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Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of allogeneic hematopoietic cell transplantation (allo-HCT) with multisystem involvement. Cases of TMA in the intestinal vasculature (intestinal TMA/iTMA) have been reported. We hypothesized that iTMA is a distinct entity from TA-TMA. To test this hypothesis, we prospectively recruited allo-HCT recipients with an indication for endoscopy. Among 20 patients, histological features of iTMA, including loss of glands, total denudation of mucosa, apoptosis and detachment of endothelial cells, mucosal hemorrhage, intraluminal fibrin and microthrombi were found in six. Only 2/6 were classified as GVHD/TA-TMA, while the other 4 as GVHD/no TA-TMA. Gastro-intestinal symptoms were similar between the patients with or without iTMA. With a median follow-up of 11.1 (2.1-67.5) months, 1-year overall survival was 22.2% for iTMA, 55% for GVHD and 60% for TA-TMA. On multivariate analysis, independent unfavorable predictors of OS were iTMA (p = 0.048), HLA mismatched donors (p = 0.008) and gastro-intestinal bleeding (p = 0.021). In conclusion, iTMA emerges as a novel distinct entity in patients with GVHD and/or TA-TMA. Distinct histological features may be useful in differential diagnosis of these severe HCT complications. The higher mortality rates of iTMA than TA-TMA highlight the need for further investigation of this condition.

Invasive aspergillosis (IA) represents a leading cause of mortality in immunocompromised patients. Although adoptive immunotherapy with Aspergillus-specific T cells (Asp-STs) represents a promising therapeutic approach against IA, the complex and costly production limits its broader application. We generated Asp-STs from a single blood draw of healthy individuals or IA patients in only 10 days, by either Aspergillus fumigatus (AF) lysate or peptide stimulation of mononuclear cells. The cells were phenotypically and functionally characterized, and safety was assessed in xenografts. Healthy donor-derived and lysate- or peptide-pulsed Asp-STs presented comparable fold expansion, immunophenotype, and Th1 responses. Upon cross-stimulation, only the lysate-pulsed Asp-STs were empowered to respond to peptide stimulation, although both cell products induced hyphal damage. Importantly, Asp-STs cross-reacted with other fungal species and did not induce alloreactivity in vivo. IA patient-derived T cells displayed an anergic phenotype that prohibited sufficient expansion and yield of meaningful doses of Asp-STs for autologous immunotherapy. Using a rapid and simple process, we generated, from healthy donors but not IA patients, functionally active Asp-STs of broad specificity and at clinically relevant numbers. Such an approach may form the basis for the effective management of IA in the context of allogeneic hematopoietic cell transplantation.

Background Graft vs host disease (GVHD) is the most severe complication of allogeneic hematopoietic cell transplantation. Conventional immunosuppressive therapy increases morbidity and mortality without improving survival. Extracorporeal photopheresis (ECP) has been introduced as an alternative treatment in steroid-dependent and steroid-refractory disease. Study design and methods We studied the safety and efficacy of ECP as a second- or third-line treatment in GVHD. Results ECP was administered in 21 patients with grade III-IV acute GVHD and 88 patients with extensive chronic GVHD, without ECP-related adverse events. Eight patients receiving four or less ECP sessions were not further analyzed. The majority of acute GVHD patients (84%) presented partial (15) or complete (1) response to ECP. Immunosuppression was reduced in 10 of 19 patients and ceased in 1 of 19 patients. One-year cumulative incidence (CI) of transplant-related mortality (TRM) (17.6%) was associated with the lack of response to ECP and steroid refractoriness. With a follow-up of 17.5 (1.8-58.3) months, 1-year overall survival (OS) (52.5%) was independently associated with a higher number of ECP sessions. Regarding chronic GVHD, complete response was achieved in 35 patients, whereas partial response in 25 patients, leading to an overall response rate of 73%. Cutaneous sclerosis manifestations were associated with higher response rates. With a follow-up of 68.1 (5.4-283.1) months, 5-year CI of TRM (24.1%) was associated only with a number of ECP sessions. The 5-year OS (64.5%) was independently associated with number of ECP sessions and cutaneous manifestations. Conclusion Our findings suggest that ECP is safe and effective for GVHD and should be considered early in the course of GVHD, before irreversible end-organ damage has been established.

