ALBERT

Description: Key Points Frontline FCA increases progression-free survival in CLL and, in a post hoc analysis, also survival in younger patients. With the low-dose approach, no increase in treatment related mortality is seen.

Description: Background: Toxicities following allogeneic hematopoietic stem cell transplantation are specific to the conditioning regimen used and its intensity. Therefore, we hypothesized that the hazard of individual comorbidities is dependent on the conditioning agents and their dose. The aim of this analysis was to study, in a regimen specific manner, the impact of individual comorbidities (cardiac disease, severe pulmonary disease, and diabetes mellitus) on mortality. Methods: We included a multi-center cohort of 3,338 patients from the registry of the Acute Leukemia Working Party of the European Society of Blood and Marrow Transplantation (EBMT), who underwent first allogeneic HSCT for treatment of AML in all disease stages, transplanted between 2005 and 2016. Patients included received grafts from a matched sibling or 10/10 HLA-allele matched unrelated donor, and who were conditioned using one of 7 common regimens (Busulfan [BU[/Cyclophposphamide [Cy], Cy/Total Body Irradiation [TBI], Flu [Fludarabine]/Bu at reduced-intensity [RIC] dosage, Flu/Bu at myeloablative [MAC] dosage, Flu/Melphalan [Mel], Flu/Treosulfan [Treo], Flu/TBI). Regimens were excluded from a given analysis if fewer than ten overall mortality events occurred among patients with or without the studied condition. We constructed a multivariable Cox model for the outcome of overall survival, adjusted for key transplantation variables, including patient age, disease status, and donor type among others. For each comorbidity, separate models were constructed within each of the seven regimens, and the comorbidity's hazard ratio was extracted. Using the same method, the hazard ratio across all regimens, as well as in the myeloablative and the reduced-intensity setting, was obtained. Results: The median age was 55 years; 70% of patients were in first complete remission (CR), and 54% of patients received grafts from matched sibling donors. The most common regimens studied were Flu/Bu at a reduced-intensity dose (22%), Flu/Mel (20%) and Bu/Cy (16%, Table 1). We find that the studied comorbidities were associated with different degrees of added risk for overall mortality in each regimen studied. For cardiac disease, hazard ratios (HR) ranged from 1.00 (95% CI: 0.63-1.60) in Flu/Treo to 1.65 (1.15-2.36) in Flu/Bu with myeloablative dose (Figure 1). Among patients with severe pulmonary disease, significant increases in hazard were seen only in patients treated with myeloablative Flu/Bu and Flu/Mel. In diabetes mellitus, no regimens were clearly associated with increased risk of overall mortality. However, Flu+TBI trended strongly toward increased risk with an HR of 1.55 (1.00-2.41, p = 0.051). Greater comorbidity-associated risk was not consistently associated with increasing conditioning, and the hazards associated with each comorbidity in the MAC and RIC settings were broadly overlapping. Similar trends were seen for the outcome of non-relapse mortality, although statistical significance (p 〈 0.05) was not observed in the setting of low event numbers. Conclusions: These results confirm our hypothesis that comorbidities exert an effect on transplantation outcome in a conditioning regimen-specific manner. Additional study, both retrospective, and prospective, may eventually allow for the precision selection of a conditioning regimen based on the individual patient's physiological status. Disclosures Finke: Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Malladi:Roche: Membership on an entity's Board of Directors or advisory committees. Mohty:MaaT Pharma: Consultancy, Honoraria.

Description: Background: Acute myeloid leukemia (AML) secondary to haematological neoplasia or other malignant diseases, defined as secondary AML (sAML), is thought to have an inferior prognosis as compared with de novo AML. However, when corrected for other risk factors such as age and cytogenetic risk, differences are less clear. In particular, it is uncertain whether outcome after allogeneic stem cell transplantation (alloSCT) is different. Thus, the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) performed a registry-based analysis to compare results after alloSCT for sAML versus de novo AML. Methods: Inclusion criteria were age 〉= 18y and alloSCT for de novo or sAML from a matched related, matched unrelated or T-cell replete haploidentical donor between 2000 and 2016. Patients without information on cytogenetics were excluded. 11439 patients with de novo and 1325 with sAML were identified. A multivariate Cox model was performed to account for imbalances of risk factors between the two cohorts; it was stratified for different stages at alloSCT, due to a significant interaction between stage at transplant and diagnosis (de novo or secondary) . In a second approach, a matched pair analysis of secondary versus de novo AML was done, using the following criteria for matching: Age (+/-3 years), stage at alloSCT, Karnofsky performance score, conditioning intensity, in and ex vivo T cell depletion, donor type, donor/recipient sex and CMV-status combination, cytogenetics, and graft source. Results: Median follow up after alloSCT was 36 and 33 months for de novo and sAML, respectively. In a multivariate Cox model focusing on transplants in first complete remission (CR1), sAML was associated with a higher non-relapse mortality (NRM; HR=1.32; p

Description: Introduction: The only curative treatment approach for patients with Chronic Myelomonocytic Leukemia (CMML) is allogeneic hematopoietic stem cell transplantation (HSCT), but disease relapse after transplantation is a major concern. Predictors for disease outcome after HSCT are limited. However, unfavorable cytogenetic abnormalities have been shown to serve as predictors for relapse after transplantation. The aim of this large multicentric, international study was to retrospectively determine the impact of cytogenetic information according to the CMML-specific prognostic scoring system (CPSS) on outcome after allogeneic HSCT. Patients and Methods: Patients were selected from the EBMT database who had received a first allogeneic HSCT for the treatment of CMML between 2000 and 2015. 268 centers participated into this study. In total, 1503 patients were included. Impact of CPSS-cytogenetic classification was analyzed regarding overall survival (OS) and cumulative incidence of relapse and non-relapse mortality after HSCT (gray test). Results: 488 female (32.5%) and 1013 male (67.5%) patients were included to the study. Median age at HSCT was 57.6 years (range 0.3-75.4). At time of HSCT, only 422 (28.1%) patients were in complete remission, whereas 1004 (66.8%) had active disease (77 missing). Matched related donor HSCT was performed in 35.7% of the patients, matched unrelated donor HSCT in 57.6%, mismatched related in 3.3% and mismatched unrelated in 3.4%. Bone marrow (12.6%), peripheral blood (84.3%), or both (0.3%) served as the stem cell graft. Cord blood was used as a graft in 2.8%. Myeloablative preparative regimens wereused in 223 patients (15.0%), and less intensive regimens were given to 1268 patients (85.0%). Median survival of patients included into this study was 52.2 months. 637 patients had sufficient cytogenetic information according to CPSS (866 missing), complete relapse information was available in 1385 patients. 143 patients could be categorized into CPSS-high, 85 in intermediate and 375 in low risk cytogenetics, respectively. In univariate analysis high risk CPSS cytogenetic information was found to be strongly associated with OS (low 38% (32-44%), intermediate 41% (30-53%), high 26% (18-34%)), and higher cumulative incidence of relapse (low 40% (35-46%), intermediate 42% (30-54%), high 48% (39-56%)), but not with non relapse mortality (low 28% (23-33%), intermediate 25% (16-35%), high 30% (22-38%)) at 60 months (Figure 1). Conclusion: In this international, multicentric analysis we show that CMML patients with high-risk cytogenetics had significantly worse OS after HSCT than patients with intermediate or low risk cytogenetics according to CPSS. New therapeutic strategies to prevent relapse after HSCT in CMML patients with high-risk cytogenetics are needed. Disclosures Koenecke: Amgen: Consultancy; abbvie: Consultancy; BMS: Consultancy; Roche: Consultancy. Beelen:Medac: Consultancy, Other: Travel Support. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding. Niederwieser:Novartis: Research Funding; Miltenyi: Speakers Bureau. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding.

Description: The use of anti-thymocyte globulin (ATG) has represented the standard of care in graft-versus-host disease (GVHD) prophylaxis in patients undergoing a mismatched unrelated donor (MMUD) transplant. The safety and feasibility of posttransplant cyclophosphamide (PTCY) in this setting have been reported recently, but no study has compared the outcomes of PTCY vs ATG in 9/10 MMUD transplants. Using the registry data of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we performed a matched-pair analysis comparing those 2 strategies in a 9/10 MMUD setting. Ninety-three patients receiving PTCY were matched with 179 patients receiving ATG. A significantly lower incidence of severe acute GVHD was observed with PTCY compared with ATG. Recipients of the former also showed higher leukemia-free survival and GVHD/relapse-free survival (GRFS). When performing a subgroup analysis including patients receiving peripheral blood stem cells, being in complete remission, or receiving the same associated immunosuppressive agents, superiority of PTCY over ATG was confirmed. Similar to the haploidentical setting, use of PTCY is an effective anti-GVHD prophylaxis in the 9/10 MMUD transplant. Use of PTCY may also provide better outcomes in long-term disease control. These results need confirmation in large prospective randomized trials.

