ALBERT

Description: Background: Allogeneic hematopoietic cell transplantation (alloHCT) is a complex therapy which can induce a multi-factorial cascade of complications, and potentially lead to patient death. The triggering event(s), sequence and severity of such complications can significantly differ between patients, but in many cases, a so-called "multi-organ failure" (MOF) is usually reported as the leading cause of death. However, a patient's clinical course can be very heterogeneous across and within cause-specific mortalities. Moreover, comorbidities present prior to alloHCT carry their own risks and represent additional confounding factors. Therefore, identification of the exact initial trigger or event leading to MOF in alloHCT patients is a critical step towards early intervention and improvement of patients' outcome. The goal of the current study was to establish and identify the exact cause of death in alloHCT patients where MOF was considered to be the main cause of death. Of note, we specifically focused on VOD/SOS because this life-threatening complication has a mortality exceeding 80% in severe cases, ending usually in MOF, and because VOD/SOS has subtle and dynamic evolution features which are not easy to capture, but could be potentially controlled by appropriate therapy (eg. defibrotide). Patients and Methods: For the purpose of this analysis, we randomly identified 241 adult patients (42% female; median age: 50 years; range 19-73) with acute leukemia (72% AML, 25% ALL, 3% other) allografted between 2010 and 2018 from a matched sibling (29%), unrelated (61%) or haploidentical donor (10%). All patients were reported to the EBMT registry to have died from MOF. Karnofsky score at time of alloHCT was 〉90 in 87% of patients. Seventy-three percent of patients underwent transplant in complete remission, and conditioning was myeloablative in 70%. Sixty patients (25%) received VOD/SOS prophylaxis treatment, mainly consisting of ursodiol and/or heparin. Patients' files were reviewed in detail in order to capture all early signs and symptoms which occurred prior to MOF, based on the classical Baltimore criteria, modified Seattle criteria, and/or the newly published EBMT criteria. These criteria included bilirubin levels, the presence of hepatomegaly or painful hepatomegaly, ascites, percentage weight gain, hemodynamic instability, and ultrasound/histologically proven VOD/SOS. Results: Using one or more of the above criteria defining VOD/SOS, we identified a total of 67 (28%) patients for whom VOD/SOS could be considered as the trigger for MOF and the leading cause of death. Interestingly, among these 67 patients, only 22 (33%) were originally reported by the centers as having developed VOD/SOS leading to MOF post-transplant. When comparing the group of 67 patients dying of VOD/SOS-related MOF and the remaining 174 patients dying of MOF not related to VOD/SOS (please see attached table), a multivariate regression analysis identified a significant increase in VOD/SOS incidence (odds ratio 3.9; 95%CI, 2.42-6.33; p

Description: Patients with relapsed or refractory (R/R) Hodgkin Lymphoma (HL) after first autologous stem cell transplantation (ASCT1) may be offered several therapeutic options. New agents such as brentuximab vedotin or checkpoint inhibitors have recently been approved for the treatment of these patients, however, their efficacy to provide long-term control or cure is still unknown. Thus, a significant proportion of patients are still considered candidates for a second hematopoietic stem cell transplantation, usually an allogeneic transplantation. A second ASCT (ASCT2) has historically been considered as an option only in a small group of patients so the published experience is scarce. We retrospectively evaluated the outcome of 56 adult patients (25% female/75% male) with R/R HL registered in the EBMT database who received an ASCT2 between 2005 and 2014. Planned tandem ASCT were excluded. The median age at ASCT2 was 33 years (range, 19-71) and most patients (n=46, 87%) had a Karnofsky performance score ≥80%. Forty (73%) and 9 (16%) patients were in complete remission (CR) and partial remission (PR), respectively, at day 100 after ASCT1. Twenty-six (46%) relapsed within 12 months after ASCT1. Patients received a median of 1 (0-5) treatment lines between ASCT1 and ASCT2. Of note, only 2 patients received brentuximab vedotin after ASCT1 and none of the patients in our series received checkpoint inhibitors as salvage after ASCT1. The median interval from relapse/progression to ASCT2 was 9.7 months (1.7-89.3). At the time of ASCT2, 38 (69%) patients had chemosensitive disease (20 of them CR; and 18 PR). Most patients (n=43, 77%) received BEAM as the conditioning regimen for ASCT1, whereas preparative regimens for ASCT2 were more heterogeneous (BEAM or similar in 27, 48%; CBV