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Blastic plasmacytoid dendritic cell neoplasia (BPDCN) is a rare myeloid malignancy with a generally poor prognosis. Although preliminary evidence suggests that hematopoietic cell transplantation (HCT) could improve outcome in patients with BPDCN, the individual contributions of conditioning and graft-versus-tumor (GVT) effects to HCT success are undefined. We present a retrospective study of 162 adult patients who underwent a first HCT (allogeneic 146, autologous 16) between 2009 and 2017, and were registered with the EBMT. Median age was 57 (range 20–73) years, and disease status at HCT was first complete remission (CR1) in 78%. Among patients receiving allogeneic HCT (alloHCT), myeloablative conditioning (MAC), reduced intensity conditioning (RIC) and in-vivo T-cell depletion (TCD) were used in 54%, 46%, and 59% respectively. Total body irradiation (TBI) was the conditioning backbone in 61% of MAC and 26% of RIC transplants. One-year overall survival (OS) and progression-free survival (PFS) rates were comparable after alloHCT and autologous HCT (autoHCT). Among alloHCT recipients, MAC with TBI significantly improved OS and PFS, independently of CR1, age, Karnofsky index and TCD. Accordingly, MAC (ideally based on TBI) should be preferred for alloHCT recipients with BPDCN. In patients who are not elegible for MAC alloHCT, autoHCT could be considered.

Purpose: We assessed the impact of donor type in acute myeloid leukemia (AML) patients transplanted with 2 Gy total body irradiation (TBI)-based nonmyeloablative conditioning regimen.Patients and Methods: Data from 1,715 adult patients, with AML in CR1 or CR2 were included in this retrospective survey.Results: Donors consisted either of HLA-matched sibling donors (MSD, n = 701), 10/10 HLA-matched unrelated donors (MUD, n = 611), HLA-haploidentical donors (haplo, n = 112) or single or double umbilical cord bloods (CBT, n = 291). Chronic graft-versus-host disease (GVHD) was less frequent in CBT (28%) and in haplo (30%) patients than in MSD (50%) and MUD (51%) recipients (P < 0.001). Two-year incidence of relapse was 32%, 30%, 34%, and 34% in MSD, MUD, CBT and haplo patients, respectively (P = 0.7). Two-year overall (OS) and GVHD-free relapse-free survival (GRFS) were 59% and 29% in MSD patients, 56% and 39% in CBT recipients, 53% and 23% in MUD recipients, and 43% and 37% in haplo patients, respectively. In multivariate analyses, MUD patients had lower GRFS than MSD patients beyond day 100 (HR 1.3, P = 0.001) while CBT was associated with a better GRFS than MSD beyond day 100 (HR 0.6, P = 0.002).Conclusions: In this large cohort of AML patients transplanted following low-dose TBI-based conditioning, the relapse incidence was not affected by donor type suggesting that the intensity of GVL effects might be comparable with these four transplant approaches. Furthermore, CBT was associated with better GRFS beyond day 100 than MSD while the opposite was observed for MUD. Clin Cancer Res; 24(12); 2794–803. ©2018 AACR.

Allogeneic transplantation (allo-HCT) is a curative treatment in CLL whose efficacy including the most severe forms had led to the 2006 EBMT recommendations. The advent after 2014 of targeted therapies has revolutionized CLL management, allowing prolonged control to patients who have failed immunochemotherapy and/or have TP53 alterations. We analysed the pre COVID pandemic 2009–2019 EBMT registry. The yearly number of allo-HCT raised to 458 in 2011 yet dropped from 2013 onwards to an apparent plateau above 100. Within the 10 countries who were under the EMA for drug approval and performed 83.5% of those procedures, large initial differences were found but the annual number converged to 2–3 per 10 million inhabitants during the 3 most recent years suggesting that allo-HCT remains applied in selected patients. Long-term follow-up on targeted therapies shows that most patients relapse, some early, with risk factors and resistance mechanisms being described. The treatment of patients exposed to both BCL2 and BTK inhibitors and especially those with double refractory disease will become a challenge in which allo-HCT remains a solid option in competition with emerging therapies that have yet to demonstrate their long-term effectiveness.

The intensity of the conditioning regimen given before allogeneic hematopoietic cell transplantation (allo-HCT) can vary substantially. To confirm the ability of the recently developed transplant conditioning intensity (TCI) score to stratify the preparative regimens of allo-HCT, we used an independent and contemporary patient cohort of 4060 transplant recipients with acute myeloid leukemia meeting inclusion criteria from the discovery study (allo-HCT in first complete remission, matched donor), but who were allografted in a more recent period (2018–2021) and were one decade older (55–75 years, median 63.4 years), we assigned them to a TCI category (low n = 1934, 48%; intermediate n = 1948, 48%, high n = 178, 4%) according to the calculated TCI score ([1–2], [2.5–3.5], [4–6], respectively), and examined the validity of the TCI category in predicting early non-relapse mortality (NRM), 2-year NRM and relapse (REL). In the unadjusted comparison, the TCI index provided a highly significant risk stratification for d100 and d180 NRM, NRM and REL risk. In the multivariate analysis adjusted for significant variables, there was an independent strong association of TCI with early NRM, NRM and REL. In summary, we confirm in contemporary treated patients that TCI reflects the conditioning regimen related morbidity and anti-leukemic efficacy highly satisfactorily and across other established prognostic factors. TCI has all the features to be used as a well-defined, easy calculated and reproducible tool to define and measure intensity of the preparative regimen.

Contains fulltext : 248798.pdf (Publisher’s version ) (Open Access) Allogeneic hematopoietic cell transplantation (allo-HCT) remains a treatment option for patients with chronic myeloid leukemia (CML) who fail to respond to tyrosine kinase inhibitors (TKIs). While imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second-generation TKI (2GTKI). We present the results of a prospective non-interventional study performed by the EBMT on 383 consecutive CML patients previously treated with dasatinib or nilotinib undergoing allo-HCT from 2009 to 2013. The median age was 45 years (18-68). Disease status at transplant was CP1 in 139 patients (38%), AP or >CP1 in 163 (45%), and BC in 59 (16%). The choice of 2GTKI was: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. With a median follow-up of 37 months (1-77), 8% of patients developed either primary or secondary graft failure, 34% acute and 60% chronic GvHD. There were no differences in post-transplant complications between the three different 2GTKI subgroups. Non-relapse mortality was 18% and 24% at 12 months and at 5 years, respectively. Relapse incidence was 36%, overall survival 56% and relapse-free survival 40% at 5 years. No differences in post-transplant outcomes were found between the three different 2GTKI subgroups. This prospective study demonstrates the feasibility of allo-HCT in patients previously treated with 2GTKI with a post-transplant complications rate comparable to that of TKI-naive or imatinib-treated patients.

Item does not contain fulltext While in vivo T-cell depletion (TCD) is widely used, its benefit in patients with MDS still remains a matter of debate. This study evaluates the impact of TCD on outcomes, and compares ATG and alemtuzumab, in patients with MDS. 1284 patients from the EBMT registry were included in this study with 470 patients in the no-TCD group and 814 in the TCD group (alemtuzumab N = 168; ATG N = 646). At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51% (p

Allogeneic hematopoietic cell transplantation (allo-HCT) is increasingly used in older myelofibrosis (MF) patients, but its risk/benefit ratio compared to non-transplant approaches has not been evaluated in this population. We analyzed the outcomes of allo-HCT in 556 MF patients aged > 65years from the EBMT registry, and determined the excess mortality over the matched general population of MF patients > 65years managed with allo-HCT (n=556) or conventional drug treatment (n=176). The non-transplant cohort included patients with intermediate-2 or high risk DIPSS from the Spanish Myelofibrosis Registry. After a median follow-up of 3.4years, the estimated 5-year survival rate, non-relapse mortality (NRM), and relapse incidence after transplantation was 40%, 37%, and 25%, respectively. Busulfan-based conditioning was associated with decreased mortality (HR: 0.7, 95% CI: 0.5-0.9) whereas the recipient CMV+/donor CMV- combination (HR: 1.7, 95% CI: 1.2-2.4) and the JAK2 mutated genotype (HR: 1.9, 95% CI: 1.1-3.5) predicted higher mortality. Busulfan-based conditioning correlated with improved survival due to less NRM, despite its higher relapse rate when compared with melphalan-based regimens. Excess mortality was higher in transplanted patients than in the non-HCT cohort in the first year of follow-up (ratio: 1.93, 95% CI: 1.13-2.80), whereas the opposite occurred between the 4th and 8th follow-up years (ratio: 0.31, 95% CI: 0.18-0.53). Comparing the excess mortality of the two treatments, male patients seemed to benefit more than females from allo-HCT, mainly due to their worse prognosis with non-transplant approaches. These findings could potentially enhance counseling and treatment decision-making in elderly transplant-eligible MF patients. This article is protected by copyright. All rights reserved.

