ALBERT

Description: Abstract 3360 Poster Board III-248 Purpose Richter's syndrome (RS) occurs in 2-8% of patients with chronic lymphocytic leukaemia (CLL). Clinical outcome has been generally poor after multiagent chemotherapy with median survival of less than 1 year. The aim of this retrospective study was to evaluate whether an autologous (AutoSCT) or an allogeneic stem cell transplantation (alloSCT) offers survival benefit. There are scant data addressing this issue. Patients and Methods As patients with RS are not identified separately in the current EBMT database a request was sent to all EBMT centres known to have performed SCT in patients with CLL, high-grade lymphoma or Hodgkin's lymphoma asking for RS transplants. Inclusion criteria included a diagnosis of RS prior to SCT, age 〉 18 years, and SCT performed 1997-2007. Centers who reported RS transplants received a questionnaire to collect detailed information on disease and transplant characteristics and outcome results. Data were analyzed by descriptive statistics and survival comparisons using log rank testing and Cox modelling. Fifty nine transplants for RS were reported by 25 centres, which is the largest cohort described. Thirty nine patients (25 (64%) male) underwent AutoSCT (of whom 8 underwent a subsequent alloSCT). The median age was 56 years (range, 30-68 years) and 44% (n=17) of transplants were performed after 2003, with a TBI-containing regimen used in 5 patients. A minority (36% of cases with data known) of patients had received ≥3 lines of prior therapy. The majority of transplants (n=32; 84%) were performed within a year of diagnosis of RS, and 91% of patients (with data known) were in CR/PR at time of transplant. With a median follow-up of 27 months, 15/39 (39%) patients were alive and 13 patients were disease-free, 21 (39%) had relapsed (19 died from relapse) and 5 (13%) died of treatment-related complications after ASCT. OS was 54% and 25% at 3 and 5 yrs respectively. Relapse incidence of 49%, NRM of 14% and PFS of 37% was observed at 3 yrs. Twenty patients (12 (60%) male) underwent alloSCT from a matched sibling donor (n=10), VUD (n=8) or an alternative donor (n=2) with PBSC used in 90% of cases. The median age was 57 years (range, 42-70 years) and 70% (n=14) of transplants were performed after 2003. A majority (80%) of patients underwent alloSCT within 1 year of diagnosis of RS and had received ≥3 lines of prior therapy (71% of known cases). Conditioning was reduced-intensity (RIC) in 14 cases and myeloablative in 6 patients, with TBI used for 4 patients and T-cell depletion strategies in 13. At time of alloSCT 14 patients were in CR/PR and 5 had progressive disease (missing data in 1 case). With a median follow-up of 15 months (range, 3-94 months) 11/20 (55%) patients were alive after alloSCT, of whom 7 were in CR/PR. Overall survival (OS) was 51% and 41% at three years and 5 years respectively. Conditioning (myeloablative vs RI-conditioning; P = 0.14) and source of donor (HLA-id sib vs VUD; P = 0.97) did not statistically influence outcome. OS was not statistically affected by the variables: prior lines of therapy 〈 3 or ≥3 lines (P = 0.72), CMV serostatus recipient/donor (P = 0.23), use of T-cell depletion (P = 0.88) or disease status at time of transplant. The 3 yr OS for patients transplanted in CR/PR was 51% compared to 27% for those transplanted with progressive disease (P = 0.18). Outcome was superior for patients 〈 60 yrs at alloSCT (p=0.04). Relapse incidence of 38%, NRM of 23% and PFS of 39% was observed at 3 yrs. Acute GVHD grade II to IV occurred in 30% of patients and there were no cases of extensive chronic GVHD within reported cases. Conclusion This is the largest study that has assessed the outcome after transplantation of patients with RS. In summary patients with RS who are chemosensitive to induction therapies may benefit from consolidation with transplantation strategies. Disclosures: No relevant conflicts of interest to declare.

Description: Non-HLA polymorphisms (NHP) influence risk of GVHD and outcome of allogeneic hematopoietic stem cell transplants (HSCT) however their influence on GvHD vs GvL remains to be defined. A cohort of 291 CML HLA matched sibling transplants with known clinical risk factors; eg stage of disease, gender mismatch (female donor/male recipient), patient age and time from diagnosis to transplant as defined by the EBMT risk score, were typed via SNPs or microsatellites for cytokines (IL-1Ra, IL-4, IL-6, IL-10, IFNγ, TNFα, TNFR 11), steroid hormone receptors (VDR and ERα) and NOD2/CARD15 mutations. TNFRII-196 allele R; IL-10 ATC/ACC; IL-1 Ra (allele 2) and IL-4T were significantly associated with survival using univariate analysis. Two clinical Cox proportional hazards models were generated for the statistical analysis and used as a basis for further development: (i) using the EBMT risk score as a single variable on an ordinal scale or (ii) using the individual clinical factors of the EBMT risk score as categorical variables. After step-wise variable selection using the significant genetic factors as candidates, the resulting multivariate models indicated that absence of TNFRII-196 R, i.e. down regulation of TNF in the recipient, absence of IL-10 ATC/ACC, i.e. intermediate IL-10 production in the donor and presence of IL-1Ra (allele 2) i.e. down regulation of IL-1 in the donor were associated with poor outcome. The addition of the genetic variables significantly improved the preferred model containing the EBMT risk score as a single variable. The Goodness of Fit of the models was assessed by Kaplan-Meier curves showing clinically relevant differences between good, intermediate and poor prognostic groups. The worst prognostic scores included the absence of ATA/ACC in the donor, evidenced by a steep change in survival probability. Relapse was associated with clinical factors; absence of female to male transplants; absence of bone marrow transplants and presence of T cell depletion but no significant association was found with genetic factors. This study suggests that distinct high risk patterns of NHP of patients and donors can be defined, which influences survival due to factors associated with an increased risk of GvHD without the potential benefit of increased GvL response. Data add to the clinical factors (eg age, sex, multiparity of the donor) where an unrelated donor might be the preferred choice compared to a high risk sibling donor.

Description: Background: With the prolonged survival and increasing cure rate for some malignancies there appears to be an increasing incidence of therapy related MDS or AML. Methods: Between 1981 and 2006, 486 patients (pts) with t-MDS or t-AML underwent allogeneic stem cell transplantation (SCT) and were reported to the EBMT registry. The median age of the pts was 40 years (r., 3–69) and primary disease were solid tumor (n=167), malignant lymphoma (n=141), myeloproliferative syndrome (n=12), acute leukaemia (n=32), aplastic anemia (n=16) and autoimmune disease (n=1). The median time from primary diagnosis to t-MDS/t-AML was 54 months (r., 1–416). Diagnosis were: RA/RARS (n=28), RAEB (n=49), RAEB-T (n=44) and t-AML (n=308). At time of transplantation, 268 pts were in complete and 186 pts not in complete remission (CR). Cytogenetic abnormalities were found in 262 pts. Results: For the entire study population the cumulative incidence of non-relapse mortality (NRM) and relapse at 3 years was 37% and 34%. In a multivariate analysis significant factors for higher incidence of relapse were “non CR” at SCT (HR:2.20; 95% CI: 1.44–3.36, p

Description: Abstract 3363 Poster Board III-251 The introduction of reduced-intensity conditioning regimens and the reduction of therapy-related complications have increased the upper age limit of the recipient and encouraging results of allogeneic stem cell transplantation in MDS-patients have been reported up to the age of 70 years. However, whether elderly patients with MDS should undergo allogeneic stem cell transplantation is a matter of debate. We used a multi-state approach to compare the outcome in elderly advanced MDS patients (aged 55 – 69 years) with RAEB or RAEB-t who received only best supportive care and were reported to the Düsseldorf registry (n = 137), to those who received allogeneic stem cell transplantation and were reported to the European Group for Blood and Marrow Transplantation (EBMT) (n = 246). A simple direct comparison is biased by non-observable patients who die before transplant. We used left-truncation and modelling of transition probabilities to obtain estimates of survival after diagnosis; moreover scenario analyses were performed to quantify sensitivity for untestable assumptions and to estimate survival for various strategies depending on the time between diagnosis and transplant. In the non-transplant cohort, diagnosis was RAEB in 100 (73%) and RAEB-t in 37 patients (27%). The median age of the 83 male and 54 female patients was 62 years. Cytogenetic data were available in 79 patients and reported to be abnormal in 60 %. In the transplant cohort 168 were male and 78 female. Disease status at diagnosis was RAEB (70%) and RAEB-t (30%). At time of transplantation, diagnosis was RAEB (54%), RAEB-t (34%) and transformed secondary acute leukemia (12%). Transplantation from HLA-identical sibling (n = 175) or unrelated donor (n = 71) was performed after standard myeloablative (n = 76) or reduced-intensity conditioning (n = 170). Cytogenetic data were available in 88 patients and reported to be abnormal in 60 %. The median follow-up of the non-transplant cohort was 21 and of the transplant cohort measured from date of transplant was 64 months. Median time between date of diagnosis and date of transplant was 7 months. The cumulative incidence of non-relapse mortality of the transplant cohort at 1 year and 3 years was 15% and 31%, respectively. The cumulative incidence of relapse was 14% and 29% at the same time points. Univariately, after accounting for left truncation and modelling of the death rate before transplant, the hazard ratio for survival is estimated as 0.72 in favour of transplant (95 % CI: 0.53 – 0.99; p = 0.04). After adjustment for year of diagnosis, the hazard ratio remained unchanged (the year of diagnosis was neither a confounder nor it showed interaction). In a multivariate analysis, adjusting for age at diagnosis, sub-diagnosis (RAEB vs. RAEB-t), cytogenetics (abnormal vs. normal), the hazard ratio for transplantation versus no-transplantation: 0.77 (95 % CI: 0.44 – 0.99; p = 0.1) while the other hazard ratio's were: 1.4 for “age 〉 60” (95 % CI: 1.10 – 1.70; p = 0.02); 1.20 for “RAEB-t” (95 % CI: 0.92 – 1.48; p = 0.2) and 1.46 for “abnormal cytogenetics” (95 % CI: 1.16 – 1.76; p = 0.01). Despite of an estimated benefit of allogeneic SCT in comparison to best supportive care in elderly MDS patients with RAEB or RAEB-t, this conclusion evidently relies on several statistical assumptions, notably about the selection mechanism among patients scheduled for transplant but never reaching that treatment. Only a prospective trial comparing hypomethylating agents with a reduced-intensity transplant approach according to donor availability is capable of answering this question appropriately but our analysis may provide sufficient indication that such a randomization is both needed and ethically justified. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3309 Poster Board III-197 Donor Lymphocyte Infusions (DLI) constitute a potent therapeutic option for treating relapse of chronic myelogenous leukemia (CML) after hematopoietic stem cell transplantation (SCT) inducing durable remissions in the majority of patients. A number of factors is known to influence the efficiency of DLI. A preliminary analysis of EBMT data had suggested that DLI efficiency might be inferior after peripheral blood stem cell transplantation (PBSCT) as compared to DLI following bone marrow transplantation (BMT) (Schmid et al. ASH, 2005). To control for a number of other factors that were not known at the time of the previous analysis, we repeated this analysis based on the results of 357 patients treated with DLI following PBSCT (N=108) and BMT (N=249). We limited the analysis to patients who relapsed after standard intensity conditioning SCT from HLA-identical family donors in first chronic phase of disease. The median age of patients was 39 years (range 18-60) with predominance of males (59%). 53% of patients with known data were CMV positive and in 44% of the patients there was a sex-mismatch with the stem cell donor. SCTs have been performed between 1994 and 2007 (median year: 1998) and the conditioning treatment included total body irradiation (TBI) in 68% and T cell depletion in 44% of patients. 92% of patients with known data achieved complete remission after SCT while grade II-IV acute GvHD occurred in 18% of patients and extensive chronic GvHD in 17% of patients. Median time to relapse was 17 months (range 0.6-129) and median time from SCT to first DLI infusion was 23 months (range 0.6-142). Looking at the patients with known data at the time of first DLI infusion, the relapse could be classified as molecular/cytogenetic in 63%, hematologic in 27% and transformed in 10% of patients. The median year of first DLI was 2000 ranging from 1995 to 2007. As the initial DLI infusion, 9% of patients received 10×10e6 CD3+ cells/kg. However, the comparative analysis of groups based on the stem cell source revealed that the group of patients transplanted with PBSCs included significantly more males (68 vs. 56%), were older (median age 42 vs. 39) and underwent more frequently T cell depletion at SCT (72 vs. 34%,). PBSCTs have been performed more recently (median year 1999 vs. 1997) and both duration of remission and time from SCT to first DLI were shorter after PBSCT (median duration: 12 vs. 21 months and 14 vs. 26 months respectively). The initial cell dose in patients from PBSCT arm was significantly lower than in BMT group (≤10×10e6 CD3+/kg in 89% vs. 65% of patients). Similarly to the previous study, we also observed a trend towards superior overall survival after DLI in BMT group compared to PBSCT group, especially in the early post-transplant period. The actuarial probability of survival at five years from DLI was 77% in PBSCT group and 79% in BMT group. However the differences were not statistically significant (p=0.77). The source of stem cells did not influence the occurrence of molecular/cytogenetic remissions after DLI (80% vs. 77%) grade II-IV acute GVHD (16% vs. 16%), chronic GVHD (23% vs. 30%) and myelosuppression (10% vs. 16%). In order to search for factors having impact on survival of analyzed patients, we performed both univariate and multivariate survival analyses. The univariate analysis revealed that interval from SCT to DLI longer than 2 years (p=0.001), date of DLI after 2000 (p=0.026) and molecular/cytogenetic stage of relapse at DLI (p

Description: Donor lymphocyte infusions and imatinib have been the mainstay of treatment for chronic myeloid leukemia (CML) patients relapsing after allogeneic hematopoietic stem cell transplantation (alloSCT) in recent years. Improvements in transplant related mortality and a reduction of lethal infections have been documented. No comprehensive data are yet available about the impact of relapse (REL) itself on survival and a possible improvement over calendar time. We analyzed 13418 patients with CML transplanted between 1980 and 2003 (60% male, median age 36 years [range 0–71]) from an allogeneic donor (65% HLA identical sibling, 1% twin, 7% other related, and 27% unrelated). Of those, 2558 (19%) were reported with REL. We investigated the impact of REL on death rate in 4 periods: A [1980–92], B [1993–96], C [1997–99] and D [2000–03], adjusting for other factors. We applied a series of Cox models where REL was used as a time-depending covariate and where we used an integrated approach in the framework of multi-state models, with REL representing an intermediate event in a patient’s post-transplantation history. We used the EBMT risk score as a propensity score to adjust for intrinsic differences in survival over calendar time and Calendar time as categorical factor to assess trends. REL increased death rate over the whole observation period. However, there was a significant improvement over the years: death hazard ratio (HR) decreased from 4.5 to 3.2, 2.7 and 2.4 for the periods A, B, C and D, respectively. The impact of REL on death rate was also influenced by the EBMT risk score [HR 1, 1.9, and 3.5 for low, intermediate, and high risk score, respectively]. We investigated, with the same methodology used above, the impact of REL on death rate in a subset of 1977 patients transplanted after 1992 and with known information on the type of relapse at its first evidence (molecular/cytogenetic [M-REL] or hematological [H-REL]). The M-REL/H-REL ratio increases over the years (1.1, 1.2, and 2.5 in periods B, C, and D, respectively). Results confirmed that the impact of REL on death rate decreases over the years, but hardly and not significantly for H-REL (HRs around 6 in periods B, C, D) and more pronounced and significantly for the M-REL (HRs 0.68, 0.52, and 0.12 in periods B, C, and D, respectively). It is notable that H-REL was associated with higher death rate, M-REL with lower. We have shown that:REL after alloSCT for CML is associated with a higher risk for subsequent death;the effect of REL on death rate is decreasing in more recent years;the effect of REL on death rate depends on the type of REL (H-REL or M-REL) and the EBMT risk score;an integrated approach like multi-state modeling is flexible and allows clinically relevant interpretations. Our findings suggest that the effect of REL on death rate is decreasing in more recent years, mainly because of the increasing proportion of patients in whom REL is first detected at pre-clinical level (ie. molecular/cytogenetic relapse). Our results will form the basis for future description and characterization of patient groups in comparative retrospective analyses and prospective trials.

Description: Early alloSCT of pts with MDS before transformation usually results in a 50% EFS, but the nonrelapse mortality (NRM) has precluded a general application of alloSCT for patients with RA. Introduction of RIC has allowed the application of alloSCT to more advanced ages. This study evaluated the impact of recipient age, transplant year, interval between diagnosis and SCT (Dx-SCT), cytogenetic characteristics, T-cell depletion (TCD), type of donor, and the intensity of the conditioning regimen on the outcome of alloSCT. The study population consisted of 374 pts, 244 of whom have received a transplant from an HLA-id. sibling. None of the pts had progressed to advanced stages of MDS. 83 Pts received TCD grafts and 102 pts received SCT after RIC. 58 Pts were 50 yrs. 86 Pts received SCT before 1996, 125 in 1997–2001, and 163 pts more recently. 184 Pts have been transplanted with a Dx-SCT of 12 months. Cytogenetic data were available for 197 pts, 85 of whom had cytogenetic abnormalities. The overall 5-year survival was 50% (SE: 3%). Relapse occurred in 44% pts resulting in a 5-year relapse risk of 21% (SE: 3%). NRM was the cause of failure in 120 pts resulting in a 5-year NRM of 41% (SE: 3%). The survival after SCT with matched related and unrelated donors was 54% and 48% resp. Young age was associated with better survival in the univariate model (p=0.04). An association exists between various factors such as between age and regimen type, transplantation year, or donor type. Therefore the outcome of the multivariable analyses was based on Cox models with age, transplant year, type of donor, Dx-SCT, stem cell source, and regimen type as main factors. Variables with a significant impact on survival were transplant year with an improved survival in more recently performed SCT (HR=0.95/year; p=0.05), TCD (HR=1.5; p=0.03) and Dx-SCT 〉12 months (HR=1.4; p=0.05) while higher age (HR=1.1/10 years; p=0.08) and RIC (HR=1.0; p=1.0) did not influence outcome significantly. The HR of RIC for relapse-free survival was 1.2; p=0.5. The fully adjusted estimate for relapse after RIC was HR=4.1 (p=0.002). The NRM was lower after RIC: HR 0.7 (P=0.22), but this difference was not significant. The donor type and the source of stem cells did not influence significantly any of the outcome variables. This data show that alloSCT results in excellent outcome nowadays, even at older age and using matched unrelated donors. The relatively high relapse rate observed after RIC warrants prospective studies.