or similar in 8, 14%; and others in 21, 37%). The median time to neutrophil (〉0.5x109/L) and platelet (〉20x109/L) recovery after ASCT2 were 11 (IQR 9-12) and 12 (IQR 10-15) days, respectively. Best response at day 100 following ASCT2 included CR in 29 (52%) patients and PR in 7 (12%); 3 (5%) had stable disease, and 3 (5%) progressed. Twenty-nine (52%) patients are currently alive, with a median follow-up for surviving patients of 73 months (2-153). Causes of death were HL progression (n=21, 79%), ASCT2 toxicity (n=3, 11%), secondary neoplasia (n=1, 3.7%), and unknown (n=2, 7%). The 4-year non-relapse mortality (NRM) was 5% (95% CI 1-14%). The 4-year cumulative incidence of disease progression/relapse was 69% (95% CI 54-80%). The 4-year overall survival (OS) and progression free survival (PFS) were 63% (95% CI 51-77%) and 25% (95% CI 16-41%). In univariate analysis, HL relapse within 12 months of ASCT1 was associated with a worse 4-year OS (44% vs. 79%, p=0.016) and PFS (16% vs. 33%, p=0.033). Chemosensitivity at ASCT2 predicted for better outcomes (4-year OS 78% vs. 30%, p=0.002; PFS 34% vs. 6%, p=0.004). Our series is the largest thus far reported of ASCT2 for patients with R/R HL after ASCT1. NRM is lower than that observed after allogeneic transplantation in this setting; however, relapse remains a major issue, especially for patients who relapse in less than one year after ASCT. For this population, a second ASCT should not be considered, whereas ASCT2 in patients with long response duration after ASCT1 might be appropriate in selected cases. The role of ASCT2 for those patients treated with new drugs such as brentuximab vedotin and checkpoint inhibitors deserves further investigation. Disclosures Martinez: BMS: Research Funding; Takeda: Consultancy. Sureda:BMS: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria; Merck: Consultancy, Honoraria.

Description: INTRODUCTION Only half of the patients with gut predominant acute graft-versus-host disease (aGvHD) respond to first-line treatment (corticosteroids). No consensus has yet been reached on treatment in the second and subsequent lines. There are several case reports supporting the role of fecal microbiota transplantation (FMT) in the treatment of steroid-resistant GvHD. Here we present the results of FMT in one of the largest cohorts of patients with acute (a) and chronic (c) GvHD, mostly with gut manifestation. MATERIAL AND METHODS 12 patients aged 26-67 years underwent a total of 15 FMTs to decolonize the gastrointestinal tract (GI) from antibiotic-resistant bacteria (ARB). In all of them steroid resistant GvHD (2 patients with cGvHD and 10 with aGvHD) coexisted. All patients with aGvHD had GI tract involvement (median grade: 3), 7 had skin (median grade: 3) and 5 had liver (median grade: 1) GvHD symptoms. Patients with cGvHD presented progressive involvement of the skin, lungs, pericardium and eyes. FMT was performed as two infusions by nasoduodenal tube of a 100g/200 ml solution of feces, on following days. OUTCOMES The median time from aGvHD diagnosis to the first FMT treatment was 46.5 days (8-489 days). Most patients were still on steroids during FMT (median dose 0.5 mg metyloprednisolone/kg of body weight). As a result, in 10/12 patients (83%) ARB decolonization was observed. Overall response rate (ORR) in the case of aGvHD reached 58% (7/12 performed FMTs), including CR in 4/12 (33%) cases. Median duration of response to relapse or death was 168 days (10-1080 days). The majority of patients who responded to FMT (5/6, 83%) underwent the procedure in a better general condition (ECOG≤2). Severe general condition (ECOG〉 2) seemed to be related with the presence of serious complications after FMT. Both patients with cGvHD achieved stabilization or improvement of organ disease, which may be related with FMT procedure (there is no data on use FMT in cGvHD). COMPLICATIONS Among the complications of FMT with a possible cause-effect relationship there were: 1 death in close relation with FMT (respiratory failure in the course of pneumonia), 3 septic episodes, 2 subileus episodes and one case of diarrhea. In the latter case, the workup revealed norovirus infection originating from the fecal material of the donor (who was asymptomatic). CONCLUSIONS The described results indicate that FMT may be an effective treatment option for severe GvH disease. Patients undergoing the procedure should be qualified early enough to avoid life-threatening complications and maximize the likelihood of responding to treatment. Figure Disclosures Jedrzejczak: Amgen: Consultancy, Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Celgene: Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Takeda: Consultancy; Novartis: Research Funding; Roche: Other: travel support for hematology meetings (ASH, EBMT, EHA) . Basak:Teva: Honoraria; Celgene: Honoraria.

