Abstract: 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.

Abstract: 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.

Abstract: 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 〈 0.001). Overall survival was also significantly improved in favor of the auto-allo (3 yr and 5 yr OS 67.9% and 58.9%) as compared to the RIC group (54.3% and 42.7%, P = 0.001). The non-relapse mortality (NRM) rates were lower in the auto-allo group as compared to RIC: 1 yr and 3 yr NRM were 8.1% and 14.1% in the auto-allo and 20.3% and 27.4% in early RIC group, p 〈 0.001. We examined potential differences in outcomes based on use of novel agents, and used the year 2004 as a surrogate for introduction of novel agents to routine clinical practice. There were no significant differences by multivariate analysis in outcomes for patients transplanted before or after 2004. Conclusion This large multicenter retrospective study suggests that cytoreductive autologous HSCT prior to allograft is associated with improved PFS and OS. We are in the process of conducting an extended analysis to control for possible confounders. If the results are confirmed, future studies should be conducted to verify the importance of autologous stem cell transplant as part of the allograft treatment strategy. Disclosures: No relevant conflicts of interest to declare.

Abstract: 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.

Abstract: 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 ( 〈 50 years) in an EBMT registry cohort with additional data collection (n=197, median follow-up 90.4 months). The most important prognostic factor for 2-year NRM in multivariate analysis was the donor HLA match: HR 2.5, 95% CI: 1.1-5.4 for an HLA-matched unrelated donor, and HR 4.0, 95% CI: 1.4-11.6 for an HLA-mismatched unrelated donor, both versus a matched sibling (Table 1). Predictors for poor 8-year PFS were "no remission at the time of alloHCT" (HR 1.7 (95% CI: 1.1-2.5)) and partially HLA-mismatched unrelated donor (HR 2.8 (95% CI: 1.5-5.2))(Table 2). High risk cytogenetics did not have a significant impact on 8-year PFS. Based on the regression model, a reference patient was created with high risk cytogenetics (del(17p) and/or del(11q)) and "good transplant" characteristics (remission at the time of alloHCT and HLA- and sex-matched sibling donor). The predicted two-year NRM for this patient was 12.1% (95% CI: 2.5%-21.7%)(Figure A) and 8-year PFS 53.5% (95% CI: 38.0%-69.0%)(Figure B). Such a low predicted NRM may keep up with the 9% "real-world" reported 1-year NRM of ibrutinib and the 8-year PFS compares favorably to outcomes after using kinase inhibitors or venetoclax. Taking into account the amount of uncertainty for predicting survival after alloHCT but also for the sequential administration of kinase inhibitors and venetoclax, alloHCT still remains a valid option for younger high cytogenetic risk refractory/relapsed CLL patients with a 10/10 HLA-allele matched donor. Figure. Figure. Disclosures Dreger: Novartis: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Delgado:Janssen: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Schoenland:Jansen: Honoraria, Other: financial support of conference participation, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schetelig:Sanofi: Honoraria.