Congenital sideroblastic anaemias (CSA) are a rare group of disorders characterized by the presence of pathologic iron deposits within the mitochondria of erythroid precursors (ring sideroblasts) in the bone marrow due to heterogenous germline mutations leading to defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Patients present with anaemia and relative reticulocytopenia, and systemic iron overload secondary to chronic ineffective erythropoiesis, leading to end-organ damage. The disease is heterogenous underlying the genetic variability and the variable response to treatment. Although a number of CSA patients have received a bone marrow transplant, the outcomes and toxicities are not known. This status makes it very difficult to understand the role of BMT in the management of CSA. A search in the EBMT database identified 28 patients receiving a HSCT for CSA between 1998 to 2018 by 24 participating centres. The median year of transplantation was 2014 (IQR 2004-2016). The distribution was equal between males (n=14) and females (n=14). The median age at transplantation was 7 years of age (3-10 years). Fifteen patients had a sibling HSCT (88%), one a family matched donor HSCT (6%) and one an unrelated matched (6%), the type of transplant being unknown in others (n=11). The source of stem cells was bone marrow in 20 cases (74%), peripheral blood in 4 cases (15%), cord blood in 2 (7%) and combined bone marrow and cord in one (4%). Five cases had a Bu/Cy based conditioning regimen, 4 had Bu/fludarabine based regimen and three fludarabine/treosulfan based conditioning with the rest having a variety of approaches. Eighty-six percent of cases had serotherapy with ATG or alemtuzumab. The median follow-up was 31.6 months (95% CI, 12.2-74.1%). The overall survival at 12 and 24 months was 88% (76-100) and 82% (66-99), respectively (figure 1). The median neutrophil engraftment was 18 (15-21) days and platelet engraftment >20 x 109/L was 29 (20-51) days, with a graft failure incidence of 7% (0-17) at 12 months. Two patients suffered from VOD. There were four deaths, three of which were related to transplant complications. The event free survival (survival without graft failure, relapse and second transplant) at 12 and 24 months was 85% (72-99) (figure 2). Six patients developed acute GvHD grade II and one case grade III; giving a grade II/III incidence of 28% (10-46). There was one case of limited and one of chronic GvHD, giving an incidence of 11% (0-26%) at 12 months and 24 months. In conclusion, whilst HSCT for CSA is a rare occurrence, these data demonstrate that HSCT for this condition is feasible and the outcomes are in keeping with those obtained for transplantation for transfusion dependent anaemias during the same time-period. Disclosures Handgretinger: Amgen: Honoraria. Moraleda:Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Takeda: Consultancy, Other: Travel Expenses. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Measurable residual disease (MRD) prior to hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML) in first complete morphological remission (CR1) is an independent predictor of outcome, but few studies address CR2. This analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation registry assessed HCT outcomes by declared MRD status in a cohort of 1042 adult patients with AML CR2 at HCT. Patients were transplanted 2006–2016 from human leukocyte antigen (HLA) matched siblings (n = 719) or HLA 10/10 matched unrelated donors (n = 293). Conditioning was myeloablative (n = 610) or reduced-intensity (n = 432) and 566 patients (54%) had in-vivo T cell depletion. At HCT, 749 patients (72%) were MRD negative (MRD NEG) and 293 (28%) were MRD positive (MRD POS). Time from diagnosis to HCT was longer in MRD NEG than MRD POS patients (18 vs. 16 months (P P P = 0.001), but there was no difference in terms of overall survival. Prognostic factors for relapse and LFS were MRD NEG status, good risk cytogenetics, and longer time from diagnosis to HCT. In-vivo T cell depletion predicted relapse.

International audience; Since cord blood transplantation (CBT) has been associated with high graft-versus-leukemia effects and a low incidence of chronic graft-versus-host disease (GVHD), we hypothesized that long-term outcomes might be better in CBT patients than in those given grafts from unrelated donors (UD). Therefore, we performed a landmark study comparing long-term outcomes in acute myeloid leukemia (AML) patients alive and disease-free 2 years after transplantation who received grafts from either CBT or UD. A total of 364 CBT recipients, 2648 UD 10/10 patients and 681 patients given grafts from UD 9/10 were included. Median follow-up was 6.0 years. Five-year leukemia-free survival (LFS) from transplantation was 86% in CBT patients, 84% in UD 10/10 patients (P = 0.36) and 84% in UD 9/10 patients (P = 0.86). On multivariate analysis, donor type had no impact on LFS. Similarly, no impact of donor type was observed on relapse incidence or non-relapse mortality. Factors associated with poorer LFS on multivariate analysis included higher age at transplantation (P < 0.001), male gender (P < 0.001), second complete remission (CR2) versus CR1 (P = 0.05), secondary AML (P = 0.01), antecedent of chronic GVHD (P < 0.001) and poor-risk cytogenetics (P = 0.01). In conclusion, our study shows that long-term outcome for AML patients in CR two years after transplantation is not impacted by donor type.

Allogeneic stem cell transplantation (SCT) is potentially curative therapy in acute myeloid leukemia (AML). Marked improvement has been achieved with SCT from matched unrelated donors (MUDs) in recent years. However, there are limited data comparing the long-term outcomes (beyond 10 years) after SCT from sibling donors and MUDs in older patients with AML. We analyzed these outcomes in a large cohort of patients with AML (n = 1134), age ≥50 years, who were alive and leukemia-free 2 years after SCT from matched siblings (n = 848) or MUDs (n = 286), with a median follow-up of 8.9 years. The median age was 56 and 58 years after SCT from siblings and MUDs, respectively (P = .005). In the sibling group, 77%, 12%, and 11% were in first complete remission (CR1), second complete remission (CR2), and active leukemia at SCT compared with 50%, 25%, and 25% in the MUD group, respectively (P.001). Sixty-one percent of siblings and 62% of MUDs had reduced-intensity conditioning (P = .78). The 10-year leukemia-free survival (LFS) of patients surviving leukemia-free 2 years after SCT was 72% and 62%, respectively (P = .30). Multivariate analysis identified active leukemia at SCT (hazard ratio [HR], 1.86; P = .0001) or CR2 (HR, 1.51; P = .02) compared with CR1, female recipients (HR, 0.71; P = .006), adverse cytogenetics (HR, 2.52; P = .01), and prior graft-versus-host disease (HR, 1.31; P = .04) as independent factors predicting LFS. Donor and conditioning type were not significant. The cumulative incidence was 15% and 17% (P = .97) for late relapse mortality and 13% and 21% for late nonrelapse mortality, respectively (P = .15). In conclusion, long-term LFS is similar, and patients who are leukemia-free 2 years after SCT can expect favorable outcomes with both donor types.

Richter syndrome (RS) represents a transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), which is associated with a dismal prognosis. Patients with DLBCL-RS have poor outcomes with DLBCL-directed therapy; thus, consolidation with hematopoietic cell transplantation (HCT) has been used, with durable remissions observed. Studies reporting HCT outcomes in patients with DLBCL-RS have been small, have not evaluated the prognostic impact of cytogenetic risk factors, and were conducted prior to the era of novel targeted therapy of CLL/SLL. We performed a Center for International Blood and Transplant Research registry study evaluating outcomes after autologous HCT (auto-HCT; n = 53) and allogeneic HCT (allo-HCT; n = 118) in patients with DLBCL-RS treated in the modern era. More auto-HCT recipients were in complete response (CR) at HCT relative to allo-HCT recipients (66% vs 34%), whereas a higher proportion of allo-HCT recipients had 17p deletion (33% vs 7%) and had previously received novel agents (39% vs 10%). In the auto-HCT cohort, the 3-year relapse incidence, progression-free survival (PFS), and overall survival (OS) were 37%, 48%, and 57%, respectively. Among allo-HCT recipients, the 3-year relapse incidence, PFS, and OS were 30%, 43%, and 52%, respectively. In the allo-HCT cohort, deeper response at HCT was associated with outcomes (3-year PFS/OS, 66%/77% CR vs 43%/57% partial response vs 5%/15% resistant; P < .0001 for both), whereas cytogenetic abnormalities and prior novel therapy did not impact outcomes. In our study, HCT resulted in durable remissions in therapy-sensitive patients with DLBCL-RS treated in the era of targeted CLL/SLL therapy, including patients with high-risk features.

Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001-2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1-77.3) and 43.2 months (range 0.3-179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study. ispartof: FRONTIERS IN IMMUNOLOGY vol:11 ispartof: location:Switzerland status: published

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Myeloproliferative Neoplasm (MPN), unclassifiable (MPN-U) is a heterogeneous disease with regards to both clinical phenotype and disease course. Patients may initially be asymptomatic or present with leucocytosis or thrombocytosis, anaemia, progressive splenomegaly, constitutional symptom, thromboses or accelerated/blastic phase disease. Treatment strategies are variable and there are no widely accepted consensus management guidelines for MNU-U. Allogeneic Haematopoietic Cell Transplantation (allo-HCT) remains the only curative strategy yet outcomes, to date, are not well defined. We hereby report on the largest retrospective study of patients with MPN-U undergoing allo-HCT, highlighting the potentially curative role and providing clinicians with robust engraftment, GvHD and outcome data to facilitate patient discussion.

Introduction. Chronic lymphocytic leukemia (CLL) has typically an indolent course but can undergo transformation into a more aggressive lymphoma so called Richter's syndrome. While the advent of novel targeted therapies is transforming the management of patients with CLL, these drugs failed to prevent the risk of RS. RS is associated with a very poor outcome and is thus becoming the main obstacle to long term CLL control. Autologous (auto-) and allogeneic (allo-) hematopoietic stem-cell transplantation (-SCT) have been recommended as the treatment of choice in eligible patients with clonally related RS (Rossi Blood 2018) but previous experience is still limited to less than 50 cases. We here aimed to investigate the safety and efficacy of both auto- and allo-SCT for patients with RS in a large cohort in a period overlapping the advent of novel agents. Methods. We report on a retrospective study of consecutive adult patients with RS who underwent auto- or allo-SCT between 2008 and 2018 in EBMT centers. Results. A total of 197 patients (M/F= 133/64) were included in the present study; 125 patients received allo-SCT and 72 auto-SCT. The main difference between these 2 cohorts was the median age at transplant that was lower in the allo- than in the auto-SCT group (median age 57 [18-71] vs 61 [39-74] years, p = 0.006). Regarding the allo-SCT cohort, median time from RS diagnosis to SCT was 10 months [1.1-322.8] and 54.2% had received >2 therapeutic lines for RS. At allo-SCT, 60 (48.4%) were in CR and 53 (42.7%) in PR or SD. Most patients received reduced intensity conditioning (RIC) regimen (n= 90, 72.6%) and peripheral blood (89.6%) as stem cell source. Donors were related (matched, n=40 (33%) or mismatched, n=4 (3%)) or unrelated (matched, n= 76 (61%) and mismatched, n=4 (3%). A total of 41 patients (33.6%) received total body irradiation (TBI). With a median follow-up of 48 months, 2-year OS was 46% (36-55%) and 2-year PFS 38% (28-48%). Two-year cumulative incidence of relapse (CIR) was 31% (22-40%) as was the 2-year NRM (Figure 1). Two-year CIR was significantly reduced in patients with ≤2 therapeutic lines for RS (12% (1-22%) vs 41% (26-55%); p=0.005). Performance status affected 2-y PFS (24% (7-42%) if Karnofsky index Regarding the auto-HSCT cohort, median time from RS diagnosis to HSCT was 7.8 months [2.6-102.7] and 66.7% had received >2 lines for RS. At auto-SCT, 36 (52.2%) were in CR and 36 (37.7%) in PR or SD. With a median follow-up of 18 months, 2-year OS was 69 % (56-82%) and 2-year PFS 47% (33-62%). Two-year cumulative incidence of relapse (CIR) was 46% (32-60%) and 2-year NRM was 7% (0-13%) (Figure 2). CR patients presented better PFS (69% (50-88%) vs 29% (9-50%); p=0.002) and OS (82% (66-97%) vs 56% (35-78%) ; p=0.03). Performance status affected 2-y PFS (25% (2-48%) if Karnofsky index 90%, p = 0.005) and 2-y OS (55% (29-82%) if Karnofsky index 90%, p = 0.04). Disclosures Guièze: Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Finke:Riemser: Honoraria, Other: research support, Speakers Bureau; Neovii: Honoraria, Other: research support, Speakers Bureau; Medac: Honoraria, Other: research support, Speakers Bureau. Chevallier:Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria.

