ALBERT

Description: Objectives: In patients with refractory chronic lymphocytic leukemia (CLL), the potential to cure is unique to allogeneic stem cell transplantation (HSCT). Clearance of minimal residual disease by suspected graft-versus-leukemia effects has been described elegantly and documented in several independent patient cohorts. Yet data from large numbers of patients which support the concept of cure by allogeneic transplantation have not been published. With the advent of new targeted therapies for patients with advanced chemo-refractory CLL, this information becomes crucial for clinical decision making and patient counselling. Therefore, we aimed at the description of long-term survival outcomes, and the estimation of excess mortality compared to the age- and sex-matched general population. Patients and Methods: Data from patients with CLL who had received a first allogeneic HSCT from an HLA-identical sibling (SIB) or alternative donor between January 2000 and December 2010, and who were registered with the EBMT database, were analyzed. Patients with Richter's syndrome and with syngeneic donors were excluded from this analysis. Survival probabilities were calculated by means of the Kaplan-Meier estimator both in the total population, and in patients who passed the 2- and 5-year landmark without previous relapse or progression. Excess mortality of the landmark populations compared to an age-, sex- and calendar year-matched general population was estimated with a Cox regression model for relative survival using the R-package relsurv. Results: In total 2589 patients were included into the analysis. The median follow-up of patients alive at the end of follow-up was 4.0 years (range: 1 to 161 months). The median age at HSCT was 55 years (range: 12 to 74 years). One hundred and fifty eight patients (6.1%) were below 40 years of age at the time of transplantation. Seventy-four percent of patients were male. The remission status at the time of transplantation was reported as complete remission in 15%, partial remission in 47%, and stable disease or progressive disease in 32%. Information on the remission status was not available for 6% of the patients. Fifty-one percent of the patients had an HLA-matched sibling donor and seventy-seven percent of patients received reduced-intensity conditioning. For the whole cohort of patients, the 5- and 10-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) were 45%, 35%, 36%, and 35%, 28%, 40%, respectively. The cumulative incidence of relapse (CIR) was 21% at two years, 29% at five years, and 32% at ten years. A total of 1023 patients and 394 patients were alive without relapse or progression, and in follow-up at two and five years after HSCT. Five years after patients had passed the 2- and 5-year landmark, OS, CIR and NRM were 73%, 22%, 16%, and 83%, 11%, 10% respectively. Compared to the general population excess mortality of the 5-year landmark population in the subsequent five years was estimated to be 3% for male patients at an age of 45 years, 10% for male patients at an age of 55 years, and 24% for male patients at an age of 65 years (see Figure 1). For female patients in this 5-year landmark population, the corresponding excess mortality rates were 4%, 11%, and 27%. Patients without progression and with CR at any time from HSCT to the two and five-year landmarks had a slightly better outcome than those who had never had CR. Surprisingly, this was not a result of a lower CIR but of a lower NRM. Conclusion: Long-term follow-up data derived from the EBMT registry show a steady decline in hazard of relapse after allogeneic HSCT, yet relapse continues to be a threat. Moreover, even patients alive and disease-free after 5 years are still confronted with substantial NRM. These results show that there is room for improvement of long-term patient care. By comparing mortality of younger patients who passed the 5-year landmark with the general population, only marginal excess mortality was observed, while elderly patients still had substantial excess mortality beyond this landmark. Nevertheless, the results indicate that a significant fraction of patients can be cured by allogeneic HSCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Background Despite the advances in the treatment of multiple myeloma using new targeted therapies and autologous hematopoietic stem cell transplant (HSCT) the disease remains largely incurable. Recent efforts in using reduced intensity allogeneic HSCT have been hampered by increased allograft-related morbidity and mortality. Several prospective studies comparing single or tandem autologous HSCT with planned tandem autologous-reduced intensity allogeneic HSCT (auto-allo) have shown no overall survival advantage despite improvements in progression-free survival (PFS) and lower relapse rates with reduced intensity allograft, mainly due to increased non-relapse related mortality (NRM) rates. However, two of these prospective studies; the European Group for Blood and Marrow Transplantation NMAM 2000 and the Italian group study with long term follow-up reported PFS and overall survival (OS) benefits in favor of the auto-allo arm. Currently allogeneic HSCT is recommended within the context of clinical trials and only in high risk multiple myeloma patients who continue to have a very poor outcome with autologous HSCT. While such clinical trials are ongoing there remains a need to address the role of autologous HSCT prior to reduced intensity allogeneic HSCT. The objective of this retrospective study is to evaluate the role of upfront cytoreductive autologous HSCT prior to allograft in the outcomes of patients who have undergone allograft following induction therapy. Study We performed a retrospective analysis of the EBMT database comparing the outcomes of patients who were planned to receive auto-allograft to those who underwent reduced intensity allograft (early RIC) without a prior autologous HSCT within one year from diagnosis. The data in 504 patients were previously reported at the ASH meeting 2010 (abstract 3512). We subsequently included additional patients and requested more information from the participating EBMT centers and updated the study. From 1996 to 2013 a total of 689 patients were registered as reduced intensity allograft. 517 patients were registered as planned auto-allograft; however, 73 did not receive the planned allograft. A total of 172 patients received reduced intensity allograft after induction treatment without prior auto-HSCT. Median age at first transplant was 53 years (range 20-72) in the auto-allo and 51 years (range 31-77) in the early RIC group. Median time from diagnosis was 6.6 months (range 2-156 months) in the auto-allo and 7.7 months (2.8-12.0) in the early RIC group. The disease status at the time of first transplant for the auto-allo group was CR - 8%, PR - 67%, other or missing - 25%; and for the RIC group was CR - 15%, PR - 62%, other or missing - 23%. Donors were HLA matched siblings in 88% and matched unrelated in 12% for the auto-allo group, and 84% siblings and 16% matched unrelated in the RIC group with no significant differences between the two groups. Results With a median follow-up of 93 months in the auto-allo and 84 months in RIC groups, PFS rates were significantly better at 3 and 5 years in the auto-allo group (45.6% and 34.2%) as compared to the RIC group (33.9% and 22.0%, p

Description: 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.

Description: Objectives: For medically-fit young patients with high-risk chronic lymphocytic leukemia (CLL) BTK-/PI3K-inhibitors or allogeneic stem cell transplantation (alloHCT) are considered. We hypothesized that given the choice between these drugs and transplantation in future only patients with a low risk of treatment failure will be selected for alloHCT. Therefore, we searched for risk factors for 2-year non-relapse mortality (NRM) and 5-year event-free survival (EFS) after alloHCT, the latter as a surrogate for long-term disease-control. Methods: Data from patients with CLL who had received a first alloHCT from a HLA-identical sibling (SIB) or unrelated donor between 2000 and 2011 were updated in an EBMT data quality initiative. Multivariable Cox regression models were fitted to assess the impact of baseline risk factors for NRM and EFS. Results: Data on 694 patients were included into the analysis. The median age of the cohort of patients was 55 years (19 years to 74 years). Seventy-nine percent of patients had a Karnofsky performance status of 90% or higher. A disease history of less than two years was reported in 20% of patients and 44% of patients had a disease history of more than 5 years. The median number of pretreatments was 3 (range, 0-15). Eleven percent of patients had received a previous autologous HCT. Only 9% of patients had never received purine-analogs (PA) during their treatment history. Sixty-three percent of patients had either PA-refractory disease or relapse within 24 months from the last PA-containing chemotherapy at the time of HCT. A deletion 17p had been diagnosed in 28% of patients in this cohort. Information on PA-sensitivity, early relapse after autologous transplantation or PA-combination therapy and del(17p)/TP53 is used to select patients for allogeneic HCT according to the EBMT 2007 consensus. EBMT consensus criteria were met in 76% of evaluable patients. Overall, the majority of patients analyzed in this subset of all registered patients had high-risk CLL. For the whole cohort 2-year NRM was 28% (95%-CI, 24% to 32%). The baseline risk factors age, Karnofsky performance status, donor type, and donor-recipient sex mismatch had a significant impact on 2-year-NRM. With the help of these risk factors the outcome of good risk and poor risk reference patients was predicted whose linear predictors were close to the 10th and the 90th percentile of all patients in the dataset. The good risk male reference patient has an age of 45 years, a Karnofsky performance index of 100%, is in partial remission at HCT and has a matched related male donor. The poor risk male reference patient has 55 years of age a Karnofsky performance index of 80%, SD/PD at HCT, and a matched unrelated female donor. The female reference patients had the same characteristics, apart from the donor sex. Two-year-NRM was predicted to be 11% (12%) for male (female) patients with a favorable risk compared to 40% (32%) with a poor risk profile (see Figure). The same approach was used to analyze risk factors for long-term disease control. Five-year-EFS was 37% (95%-CI, 33% to 41%) for all patients. Age, Karnofsky performance status, history of an autologous HCT, remission status, and donor-recipient sex mismatch had a significant impact. The model-based prediction of 5-year EFS was 54% (64%) for a male (female) patient with a favorable risk profile compared to 15% (30%) with a poor risk profile. Current knowledge suggests that allogeneic HCT can overcome the negative prognostic impact of high risk cytogenetic abnormalities, especially of a deletion(17p) or TP53 -mutation. Even in this large cohort we observed only a trend for a lower incidence of relapse/progression in patients without deletion(17p) CLL within the first two years after HCT with translated into a trend for better EFS at that time. The impact on long-term disease-control and mortality was even smaller. Conclusion: Information on predicted 2-year-NRM and 5-year-EFS for good and poor risk reference patients derived from a large CLL dataset may be instrumental to select patients for future alloHCT. Model-based prediction of non-relapse mortality and relapse/progression. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 4115 Introduction: Polyneuropathy, organomegaly, endocrinopathy, skin changes associated with a paraproteinaemia (POEMS syndrome) is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. Effective treatment, including ASCT, of the underlying plasma cell dyscrasia can control the disease and often dramatically control symptoms. Limited data is available for ASCT in POEMS. Specific Aim: The aim of this study was to describe the clinical outcome of ASCT for patients with POEMS syndrome, determining the impact of patient and disease-specific factors on prognosis. The incidence of engraftment syndrome and the presentation of relapse were examined. Methodology: Patient-, disease-, and transplant-related variables were collected according to the data entries in the EBMT database, including tracking incomplete data entries from participating centers. Results: 116 patients underwent an ASCT between 1997–2009 and satisfied the entry criteria. The median age was 50 yrs (range 26–69) with 56.8% of patients '50 year of age. 58.6% had peripheral neuropathy, 66.2% volume overload, 48.3% had organomegaly, 19.8% had papiloedema, 46.6% had dermopathies and 34.5% had sclerotic bone lesions at presentation. The median time from diagnosis to ASCT was 7.8 mns (range 1–346) with 34.5% of patients receiving an ASCT 〉12 months from diagnosis. The graft source was PBSC in 100% of patients. Disease status at ASCT was: 32% CR/PR, 30% SD/MR/untreated and 5 in PD. Missing information on stage in 33% of the cases. The conditioning regimen was Melphalan ≥200mg/m2 in 52.5%, Melphalan

Description: Patients with relapsed/refractory chronic lymphocytic leukemia (CLL) have excellent responses with kinase or BCL2 inhibitors, but patients with high risk cytogenetics (del(17p) and/or del(11q)) do not seem to achieve long-term disease control. Allogeneic hematopoietic stem cell transplantation (alloHCT) can result in sustained progression-free survival. As non-relapse mortality (NRM) after alloHCT is partly age-dependent, alloHCT is preferably considered in younger high cytogenetic risk CLL patients, but data of early NRM and longer-term PFS lack for this age group. We focused in this study on younger allo-transplanted CLL patients (

Description: Abstract 1261 Allogeneic stem cell transplantation is a poorly standardized treatment. Reported outcomes vary markedly, partly due to differences in treatment procedures. The EBMT performed a survey among its member centers about their present strategies in preventing and treating graft versus host disease (GvHD). Seventy-three centers from 23 countries participated in this survey. The main prophylactic regimens used in transplantations with myeloablative conditioning were cyclosporine (CsA) + methotrexate (MTX) in 83%, CsA + mycophenolate mofetil (MMF) in 14 %, tacrolimus (tacro) + MTX in 6%, CsA alone in 8%, and tacro alone, tacro + MMF and ex vivo T-cell depletion (TCD) in 1% of the centers. The administration of CsA was initiated on day -6 (1%), day -3 (13%), day -2 (7%), day -1 (78%) or day 0 (1%). CsA was initially given as short i.v. infusions in 56% (twice daily 91%), continuous infusion in 39% and orally in 5% of the centers. The initial CsA dose was most commonly 3 mg/kg/day (49%); 1–2,5 mg/kg/day was given in 16%, 4–6 mg/kg/day in 31%, and 10–12,5 mg/kg/day in 4% of the centers. Further doses were then usually adjusted according to CsA concentrations (88%), measured from whole blood (81%) or serum (19%). When measured from whole blood, the target CsA concentrations at 1 wk post-Tx ranged from 80 to 400 (mean 230) ng/ml, and at 2–4 wks and 2 mths the ranges (means) were 95–400 (210) and 60–350 (200) ng/ml, respectively. The typical duration of CsA prophylaxis was 60–100 (32%), 120–150 (10%), 180 (54%), or 210–365 (14%) days. In 56% of the centers the estimated risk of relapse affected the length of prophylaxis. MTX was given in the dose of 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, and +11 in 63% and without the last dose in 28% of the centers. There were 6 other variants. Leucovorin rescue was given in 43% of the centers with variable dose and timing. ATG was included in the prophylaxis for one or more subgroups (one center all patients) in 79%, alemtuzumab in 25%, corticosteroids in 10%, and TCD in 24% (one center all patients) of the centers. The main prophylactic regimens in reduced intensity transplantations (RIC) were CsA + MMF (67%), CsA + MTX (33%), CsA (23%), in vivo TCD (19%), tacro + MMF (10%), ex vivo TCD (3%), and tacro alone and tacro + MTX (1% each). ATG was used in some groups of patients in 73% of the centers. The development of chimerism affected the intensity of prophylaxis in 82% of the centers. All centers used corticosteroids as first line treatment of acute GvHD. The treatment was started at first signs likely to be caused by GvHD (17%) or for grade II or higher (83%). The decision to treat was based on clinical signs only in 70% of the centers while in 30% histological documentation was needed. The corticosteroid of choice was methylprednisolone (83%) or prednisolone (17%). The initial daily dose/kg was 1-1, 5 mg (19%), 2 mg (76%), 3 mg (6%), 5–10mg (3%), or 20 mg (1%), given in 1 (16%), 2 (69%), 3 (9%) or 4 (6%) doses, i.v. (79%) or orally (21%). The severity of aGvHD affected the initial dose in 53% and the organ manifestation in 27% of the centers. The dose per kg/day indicating corticosteroid resistance and need for second line treatment was 1mg (3%), 2 mg (72%), 4–5 mg (13%), or 10 mg or more (12%). The minimum time to confirm corticosteroid resistance was 2 (2%), 3 (11%), 4–5 (27%), 6–7 (44%), 10–14 (13%) or 21 (3%) days. The most widely used second line treatments were MMF (33%), anti-TNF antibodies (31%), other monoclonal antibodies (16%), ATG (27%), extracorporeal photopheresis (ECP, 14%), mesenchymal stem cells (7%), alemtuzumab (7%), pentostatin (5%) and “keep going with corticosteroids” (12%). The initial treatment for newly diagnosed chronic GvHD in patients with no ongoing immunosuppressive treatment was corticosteroid (57%), calcineurin inhibitor (CNI) + corticosteroid (38%), or CNI alone (10%). The minimum duration of first line treatment of chronic GvHD to allow the evaluation of efficacy was 2 wks or less (21%), 2–4 wks (12%), 1 mth (42%), 1,5-4 mths (21%), or 9–12 mths (4%). The most commonly used second line treatments were ECP (53%), MMF (36%), rituximab (12%), CNI (12%), mTOR inhibitors (9%), corticosteroids (8%), and tyrosine kinase inhibitors (6%). In conclusion, the present results show marked differences between centers in the prophylaxis and management of GvHD. These findings underline the need for standardization and prospective controlled studies in GvHD prevention and treatment. Disclosures: No relevant conflicts of interest to declare.