Abstract: Abstract 469 Background: After allogeneic HSCT, graft-versus-host disease (GvHD) occurs through recognition of minor or major histocompatibility mismatches by donor derived T lymphocytes. The same mechanism also operates in the elimination of residual malignant cells (the graft-versus-leukemia or GvL effect). Earlier studies have already shown reduced relapse risks for patients developing GvHD (Weiden et al, NEJM 1979; Horowitz et al, Blood 1990). In particular, a large study in CML patients (Gratwohl et al, Blood 2002) showed that increasing grades of acute and chronic GvHD are associated with a proportional decrease in relapse risk. Incidence and severity of acute and chronic GvHD might therefore be used as surrogate markers for GvL effects. Transplant procedures have changed significantly since these publications. Increased use of unrelated donors, peripheral blood as stem cell source, and the introduction of reduced intensity conditioning regimens might affect the relationship between GvHD and GvL. Furthermore, previous studies have only analyzed transplants for AML, ALL and CML, the prevailing transplant indications at the time. Today, many patients receive transplants for MDS, plasma cell disorders (PCD) or lymphoma. We hypothesized that comparing the effect GvHD on relapse incidence might provide a useful surrogate marker for the susceptibility of different diseases to allo-immune effects. Methods: We studied 48,111 first allogeneic transplants carried out and reported to EBMT between 1998 and 2007. The impact of GvHD on relapse risk was assessed by including acute and chronic GvHD as time-dependent covariates in Cox models for cause-specific hazards adjusted for patient age, year of transplant, donor type, stem cell source, and type of conditioning regimen. Results: Diseases were CML (N=7,711), AML (14,539), ALL (6,802), MDS/MPN (6,958), lymphoma (N=8,231), or PCD (3,870). Donors were HLA identical family donor (N=28,030), and HLA-identical unrelated donors (N=14,422) or mismatched donors (N=5,659). Stem cell source was bone marrow (N=13,273), peripheral blood (N=34,022), or cord blood (N=816). Conditioning intensity was myeloablative (N=28,843), reduced intensity (15,889) or unknown (N=3,379). 14,764 (31%) of grafts were T-cell depleted. Incidence of grade I-IV acute GvHD was 49%, that of grade II-IV acute GvHD 30%. Limited chronic GvHD was diagnosed in 17% and extensive chronic GvHD in 20% of patients. Incidence of disease relapse was 22%, 28%, and 31% at 1, 2, and 4 years respectively. As shown previously, development of GvHD was associated with a reduced risk of relapse in our data. In CML, a clear reduction of relapse risk occurred with hazard ratios declining proportionally to severity of both acute and chronic GvHD (Figure 1). The protective effect of severe acute (grade III-IV) GvHD was similar to that of extensive chronic GvHD, whereas the protective effect of mild acute (grade I-II) GvHD was comparable to that of limited extensive GvHD. ALL was almost equally sensitive to GvHD as CML, whereas MDS/MPN and lymphomas showed intermediate sensitivity (Figure 1). Acute and limited chronic GvHD were only associated with modest reductions in relapse risk in AML and PCD. The limited sensitivity of PCD to allo-immune effects was also evident in Kaplan-Meier curves of disease-free survival where – in contrast to other diseases – no plateau developed during follow-up (Figure 2, upper panel). Similarly, hazard rates of disease relapse failed to drop to values near zero in patients with PCD (Figure 2, lower panel). Interestingly, despite a comparatively poor association of GvHD and relapse in AML patients, a plateau in the survival curve occurred and hazard rates dropped in parallel to other diseases, suggesting that curative GvL effects operating independently of GvHD might occur in this disease. Discussion: These data confirm earlier observations of a potent GvL effect associated with GvHD. While GvHD and GvL are significantly associated in all diseases, the strength of this association strongly differs between disease entities (strongest correlation in CML and ALL, weakest correlation in AML and PCD). A poor correlation might point to either insensitivity of a particular disease to GvL effects, to GvL effects operating in the absence of and independent from GvHD, or to a significant fraction of patients already cured before allogeneic SCT. Disclosures: No relevant conflicts of interest to declare.

Abstract: Abstract 578 Introduction Monosomal Karyotype (MK) has been shown to be associated with a very poor prognosis in AML patients. Last year at ASH, we presented data from the EBMT on patients diagnosed with MDS and chromosome 7 abnormalities, showing that MK predicts better than complex karyotype (CK) for a dismal outcome after allogeneic HSCT (abstract #293). We now performed a retrospective analysis on data from the registry in the complete cohort of patients with MDS and secondary AL (sAL) to determine the effect of MK on outcome after allogeneic HSCT. Methods A total of 1689 patients from 172 centres in 23 countries with diagnosis MDS or secondary acute leukemia (sAL) with known cytogenetic abnormalities (karyotype only) at diagnosis or later in the disease course were assessed. 1437 were included in the analysis; 226 were excluded because of insufficient data. Kaplan-Meier survival curves were used and log rank test to determine statistical significance. Results 1041 patients were diagnosed with MDS and 396 with sAL. Median follow up for sAL patients was 7.5 months (range 0–253) and MDS 8.0 months (range 0–276). 201 patients fulfilled criteria for MK and 279 patients for complex karyotype (CK). MK outcome was worse than no MK: overall survival 32 months versus 97 months (p=0.002). CK outcome was worse than no CK: overall survival 26 months versus 100 months (p & lt;0.0001). No difference in outcome between MK and CK existed: overall survival of 32 months and 26 months respectively (p= 0.274). There was considerable overlap between MK and CK (i.e. patients fulfilling criteria both for MK and CK). To see how we could further differentiate, we analyzed three subgroups: MK but not CK (43 patients; MK+CK−), no MK but CK (98 patients; MK−CK+) and MK and CK (150 patients; MK+CK+). The survival of patients in each of these groups was compared with the group having no MK and no CK (n=1050). Overall survival was not different for patients with MK+CK− (median 13 vs 19 months, p=0.983), but for patients with MK-CK+ or MK+CK+ a significant difference in survival was observed with a median of 8 months (p=0.008) and 7 months (p & lt; 0.0001) respectively. MK−CK+ and MK+CK+ did not differ statistically (p=0.42) from each other. See figure. These results differ from the results presented at ASH last year. Since this cohort consists of patients with and without chromosome 7 abnormalities, we suspect that presence of this specific chromosomal aberration is the main reason for the observed difference. Multivariate analysis will be performed the coming months. Conclusion These results indicate that CK is a better predictor for poor outcome than MK after allogeneic HSCT in this cohort of MDS and sAL patients with and without chromosome 7 abnormalities. Disclosures: No relevant conflicts of interest to declare.

Abstract: Background. Autologous stem cell transplantation (ASCT) remains a gold standard treatment for younger patients with multiple myeloma (MM). With the aid of new drugs, the patients live longer and third salvage ASCT is an increasingly used option. However, the outcome of third salvage ASCT has not yet been analyzed. Methods. Between 1997 and 2010, 1288 MM patients who had received at least 3 ASCT were registered in the EBMT database. We excluded patients older than 75 years, those with a time from diagnosis to first ASCT of more than 10 years, patients transplanted with bone marrow, those with a time between relapse and ASCT of less than one month and those with an uncertain relapse date. Planned tandem ASCT was considered to be performed within a 6 month interval and at least 1 month apart. The conditioning regimen for the third transplant was high dosemelphalan alone or in combination withbusulfan orbortezomib. We could distinguish two main groups: 417 patients who received tandem ASCT and then a third ASCT after single relapse (AARA group) and 72 patients who received one ASCT, a second ASCT after first relapse, and a third ASCT after second relapse (ARARA group). A third group, who received tandem ASCT after relapsing following single ASCT comprised only 25 patients and was not studied. Results. We compared the two groups AARA vs ARARA. A third ASCT was performed in the AARA group in more recent years (p=0.047). There were more males than females (65% vs 72%) in both groups (p=NS). The main myeloma isotype was IgG (56% vs 58%). The ISS stage at diagnosis was similar (stage III in 70% vs 72% of cases). The time interval between diagnosis and first ASCT tended to be shorter in the AARA group (p=0.089), being within the first 6 months in 50% vs 38% of patients. The status at third ASCT was different: CR, 5% vs 4%: VGPR or PR, 45% vs 19%: MR or stable disease, 12% vs 15%: primary