Acute graft-versus-host disease (aGVHD) remains a cause of excessive morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Primary treatment consists of high-dose corticosteroids, but a small group of patients develop steroid-refractory disease, and their prognosis is especially poor. There is experimental evidence that coexisting inflammation aggravates aGVHD. Because C-reactive protein (CRP) is a systemic inflammatory marker, we aimed to investigate whether plasma CRP concentrations at the diagnosis of aGVHD can predict the risk of failing first-line therapy and developing steroid-refractory disease. We retrospectively studied 461 patients who underwent HSCT between 2010 and 2015. aGVHD grade II-IV was diagnosed in 148 patients (32%). CRP level and total white blood cell, lymphocyte, and neutrophil counts were available for all patients at the time of aGVHD diagnosis. According to local protocol, patients with failed response to high-dose steroid therapy (2 mg/kg) were treated with the TNF-α inhibitor infliximab and categorized as having steroid-refractory disease. Of 148 patients with grade II-IV aGVHD, 28 (19%) developed steroid-refractory disease. In these patients, plasma CRP concentration at diagnosis ranged between

Introduction: The role of allogeneic hematopoietic cell transplantation (allo-HCT) in Philadelphia-positive chronic myeloid leukemia (Ph+ CML) changed profoundly after the introduction of tyrosine kinase inhibitors (TKIs). Nevertheless, allo-HCT still represents the preferred treatment option for selected high-risk patients in Europe, with TKI resistance as the most common indication in first chronic phase (CP1). Reported survival outcomes for patients transplanted in CP1 with matched related (MRD), matched unrelated (MUD) and mismatched unrelated donors (MMUD) are generally good, but there are no published data on transplants from haploidentical donors (HD). In this retrospective study, we aimed to compare HD outcomes with those using MRD/MUD/MMUD. Patients and Methods: Patients who had received a first allo-HCT for Ph+ CML between 2012 and 2019 were selected from the EBMT database. Following the exclusion of patients transplanted using MRD, MUD, or MMUD and who received post-Cy GvHD prophylaxis, 1686 patients were included in the analysis. The impact of donor type on overall survival (OS) and relapse-free survival (RFS) was assessed using the Kaplan-Meier method; the cumulative incidence of relapse (REL) and non-relapse mortality (NRM) were estimated as competing events. Univariate comparisons were tested by log-rank or Gray's test, as appropriate. Cox proportional hazard models were applied to compare the risk of OS, RFS, REL and NRM in patients transplanted from MRD, MUD, MMUD and HD, adjusted for baseline disease and transplant characteristics, and to analyze the cause-specific hazard of NRM and REL. Two-sided p values of p Results: Overall, the median age at transplant was 46 years (range 18-74). 62% were male. The median interval from diagnosis to transplant was 17.5 months. Disease status at transplant was CP1 in 43%, CP2 or later in 27%, accelerated phase (AP) in 12%, and blast phase (BP) in 18%. Karnofsky Performance Status (KPS) was ≥90 in 78% of patients. Donor was MRD in 661 patients (39.2%), MUD in 677 (40.2%), MMUD in 212 (12.6%) and HD in 136 (8%). The stem cell source was peripheral blood (PB) in 84% (52% in HD, p20 x 10 9/L) engraftment was 25 days in HD, 14 days in MRD/ MUD and 15 days in MMUD transplants. 53% of patients were serologically CMV positive pre-transplant. The cumulative incidence of grade II-IV acute GvHD at Day +100 was 25%, 27%, 31% and 39% in HD, MRD, MUD and MMUD, respectively (p=0.008). Chronic GvHD at +60 months was observed in 36%, 49%, 40% and 48% in HD, MRD, MUD and MMUD transplants (p=0.006), respectively. With regard to transplant outcomes at 60 months in HD, MRD, MUD and MMUD, OS was 51%, 51%, 62% and 58% (p=0.22), RFS was 42%, 46%, 51% and 45% (p=0.03, Fig.1), REL was 37%, 35%, 28% and 31% (p=0.064), NRM was 21%, 20%, 21% and 24% (p=0.34), and GVHD-free/relapse-free survival (GRFS) was 23%, 22%, 32% and 26% (p Conclusions: Apart from confirming the stage of disease at transplant as being a major prognostic factor, this study identified a trend to better RFS and GRFS in patients with Ph+ CML transplanted using MUD when compared to MRD/HD/MMUD. These results should be interpreted with caution given the limited number of patients who had HD. Figure 1 Figure 1. Disclosures Byrne: Incyte: Honoraria. Apperley: Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau; Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ganser: Novartis: Honoraria; Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria. Hayden: Amgen: Honoraria; Jansen, Takeda: Other: Travel, Accomodation, Expenses. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