Description: BACKGROUND: Recent EBMT analysis showed that infections are responsible for 21% of deaths after allo-HCT and 11% after auto-HCT. However, the risk, types and outcome of infections vary between age groups. The aim of the study is the direct comparison of risk factors of incidence and outcome of infections in children and adults. PATIENTS AND METHODS: We analyzed risk factors for the incidence and outcome of bacterial, fungal, and viral infections in 650 children and 3200 adults who received HCT between 2012-2015. The risk factors were determined by multivariable logistic regression analysis. RESULTS: A total number of 395/650 (60.8%) children and 1122/3200 (35.0%) adults were diagnosed for microbiologically confirmed infection, including 345/499 (69.1%) and 679/1070 (63.5%), respectively after allo-HCT, and 50/151 (33.1%) and 443/2130 (20.8%) respectively, after auto-HCT. At 2 years after HCT, the incidences of microbiologically documented bacterial infection were 36.0% and 27.6%, (p

Description: Background: Allogeneic stem cell transplantation (alloSCT) is a potential curative treatment for patients (pts) with myelodysplastic syndrome (MDS), with reported long-term survival of 27% to 54% depending on risk group. Myeloablative conditioning (MAC) considered as standard therapy is associated with substantial treatment related mortality (TRM), especially in older pts or those with therapy related disease (tMDS); on the other hand, high rate of relapse have been reported after reduced intensity conditioning (RIC). Therefore, Polish Adult Leukemia Group (PALG) in cooperation with Polish Pediatric Group for Hematopoietic Stem Cell Transplantation analyzed the outcome of MDS pts transplanted between 2000 and 2013 with respect to conditioning intensity. Material and methods. Three hundred and four pediatric and adult patients with median age of 38 years (range: 1-69) were retrospectively analyzed. The study cohort included pts with intermediate-2/high risk according to IPSS (136), unfavorable cytogenetics (86), secondary AML (43) and tMDS (35). Among adult pts (216), 74 (34%) were older than 50. The median time between diagnosis and transplant was 8 months (range:1-117). Before transplantation 202 pts had 10%. For conditioning, RIC protocols based on fludarabine were used in 180 pts and 102 pts were treated with myeloablative therapy based on busulphan. Stem cells from related (144) or unrelated (160) donors were grafted in median dose 4.75 (1.3-27.4)x106 of CD34+ cells/kg. Peripheral blood (PB) stem cells were transplanted in 222 pts. Thirty nine pts received allograft from HLA mismatched donors. Results: Engraftment occurred in 285 (94%) pts and 8 pts died before +21 day after transplantation. Infectious complications were observed in 252 (82%) pts during neutropenia (febrile of unknown origin 163, bacterial 53, fungal 24, bacterial and fungal 12). Late infections, assessed in those who survived 100 days, occurred in 130 (50%) pts, and were related mainly to CMV infection. Severe toxic complications (CTCAE grade 3-4) developed in 67 (22%) pts. Acute graft versus host disease (GVHD) grade 2-4 occurred in 77 (27%) pts, while chronic extensive GVHD in 37 (14.5%) pts. Forty seven pts experienced disease relapse after treatment. Over a median follow-up of 43 months (range: 15-70) 156 (51%) pts were alive. In 44 cases deaths were related to relapse, 36 pts died due to GVHD, 43 due to infection and 25 because of organ toxicity. Probability of 3-years overall survival (OS), disease free survival (DFS), relapse incidence (RI) and TRM were 0.51±0.03, 0.50±0.03, 0.18±0.03 and 0.47±0.03, respectively. OS (0.56±0.04 vs 0.44±0.04, p=0.036) and TRM (0.31±0.04 vs 0.43±0.04, p=0.040) were statistically better for pts transplanted after 2007 (Figure 1). In multivariate analysis the only factors associated with lower OS were bone marrow blasts before alloSCT 〉10% (p=0.05, HR 1.5), mismatched donor (p=0.015, HR 1.8), PB as source of stem cells (p=0.048, HR 1.5) and alloSCT performed after 2007 (p=0.029, HR 1.6). There were no statistically significant differences in OS, DFS, RI and TRM between pts conditioned with RIC or MAC when analyzed in whole study cohort or with respect to age group, IPSS risk group, cytogenetics, interval from diagnosis to alloSCT. Conclusions: Allogeneic SCT is an option for MDS patients in different age groups. Disease status at time of transplant, mismatched donor and PB source of stem cells, but not conditioning intensity are the most important determinant for the outcome. High rate of TRM remains a concern, despite improvement over time. Fig 1. Results of alloSCT in MDS Fig 1. Results of alloSCT in MDS Disclosures Jedrzejczak: Amgen, Novartis : Consultancy, Research Funding.

