute GVHD was 15%, whereas chronic GVHD at 1 and 2 years were 16% and 25%, respectively. Two-years GRFS was 46%; primary (at 42 days) and secondary (at 2 years) GF were 4% and 8%, respectively. One and 2-years EFS were 62% and 55%; 1- and 2-years OS were 74% and 68%, respectively. These outcomes were in line with those of the old cohort whose 5- and 10- years OS further declined to 59% and 42%, respectively. Moreover, early (0-2 years) mortality was mostly due HCT related causes in both cohorts (infections 58% and 53%, GVHD 5% and 11%, in old and new cohort, respectively). Late (3-5 years) mortality was similarly distributed in both cohorts between HCT (infections 33% and GVHD 25% in the old and new cohort, respectively) and DKC-related causes (organ dysfunction in both groups).In contrast, the very late (>5 years) mortality, observed (so far) only in the old cohort, was almost exclusively due to DKC-related causes (50% secondary malignancies, 40% lung/organ failure). Conclusions Despite general advances, post-HCT survival for DKC still has limited if any improvement, with persistent late and very late mortality driven by organ failure and malignancies. Future efforts should focus on identifying factors influencing long-term outcomes to mitigate non-hematological complications.