Introduction: Accurate assessment of the risk of non-relapse mortality (NRM) is important for making the shared decision about treatment with allogeneic hematopoietic cell transplantation (allo-HCT). We have shown that the pre-transplantation plasma level of suppression of tumorigenicity 2 (ST2)-a protein that is released to the bloodstream upon inflammation, cellular stress and endothelial damage-was associated with NRM after myeloablative allo-HCT [Gjærde et al., ASH Annual Meeting 2020, abstract #1524]. In an expanded cohort of both myeloablative- and non-myeloablative conditioned patients, we aimed to validate the value of pre-transplant ST2 in predicting 1-year NRM after allo-HCT. Methods: Pre-transplantation plasma ST2 levels were measured by enzyme-linked immunosorbent assays in 374 adult patients who underwent allo-HCT at Rigshospitalet between July 2015 and December 2019 (Table 1), using stored plasma samples collected at a median (Q1, Q3) of 23 (21, 24) days before allo-HCT. All patients were followed-up for at least 1 year after transplant. NRM was defined as all deaths in relapse-free patients. Given our sample size and outcome proportion, we could include four parameters in a logistic regression model of 1-year NRM to avoid severe overfitting [Riley et al., BMJ, 2020]. Based on our current clinical risk assessment practice, we included age (linear), comorbidity index (HCT-CI [Sorror et al., Blood, 2005], linear) and conditioning intensity (myeloablative vs. non-myeloablative) in a base model, to which we added the pre-transplantation ST2 level (linear) and assessed its incremental prognostic value [Steyerberg et al., Epidemiology, 2019]. The internal validity of the full model was estimated by bootstrapping [Steyerberg et al., J Clin Epidemiol, 2001]. Results: The median (Q1, Q3) pre-transplantation plasma ST2 level was 20.4 (15.2, 27.2) ng/mL. NRM at 1-year was 9% (N = 33). The main causes of NRM were organ failure (39%), infection (23%) and acute graft-versus-host disease (21%). Relapse risk at 1-year was 18%. The patients who constituted the 33 cases of 1-year NRM had a 2.7 ng/mL higher median pre-transplantation ST2 level than the remaining 341 patients (95% bootstrap confidence interval [CI] of the difference: -1.9, 6.2 ng/mL, Figure Panel A). In the full logistic regression model-including age, HCT-CI, conditioning intensity and ST2-ST2 was associated with 1-year NRM with an odds ratio of 1.32 (CI: 1.05, 1.65) per 10 ng/mL increase. Adding ST2 to the base model increased the model likelihood ratio χ 2 from 12.1 to 17.3 (p = 0.02), i.e. ST2 added a fraction of 30% (12.1/17.3) of new predictive information to age, HCT-CI and conditioning intensity. However, the ability of the full model to discriminate cases of NRM at 1-year remained poor with minimal improvement after adding ST2 (AUC up to 0.675 from 0.674 in the base model). The bootstrap-corrected AUC (the expected AUC of the full model used in a new population) was 0.63. Moreover, bootstrap-corrected estimates of predicted vs. observed risk revealed slight model miscalibration: lower predicted risks were generally underestimated, while higher predicted risks were overestimated (Figure Panel B). Conclusion: Pre-transplantation plasma levels of ST2 was a prognostic biomarker of 1-year NRM after allo-HCT, adding new predictive information to age, HCT-CI and conditioning intensity. However, internal validation of the full ST2-based prediction model revealed poor overall performance, precluding further validation and use of the model in clinical practice. When identifying prognostic biomarkers, investigation of overall predictive performance (in addition to already known prognostic factors) is needed before clinical usefulness can be evaluated. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) yet the major cause of death remains relapse after transplantation which occurs in 30-70% of patients for whom the prognosis is dismal. Since the 1990's donor lymphocyte infusion (DLI) has been proven able to induce remission after allo-HSCT and the use of therapeutic DLI at relapse has widely increased. The immunological mechanism in DLI is primarily T-cell-mediated graft-versus-leukemia (GVL) effect driven by genetic differences between donor and recipient in minor and major histocompatibility antigens. DLI treatment at relapse can additionally reverse T-cell exhaustion and increase T-cell receptor diversity, both of which are GVL-enhancing mechanisms. Risks and complications with DLI-treatment are primarily graft-versus-host disease (GVHD). Though dose escalation schedules have been suggested to increase the GVL-effect while minimizing the risk of GVHD, uniform therapeutic algorithms are still lacking, treatment is often individually scheduled, and outcome results are often disappointing with reported 2-year overall survival rates at 14-29% in AML relapse patients (Greiner J, Götz M, Bunjes D, Hofmann S, Wais V. Immunological and Clinical Impact of Manipulated and Unmanipulated DLI after Allogeneic Stem Cell Transplantation of AML Patients. J Clin Med. 2019;9(1):39). During the last decade, treatment with the hypomethylating agent azacitidin (Aza) has become another potential treatment in patients with myeloid malignancies. Immunological mechanisms of GVL in Aza-treatment for relapse include epigenetically reactivation of pro-apoptotic pathways and demasking of tumor-antigens while increased expression of regulatory T-cells protects from GVHD. In recent years DLI and Aza have been used for synergistical effect post-HSCT relapse both in patients who are un-fit to receive high-dose cytoreductive therapy as well as consolidation after reinduction. The aim of this analysis is to report results of retrospective single center-study of patients treated with DLI +/- Aza over a period of twenty years. Methods: Between 2001 and 2020 50 adult patients with relapse after allo-HSCT for AML(n=38) or MDS (n=12) were treated with DLI at the Department of Hematology, Transplant Unit, at Rigshospitalet, Copenhagen University Hospital, table 1. Only patients free from active GVHD were selected as DLI-candidates. Median follow-up time was 57 (1-170) months. Reinduction with high-dose chemotherapy was administered in 35 (70%) of patients prior to DLI and 34 (68%) patients were in complete morphological remission (CR) before DLI. DLI-products were unmanipulated and obtained from leukapheresis of unstimulated peripheral blood in matched related or unrelated donors of the original stem cell graft. Patients received a median of 3 (1-5) doses of DLI with median total doses of 6,1x10 7 (5x10 6- 4,65x10 8) CD3 postive T-cells per kg. Aza was used together with DLI from 2012 and administrered in 28 (56%) patients with a median of 6 (2-20) cycles. Reported outcomes are overall survial (OS) and relapse-free survival (RFS) in patients in CR prior to DLI. Results: At end of follow-up 20 patients were alive, 11 of these in CR and 2 in partial remission. In 7 patients, DLI was discontinued due to the development of GVHD after 1-2 doses, 6/7 of these patients had unrelated donors. Overall, 2 (4%) patients died from GVHD after DLI. Seven patients received a second HSCT after DLI treatment and were censored at this date in survival analyses. Figure 1a+b shows OS in all patients (n=50) and RFS in patients in CR prior to DLI (n=34). 2-year OS was approximately 59% and 5-year OS was 20%. 2-year RFS was approximately 32% and 5-year RFS was 8%. None of the analyzed baseline factors showed significant associations to the probability of OS, table 2, or RFS (data not shown). Reinduktion before first DLI and increasing doses of transplanted CD3 T cell per kg showed trends towards superior survival probability but failed to reach significant levels, possibly due to the limited patient number. Conclusion: Treatment vith DLI +/- Aza is effective and safe as relapse-treatment after allo-HSCT in myeloid diseases. In selected patients, a short-term (2-year) overall survival of 59% is achieved, and 20% of the patients remain long term survivors. Figure 1 Figure 1. Disclosures Fischer-Nielsen: A.F.N. is employee and shareholder of StemMedical A/S, a biotech company working with cell-enriched fat grafting.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

IPSS-R is a well established prognostic factor for transplant outcome in patients with MDS, irrespective whether it is assessed at diagnosis or at transplant. However it is unclear how a change in IPSS-R, e.g. by reducing bone marrow blasts through therapy, would potentially affect transplant results. In particular the decision to treat patients before transplant or perform an upfront allogeneic transplantation can so far not be based on evidence. We did a registry search based in the MDS quality initiative conducted by EBMT to identify transplanted patients with MDS and sufficient data to calculate IPSS-R at diagnosis and before transplant. The search was limited to patients reveiving a first allogeneic stem cell transplantation in the period 2005 -2018. 1482 patients were identified. Median age at alloHCT was 59 (interquartile range 51-64) years, 60% were male. Donors were related in 36%, graft source was PBSC in 85% of cases. Conditioning was standard dose in 33% and reduced intensity in 67%. IPSS-R both at diagnosis and at transplant had a significant impact on OS and RFS after alloHCT. To investigate the effect of a change in IPSS-R between diagnosis and transplant we constructed 3 subgroups: stable IPSS-R, improved IPSS-R, worsened IPSS-R. A change in IPSS-R was noted in 77.5% of patients with prior chemotherapy, 72% with prior HMA and 59.8% of untreated patients. Univariate analysis showed no significant difference in OS or RFS in patients with stable IPSS-R compared to improved or worsened IPSS-R. In patients treated with chemotherapy before transplant OS and RFS was significantly worse with worsened IPSS-R, while this effect was not found in patient treated with hypomethylating agents (HMA) or untreated patients. The same analysis was performed regarding the difference in bone marrow blasts and the cytogenetics score: OS and RFS after transplant were significantly worse with increased blasts (p=0.04 and p=0.001) and a worsened cytogenetic score before transplant (both p In this retrospective analysis from a large cohort of patients with MDS we found that worsening of IPSS-R, blast count or cytogenetic score had a negative prognostic impact in chemotherapy-treated patients, while only worsened blast count and cytogenetics were significant negative factors in HMA-treated or untreated patients. Conversely we did not find a positive effect of improved IPSS-R, decreased blasts or improved cytogenetics in any of the subgroups of treated or untreated patients. Thus for MDS patients receiving an allogeneic transplantation our results provide no clear signal that prior therapy is able to improve transplant outcome. Disclosures Scheid: Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding. Blaise:Jazz Pharmaceuticals: Honoraria. Chevallier:Incyte Corporation: Honoraria. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria.

Early immune reconstitution plays a critical role in clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Natural killer (NK) cells are the first lymphocytes to recover after transplantation and are considered powerful effector cells in HSCT. We aimed to evaluate the clinical impact of early NK cell recovery in T cell–replete transplant recipients. Immune reconstitution was studied in 298 adult patients undergoing HSCT for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome from 2005 to 2013. In multivariate analysis NK cell numbers on day 30 (NK30) > 150 cells/µL were independently associated with superior overall survival (hazard ratio, .79; 95% confidence interval, .66 to .95; P = .01). Cumulative incidence analyses showed that patients with NK30 > 150 cells/µL had significantly less transplant-related mortality (TRM), P = .01. Patients with NK30 > 150 cells/µL experienced significantly lower numbers of life-threatening bacterial infections as well as viral infections, including cytomegalovirus. No association was observed in relation to relapse. These results suggest an independent protective effect of high early NK cell reconstitution on TRM that translates into improved overall survival after T cell–replete HSCT.

Introduction The only curative treatment approach for patients with myelodysplastic syndromes (MDS) 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 MDS-relapse after transplantation. Similar to the data available in MDS-patients not undergoing HSCT (Schanz et al. J Clin Oncol 2012), there is evidence that the novel 5-group cytogenetic classification has a better predictive value for outcome after HSCT than standard IPSS cytogenetics (Deeg et al. Blood 2012). The aim of this large multicentric, international study was to retrospectively determine the impact of the new 5-group cytogenetic MDS classification on outcome after HSCT. Patients and Methods Patients were selected from the EBMT database who had received HSCT for the treatment of MDS between 1982 and 2010 and for whom sufficient cytogenetic information was available. In total, 903 patients were included into the study. At time of HSCT, 97 (10.7%) patients had untreated MDS, 218 (24.1%) patients had advanced MDS or AML evolving from MDS in complete remission, and 227 (25.1%) patients were not in remission after treatment (in 12.3% information on stage of the disease was not available). Median time between diagnosis and transplant was 6.6 months (range 0.2-359.3). Matched related donor HSCT was performed in 574 patients (63.6%), and matched unrelated donor HSCT in 329 patients (36.4%). Bone marrow (35.4%) or peripheral blood (64.6%) served as stem cell graft. Myeloablative preparative regimens were used in 582 patients (64.5%), and a non-myeloablative regimen was given to 320 patients (35.4%). Impact of cytogenetic classification was analyzed in uni- and multivariate models regarding overall survival (OS) and relapse free survival (RFS) after HSCT. Predictive performance of the 2 classifications was compared by means of the cross-validated log partial likelihood. Results Estimated 5-year RFS and OS were 32% and 36% respectively. According to the 5-group cytogenetic classification 19 (2.1%) patients had very good risk cytogenetics, 204 (22.6%) normal risk cytogenetics, 438 (48.5%) intermediate risk cytogenetics, 178 (19.7%) poor risk cytogenetics, and 64 (7.1%) very poor risk cytogenetics. Good, intermediate, and poor risk cytogenetics according to IPSS were found in 192 (38.0%), 500 (40.2%), and 211 (23.7%) patients, respectively. In univariate analysis 5-group cytogenetic information was found to be strongly associated with OS and RFS (OS: log-rank test P

Introduction Myeloproliferative Neoplasm (MPN) unclassifiable (MPN-U), is a heterogeneous disease that presents with an MPN-type clinical/ histological phenotype yet fails to meet diagnostic criteria for other MPN entities. Incidence is Methods This registry-based analysis was approved by the Chronic Malignancies Working Party of the EBMT. Patient selection was performed by identifying adult patients who underwent first allo-HCT for MPN-U between 2000-2015, using either Reduced Intensity Conditioning (RIC) or Myeloablative conditioning (MAC) as defined by standard EBMT criteria. Further data collection requests (MED-C) forms were sent to centres to improve data completeness. Statistical analyses were performed with SPSS 22 (SPSS Inc./IBM, Armonk, NY) and R. Overall Survival (OS) was calculated from the date of transplant until death or last observation alive. Cumulative incidence functions were used to estimate Non-Relapse Mortality (NRM) and Relapse Incidence (RI) within a competing risk setting. Results A total of 70 patients, 48 (69%) male and 22 (31%) female, with a confirmed diagnosis of MPN-U were analysed. Median age was 57 years (range (r), 22-70 years). Of these patients, 37 (53%) underwent allo-HCT in the period 2001-2010 and 33 (47%) between 2011-2015. MAC regimens were utilised in 31 (44%) patients while 39 (56%) received RIC. Patients were most frequently transplanted within the first two years from diagnosis, with a median time to allo-HCT of 13 months (r, 3-244 months). Diagnostic karyotype was normal in 36 (51%) and abnormal in 23 (33%) patients, with data missing for 11 (16%) patients. A total of 45 (64%) patients had received prior treatment, 23 (33%) patients were untreated and data was incomplete in 2 (3%) patients. Regarding donor type, 27 (39%) patients had a Matched Sibling Donor (MSD) and 43 (61%) an Unrelated Donor (URD). Most frequent conditioning regimens were TBI-based in the MAC cohort and Fludarabine-Busulphan in the RIC cohort. A trend towards higher rates of delayed/failed engraftment was noted in the RIC compared to MAC cohort (p=0.09). Where successful, median time to neutrophil engraftment in both cohorts was similar (18 days for MAC and 17 for RIC) and both platforms demonstrated similar platelet engraftment times (17.5 days). Incidence of grade II-IV aGVHD at 3 months was higher in the MAC (37%) compared to RIC cohort (16%; p=0.05) and the 12-month cumulative incidence of cGVHD for MAC was 52% (95%CI: 32.4, 71.6) and for RIC 32.1% (95%CI: 14.8, 49.4; p=0.117)). Median follow-up was 87 months (minimum and maximum of censored cases: 31 and 196 months). The median OS estimates at 1, 3 and 5-year were 77%, 55% and 42% (MAC) and 59%, 44% and 41% (RIC), respectively (p=0.33). No significant difference existed in OS rates between those who had pre-transplant therapy versus not. Relapse remained significant: cumulative incidences of relapse at 1,3 and 5-years were 10%, 23% and 27% (MAC) and 28%, 36% and 36% (RIC), respectively (p=0.28). NRM probabilities at 1, 3 and 5-years post allo-HCT were also considerable: 19%, 29%, and 34% (MAC) and 28%, 28% and 28% (RIC), respectively (p=0.84). Main causes of NRM were infection and GVHD. Univariate analysis associated use of an URD with a significantly worse OS and NRM compared with MSD. Moreover, the presence of abnormal karyotype at time of allo-HCT was associated with a trend towards a higher risk of relapse (p=0.06). Conclusions This study highlights the potentially curative role of allo-HCT in MPN-U and provides clinicians with robust engraftment, GVHD and outcome data. Both engraftment and OS rates appear acceptable yet NRM and CIR rates in both settings remain high and need to be addressed. The impact of abnormal karyotype at the time of allo-HCT and a trend towards higher risks of relapse requires further elucidation. Disclosures McLornan: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Robin:Novartis Neovii: Research Funding. Chalandon:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte Biosciences: Consultancy, Honoraria. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Kröger:Sanofi-Aventis: Honoraria; Riemser: Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Medac: Honoraria; JAZZ: Honoraria; DKMS: Research Funding; Celgene: Honoraria, Research Funding. Milojkovic:Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Hernandez Boluda:Incyte: Other: Travel expenses paid.

Introduction: The only curative treatment for myelofibrosis (MF) remains allogenic haematopoietic cell transplantation (allo-HCT) although the risks of non-relapse mortality (NRM), relapse and graft rejection need to be taken into consideration. Therapeutic approaches following relapse after allo-HCT include symptom-directed management, chemotherapy, JAK2 inhibitors, adoptive immunotherapeutic approaches with donor lymphocyte infusion (DLI) and, in a minority, a second allo-HCT. Frequently, due to the advanced age of the recipient, early relapses, and numerous complications, 2nd allo-HCT can only be considered in a limited number of patients. Few studies evaluating the role of 2nd allo-HCT in MF following 1st relapse or primary/secondary graft rejection have been published to date. Methods and results: Patient selection was performed by identifying adult patients who underwent 2nd allo-HCT for MF between 2010-2017: 216 patients were analyzed; 64% were male, 78% had primary MF (PMF) and 22% secondary MF (sMF). Median age at the time of 2nd allo-HCT was 57 years, and median time from 1st allo-HCT was 8 months. Of this cohort, 56% of patients received a 2nd allo-HCT for relapse, 31% for graft failure and the reason was missing in 13%. A greater proportion was transplanted within 1 year from 1st allo-HCT (61 %) whilst 39% had 2nd allo-HCT > 1 year. A reduced Karnofsky performance status (KPS12 months, p=0.02). The 2-year relapse-free-survival (RFS) for the entire cohort was 44%. Only time elapsed from the 1st allo-HCT to 2nd was significantly associated with 2-year RFS (41% for ≤12 months, 49% for >12 months, p=0.05). Of note, the 2-year OS and RFS were comparable following use of the same or a different donor. The 2-year cumulative incidence of relapse and NRM were 22 and 34%, respectively. The time interval from 1st to 2nd allo-HCT appeared to be highly significant for NRM with patients transplanted ≤12 months having a higher 2-year NRM compared to those transplanted >12 months (40 vs 24%, respectively, p=0.008). A trend for higher NRM was the reason for 2nd allo-HCT: patients transplanted for graft rejection had a 2-year NRM of 45% compared to 31% for those with relapse (p=0.06). Conclusions: This analysis supports the utilization of a 2nd allo-HCT for patients with MF who have presented with graft failure or relapse following a 1st allo-HCT. In univariate analysis, overall outcome appears worse in patients being transplanted after graft failure as well as for those transplanted within 1 year after 1st allo-HCT, due to increased NRM. Of note, the use of either the original or a different donor are associated with similar outcomes. Further work is required to elucidate other risk factors, GVHD rates and to define the optimal conditioning regimen in this setting. Table. Disclosures Robin: Novartis Neovii: Research Funding. Kröger:Sanofi-Aventis: Honoraria; Riemser: Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Medac: Honoraria; JAZZ: Honoraria; DKMS: Research Funding; Celgene: Honoraria, Research Funding. Angelucci:Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC; Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol. Dreger:AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Neovii, Riemser: Research Funding. Platzbecker:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Rambaldi:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Ladetto:ADC Therapeutics: Honoraria; Pfizer: Honoraria, Speakers Bureau; Celgene: Honoraria; J&J: Honoraria; Roche: Honoraria; AbbVie: Honoraria; Acerta: Honoraria, Speakers Bureau. Hernandez Boluda:Incyte: Other: Travel expenses paid. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria. Chalandon:Incyte Biosciences: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Purpose: We assessed the impact of donor type in acute myeloid leukemia (AML) patients transplanted with 2 Gy total body irradiation (TBI)-based nonmyeloablative conditioning regimen. Patients and Methods: Data from 1,715 adult patients, with AML in CR1 or CR2 were included in this retrospective survey. Results: Donors consisted either of HLA-matched sibling donors (MSD, n = 701), 10/10 HLA-matched unrelated donors (MUD, n = 611), HLA-haploidentical donors (haplo, n = 112) or single or double umbilical cord bloods (CBT, n = 291). Chronic graft-versus-host disease (GVHD) was less frequent in CBT (28%) and in haplo (30%) patients than in MSD (50%) and MUD (51%) recipients (P < 0.001). Two-year incidence of relapse was 32%, 30%, 34%, and 34% in MSD, MUD, CBT and haplo patients, respectively (P = 0.7). Two-year overall (OS) and GVHD-free relapse-free survival (GRFS) were 59% and 29% in MSD patients, 56% and 39% in CBT recipients, 53% and 23% in MUD recipients, and 43% and 37% in haplo patients, respectively. In multivariate analyses, MUD patients had lower GRFS than MSD patients beyond day 100 (HR 1.3, P = 0.001) while CBT was associated with a better GRFS than MSD beyond day 100 (HR 0.6, P = 0.002). Conclusions: In this large cohort of AML patients transplanted following low-dose TBI-based conditioning, the relapse incidence was not affected by donor type suggesting that the intensity of GVL effects might be comparable with these four transplant approaches. Furthermore, CBT was associated with better GRFS beyond day 100 than MSD while the opposite was observed for MUD. Clin Cancer Res; 24(12); 2794–803. ©2018 AACR.