refractory/progressive disease, 38% vs 62% (p 〈 0.001). A Karnofsky score of 〉 70% at third ASCT was reported in 91% vs 90% of cases. The conditioning regimen at third ASCT was different between the two groups: melphalan 200 mg/m2, 42% vs 18%: melphalan 140 mg/m2, 6%vs 12%: other 52%vs 70% (p=0.018). The median age at third ASCT was 59vs 61 years. There was a trend to a longer time between first ASCT and first relapse (27vs 22 months (p=0.056)) in the AARA group while the interval between first ASCT and third ASCT was much shorter (44vs 64 months (p 〈 0.001)). The time between the last relapse and third ASCT was similar (9vs 11 months (p=0.4)). The median follow-up was similar (70vs73 months (p=0.9)). Engraftment was similar (96%vs93% (p=0.35)).The best response achieved after the third ASCT was superior in the AARA group: CR, 32%vs12%: VGPR or PR, 60%vs71% :MRor SD, 4%vs14%: progression, 4%vs3% (p 〈 0.001). The median OS after third ASCT was much higher in the AARA group: 30vs19 months (p=0.01) (Figure 1). The causes of death were: relapse/progression, 84%vs84%: second primary malignancies (SPM), 0.4%vs3.6%: other, 16%vs13%. There was a trend to more SPM including both hematologic and solid tumors in the ARARA group (p=0.068) with a shorter median time to SPM, 12vs42 months (p=0.004). Focusing on the AARA group, the longer the time from tandem ASCT to first relapse, the better the OS after the third transplant: if relapse occurred within 12 months of tandem ASCT, median OS of 13 months: within 18-24 months, OS of 29 months: within 36-60 months, OS of 59 months (Figure 2). Conclusions.A third ASCT is feasible in MM with more than 80% of patients achieving at least PR although with increased non relapse mortality. This treatment is mostly used in one of two scenarios: tandem ASCT followed by relapse and a third ASCT, or less commonly a first ASCT followed by a first relapse, a second ASCT, a second relapse and subsequently a third ASCT. The first scenario gives much better results, partly due to a better remission status at the third ASCT with no sign of increased SPM. In this AARA group, if relapse occurred more than 3 years after the initial tandem ASCT, the median OS after third ASCT was more than 4 years. These results should be compared with those obtained with the new drugs, especially in combination. Figure 1. AARAvsARARA groups: Overall Survival after the third transplant Figure 1. AARAvsARARA groups: Overall Survival after the third transplant Figure 2. AARA group: Overall Survival after the third transplant according to the time to relapse following tandem ASCT. Figure 2. AARA group: Overall Survival after the third transplant according to the time to relapse following tandem ASCT. Disclosures Garderet: Takeda: Consultancy; Amgen: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy. Dreger:Janssen: Consultancy; Gilead: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Peschel:MophoSys: Honoraria. Meuleman:Bristol-Myers-Squibb: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Ciceri:MolMed SpA: Consultancy. Schönland:Janssen, Prothena, GSK: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommations, Patents & Royalties, Research Funding, Speakers Bureau. Kröger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Abstract: We analysed the results of 67 patients with MDS/sAML who were transplanted with allogeneic stem cell transplantation from unrelated donors after a reduced intenisity conditioning and reported to the EBMT. The median age was 52 years (range 17–70 years) and stem cell source was bone marrow (n = 30) or peripheral blood progenitor cells (n = 33).. The graft was HLA matched in 57 patients while 8 patients received SCT from HLA-mismatched donor. The MDS classification was as follows: RA/RARS: n=8, RAEB/CMML: n = 14, RAEB-t/sAML: n = 22. The conditioning regimen consisted of fludarabine/busulfan (n=15), fludarabine/melphalan (n=6), fludarabine and TBI (n=8) or fludarabine and others (n=36)At time of transplantation only 12 (18%) were in first complete remission. The Kaplan-Meier estimates of the probability of 2 years overall and disease free survival were 33 % (95% CI: 21–45 %) and 24 % (95% CI: 12–36 %), respectively. The probability of relapse at two years was 58 % (95% CI: 40–76 %) and of one year treatment-related mortality 37 % (95% CI %: 23–51 %). In an univariate analysis assessing source of stem cells, age, disease type, T-cell depletion, and HLA-matching no factor was significant for OS, EFS, TRM and Relapse. Allogeneic stem cell transplantation after a reduced intensified conditioning followed by unrelated SCT seems to be a feasible approach in those patients who were no candidates for a standard conditioning but is associated with a considerable number of relapses.

Abstract: Abstract 3512 Recent studies in multiple myeloma patients using reduced intensity conditioning (RIC) allograft following autologous stem cell transplant in a planned tandem fashion (auto-allo) have reported low transplant related mortality (TRM) in a range of 10–15% and long term disease control in approximately one third of the patients. Similar results are reported with reduced intensity allogeneic stem cell transplant either as upfront or salvage treatment for patients who have failed prior autologous stem cell transplant. It is not clear if RIC allograft without preceding autologous stem cell transplant can produce the same outcome. The objectives of this retrospective study are to evaluate and compare the results of planned tandem autologous-RIC allograft (auto-allo) and early RIC allograft as first transplant in order to address whether or not cytoreductive autologous stem cell transplant (ASCT) is needed in patients who are candidates for RIC allograft and patients can be spared from morbidities of autologous stem cell collection and transplant. Study: We performed a retrospective analysis of the EBMT database. Five hundred and four multiple myeloma patients were identified as auto-allograft or early RIC allograft recipient between 1998 – 2007. Three hundred and fifty six patients were assigned to planned tandem auto-allograft and 148 patients received early RIC allograft as their first transplant. All patients underwent transplant within 1 year from diagnosis. Two hundred and fifty-three of 356 patients in the auto-allo group received their planned allograft, 88 patients did not undergo the planned allograft and 15 patients had a second autologous stem cell transplant. There were no significant differences in disease stage, disease subtype, sex, use of T-cell depleted allograft and donor type (sibling vs. unrelated donor) between the 2 groups. However patients in the early RIC group were younger (median age 51 vs. 53 years old P=0.03), received transplant in earlier calendar period (51% between 1998–2002 vs. 33% P 〈 0.001), had longer interval from diagnosis to transplant (9 vs. 6 mo. P=0.0001) and were more in CR at the time of transplant (17% vs. 9% P=0.008). The B2 microglobulin and cytogenetic data were missing in the majority of patients and therefore not included in this analysis. Results: Results are reported on an intention to treat (ITT) analysis. With a median follow up of 52 mo. (48-55) in the auto -allo and 48 mo. (39-55) in the early RIC group best response occurred more frequently in the auto-allo group than early RIC with complete response rate of 62% vs. 47% respectively. Progression-free survival at 3 and 5 years were significantly better in the auto-allo group (43% and 31% respectively) as compared to the early RIC group (30% and 17% respectively, P 〈 0.001). Overall survival was also significantly improved in favor of the auto-allo group with 3 and 5 year OS of 68% and 60% as compared to 52% and 37% in the early RIC group (P 〈 0.001). Non Relapse Mortality (NRM) rates at one year were 9% and 18% in the auto-allo and early RIC group respectively (p 〈 0.001). There were no differences in the incidence of acute GVHD (41% vs. 43% P=0.13) and chronic GVHD (60% vs. 56% P=0.19) between the auto-allo and RIC groups respectively. Given the differences in the calendar year we compared the PFS and overall survival between the two groups within the same calendar period (1998-2002 and 2003–2007). Log rank test confirmed significantly better outcome in favor of the auto-allo group in each calendar period suggesting that the observed differences between the 2 groups were independent of the calendar period. (P 〈 0.001). Conclusion: This large retrospective study on an ITT analysis suggest cytoreductive autologous stem cell transplant (ASCT) prior to RIC allograft is associated with improved disease free survival and overall survival in patients with multiple myeloma who are candidates for RIC allograft. Disclosures: Sahebi: Millennium Pharmaceuticals, Inc: Research Funding.