Description: Introduction: Optimal HLA matching is associated with clinical outcome of unrelated donor (UD) hematopoietic cell transplantation (HCT)(Pidala, Blood2014, Morishima, Blood2015, Fürst, Blood2013), but a comprehensive analysis addressing this question in European transplant centers has not yet been performed. Within the CTIWP of EBMT, we have addressed this issue in adultsreceiving an UD-HCT from 2000 to 2015. Methods: All consecutive cases of UC-HCT with available 6-loci high resolution (2nd field) HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 typing for both patient and donor and ARD-level matching for at least 7/8 HLA-A,B,C,DRB1 alleles reported to the EBMT were selected. Further inclusion criteria were first allogeneic HCT for hematological malignancies, patient age 〉=18 years, availability of donor age and use of either bone marrow or peripheral blood (PB) as stem cell source. Overall, 9575 patient-donor pairs were included from 29 countries and 198 transplant centers. Median follow-up was of 28.3 months, main diagnosis was acute leukemia (AL)(51.5%), disease stage was early in 44.1% of cases. UD-HCT were performed with PB in 84.7%, in vivo T cell depletion (TCD) in 64.4% and reduced intensity conditioning regimen in 57.3% of cases, and mostly standard graft-versus-host-disease (GvHD) prophylaxis with calcineurin inhibitors. HLA data were validated using the HLAcore library and a haplotype based probability check from the German Donor Registry. Pairs were stratified by: 1) In the overall cohort, according to HLA-A, -B, -C, -DRB1 matching status (8/8 N=7724 and 7/8 N=1851) and 2) in informative 8/8 matched pairs (N=7480), according to HLA-DPB1 matching status as identical (23.7%), permissive (26.6%) or non-permissive (32.9%) by the 3-group T Cell Epitope (TCE3) model, or by the 4-group TCE4 model (Fleischhauer, Blood2017). Primary endpoint was overall survival (OS), secondary endpoints were non-relapse mortality (NRM), relapse and acute GvHD grade II-IV, and relapse free survival (RFS). Results: At 5 years, OS and RFS in the entire cohort were 47% and 40.5%. The cumulative incidence of 5-y NRM, relapse and 1-y grade II-IV aGvHD was 28.1%, 31.4% and 19.4%, respectively. In multivariate analysis, a single mismatch at HLA-A, -B, -C, -DRB1 (7/8) was associated with a significantly higher risk of death compared to full match (8/8; HR 1.16, p

Description: Introduction: The prognosis of patients diagnosed with blast crisis (BC) chronic myeloid leukemia (CML) is dismal. Allogeneic stem cell transplantation (alloSCT) represents the only curative treatment option. In the current tyrosine kinase inhibitor (TKI) era, however, data on transplant outcomes in patients with BC CML, particularly those with active BC at transplant, are scarce. We hereby report on a multicentre, EBMT-registry based retrospective study of adult patients allografted for BC CML focusing on patients with active disease at transplant and pre-transplant prognostic factors. Patients and methods: Patients with BC CML at transplant (i.e. prior to the start of the conditioning) who underwent alloSCT after the year 2004 within the EBMT database were identified. Next, transplant centers were asked to report the exact disease status at transplant (including blood count, blast count in peripheral blood and bone marrow, achievement and type of remission with corresponding assessment dates, and the reason to proceed with alloSCT in BC CML). A total of 170 patients allografted for BC CML between 2004 and 2016 had complete data for analysis. Overall survival (OS) and leukemia-free survival (LFS) were calculated from date of alloSCT to the appropriate endpoint. For multivariable analysis of predictors of OS and LFS, Cox proportional hazard regression models were performed. Confounding prognostic factors (full models) were: age, disease status prior to alloSCT, Karnofsky performance status (KPS) prior to transplant, interval from diagnosis to transplant, year of transplant, stem cell source, conditioning intensity, donor type, and donor/recipient sex match. All patients provided informed consent for data collection and analysis. Results: Median age at alloSCT was 45 years (range [r], 18-75). Median time from diagnosis to alloSCT was 13.9 months (r, 1.6-367.4). Median follow-up time was 54.7 months (r, 0.1-135.2). Stem cell source was peripheral blood, bone marrow and cord blood in 145 (85%), 18 (11%) and 7 (4%) patients, respectively. Donor types were: unrelated (UD), matched related, and mismatched related in 91 (54%), 64 (38%), and 15 (9%) patients, respectively. Conditioning was myeloablative in 108 (64%) of patients. KPS at alloSCT was ≤80% in 31% of patients. Information on BCR-ABL mutations was available for 41 patients; T315I was present in 28 patients. After thorough analysis of disease parameters, a total of 95 patients had any kind of remission of BC CML (including secondary chronic phase) prior to transplant (termed BC in remission); 75 patients had active BC CML prior to transplant (termed BC active). Main reason for proceeding with alloSCT despite active disease was resistance/refractoriness towards TKI in combination with polychemotherapy. Extramedullary disease was documented in 4 patients. In uni- and multivariable analyses of the entire cohort, besides low KPS, only disease status prior to transplant was significantly associated with shorter OS and LFS (for BC active: HR 2.00, 95%CI 1.35-2.96, p=0.001 and HR 1.80 95%CI 1.27-2.57, p=0.001, respectively). Accordingly, for patients allografted for active BC estimated 3-year OS and LFS was rather short (23.8% 95%CI 13.6-34.0 and 11.6% 95%CI 3.0-20.2, respectively) and significantly lower as compared to patients allografted for BC in remission (3-year OS and LFS: 51.1% 95%CI 40.5-61.7 and 33.8% 95% CI 23.6-44.0, respectively) (Figure 1A and B). Consequently, prognostic factors for survival were analyzed separately according to disease status at alloSCT (slim models, Table 1). For patients with BC in remission at transplant advanced age, lower KPS, shorter interval from diagnosis to transplant, myeloablative conditioning, and UD transplant were risk factors for inferior survival, whereas in patients allografted for active BC, only UD transplant was associated with prolonged LFS and with a trend towards improved OS (Table 1). Conclusion: Survival of BC CML patients after alloSCT in the TKI era remains poor unless disease remission could be achieved. In patients who achieve remission prior to alloSCT, conventional prognostic indicators remain the determinants of transplant outcomes. In patients with active BC CML, UD transplantation appears to be associated with a survival advantage in our study. Disclosures Finke: Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Mayer:Eisai: Research Funding; Roche: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding. Byrne:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

Description: Introduction. Several alternative donor sources are currently available for patients who lack an HLA-matched related or unrelated donor, including haploidentical, cord blood and one antigen HLA-mismatched donors (9/10 mMUD). Use of post-transplant (allo-HSCT) cyclophosphamide (PTCY) as graft-versus-host disease (GVHD) prophylaxis allowed outcome improvements in the haploidentical setting. Its use has also been reported as a safe and feasible option in 9/10 mMUD transplants. However, to date, the main strategy used as GVHD prophylaxis in 9/10 mMUD allo-HSCT is in vivo T-cell depletion with antithymocite globulin (ATG). Data comparing these two different anti GVHD prophylaxis strategies in 9/10 mMUD allo-HSCT are limited. Methods. We compared PTCY versus ATG as GVHD prophylaxis in patients undergoing 9/10 mMUD allo-HSCT for which high-resolution HLA-allele typing was available in the ALWP/EBMT data registry. Included were adult patients (age〉18 years) undergoing their first allo-HSCT for acute myeloid leukemia (AML) during the period 2007-2017. All disease status were allowed. Propensity score matching was performed to reduce and eliminate confounding effects. Each patient receiving PTCY was matched with two patients receiving ATG using the nearest neighbor or exact matching. Variables included in the propensity score model were: disease status at time of allo-HSCT, conditioning regimen, age, secondary AML, female donor to male recipient, source of stem cells, patient and donor CMV serology status. Results. Globally, 93 patients receiving PTCY were identified and matched with 179 patients receiving ATG. Secondary AML was reported in 20% and 18% of patients in ATG and PTCY groups, respectively. Most patients were in first complete remission at time of allo-HSCT (55% and 56% in PTCY and ATG group, respectively), while nearly 29% of patients in both groups underwent allo-HSCT with active disease. Ciclosporine (csA) and mycophenolate mofetil (MMF) were the systemic immunosuppressive agents more frequently associated to either PTCY (42%) or ATG (49%). Other well represented associated immunosuppressive agents were tacrolimus and MMF in ATG group (20%), followed by 14% of patients receiving csA alone with ATG. In PTCY group, 39% of patients received csA and methotrexate as associated immunosuppressive agents. Conditioning regimen was myeloablative in 50% of patients in both groups. Peripheral blood was the preferred stem cell source (91% in both groups). Among the variables not included in the propensity score model, some differences were observed between the two groups. Median follow-up was longer in the ATG group (27.4 versus 14.2 months, p