Description: Salvage chemotherapy and autologous stem cell transplantation (auto-SCT) results in the cure of around 50% of patients with Hodgkin lymphoma (HL) failing first line therapy. In historical data, patients who progressed after auto-SCT had a poor outcome, with a median overall survival (OS) of around 1-2 years. Significant progress has been achieved in the last decade with the use of brentuximab vedotin (BV) or check-point inhibitors (CPI) and the increasing use of haploidentical transplant. However, little information is available about the characteristics and real-world outcomes of patients with HL relapsing after auto-SCT in the current era. To assess prognosis of patients with recurrent-HL post auto-SCT over time, we analyzed the European Blood and Marrow Transplant registry data of 1781 adult HL patients who relapsed between 2006 and 2017 after a first auto-SCT. A specific questionnaire was sent to all participant centers to obtain additional data regarding characteristics of the patients, treatment of relapse and outcome after auto-SCT failure. Detailed data were collected for 760 patients [median age 32; interquartile range (IQR) 25-42] included in this study. After a median follow-up for alive patients of 57 months (IQR: 29-89), the 4-year OS after relapse for the 760 included patients was 46% (95%CI: 43-50) and similar to that of 1021 non-included patients (45%, 95%CI: 41-48). The 4-year OS after relapse continuously increased from 35% (95%CI: 27-45) for 136 patients relapsing in 2006-2008, to 43% (95%CI: 37-49) for 258 patients relapsing in 2009-2011, 49% (95%CI: 43-56) for 238 patients relapsing in 2012-2014, and 61% (95%CI: 52-72) for 128 patients relapsing in 2015-2017 (p=0.001) (Figure 1). Improvement over time was predominantly noted in patients who had an early relapse (within 12 months) after auto-SCT (p=0.01) but not in those with a late relapse (p=0.6). On multivariate analysis, patients who relapsed in more recent years and those with a longer interval from transplant to relapse had a better OS, whereas increasing age, poor performance status at relapse, bulky disease at relapse, extranodal disease at relapse and presence of B-symptoms at relapse were associated with a worse OS. Regarding treatment at relapse, BV was used in 233 patients (31%) after a median of 2 months from relapse (IQR: 0.8-8), predominantly as first treatment of relapse (155 patients). BV use increased over the 4 time periods from 3% to 19%, 49% and 49% respectively, and resulted in a complete remission (CR) in 46% and a partial response (PR) in 32%. The 4-year OS from BV use for relapse after auto-SCT was 56% (95%CI: 49-64). CPI were used in 91 patients (12%) including nivolumab in 75 patients and pembrolizumab in 12 patients after a median of 18 months from relapse (IQR: 5-35). CPI use increased over the 4 time periods from 1% to 4%, 14% and 35% respectively, and resulted in a CR of 44%, PR 32%, with a 4-year OS from CPI use of 44% (95%CI: 30-63). Finally, a second SCT (SCT2) was performed in 330 patients (43%) predominantly allogeneic SCT (285 patients, 86%) including a haploidentical SCT in 54 patients (16%). SCT2 was performed in 40% and 37% of patients relapsing in 2006-2008 and 2009-2011 respectively but its use increased to 49% and 51% of patients relapsing in 2012-2014 and 2015-2017 respectively. Four-year OS after SCT2 was 55%. In conclusion, outcome after post-transplant relapse has improved significantly in recent years, particularly in the case of early relapse, possibly reflecting, among other factors, the efficacy of post-transplant salvage including BV, CPI and second transplant. These large-scale real-world data can serve as benchmark for future studies in that setting. Figure 1 Disclosures Blaise: Jazz Pharmaceuticals: Honoraria. Sureda Balari:Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria.