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Introduction:Even in the era of novel targeted therapies for the treatment of Chronic Lymphocytic Leukemia (CLL) patients, such as BTK, PI3K and BCL2 inhibitors, allogeneic hematopoietic stem cell transplantations (alloHCT) will remain an important treatment option for a subset of patients with very high risk CLL. The current study focused on the impact of center and procedure-related factors on outcomes after alloHCT, taking into account the impact of patient- and disease-related risk factors. Patients and Methods:Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analyzed. Their data were collected as part of the EBMT CLL Data Quality Initiative. Outcomes of interest were Event-Free Survival (EFS) up to 5 years after transplantation and mortality in the first 100 days after alloHCT. Outcomes were analyzed by means of the Kaplan-Meier method and Cox proportional hazards models with a frailty (random effects) component to take into account unexplained center heterogeneity. The following factors describing center characteristics or the transplant procedure were analyzed: experience in alloHCT in general and, for CLL specifically, accreditation by the Joint Accreditation Committee-ISCT & EBMT (JACIE), Gross National Income (GNI)/capita based on purchasing power parity (PPP) (GNI/cap), donor type, donor-patient sex-match, type of conditioning, stem cell source and T-cell depletion (TCD). Results:Five-year EFS of the whole cohort was 37% (95% Confidence Interval, 33%-42%), Day-100 survival was 90% (88%-92%). Experience of the transplant center was measured by the number of all alloHCTs, and alloHCTs for patients with CLL respectively. The median total number of alloHCTs per center per year was 45 (range 0-169) and the median number of CLL alloHCTs was only 2 per center per year (range 0-19). Greater experience with transplantation of patients with CLL (Hazard Ratio (HR) 0.96 per additional transplant, p=0.002), JACIE accreditation (HR 0.7, p=0.045) and a higher GNI/cap (HR 0.4, 95% CI 0.2-0.96, p=0.04) showed a protective impact on 5-year EFS in the Cox model. In vivo TCD with alemtuzumab (HR 1.5 compared to no TCD, p=0.03) and a female donor for a male patient (HR 1.4 compared to a male donor for a male patient, p=0.02) were the only procedure-related factors significantly associated with EFS. Event-Free Survival after in vivo TCD with Anti-Thymocyte-Globulin or after ex vivo TCD was comparable to EFS without TCD (HR 0.9, 0.7-1.3, p=0.6; HR 0.9, 0.5-1.6, p=0.8). Non-myeloablative conditioning did not have a negative impact on 5-year EFS, and exposed patients to a lower risk of non-relapse mortality. Measured and unmeasured center characteristics did not have a significant impact on 100-day mortality. Even when correcting for patient-, procedure- and center-related characteristics, there was still significant variation in center outcome, expressed by center-specific HRs derived from the frailty models, ranging from 0.6 to 1.2. Their impact is illustrated in a model-based plot for EFS (see Figure) which shows outcomes for three reference patients with the same characteristics who would be transplanted in three centers with the same measured characteristics but with the highest, average and lowest HRs in the dataset. These unexplained center effects likely represent a mixture of differences which could apply to the location of the transplant center, unmeasured characteristics of the patient population transplanted at this center, selection criteria which were not reported and factors determining the success of the transplant procedure which might differ between centers. Conclusion: We have confirmed that both center- and procedure-related factors have a significant impact on the EFS of patients with CLL undergoing alloHCT. Our results may help to interpret outcomes of single or multicenter studies better. Since non-myeloablative conditioning did not have a negative impact on EFS and exposed patients to a lower risk of non-relapse mortality, this approach should be favored for future alloHCT for CLL. Probability of Event-Free Survival up to Five Years Post-HCT for three Reference Patients Contribution: J.S. designed the research and wrote the paper. L.C.d.W conducted the statistical analysis and produced the figure. Figure Figure. Disclosures Schetelig: Sanofi: Honoraria. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Dreger:Gilead: Consultancy; Gilead: Speakers Bureau; Janssen: Consultancy; Novartis: Speakers Bureau; Novartis: Consultancy; Roche: Consultancy.

Background Competent authorities, healthcare payers and hospitals devote increasing resources for quality management systems (QMS) and accreditation/certification of parts or all of their activities. Scientific analyses searching for an impact on clinical outcome remain scarce. Hematopoietic Stem Cell Transplantation (HSCT) involves complex processes and requires the collaboration of multiple categories of health care professionals. Despite major improvements over time, it remains associated with significant mortality and might serve as a role model for any QMS. The Joint Accreditation Committee of the International Society of Cellular Therapy Europe (ISCT) and the European Group for Blood and Marrow Transplantation (EBMT) – JACIE – has developed in collaboration with its US counterpart FACT standards that require a QMS. These principles apply to clinical management, cell collection and cell processing. Centers seeking accreditation are subject to a detailed document review, on-site inspection and auditing procedures. Earlier data indicated a stepwise improvement with each phase of the accreditation process (JCO 2011). Objective To test the hypothesis that working towards and achieving accreditation for the QMS “JACIE” would accelerate improvement in outcome over calendar time and, to quantify the potential impact on outcome. Design, setting and Patients A retrospective observational study of the previously published and well defined cohort of 107,904 patients treated with HSCT (41,623 allogeneic, 39%; 66,281 autologous, 61%) between 1999 and 2006, reported to the EBMT database and with substantially increased, complete follow-up information up to November 2012. A “JACIE+ “ center was defined as one which initiated the accreditation process and achieved accreditation at some point during the 14 year period, the latest by November 2012. Focus of the statistical approach was on the interaction between “JACIE+“ and calendar time on mortality reduction with adjustments for the key known risk factors. A completely different analysis framework has been chosen to test the hypothesis and to verify consistency between the two approaches. Main outcomes and measures: The primary outcome measure was reduction in overall mortality at 72 months over calendar time for 49,459 patients having received their transplant in a “JACIE+ “ center; 58,445 patients whose center never obtained accreditation served as baseline (“JACIE-”). Results Overall mortality of the entire cohort decreased over the 14 years observation period by a factor of 0.67 per 10 years (HR: 0.67; 0.62-0.73). This improvement was significantly faster in “JACIE+ “ (approx. 5% per year; HR per 10 years: HR: 0.62) than in “JACIE- “ (approx. 3% per year; HR per 10 years: HR: 0.73) centers. This difference in speed of mortality reduction was quantified by a HR of 0.85 (0.73-0.99) and resulted in a marked difference in outcome between the “JACIE+” and “JACIE-” centers: adjusted non relapse mortality (HR 0.93; 0.83-1.04) and relapse incidence (HR 0.94; 0.88-0.99) were lower, while relapse free (HR 0.94; 0.88-0.99) and overall survival (HR 0.91; 0.85-0.97) were significantly higher at 72 months after allogeneic transplantation for those patients transplanted in the 162 “JACIE+ “ centers. No effects of “JACIE” accreditation were observed after autologous HSCT, not on speed of mortality reduction nor on overall survival (HR 1.06; 0.99-1.13). Conclusions and relevance Working towards and implementation of a QMS triggers a dynamic process which is associated with a steeper reduction in mortality over the years and a significantly improved survival after allogeneic HSCT. Our data support the use of a QMS for allogeneic HSCT as well as for other forms of complex medical procedures. Disclosures: No relevant conflicts of interest to declare.

Dyskeratosis congenita (DC) is a genetic multisystem disorder with frequent involvement of the bone marrow. Haematopoietic stem cell transplantation (HSCT) is the only definitive cure to restore haematopoiesis, even though it cannot correct other organ dysfunctions. We collected data on the outcome of HSCT in the largest cohort of DC (n = 94) patients ever studied. 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 damage, this should be carefully evaluated. Further efforts to investigate treatment alternatives to HSCT should be encouraged.