Introduction: Allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning (RIC) has been used in heavily pretreated lymphoma patients with the promise of decreased treatment-related mortality. Despite overall improvements in outcomes of patients with lymphoid malignancies, several new agents are emerging as potential therapies. However, investigation is ongoing. Therefore, we aimed to describe our long-term experience in Hodgkin (HL), non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL). Methods: In this retrospective study, we enrolled consecutive patients who underwent allo-HCT for lymphoid malignancies in our institution between 2001-2018. We performed a retrospective review of data in our prospectively acquired database. Results: In total, 50 patients (male=35, female=15, median age 36 years, range 15-64) underwent allo-HCT for HL (n=24), NHL (n=21, including mantle cell n=12, follicular n=3, aggressive B-NHL n=4, T-NHL n=2) and CLL (n=5). The majority of patients were diagnosed at stage IV (48%), 34% had bone marrow involvement and 66% had previously undergone autologous HCT. Most patients were heavily pretreated (median treatment lines=4, range 1-11), 21 of them had received more than 4 treatment lines and at the time of transplantation only 14 had complete response of the disease, while 9 had partial response and 27 were refractory. According to Disease-Risk Index (DRI), patients were stratified at low (n=11, 23.4%), intermediate (n=12, 25.5%), high (n=20, 42.6%) or very high (n=4, 8.5%) category. Among patients with Hodgkin lymphoma, Brentuximab vedotin was administered in 7, and 4 of them were effectively bridged to AHCT. All patients received RIC, mainly Fludarabine (150mg/m2)-Cyclophosphamide (2g/ m2) in CLL and NHL and Thiotepa (10mg/kg)-Fludarabine (120 mg/m2)-Cyclophosphamide (60mg/kg) in HL from matched sibling (n=27), matched unrelated (n=15) or mismatched unrelated (n=8) donor. GVHD prophylaxis consisted of cyclosporine or tacrolimus and mycophenolate mofetil or short- term methotrexate and additional low dose antithymocyte globulin (5mg/kg) in unrelated donors. Peripheral blood was the main stem cell source (only two patients received bone marrow graft) and median number of CD34+ cells infused was 6.37 x106 /kg (1.33-14.5). Two patients succumbed to advanced underlying disease before engraftment, in all other engraftment was successful. Median time until neutrophil engraftment was 10 days (7-23) and until platelet engraftment 12 days (7-28). Eighteen patients (36.7%) developed acute GVHD (grade I,n=1,grade II, n=12,grade III-IV, n=5), steroid sensitive in 10 (62.5%). Cumulative incidence (CI) of chronic extensive GVHD at first year was 78.2%, and 13 patients required more than one additional line of immunosuppression (range 1-5 lines). Ten patients presented CMV reactivation successfully treated with antiviral medication and 1 patient died from HSV7 encephalitis. With a median follow of 3 years (1-16 years), 10-year OS was 40.4%, 10-year non-relapse mortality CI 23.4% and 10-year DFS 32%. There was no difference in survival according to original disease (5yr, NHL=61.1%, HL=47.1%, CLL=30%%, p=0.67). Multivariate analysis revealed high and very high DRI as the single predicting factor for OS (HR 9.69, CI 1.55-60.55, p=0.015), when assessing impact of disease, DRI, number of prior treatment lines, cGVHD and bone marrow infiltration at diagnosis. Conclusions: Our data suggest that RIC allo-HCT provides encouraging survival rates, potentially offers the chance of cure, with acceptable 10-year TRM in selected high risk patients with lymphoid malignancies, despite high risk of chronic GVHD. Disease risk index that is mainly associated with disease stage at transplant independently affects survival. Therefore, efforts need to continue to improve clinical application of novel agents targeting specific pathways with the aim of lowering disease stage pre-transplant. These therapeutic strategies merit further investigation in prospective studies in order to select potential therapeutic targets and best regimens for individual patients. Disclosures Gavriilaki: European Hematology Association: Research Funding.