Background Allogeneic haematopoietic stem cell transplantation (alloHSCT) is considered a standard treatment for patients with Philadelphia chromosome–positive acute lymphoblastic leukaemia (Ph+ ALL) achieving complete remission after induction containing tyrosine kinase inhibitors (TKIs). Methods We retrospectively compared results of myeloablative alloHSCT from either matched sibling donor (MSD) or unrelated donor (URD) with autologous (auto) HSCT for adults with Ph+ ALL in molecular remission, treated between 2007 and 2014. Results In univariate analysis, the incidence of relapse at 2 years was 47% after autoHSCT, 28% after MSD-HSCT and 19% after URD-HSCT (P = 0.0002). Respective rates of non-relapse mortality were 2%, 18%, and 22% (P = 0.001). The probabilities of leukaemia-free survival were 52%, 55% and 60% (P = 0.69), while overall survival rates were 70%, 70% and 69% (P = 0.58), respectively. In multivariate analysis, there was a trend towards increased risk of overall mortality after MSD-HSCT (hazard ratio [HR], 1.5, P = 0.12) and URD-HSCT (HR, 1.6, P = 0.08) when referred to autoHSCT. The use of total body irradiation (TBI)–based regimens was associated with reduced risk of relapse (HR, 0.65, P = 0.02) and overall mortality (HR, 0.67, P = 0.01). Conclusion In the era of TKIs, outcomes of myeloablative autoHSCT and alloHSCT for patients with Ph+ ALL in first molecular remission are comparable. Therefore, autoHSCT appears to be an attractive treatment option potentially allowing for circumvention of alloHSCT sequelae. Irrespective of the type of donor, TBI-based regimens should be considered the preferable type of conditioning for Ph+ ALL.

International audience; Usually, after double umbilical cord blood transplantation (DUCBT), only 1 of the transplanted units persists in the long term. The characteristics of the winning cord blood unit (W-CBU) that determine unit dominance and how they influence the outcomes of DUCBT remain unclear. We retrospectively analyzed 347 patients with acute leukemia transplanted with a DUCBT (694 CBU) from 2005 to 2013 who had documented neutrophil engraftment and a W-CBU identified by chimerism analysis, to identify unit characteristics impacting on dominance. Median age at DUCBT was 40 years and median follow-up was 35 months. Among W-CBUs, 41% were ≥5/6 HLA matched to the recipient and 59% were ≤4/6. Multivariate analysis indicated that ≤4/6 HLA-matched W-CBUs led to lower leukemia-free survival (44% versus 56%; hazard ratio [HR], 1.5; P = .032) and overall survival (49% versus 62%; HR, 1.5; P = .028), increased nonrelapse mortality (26% versus 18%; HR, 1.9; P = .027), and acute graft-versus-host disease (46% versus 35%; HR, 1.7; P = .013). We were unable to predict unit dominance, but we demonstrated that outcomes were strongly influenced by the degree of HLA mismatch between W-CBU and recipient. Therefore, selection of both units with the lower number of HLA mismatches with the recipient is indicated.

We analyzed 661 adult patients who underwent single-unit (n = 226) or double-unit (n = 435) unrelated cord blood transplantation (UCBT) following a reduced-intensity conditioning (RIC) consisting of low-dose total body irradiation (TBI), cyclophosphamide, and fludarabine (Cy/Flu/TBI200). Eighty-two patients received rabbit antithymocyte globulin (ATG) as part of the conditioning regimen (ATG group), whereas 579 did not (non-ATG group). Median age at UCBT was 54 years, and diagnoses were acute leukemias (51%), myelodysplastic syndrome/myeloproliferative neoplasm (19%), and lymphoproliferative diseases (30%). Forty-four percent of patients were transplanted with advanced disease. All patients received ≥4 antigens HLA-matched UCBT. Median number of collected total nucleated cells was 4.4 × 10(7)/kg. In the ATG group, on 64 evaluable patients, ATG was discontinued 1 (n = 27), 2 (n = 20), or > 2 days before the graft infusion (n = 17). In multivariate analyses, the use of ATG was associated with decreased incidence of acute graft-versus-host disease (hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.17-0.55; P < .0001), higher incidence of nonrelapse mortality (HR, 1.68; 95% CI, 1.16-2.43; P = .0009), and decreased overall survival (HR, 1.69; 95% CI, 1.19-2.415; P = .003). Collectively, our results suggest that the use of ATG could be detrimental, especially if given too close to graft infusion in adults undergoing UCBT following Cy/Flu/TBI200 regimen.

BACKGROUND The objective of the current study was to investigate the role of postremission consolidation chemotherapy before reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (alloSCT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). METHODS Of the 789 consecutive patients with AML in CR1 who underwent RIC alloSCT from a human leukocyte antigen-matched sibling or matched unrelated donor peripheral stem cell grafts between 2001 and 2010, 591 patients received at least 1 cycle of consolidation chemotherapy and 198 patients did not receive any consolidation chemotherapy before alloSCT. To minimize inherent survival bias in favor of patients who underwent transplant long after achieving CR1, the study focused on 373 patients who underwent transplant within the median time frame between achievement of CR1 and alloSCT (3 months for patients who underwent alloSCT from matched siblings and 4 months for patients who underwent alloSCT from matched unrelated donors). In this subgroup, 151 patients did not receive any consolidation chemotherapy and 222 patients received ≥ 1 consolidation chemotherapy cycle. RESULTS With a median follow-up of 36 months (range, 2 months-135 months), the 3-year cumulative recurrence incidence (RI) was not significantly different between the groups (36% ± 4% for the group treated without consolidation chemotherapy vs 38% ± 3% for patients who received consolidation chemotherapy; P = .89). In addition, leukemia-free survival was similar between the groups (45% ± 4% and 47% ± 3%, respectively; P = .41). Dose intensity of cytarabine given during consolidation chemotherapy appeared to have no influence on RI. On multivariate analysis, pretransplant consolidation (≥ 1 cycle vs 0 cycles) was found to have no significant impact on RI (hazards ratio, 1.29; 95% confidence interval, 0.84-1.97 [P = .24]) or leukemia-free survival (hazards ratio, 1.00; 95% confidence interval, 0.71-1.42 [P = .99]). CONCLUSIONS The data from the current study suggest no apparent advantage for postremission consolidation chemotherapy before RIC alloSCT, provided a donor is readily available. Cancer 2014;120:855–863. © 2013 American Cancer Society.

Introduction: The role of T cell receptor (TCR) γδ cells in allogeneic hematopoietic stem cell transplantation (HSCT) is becoming of increasing interest1,2. In contrast to conventional alloreactive TCR αβ cells, TCR γδ cells are believed to have anti-tumor effects without causing graft-versus-host disease (GVHD). We conducted a single-center, prospective study to assess the impact of early TCR γδ cell immune reconstitution on overall survival, relapse and acute GVHD after HSCT. Methods: From October 2015 to March 2017, 108 consecutive patients transplanted for malignant diseases at the Bone Marrow Transplant Unit, Department of Hematology, Copenhagen University Hospital, Rigshospitalet, were included in the study, table 1. Fresh blood samples days 28, 56, 91, 180 and 360 after transplantation were analyzed for absolute concentrations of CD3-, CD4- and CD8 positive T cells together with a multi-color flow cytometry panel with staining for TCRαβ, TCRγδ, Vδ1, Vδ2, CD3, CD4, CD8, HLA-DR, CD196, CD45RO, CD45RA, CD16, CD56, CD314 (NKG2D) and CD337 (NKp30) for immune phenotyping. Results: After a median of 673 (386-913) days, 28 (26%) patients had died from relapse (n=14) and from transplant-related-mortality(n=14), respectively. A total of 24 (22%) patients experienced relapse during the observation time with median time to relapse of 177 (56-778) days. Acute GVHD grade 2-4 was diagnosed in 38 (35%) of patients. Patients were divided into two groups by dichotomization at the median value of TCR γδ cell concentrations for Kaplan-Meier analyses of overall survival (OS), relapse-free survival (RFS) and cumulative incidence analyses (Gray's test for competing risks) of relapse and acute GVHD. Patients with high concentrations of TCR γδ cells 56 days after transplantation had significantly higher OS and RFS compared with patients with low concentrations, p Conclusion: The results of this prospective study suggest a protective effect of early robust TCR γδ cell immune reconstitution on relapse and acute GVHD resulting in increased OS after HSCT, and support further research in adoptive TCR γδ cell therapy in transplant patients. Handgretinger, R. & Schilbach, K. The potential role of gd T cells after allogeneic HCT for leukemia. Blood131, 1063-1072 (2018). Scheper, W., Grunder, C., Straetemans, T., Sebestyen, Z. & Kuball, J. Hunting for clinical translation with innate-like immune cells and their receptors. Leukemia28, 1181-1190 (2014). Disclosures No relevant conflicts of interest to declare.

The introduction of tyrosine kinase inhibitors (TKIs) to treat chronic myelogenous leukemia (CML), has largely replaced curative strategies based on allogeneic hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT continue to be recommended for patients progressing to a more advanced phase of the disease and those in first chronic phase (CP1) failing second and third generation TKIs. Although the role of allogeneic HSCT using matched related or unrelated donor remains well established in the post-TKI era, controversies exist in transplant using alternative donors, and data in this setting is scarce. Umbilical cord blood (UCB) can be used as an alternative stem cell source for patients in whom allogeneic HSCT is indicated, but lack an appropriate human leucocyte antigen (HLA)-matched adult donor. The advantages of UCBT include rapid availability, absence of donor risk, and the relatively lower risk of GVHD with preserved graft versus leukemia effect. Because of the lack of large studies on the outcome of UCBT for CML patients in the TKI era, we performed a retrospective analysis to identify risk factors for outcomes after unrelated cord blood transplants in adults with CML. Through the EBMT database, 150 CML patients were identified as UCBT recipients. Median year of UCBT was 2008 (range, 2000 to 2015) with a median follow up of 62.2 months (range, 3 to 203.1 months). Median age at the time of transplant was 40.4 years (range, 18.8 to 66.5) with a male to female ratio of 92/58. The median time from CML diagnosis to UCBT was 29.9 months (range, 3.4 to 273.6) with first (Q1) and third (Q3) quartile at 12.4 and 57.3 months respectively. Eleven patients received an UCBT as a second allogeneic HSCT. Conditioning regimen was of reduced intensity (RIC) in 44 patients while 92 received a myeloablative conditioning (MAC), and 61 out of 128 evaluable patients received T-cell depletion. Disease status at the time of transplant was first chronic phase (CP1, n=45), second or third chronic phase (CP2 and CP3, n=48) or advanced phase (accelerated phase or blastic phase, AP/BP, n=55). Overall survival (OS) at 12, 24 and 36 months were 52.1% (95% CI 44.0 to 60.1%), 44.5% (95% CI 36.3 to 52.6 %) and 41.2% (95% CI 33.0% to 49.4%) respectively. Median time to neutrophil and platelet engraftment were 23 and 47 days respectively in 119 patients who engrafted, while 24 and 7 patients experienced primary (16%) or secondary (4.6%) graft failure respectively. At 24 months, the cumulative incidence of non-relapse mortality (NRM) and relapse were 38.9% (95% CI 31.0 to 46.9%) and 25.3% (95% CI 18.2% to 32.3%), while cumulative incidence of grade 2-4 acute GvHD was 34.3% (95% CI 26.1 to 42.5%) and 24 months cumulative incidence of chronic GvHD was 24.8% (95% CI 15.6 to 34.0%). OS and disease-free survival (DFS) were significantly reduced for patients in AP/BP at the time of transplant compared to patients in CP1 or CP2/CP3 (24 months OS, 27.1% vs 55.3% and 53.7%, p=0.0026; 24 months DFS, 21.5% vs 39.4% and 47.1% respectively, p=0.0059, Figure 1). Cumulative incidence of relapse was significantly increased in patients in AP/BP at the time of HSCT compared to patient in CP1 or CP2/3 (24 months relapse incidence of 37.6% vs 20.6% and 17.1% respectively, p=0.0178). There was no significant difference in OS and DFS in patients receiving RIC compared to MAC (24 months OS 47.1 and 48.1% respectively, p=0.8; 24 months DFS 33% vs 40.6%, p=0.36). Cumulative incidence of relapse at 24 months was 34.7% in RIC and 24.6% in MAC, although this was not statistically significant (p=0.14). In conclusion, UCBT is more effective in CML patients who are in first CP but also in those who are in second or third CP at the time of transplant. NRM remains high, possibly related to differences in practices of UCBT over time and between centers. Comparison with alternative graft source such as haploidentical HSCT is needed, although little data is available in this setting. Patients who are in advanced phase disease at the time of transplant have a dismal prognosis comparable to those who receive an allogeneic HSCT from HLA-matched adult donors, although pre and post-transplant intervention with 3rd generation TKI may help improve outcome of these patients. Finally the use of RIC regimen for UCBT is an alternative for patients who cannot tolerate a MAC regimen; further analysis will help identify patients who would benefit from this approach. Figure 1. Figure 1. Disclosures De Lavallade: Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Angelucci:Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Roche Italy: Other: Local (national) advisory board; Celgene: Honoraria, Other: Chair DMC; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

Umbilical cord blood transplantation (UCBT) from unrelated donor is a valid alternative for patients (pts) with acute leukemia (AL) who lack an HLA matched donor. Double UCBT (dUCBT) has extended the use of UCBT to adults. In the majority of the cases, chimerism analysis shows that one unit emerges as the sole source of long term hematopoiesis in the recipient (rcp) following dUCBT. However, no clear factor has yet been identified to reliably predict which unit will emerge as the predominant one. With the aim of analyzing factors that may predict cord blood unit (CBU) predominance and the impact of the winning CBU characteristics on outcomes after dUCBT, we studied adults with AL who underwent dUCBT as first transplant between 2004 and 2013 at EBMT centres. We selected pts who achieved engraftment and who had available chimerism data assessed within day 130 after dUCBT, with one of the CBUs representing at least 50% of the rcp hematopoiesis (winCBU). According to these criteria, 347 pts were included: 323 had full donor (18 being dual chimera) and 24 had mixed chimerism (>5% of donor cells). At diagnosis, 35% had ALL and 65% AML. At dUCBT 45% were in first complete remission (CR), 44% in second CR and 11% had more advanced disease. Overall, 33% had high risk cytogenetic features. Median time from diagnosis to dUCBT was 12 months (range, 2-202), median age was 40 years (y) (18-76). Conditioning regimen (CT) was reduced intensity (RIC) in 52%. Cyclophosphamide+fludarabine+total body irradiation was the most frequent CT (63%). Anti-thymoglobulin (ATG) was administrated in 25% of the transplants. Median number of total nucleated cells (TNC) and CD34+ cells at cryopreservation were 5.1x107/Kg (range, 2.3-13.7) and 1.3x105/Kg (range, 0.4-10.7), respectively. Considering the unit with the highest number of HLA mismatches (MMs) with the rcp, 73% of the donors were matched at 4 or less loci (≤4/6). For winCBUs, median number of TNC and CD34 cells at cryopreservation were 2.5x107/Kg (range, 0.95-6) and 1x105/Kg (range, 0.06-10), respectively. Only 4% of the winCBUs were 6/6 HLA-matched to the rcp, while 37% were 5/6, 55% were 4/6 and 4% were 3/6 HLA-matched. Overall, 54% of the winCBUs were gender matched and 38% were ABO compatible with the rcp. WinCBUs median age was 3.4 years (range, 0.2-14). As for inter unit characteristics, 50% of the pts received gender matched units. Units were ABO compatible in 40% of the cases, while 30% had minor and 30% had major ABO incompatibility. In our study population, median follow-up for survivors was 35 months (range, 3-99). All pts engrafted with neutrophil >0.5x109/L in a median time of 25 days (range, 6-66) post DCBT. No secondary graft failure was reported. The cumulative incidence (CI) of acute GvHD grade II-IV at 100 days was 41% with a median time of onset of 29 days (range, 7-106). The 3y-CI of chronic GvHD was 41% (50% of the pts had extensive). The 3y-CI of relapse (RI) and transplant related mortality (TRM) were 27% and 24%, respectively. At 3y, leukemia free survival (LFS) was 49% and overall survival (OS) was 54%. In multivariate analysis (MVA) including unit characteristics (HLA and gender matching, type of HLA MMs, number of TNC and CD34 cells at cryopreservation, ABO compatibility and unit age) and inter unit features (gender match, ABO compatibility), no significant factor predicting the winCBU was identified. Analyzing the impact of winCBU on dUCBT outcomes, the HLA matching between CBU and the rcp was the only characteristic related to the winCBU significantly affecting results. The 3y-LFS for pts with 6/6 or 5/6 HLA-matched winCBUs was 56% as compared to 44% for those with 4/6 (p=0.03), while OS was 62% versus 49% (p=0.01), respectively. Acute GvHD was increased in pts receiving a 4/6 HLA-matched winCBU (46% versus 35% for those 6/6 or 5/6, p=0.04). In MVA, 4/6 HLA-matched winCBU was associated with decreased LFS (HR 1.5, p=0.03) and OS (HR 1.5, p=0.03), and with increased TRM (HR 1.9, p=0.03) and acute GvHD (HR 1.7, p=0.01). Notably, older winCBUs (>3.4y) were associated with higher acute GvHD (48% versus 35%; HR 1.6, p=0.02). Other factors associated with poor outcomes were advanced disease status and the use of ATG. Although we failed to identified any factor predicting CBU predominance, we were able to demonstrate that a 4/6 HLA matched winCBU is associated with poor outcomes. Therefore, selecting units with lower number of HLA MMs for dUCBT may improve final outcomes. Disclosures Russell: Therakos: Other: shares. Mohty:Riemser: Honoraria, Research Funding. Nagler:Biokine LTD: Consultancy.

Abstract 2260 Poster Board II-237 Several studies have demonstrated that genetic variation in cytokine genes can modulate the immune reactions after allogeneic hematopoietic cell transplantation (HCT). High mobility group box 1 protein (HMBG1) is a pleiotropic cytokine that functions as a proinflammatory signal, important for the activation of antigen presenting cells (APC) and propagation of inflammation. HMGB1 is implicated in the pathophysiology of a variety of inflammatory diseases, and we have recently found the variation in the HMGB1gene to be associated with mortality in patients with systemic inflammatory response syndrome (SIRS). To assess the impact of the genetic variation in HMGB1 on outcome after allogeneic HCT, we genotyped 276 and 146 patient/donor pairs treated with allogeneic HCT for hematologic malignancies following myeloablative or non-myeloablative conditioning. Associations between genotypes and outcome were only observed in the cohort treated with myeloablative conditioning. Patient homozygosity or heterozygosity for the –1377delA minor allele was associated with increased risk of relapse (hazard ratio (HR) 2.11, P=0.02) and increased relapse related mortality (RRM) (P=0.03). The –1377delA minor allele has previously been associated with mortality in patients with SIRS, and although SIRS and allogeneic HCT are different entities the confirmative association of this polymorphic locus with mortality in 2 independent studies suggests that it is of pathophysiological importance. The three polymorphisms, 3814C>G, 1177G>C and 2351insT, tended to have the same effect on transplantation outcome, due to a moderate to strong linkage disequilibrium between loci. Of these three polymorphisms, patient homozygosity for the 3814C>G minor allele showed the strongest association with increased overall survival (HR 0.13, P=0.04), progression free survival (HR 0.30, P=0.05) and decreased probability of RRM (P=0.03). Patient carriage of the 2351insT minor allele reduced the risk of grade 2 to 4 acute graft versus host disease (GVHD) (HR 0.60, P=0.01), while donor carriage of the minor allele displayed a gene dosage effect, with a successive increase in risk of developing limited or extensive chronic GVHD per minor allele carried (HR 1.54, P=0.01). That patient HMGB1 genotypes were associated with outcomes dependent on primarily patient APCs, and that donor genotypes were associated with a, in part, donor APC dependent outcome, could suggest that the polymorphisms in HMGB1 influence the transcription of HMGB1 in APCs induced by the proinflammatory milieu after myeloablative conditioning, rather than the passively released from damaged cells, although these two mechanisms are not mutually exclusive. Our findings suggest that the inherited variation in HMGB1 is associated with outcome after allogeneic HCT following myeloablative conditioning. None of the polymorphisms were associated with treatment related mortality. Disclosures: No relevant conflicts of interest to declare.

SummaryUmbilical cord blood (UCB) from an human leucocyte antigen (HLA)-identical sibling can be used for transplantation of patients with malignantand non-malignant diseases. However, the low cellular content of mostUCB units represents a limitation to this approach. An option to increasecell dose is to harvest bone marrow (BM) cells from the same donor andinfuse them along with the UCB. We studied 156 children who receivedsuch a combined graft between 1992 and 2011. Median age was 7 yearsand 78% of patients (n = 122) were transplanted for non-malignant dis-eases, mainly haemoglobinopathies. Acute leukaemia (n = 26) was the mostfrequent malignant diagnosis. Most patients (91%) received myeloablativeconditioning. Median donor age was 1 7 years, median infused nucleatedcell dose was 24 4 9 10 7 /kg and median follow-up was 41 months. Sixty-days neutrophil recovery occurred in 96% of patients at a median of 17 d.The probabilities of grade-II-IV acute and chronic graft-versus-host disease(GVHD) were 19% and 10%, respectively. Four-year overall survival was90% (68% malignant; 97% non-malignant diseases) with 3% probability ofdeath. In conclusion, combined UCB and BM transplantation from anHLA-identical sibling donor is an effective treatment for children withmalignant and non-malignant disorders with high overall survival and lowincidence of GVHD.Keywords: haematopoietic stem cell transplantation, cord blood, bonemarrow.

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% (p70% 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 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 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.

on behalf of Eurocord-Netcord and the Lymphoma Working Party and the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation; International audience; We have reported encouraging results of unrelated cord blood transplantation for patients with lymphoid malignancies. Whether those outcomes are comparable to matched unrelated donor transplants remains to be defined. We studied 645 adult patients with mature lymphoid malignancies who received an allogeneic unrelated donor transplant using umbilical cord blood (n=104) or mobilized peripheral blood stem cells (n=541) after a reduced-intensity conditioning regimen. Unrelated cord blood recipients had more refractory disease. Median follow-up time was 30 months. Neutrophil engraftment (81% vs. 97%, respectively; P

WM is an indolent lymphoma that has benefited from the introduction of novel agents with the achievement of higher response rates. However, WM remains incurable with conventional treatment. In addition, patients with high risk disease have either transient short lived responses or are refractory to conventional treatments. Although international treatment recommendations suggest considering allo-SCT in late relapses or in refractory younger patients, the place and timing of allo-SCT in the treatment algorithm of WM remains unclear. The aim of the present study was to analyse the long-term outcome of allo-SCT in WM. Patients and methods: Eligible for this retrospective study were patients aged 18 years or older who had a first reduced intensity (RIC) or myeloablative (MAC) conditioning allo-SCT (10/10 matched donor, sibling or unrelated) for WM between 2001 and 2013 and were registered with the EBMT. Baseline patient, disease and transplant data were collected from MED-A forms. Centers were requested to provide additional diagnostic, treatment and follow-up information. Statistical analysis used log rank test to assess the impact of baseline characteristics on survival endpoints. In multivariate analysis, prognostic factors for survival were estimated using Cox regression models and for relapse incidence (IR) and non-relapse mortality (NRM) by Fine and Gray models. Results: 260 patients (72% male) fulfilling the inclusion criteria of this study were identified in the database. The median age was 52 (range 19-72) years. Disease status at allo-SCT was sensitive in 78% and refractory in 22% of the patients. Conditioning was reduced-intensity (RIC) in 66%, with PBSC (92%) being the predominant stem cell source (bone marrow 7%, cord blood 1%). Patients receiving RIC were significantly older and had a longer interval between diagnosis and transplant but were otherwise comparable to patients with myeloablative conditioning (MAC). Donors were related in 65% and unrelated in 35% of the transplants. The median number of treatment lines prior to alloSCT was 3. Pretreatment details were available for 118 patients. Of these, first-line treatment was alkylator-based in 80%, purine analogue (PA)-based in 17%, and contained rituximab in 23%; for 2nd-line treatment, these figures were 50%, 36%, and 34%; and for 3rd-line treatment 41%, 32%, and 44%. Less than 10% of the patients had received bortezomib or imide-based regimens in any pretreatment line. At 100 days the cumulative incidence of acute graft versus host disease (aGVHD) grade I-II was 35%, and grade III-IV was 12%. At 2 years the cumulative incidence of chronic GVHD (cGVHD) was 41%. The development of cGVHD did not significantly impact on any outcome on a landmark analysis. After a median follow-up for living patients of 57 months (IQR 31-97), 5-year NRM, IR, progression-free survival (PFS) and overall survival (OS) were 29%, 24%, 47% and 55%. Risk factor analyses considering age, sex, performance status (PS), disease status, pretreatment lines, rituximab exposure, year of transplant, donor, and conditioning identified PS for NRM, disease status for IR, and PS and MAC for OS as significant predictors of an adverse outcome after multivariable adjustment. Although RIC patients tended to have a lower NRM and a better PFS than MAC patients, this was not statistically significant, suggesting that RIC patients had a better survival after relapse. 45 patients were treated with donor lymphocyte infusions (DLI) and results of DLI were reported in 22 patients. Of these, a response was observed in 60%, which was complete in 55%. Conclusions: This large study demonstrates that allo-SCT can effectively induce long-term disease control in heavily pre-treated patients with WM, suggesting that graft-versus-lymphoma effects are active and stable in WM. Accordingly, DLI seems to be a promising treatment option in case of post-transplant disease recurrence. Additional studies are needed to elaborate the place of allo-SCT in the treatment algorithm of WM in the era of novel agents. Disclosures No relevant conflicts of interest to declare.

Introduction: Allogeneic stem cell transplantation (SCT) remains a treatment option for patients with chronic myeloid leukemia (CML) that fail to respond to tyrosine kinase inhibitors (TKI). While the use of Imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second generation TKI (2GTKI). We present the results of a prospective non-interventional study (NIS) performed by the European Group for Blood and Marrow Transplantation (EBMT) of all consecutive allogeneic SCT for patients diagnosed with CML from 2009 to 2013. Methods: A prospective follow up of pre and post-transplant data was carried out by the EBMT Leiden office, including TKI therapy data, MED-B and a specific MED-C post transplant data. A total of 94 EBMT centers from 32 countries included 437 patients. Results: We present the results of the 383 patients that fulfilled all the inclusion criteria and had median follow-up of 37 months (1-77). The median age was 45 years (18-68) and 251 (65%) were males. Disease status at the start of 2GTKI was: First chronic phase - CP1 (123, 46%), Accelerated phase or >CP1 (67, 25%) and blast crisis (75, 28%). The choice of 2GTKI was: Dasatinib (155, 40%), Nilotinib (64, 17%) and a sequential combination of Dasatinib/Nilotinib with or without Bosutinib/Ponatinib (164, 43%). In addition, 29% of patients that received Dasatinib were in CP1 at the start of 2GTKI and at the time of SCT compared with 45% at the start and 40% at SCT for patients treated with Nilotinib. For patients that received both TKI in sequential combination, 63% were in CP1 at the start of 2GTKI but only 46% reached the SCT in CP1. Overall disease status at SCT was CP1 in 139 patients (38%), AP in 163 (45%) and BC in 59 (16%). The median interval from diagnosis to SCT was 22 months (2 - 267) and the median interval between starting 2GTKI and SCT was 10 months (1 - 191). The donor was an HLA identical sibling in 130 cases (35%) and unrelated in 244 (65%). The majority of SCT were performed using PBSC (295, 77%), while 272 (71%) were myeloablative and 111 (29%) reduced intensity conditioning. The EBMT score was low (0-2) in 26 (7%), intermediate (3-4) in 216 (62%) and high (5-7) in 107 (31%). Primary graft failure (PGF) occurred in 10 (3%) cases, while the incidence of acute GVHD was 34% (95% CI 29-39) and chronic GVHD (CGVHD) was 60% at 5 years (95% CI 54-66). CGVHD occurred at a median of 5.7 months (3-61) post SCT. Other post SCT complications included veno-occusive disease of the liver (VOD) in 6 cases (2%) and severe infection in 195 (65%). There were no differences in post-transplant complications amongst the 3 different 2GTKI subgroups. Overall non-relapse mortality was 18% (95% CI 14-22) at 12 months and 24% (95% CI 19-29) at 5 years. Relapse incidence was 36% (95% CI 29-42), overall survival was 56% (95% CI 50-62) and relapse-free survival was 40% (95% CI 33-47) at 5 years. Overall survival was 67% (95% CI 59-75) at 5 years for patients in CP1. No differences in post-transplant outcomes were found amongst the 3 different 2GTKI subgroups. However, the EBMT score, performance status and disease stage at 2GTKI and at SCT were predictive of overall and progression-free survival. Discussion: This prospective study demonstrates the feasibility of performing allogeneic SCT in CML patients previously treated with 2GTKI. The rate of post-transplant complications including graft failure, VOD, infections, GVHD and non-relapse mortality seems comparable to that of patients treated with Imatinib or TKI-naïve. We observed no differences between outcomes for patients receiving Dasatinib, Nilotinib or any other combination of 2GTKI (including Bosutinib and Ponatinib) pre-SCT. However, patients receiving Dasatinib were more likely to proceed to SCT in advanced phase than in CP1. Patients in CP1 have a very good overall survival despite prior treatment with 2GTKI. Of note, even after 2GTKI, the EBMT score remains a strong predictor of overall and disease-free survival for CML patients undergoing allogeneic SCT. Disclosures Schouten: Sanofi: Consultancy; Novartis: Consultancy. de Witte:Novartis: Honoraria, Research Funding; Celgene: Consultancy; Incyte: Consultancy. Kröger:Neovii: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.