Description: Introduction Multiple myeloma (MM) is characterized by a proliferation of plasma cells with a strong dependence on the bone marrow (BM) microenvironment. However, in some MM patients this proliferation escapes the BM resulting in extramedullary disease (EMD) with two types of involvement: 1) paraskeletal (PS) and 2) extramedullary (EM), involving either skin/lymph nodes (EMS) or organs (EMO). EMD is considered to be associated with poor prognosis. Autologous stem cell transplantation (ASCT) in MM is standard therapy in first line therapy in eligible patients, but only limited reports on outcome of EMD after ASCT exist. Methods Within the European Society for Blood and Marrow Transplantation (EBMT) registry, 4658 patients (female n=1898, male n=2760) who received upfront ASCT were reported between January 2005 and December 2014 with available data on EM involvement at time of diagnosis. 3802 patients had no EMD (MM group), while 677 had PS and 179 EM involvement, including EMS (n=68) or EMO (n=111). The median age of the patients was 59 years (range 22 - 77). The stage according ISS at diagnosis was I (n=1229), II (n=1174) and III (n=865). All patients received an upfront single (n=4250) or tandem (n=408) ASCT. Salmon and Durie classification stage B was seen more frequently in EM (31%), than in MM (17%) or PS (16%) (p〈 0.001). More EM had ≥ 2 different sites of involvement than PS patients (20% versus 4%, p〈 0.001). Tandem ASCT was applied to 15% in the PS group compared to 8% in the MM and 10% in the EM group (p〈 0.001). Primary end point was 5 year progression-free survival (PFS). Results At ASCT 18% of MM patients achieved a complete remission (CR) compared to 20% of PS and 12% of EM patients (p=0.058). MM and PS patients showed similar 5 year PFS (28% versus 29%, p= 0.74) in the univariate analysis with a median PFS of 31 versus 33 months. In contrast, EM patients had a significant worse median PFS (21.5 months) and 5 year probability (22%) than MM patients (28%) as well as PS patients (29%) (p〈 0.001). Five year probability of OS were higher in MM compared to PS (67% versus 63%, p=0.05) and to EM (67% versus 49%, p〈 0.001). Furthermore, the difference in 5 year OS between PS and EM involvement reached statistical significance (63% versus 49%, p〈 0.001). When analyzing PFS according to the number of sites involved, the median PFS in PS patients was 35 for 1 versus 24 months for ≥ 2 sites and in EM patients 24 versus 17 months (p=0.003). Other significant factors for worse PFS in the univariate analysis were: IgA-type (p〈 0.001), Salmon and Durie stage B (p〈 0.001), ISS II and III (p〈 0.001, respectively), while favorable factors were CR (p〈 0.001) and female sex (p〈 0.001). In a subanalysis comparing EMS and EMO, the median PFS was significantly worse for EMS than EMO (20 versus 25 months, p=0.024). Cox proportional hazards regression considering independent factors for worse PFS yielded: EM (HR 2.88, 95% CI 1.90 - 4.37), IgA (HR 1.31, 95% CI 1.15 - 1.48) as well as Salmon and Durie stage B (HR 1.26, 95% CI 1.06 - 1.51), while improved PFS was seen for CR (HR 0.47, 95% CI 0.36 - 0.61) and ISS I (HR 0.70, 95% CI 0.60 - 0.83). Conclusion This EBMT registry study demonstrates that EMD manifestation in patients with MM is an independent risk factor for worse outcome after ASCT. Within the EMD group, non-paraskeletal extramedullary manifestation, EMS and involvement of 2 or more sites resulted in worse PFS. Disclosures 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. Delforge:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Kröger:Riemser: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding.