Search

IntroductionB-cell-activating factor (BAFF) is associated with donor-specific antibodies and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the effects of BAFF on T-cell physiological function have not been fully elucidated in acute GVHD.MethodsWe examined the effects of belimumab, a monoclonal antibody targeting BAFF, for the treatment of acute GVHD. We examined the effects of T cells and B cells separately when inducing GVHD in mouse model.ResultsTherapeutic functional manipulation of endogenous BAFF can improve acute GVHD during the early post-transplant period. In this study, BAFF was shown to increase the proportions of CD4+IL-17+, CD4+IL-6+ Th17, and CD4+IFN-γ+ Th1 cells and to reduce the proportion of regulatory T (Treg) cells. Furthermore, the belimumab therapy group showed increased B220+IgD+IgM+ mature B cells but decreased B220+IgD−IgM− memory B cells, B220+Fas+GL-7+ germinal center formation, and B220+IgD−CD138+ plasma cells. These results indicate that BAFF can alleviate acute GVHD by simultaneously regulating T and B cells. Interestingly, the BAFF level was higher in patients with acute GVHD after HSCT compared with patients receiving chemotherapy.ConclusionThis study suggests that BAFF blockade might modulate CD4 +T-cell-induced acute GVHD early after allo-HSCT and the possibility of simultaneously controlling chronic GVHD, which may appear later after allo-HSCT.

Clamydophila psittaci (C. psittaci) has been proposed to be an etiologic factor in extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in the ocular adnexa. However, the pathogenetical significance of the infection has not been fully elucidated. Many previous studies have shown controversial results regarding C.&nbsp, psittaci detection rates in said patients, ranging from 0 to 87%. We investigated the presence of C. psittaci in a single institutional cohort (n = 150) of ocular adnexal MALT lymphoma (OAML) patients in Korea. We tried to exclude the methodological biases derived from the different primer sets in polymerase chain reaction-based studies. For that reason, we applied five sets of primers, including four previously reported and one newly designed primer set. There was no case of C. psittaci-positive OAML in repeated trials validated with appropriate positive and negative controls. All 150 cases showed negative results with five primer sets. These results suggest that the pathogenetic role of C. psittaci in ocular adnexal MALT lymphoma might have been overestimated to date, at least in the Korean population. Therefore, the molecular diagnosis of C. psittaci is considered a very low priority.

Objectives This study aimed to identify the natural course of cytomegalovirus (CMV)/Epstein-Barr virus (EBV) after rabbit antithymocyte globulin and cyclosporine (rATG-CsA) for aplastic anemia (AA). Methods In 113 prospectively observed AA patients treated with rATG-CsA, the CMV/EBV cohort was classified into two groups by baseline viremic status: no viremia (CMV-G1, n = 112; EBV-G1, n = 98) and the presence of viremia (CMV-G2, n = 1; EBV-G2, n = 13). Results In CMV-G1, the mean CMV load increased up to 3 months but was completely resolved from 6 months. The mean EBV load of EBV-G1 showed a peak at 1 month and then gradually decreased over time but remained detectable throughout the observation period. EBV-G2 showed fluctuating EBV dynamics. With reactivation rates of 38.4% in CMV-G1 and 62.2% in EBV-G1, a longer time to rATG-CsA from diagnosis and a lower absolute lymphocyte count at 1 month from rATG-CsA were significantly associated with CMV and EBV reactivation, respectively. The mean peak CMV and EBV loads of patients with CMV-related (3.5%) and EBV-related (0.9%) diseases were evidently higher than those of the remaining patients without CMV and EBV diseases in the respective cohort. Conclusion Considering frequent reactivation and distinct courses of CMV/EBV, virologic surveillance is recommended after rATG-CsA for AA.

Given that there are only a few prospective studies with conflicting results, we investigated the prognostic value of multiparameter geriatric assessment (GA) domains on tolerance and outcomes after intensive chemotherapy in older adults with acute myeloid leukemia (AML). In all, 105 newly diagnosed patients with AML who were older than age 60 years and who received intensive chemotherapy consisting of cytarabine and idarubicin were enrolled prospectively. Pretreatment GA included evaluations for social and nutritional support, cognition, depression, distress, and physical function. The median age was 64 years (range, 60-75 years), and 93% had an Eastern Cooperative Oncology Group performance score

Background: Hemophagocytic lymphohistiocytosis (HLH) can be life-threatening if not detected and treated appropriately. The diagnosis of HLH can be confusing due to other similar febrile diseases that present with cytopenia. Natural-killer cell (NK)-cytotoxicity is an important diagnostic parameter for primary HLH; however, its role in secondary HLH in adults has not been well-elucidated. Methods: We prospectively enrolled 123 adult patients with febrile conditions accompanied by cytopenia or marrow hemophagocytosis. A diagnosis of HLH was based on HLH-2004 criteria and treated based on HLH-94 protocol. NK-cytotoxicity was calculated at the time of diagnosis by K562-cell direct lysis using flow-cytometry. Results: HLH ( n = 60) was determined to be caused by Epstein–Barr virus (EBV) ( n = 11), infection other than EBV ( n = 16), malignancies ( n = 19), and unknown ( n = 14). Febrile diseases other than HLH ( n = 63) were diagnosed as autoimmune disease ( n = 22), malignancies ( n = 21), infection ( n = 12), non-malignant hematological diseases ( n = 6), and unknown ( n = 2). A lower NK-cytotoxicity level was observed at diagnosis in patients with HLH, compared with other causes of febrile disease (12.1% versus 26.2%, p Conclusions: Febrile disease with cytopenia was associated with decreased NK-cytotoxicity, especially in adults with HLH; however, its diagnostic role for adult HLH is still arguable. The diagnostic criteria for adult HLH should be further discussed. Trial registration: Clinical Research Information Service [Internet]; Osong (Chungcheongbuk-do), Korea, Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea); https://cris.nih.go.kr/cris/index.jsp ; Feb, 16th 2016; KCT0001886 (KC15TISE0936)

Purpose To evaluate changes in choroidal vascular structure and aqueous cytokine levels in eyes with vitreoretinal lymphoma (VRL) after intravitreal methotrexate (MTX) treatment. Methods In this retrospective study, VRL patients who visited our hospital between October 2018 and July 2020 were reviewed. Aqueous samples were obtained before treatment and at clinical resolution after intravitreal MTX therapy. Interleukin (IL)-6 and IL-10 levels and the IL-10-to-IL-6 ratio were evaluated. Swept-source optical coherence tomographic images were obtained along with the aqueous samples. Subfoveal choroidal thickness (SFCT), total vascular area of the choroid (TCA), stromal area (SA), luminal area (LA), and choroidal vascularity index (CVI) were assessed. Results Twelve patients were enrolled (female:male—5:7). The mean age (± standard deviation) at diagnosis was 60.9±8.5 years. In the 16 eyes diagnosed with VRL, values of SFCT, TCA, LA, and SA significantly decreased after treatment (all p-values Conclusion Eyes with active VRL exhibited choroidal thickening with increased vascular and stromal areas that decreased after remission following MTX treatment. Higher aqueous IL-10 and IL-6 levels and lower visual acuity in the active phase may indicate the number of injections required for remission; this should be considered in the treatment of patients with VRL.

Background/aims Adoptive therapy with regulatory T (Treg) cells to prevent graft-versus-host disease (GVHD) would benefit from a strategy to improve homing to the sites of inflammation following hematopoietic stem cell transplantation (HSCT). Although donor-derived Treg cells have mainly been used in these models, third-party-derived Treg cells are a promising alternative for cell-based immunotherapy, as they can be screened for pathogens and cell activity, and banked for GVHD prevention. In this study, we explored major histocompatibility complex (MHC) disparities between Treg cells and conventional T cells in HSCT to evaluate the impact of these different cell populations on the prevention of acute GVHD, as well as survival after allogeneic transplantation. Methods To induce acute GVHD, lethally irradiated BALB/c (H-2d) mice were transplanted with 5 × 105 T cell-depleted bone marrow cells and 5 × 105 CD4+CD25- splenic T cells from C57BL/6 (H-2b) mice. Recipients were injected with 5 × 105 cultured donor-, host-, or third-party-derived CD4+CD25+CD62L+ Treg cells (bone marrow transplantation + day 1). Results Systemic infusion of three groups of Treg cell improved clinicopathological manifestations and survival in an acute GVHD model. Although donor-derived Treg cells were immunologically the most effective, the third-party-derived Treg cell therapy group displayed equal regulation of expansion of CD4+CD25+- Foxp3+ Treg cells and suppressive CD4+IL-17+ T-helper (Th17) cells in ex vivo assays compared with the donor- and host-derived groups. Conclusion Our findings demonstrate that the use of third-party Treg cells is a viable alternative to donor-derived Treg cellular therapy in clinical settings, in which human leukocyte antigen-matched donors are not always readily available.

The recovery of myeloid-derived suppressor cells (MDSCs) and its relevance in clinical acute graft-versus-host disease (GVHD) and post-hematopoietic stem cell transplantation (HSCT) infections remain to be fully characterized. We examined the expansion of circulating monocytic (M-) MDSCs and granulocytic (G-) MDSCs at the time of engraftment in 130 patients undergoing allogeneic HSCT (allo-HSCT). Compared with the G-MDSC group, the high M-MDSC group had a higher infection rate within 100 days, along with worse 1-year cumulative incidence of treatment-related mortality (TRM) and 2-year probability of event-free survival (EFS). The frequency of M-MDSCs was associated with preceding severe mucositis. Transcriptome profiling analysis of 2 isolated MDSC subtype showed significantly greater matrix metalloproteinase-9 (MMP-9) expression in M-MDSCs than in G-MDSCs. M-MDSCs produced abundantly more MMP-9. Importantly, compared with G-MDSCs, M-MDSCs isolated from patients post-HSCT had a greater capacity to suppress T cell responses, and MMP-9 blockade more forcefully inhibited their immunosuppressive effect. MMP-9 levels also were associated with the occurrence of infections and with transplantation outcomes. Based on these findings, we identify M-MDSCs as a major contributor to infections early after allo-HSCT and worse clinical outcomes via MMP-9.

Despite recent emergence of novel target agents, allogeneic stem cell transplantation is still the favored option for disease control in relapsed patients with acute myeloid leukemia (AML). Allotransplant from alternative donors such as haploidentical donor or cord blood can be done when fully HLA matched donor is not available. As for patients relapsed after the first stem cell transplantation (SCT1), these alternative stem cell sources often become only available options for the second transplantation. However, there has been no report comparing haploidentical stem cell (HIT) and cord blood transplantation (CBT), especially for the second transplantation. We performed a retrospective cohort study on AML patients who relapsed after SCT1 and underwent second allogeneic SCT from either alternative donor at our institution. We identified a total of 50 corresponding patients between January 2008 and February 2021 where 31 HIT and 19 CBT were included, and analyzed SCT outcomes including overall survival (OS), disease free survival (DFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and the incidence of SCT complications with comparing between the 2 groups. Conditioning regimens for HIT and for CBT were as follows: Fludarabine (30mg/m2/day intravenous (IV) for 5 days), busulfan (3.2mg/kg/day IV for 2 days), fractionated total body irradiation (fTBI, 4-8Gy total) and rabbit antithymoglobulin at a dose of 1.25mg/kg/day for four days for in vivo T cell depletion from D-5 to D-2 was given for HIT. G-CSF-mobilized peripheral blood stem cell was used as allograft. Graft-versus-host disease (GVHD) prophylaxis was done with tacrolimus and methotrexate. For CBT, fludarabine (30mg/m2/day IV for 5 days), cytarabine (1.5g/m2 twice daily for 3 days) with fTBI (12Gy). All CBT patients received double cord blood units. GVHD prophylaxis was done with tacrolimus and mycophenolate mofetil. The median follow-up period for survivors was 64.6 months (range 5.3-154.1). The type of SCT1 differed between the two groups; more patients of HIT were the recipient of prior autologous transplantation (41.9%), and 63.2% of CBT had underwent prior HIT (p Overall respective outcomes of HIT and CBT were as follows; 41% and 29% for 2-year OS (p=0.017), 41% and 16% for 2-year DFS (p=0.016), 36% and 36% for 2-year CIR (p=0.91) and 23% and 48% for 2-year NRM (p=0.021). Early NRM within 100 days of SCT2 was more frequent in CBT than HIT although not statistically significant (26.3% vs 9.7%, p=0.23). Median days to neutrophil and platelet engraftment were 12 (range 11-23) and 13 (range 9-38) in HIT, and 29 (range 16-48), 51 (range 27-167) for CBT, respectively (p This is the first report, to the best of our knowledge, to compare outcomes of the second transplantation from alternative donors for relapsed AML patients after SCT1. Our unique T-cell replete HIT using a reduced-toxicity conditioning regimen seems to provide better survival than CBT. Figure 1 Figure 1. Disclosures Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria.

Background Although European Leukemia Net (ELN) risk classification was introduced in 2017 and has been applied as an important prediction tool for prognosis, there has been limited data on its value among the patients with allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the prognostic value of ENL 2017 criteria on post-HSCT outcomes and compared it with pre-HSCT measurable residual disease (MRD) status determined by Wilms tumor gene 1 (WT1) expression level. Methods: Patients who underwent HSCT and fulfilled following criteria were eligible in this current study: first HSCT in complete remission (CR) or CR with incomplete hematologic recovery and having bone marrow WT1 expression results before transplant. We found a total of 275 patients between Nov 2017 and July 2020, and we adopted the WT1 cut-off level of 250 copies per 10 4 ABL for defining MRD negative vs positive (Biol Blood Marrow Transplant. 2019;25:1925) . Results: Among 180 patients, , 110 (61%) and 70 (39%) patients were classified as a , intermediated (INT) and adverse (ADV) risk group by ELN 2017 classification. After a median follow-up of 18.3 months (range, 0.4 to 43.2 months), the Kaplan-Meier survival curve could not discriminate overall survival (OS), relapse free survival (RFS), or cumulative incidence of relapse (CIR) between the INT and ADV risk groups (p=0.2, p=0.68, p=0.061, respectively). On the other hand, we found that OS, RFS and CIR were unfavorable in MRD (+) group compared to either MRD negative INT or ADV risk group (35.8 % vs 59.1 % for OS, p=0.05; 24.7% vs 55.9% for RFS, p=0.002; 60.9% vs 20.4 % for CIR, p C onclusions: The ELN 2017 risk classification was not available to predict post-HSCT outcomes in INT and ADV risk group. We found that pre-HSCT MRD rather than ELN 2017 could more likely to predict post-HSCT relapse. The prognostic value of WT1 MRD was more prominent in ELN INT group compared to ADV group. A subset of INT patients had the worst prognosis if their pre-HSCT WT1 MRD remained positive, who they need additional therapeutic strategies to prevent relapse. Figure 1 Figure 1. Disclosures Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria.

Background: Complete remission (CR) rate and long-term overall survival (OS) is very poor in patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Previous clinical trials revealed a good remission rate and a safe bridging role to allogeneic-HCT compared to various standard treatments, and several real-world data have been reported. Aim: Here, we analyzed outcome of blinatumomab versus our conventional intensive chemotherapy by propensity score-matched analysis. Methods: From 2009 to 2020, 197 consecutive R/R BCP-ALL were treated with mitoxantrone-etoposide-cytarabine (MEC, n=113) or blinatumomab (n=84), and allogeneic-HCT was planned in patients with CR. For propensity score-matching, the MEC and blinatumomab cohorts were matched in a 1:1 ratio using 5 criteria of age < 35 years old, short CR duration < 12 months, adverse-risk karyotype including Ph-chromosome at relapse, previous allogeneic-HCT, and first-line salvage or not. We compared CR rate, regiment related mortality, and OS with cumulative incidence of relapse (CIR) and non-relapse mortality (NRM). Results: Matched cohort consisted of 52 patients for each salvage group and matched criteria were the same exactly. Median age was 42 years and 34 (65.4%) patients were > 35 years old. There were 22 (42.3%) primary refractoriness, 9 (17.3%) post-chemotherapy relapse and 21 (40.4%) post-HCT relapse. Among 30 relapsed patients, 19 (63.3%) were early relapse with CR duration less than 12 months. There were 25 (48.1%) with poor-risk karyotype at relapse of which 10 were Philadelphia-chromosome. Extramedullary relapse was observed in 14 (26.9%) and 8 (15.4%) were advanced-line salvage. CR rate was significantly higher in blinatumomab (78.8% vs. 53.8%, p=0.012) and more patients proceeded to allo-HCT (80.8% vs. 46.2%, p Conclusion: Our matched cohort analysis clearly showed that blinatumomab is superior to MEC salvage regimen. However, we are observing relapse in up to 50% after blinatumomab and following allo-HCT still shows high NRM. Further combinatorial using novel therapeutics are needed for R/R BCP-ALL. Figure 1 Figure 1. Disclosures Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction Geriatric assessment (GA) typically refers to a multidimensional evaluation designed to evaluate an older person's functional ability, physical health, cognition, psychological health, nutritional status, and social support. The purpose of GA is to develop time-efficient and straightforward tools to evaluate multiple patient characteristics, which may be predictive of treatment outcomes of elderly acute myeloid leukemia (eAML) patients treated with intensive chemotherapy. Given that there have been few prospective studies with conflicting results, we performed a single-center prospective observational cohort study (#KCT0002172) investigating the prognostic value of multiparameter GA domains for eAML patients' tolerance and survival outcomes after intensive chemotherapy. Patients and methods Newly diagnosed eAML patients aged over 60 years who received intensive chemotherapy (n=105) were prospectively enrolled between November 2016 and December 2019. The median age was 64 years (range, 60-75), and they were all considered fit for intensive chemotherapy, with adequate performance and organ function. All the enrolled patients were administered various questionnaires for pretreatment GA and functional evaluation, which included evaluation for social and nutritional support, cognition, depression, distress, and physical function. Results Of the 105 enrolled patients, 93% had an Eastern Cooperative Oncology Group performance score of 1 and received intensive chemotherapy. Among them, between 32.4% and 69.5% of patients met the criteria for impairment on each GA domain. Physical impairment measured by the Short Physical Performance Battery (SPPB) was significantly associated with non-fatal toxicities of Grade III-IV severe infection (odds ratio (OR) 3.000, 95% confidence interval (CI), 1.159-7.788, p=0.024) and acute renal failure (OR 3.891, 95% CI, 1.329-11.39, p=0.013). Cognitive dysfunction measured by the Mini-Mental Status Examination- Korean version of CERAD Assessment Packet was significantly associated with a higher risk of Grade III-IV infection (OR 2.667, 95% CI, 1.025-6.939, p=0.044) and prolonged hospitalization (OR 4.208, 95% CI, 1.485-4.229, p=0.005). Reduced physical function measured by the SPPB and depressive symptoms measured by the Korean version of Short form Geriatric Depressive Scale (SGDS-K) were predictive of worse overall survival (OS; hazard ratio (HR) 1.917, 95% CI, 1.074-3.420, p=0.027 and HR 1.902, 95% CI, 1.005-3.602, p=0.048). SPPB impairment was also significantly related to higher treatment-related mortality (TRM; HR 2.023, 95% CI, 11.057-3.874, p=0.033). Furthermore, gait or sit-and-stand speed, a component of SPPB, was the single most powerful tool to predict survival outcomes of both OS (HR 2.766, 95% CI, 1.471-5.200, p=0.002 and HR 3.615, 95% CI, 1.868-6.999, p Conclusions We prospectively demonstrated the prognostic value of physical and psychological assessment by GA for survival outcomes in intensively treated eAML patients. Gait or sit-and-stand speed was the single most powerful tool to identify frailty and predict survival outcomes. The prognostic value of preexisting survival prediction models, Wheatley index scores, and AML scores was reconfirmed.. The addition of measures for physical function and depression improved the predictability of those prediction models for survival. Cognitive and physical impairment were able to identify non-fatal toxicities during intensive chemotherapy in eAML patients. Our data will facilitate the incorporation of GA measures into validated survival prediction models to determine initial treatment for eAML patients in routine clinical care and clinical trials. Further studies are warranted to determine the best ways to adjust the care provided for frail patients to improve treatment tolerance and outcomes. Disclosures Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria.

Backgound The Philadelphia-negative myeloproliferative neoplasms (MPNs) share similar molecular characteristics, in which the excessive myeloproliferations are driven by mutations in JAK2, CALR, MPL, and uncommon variants. More recently, the biological basis on acquisition of somatic mutations have been accumulated. However, symptoms, histomorphologic characteristics, and natural histories are different between MPN subsets. Although there are increasing evidences that inflammation have a key role in promoting MPN initiation and influencing disease evolution, characteristics of the bone marrow immune microenvironment between MPN subsets remains unclear exactly. Aims To characterize the bone marrow immune microenvironment of Philadelphia-negative MPNs, we carried out immune-related gene expression profiling of bone marrow aspirates (BMAs) from 33 MPN patients (6 PV, 6 ET, 6 early PMF, and 15 overt MF including 10 primary MF, 5 post-PV/ET MF) using nCounter Immunology Panel. Methods BMA samples collected at diagnosis using EDTA-coated tubes. Those samples were processed within 24 hours from collection to obtain mononuclear cells by density centrifugation using Ficoll-Paque. NanoString analysis using a 594-gene nCounter Immunology panel (Human v2 - nanoString) was performed on RNAs extracted from 33 MPN bone marrow aspirates. Results First, to investigate whether there are distinct gene expression signatures of immune cells between three subcategories of MPNs, we compared gene expression profiles (GEPs) between ET, PV, and overt PMF. Using a P-value cutoff of ≤0.05 and fold-change ≥ 2, 10 upregulated and 32 downregulated differentially expressed genes (DEGs) were identified in ET than PMF, and 9 upregulated and 11 downregulated DEGs were identified in PV than PMF, while we found no significant DEGs between ET versus PV, except seven genes. Second, we investigated differences in GEPs between early PMF and overt PMF. Thirty-two downregulated and 4 upregulated DEGs were identified in early PMF than overt PMF. Gene set analysis revealed that the expression of genes related to almost processes decreased in early PMF than overt PMF. Then, we questioned differences between PMF and post-PV/ET MF. Using a P-value cutoff of ≤0.05 and fold-change ≥ 2, 12 upregulated and 12 downregulated DEGs were identified. Next, we computed relative abundances of immune cell subpopulations, estimated based on expression counts from the entire panel of surveyed genes, and compared them between the subcategories of MPNs. The abundance measurement of exhausted CD8 + T cell genes were significantly lower in ET and PV, compared with overt PMF, suggesting T cell exhaustion was distinct in overt PMF, compared to ET and PV. Conclusions The results demonstrated that immune microenvironment signature was distinguishable in the subcategories of MPNs. In addition, inflammatory signature was enriched in the bone marrow of overt PMF and exhausted CD8 + T cell genes were distinct in overt PMT. Further investigation is warranted to determine the immunological factors critical for potential therapeutic targets to alleviate progress to myelofibrosis. Disclosures Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction Although many new therapeutic agents have been introduced in the field of AML, the most important intensive induction regimen of AML patients is still 7+3 chemotherapy based on cytarabine and anthracycline. Currently, major guidelines recommend to exam bone marrow (BM) assessment in 14-21 days after the initiation of induction to determine whether to proceed with intensification chemotherapy. However, there is no solid evidence that these timings are most optimal. If the evaluation at an earlier time point is prognostic for response, earlier intensification could be considered. In this regard, we investigated if the BM blast rate at the 7th day after the start of 7+3 chemotherapy (D7 BM blast) was useful in predicting the treatment response of induction chemotherapy. Methods We retrospectively collected the data of patients who were newly diagnosed with AML from February 2002 to February 2021, received induction chemotherapy by 7+3, had a D7 BM examination without any intensification. A total of 665 patients were enrolled and we analyzed the prognostic significance of the D7 BM blast for the induction treatment response (complete remission or complete remission with incomplete hematologic recovery (CR/CRi)). In addition, we analyzed whether the predictive significance of the D7 BM blast varies by the patient's cytogenetic features by Medical Research Council classification (MRC risk). Then, we evaluated the diagnostic ability of the D7 BM blast by the receiver operating characteristic (ROC) curve for treatment response prediction. To find an optimal D7 BM blast cut-off value, the value that maximizes Youden's index was investigated. Results Among 665 AML patients who underwent 7+3 without intensification, the proportion of patients who acquired CR/CRi after single induction was 68.3%. A significant decrease in the CR/CRi rate was observed in the intermediate/adverse MRC group according to the increase of the D7 BM blast (tests for the trends in the intermediate and adverse group, p Conclusion The BM assessment performed at 7 days after 7+3 chemotherapy was available to predict the treatment response in intermediate and adverse cytogenetic risk patients. In particular, it can be practically used in patients with adverse cytogenetics, and a value of around BM blast 5% can be used as cut-off for response prediction. Early intensification in these patients could be considered, which would be beneficial in various aspects such as shorter nadir period or hospital stay and possibly better treatment response compared with the current strategies of later intensification or second induction. Figure 1 Figure 1. Disclosures Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria.

Introduction: Venetoclax (VEN) combined regimen received FDA approval for newly diagnosed elderly or unfit acute myeloid leukemia (AML) patients. Recently, with increasing use as off-label for relapsed or refractory setting in real practice, the evidence that the regimen is potentially effective in R/R AML is emerging. However, there is no answer to the question how VEN combined treatment compares to intensive chemotherapy (IC) in R/R AML when the patients were intended to be cured with bridging to stem cell transplantation (SCT) after either of these treatments. Methods: Adult AML patients (age ≥18 years) who were refractory to or relapsed after anthracycline plus cytarabine induction were subjected to this analysis. As a group of interest, R/R AML patients who received VEN combined regimen were screened first, and we found a total of 54 corresponding patients between Feb 2020 and Jan 2021. As a comparison, we searched historical controls who were treated with salvage IC during the past two years, revealing a total of 89 patients between Jan 2018 and Jan 2020. Patients analyzed here received VEN-combination or IC as their first or second-line salvage therapy. Results: Overall, the median age was 49 years (range, 18 to 72), and the patients of first line salvage (n=125, 87.4%) were more included. When comparing IC and VEN-combination groups, there were no differences in age, sex, ELN risk groups, cytogenetics, disease type or mutation status. However, more patients in VEN-combination group were in their second line salvage setting (IC vs VEN-combination; 5.6% vs 24.1%, p Conclusion: These findings suggest that VEN-combined treatment is a feasible option for R/R AML and could be chosen over salvage IC in R/R AML based on its anti-leukemic response, bridging to SCT with disease control and survival, which were comparable to IC in overall patients and were tended to be superior in patients of first salvage setting only. Disclosures Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: venetoclax use in R/R AML: off label use

Background: Cytomegalovirus(CMV)-related diseases are a serious cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). CMV-specific cytotoxic T lymphocytes (CMV-CTLs) have been reported as an alternative to antiviral drugs that provide long-term CMV-specific immunity without major side effects. However, their application has been limited by the prolonged manufacturing process required. Methods: In this study, we applied the IFN-γ cytokine capture system (CCS) using the fully automated CliniMACS Prodigy device for rapid production of CMV-CTLs, which may be applicable in clinically urgent CMV-related diseases. Five validation runs were performed using apheresis samples from randomly selected CMV-seropositive healthy blood donors. Successive processes, including antigen stimulation, anti-IFN-γ labeling, magnetic enrichment and elution, were then performed automatically using the CliniMACS Prodigy, which took approximately 13 h. Results: The original apheresis samples consisted mainly of CD45RA+ CD62L+ naïve T cells as well as 0.3% IFN-γ-secreting CD3+ T cells that showed a response to the CMV pp65 antigen (CD3+ IFN-γ+ cells). Following IFN-γ enrichment, the target fraction contained 51.3% CD3+ IFN-γ+ cells with a reduction in naïve T cells and selection of CD45RA- CD62L- and CD45RA+ CD62L- memory T cells. Furthermore, extended culture of these isolated cells revealed functional activity, including efficient proliferation, sustained antigen-specific IFN-γ secretion, and cytotoxicity against pp65-pulsed target cells. Conclusion: The findings reported here suggest that the IFN-γ CCS by the CliniMACS Prodigy is a simple and robust approach to produce CMV-CTLs, which may be applicable for the treatment of clinically urgent CMV-related diseases.

This retrospective study aimed to compare the clinical features of paramedullary lesions (PLs) and extramedullary lesions (ELs) of plasmacytomas at diagnosis, using positron emission tomography integrated with computed tomography, using glucose labeled with the positron-emitting radionuclide 18F (18F-FDG-PET/CT) in newly diagnosed multiple myeloma (NDMM), and to address their prognostic impact. Sixty-four patients with NDMM presenting ELs (n=22) and/or PLs (n=42) were included. Patients with ELs at initial presentation had unfavorable laboratory parameters of calcium and lactate dehydrogenase, a higher percentage of bone marrow plasma cells, and showed a trend toward advanced international staging system (ISS), compared to patients with PLs. Using X-ray imaging, high bone disease (HBD) was observed in 50% and 71% of patients with ELs and PLs, respectively. After a median follow-up of 29.2 months (range, 3.4-76.5 months) in survivors, patients with ELs had a significantly lower overall survival (OS) (p=0.033) than patients with PLs did, whereas the progression-free survival (PFS) did not differ significantly (p=0.818). However, the PFS after 1st progression was significantly worse in patients with ELs than in those with PLs (p=0.017). In the multivariate analyses, the negative impact of initial ELs on OS (p=0.033) was sustained. Our results demonstrated the different clinical features and outcomes of ELs and PLs in NDMM. Patients with initial ELs showed a shorter PFS after 1st progression, which translated into poor OS, providing insight into the different biological effect of ELs.

We assessed long-term safety and efficacy of CT-P10 and rituximab in patients with newly diagnosed low-tumour-burden follicular lymphoma (LTBFL), and following a single transition from rituximab to CT-P10. This double-blind, parallel-group, active-controlled phase 3 trial randomized patients with CD20+ LTBFL to receive CT-P10 or US-sourced rituximab (375 mg/m2 intravenous). Induction therapy (weekly for 4 cycles) was followed by a 2-year maintenance period for patients achieving disease control (CR, CRu, PR and SD). During the maintenance, CT-P10 or rituximab were administered every 8 weeks (6 cycles) in the first year and additional CT-P10 was administered every 8 weeks (6 cycles) in the second year. Secondary endpoints (reported here) were overall response rate during the study period, progression-free survival, time-to-progression, and overall survival. Safety and immunogenicity were also evaluated over the study period. Between Nov 9, 2015 and Jan 4, 2018, 258 patients were randomised (130 CT-P10; 128 rituximab). Over the study period, 115 (88%; CT-P10) and 111 (87%; rituximab) patients achieved overall response. At a median follow-up of 29·2 months (IQR: 26·1-33·7), median progression-free survival, time-to-progression, and overall survival were not estimable. The KM estimates (95% CI) for OS at 36 months were 98% (93-99) and 97% (89-99) in the CT-P10 and rituximab groups, respectively. Corresponding values for PFS were 80% (70-87) and 68% (54-79), while results for TTP were 82% (72-88) and 68% (54-79) in the CT-P10 and rituximab groups, respectively. (Figure A. OS; Figure B. PFS and Figure C. TTP) Over the study period, 114 (88%) and 104 (81%) patients in the CT-P10 and rituximab groups, respectively, experienced at least one treatment-emergent adverse event (TEAE) and 14 (11%) patients in each group experienced TE-serious adverse events (TESAEs). There were no unexpected safety findings observed during the second year of the maintenance period after single transition from rituximab to CT-P10. Figure 1 Disclosures Kwak: Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Xeme Biopharma/Theratest: Other: equity; CJ Healthcare: Consultancy; Sellas Life Sciences Grp: Consultancy; Enzychem Life Sciences: Membership on an entity's Board of Directors or advisory committees; Antigenics: Other: equity; InnoLifes, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pepromene Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Consultancy. Sancho:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gelgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Menne:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Speakers Bureau; Novartis: Honoraria, Other: Travel costs, Speakers Bureau; Pfizer: Honoraria, Other: Travel costs, Speakers Bureau; Celgene: Honoraria, Other: Travel grants; Roche: Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Astra Zeneca: Research Funding; Takeda: Honoraria, Speakers Bureau. Jurczak:Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Acerta: Research Funding; Bayer: Research Funding; Janssen: Research Funding; MeiPharma: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Trneny:Gilead: Consultancy, Honoraria, Other: Travel Expenses; Janssen: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb Company: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel Expenses. Ogura:Cellgene: Honoraria; Chugai: Honoraria; Denovo Biopharma: Membership on an entity's Board of Directors or advisory committees; MejiSeika Pharma: Membership on an entity's Board of Directors or advisory committees; Mundi Pharma: Membership on an entity's Board of Directors or advisory committees; SymBio: Membership on an entity's Board of Directors or advisory committees; TevaTakeda: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Membership on an entity's Board of Directors or advisory committees. Kim:Pfizer: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; F. Hoffmann-La Roche: Research Funding; Kyowa Kirn: Research Funding; Celltrion: Research Funding; JJ: Research Funding. Lee:Celltrion, Inc.: Current Employment. Kim:Celltrion, Inc.: Current Employment. Ahn:Celltrion, Inc.: Current Employment. Buske:Roche, Janssen, Bayer, MSD: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen, AbbVie, Pfizer, Celltrion: Honoraria, Speakers Bureau. OffLabel Disclosure: Rituximab monotherapy to LTBFL patients

Introduction Acute myeloid leukemia (AML) has been considered as a hematological emergency. However, debates on how much the time from diagnosis to treatment (TDT) can be justified to choose the optimal treatment in AML have been raised due to the increased possibility of customized treatment with novel targeted agents based on genetic abnormalities tested by newly applicable diagnostic tools. Three recent studies with a large data set from Western countries showed conflicting results about the relationship between TDT and prognosis. Thus, we evaluated the influence of TDT on patients' outcomes from a large data set of Asian patients. Methods We retrospectively evaluated a cohort of AML patients aged 18 and older who visited the Catholic Hematology Hospital in Korea and received anthracycline-based intensive chemotherapy from 2002 to 2016. A total of 1313 patients were included in this analysis, of which 1282 were used for analysis, excluding 26 patients with incomplete documentation and with more than 90 days of TDT. Patients under the age of 60 (Young group, YG) and patients over 60 years of age (Elderly group, EG) were analyzed as an individual cohort. In both cohorts, the effects of TDT on complete remission (CR/CRi), early death (ED), and overall survival (OS) were analyzed. The TDT was analyzed as a continuous variable to minimize the loss of information, while also grouped into four ordinal groups of 1-5, 6-10, 11-15, and 16- to visualize data and find appropriate cutoff. In order to adjust for the influence of established prognostic variables on the outcomes, we used multivariate regression models. In both univariate and multivariate analyses, the transformation of variables or relaxing the linearity such as restricted cubic splining (RCS) were considered to reflect the data properly and not to violate the model assumptions. When TDT was treated as an ordinal variable, the effects of TDT on CR/CRi and ED were evaluated by Cochran-Armitage trend tests, and the effect on OS was checked by the log-rank test. Results Median age of YG (n=1104) and EG (n=178) were 40 years (interquartile range, IQR; 32-49) and 63 years (IQR; 61-64), respectively. Median TDT of both groups was 8 in days (IQR; 6-11 in YG and 6-13 in EG). When TDT was categorized into 4 groups, patients with higher WBC count tended to belong to earlier TDT groups in both YG and EG cohorts, and secondary AML patients were more placed in the later TDT groups especially in YG cohort. Univariate analyses of TDT in YG showed that TDT had significant correlation with CR/CRi rate, ED rate, and OS. Odds ratio (OR) of CR/CRi per one day treatment delay was -0.0206 (95% CI; -0.0412~-0.0000), and OR of ED per one day delay was 0.0439 (95% CI; 0.0126~0.0752) (Table 1 and Figure 1). RCS method was applied on OS model, so a single value of the hazard ratio (HR) per one day treatment delay was not available, but we could say HR of patients of TDT 2 versus (vs.) patients of TDT 16 was 0.6063 (95% CI; 0.4450-0.8259) in our model (Figure 2). Even after TDT was treated as a grouped variable, TDT was still significant on the ED rate and OS in YG. Especially, High ED rate and low 2-year OS of a group of TDT more than 15 days were noticed (Table 1). In EG, there was no significant effect of TDT on all patients' outcomes (Table 1). Multivariate analyses including age, WBC, AML type, MRC risk, and HSCT status showed that, in YG, TDT effect on CR/CRi rate turned to be insignificant, but TDT still acted as a significant variable for ED and OS. In EG, there was no significant effects of TDT on ED and OS, as like univariate analyses. When the treatment course was divided into 'during induction', 'between induction and HSCT', and 'after HSCT' in YG, there was no significant difference in the rate of death between TDT groups except for the deaths during the induction period (Table 3 and Figure 3). Conclusion Our data revealed the effects of TDT on OS and ED in YG, which were significant in multivariate analyses adjusting the effects of other variables. When the timing of death was divided in YG, the only ED was significantly different between TDT groups, especially in the group with more than 15 days of TDT. These results suggest that TDT matters in YG and delayed initiation of treatment over 15 days after diagnosis would increase risk of early mortalities. On the other hand, little effects of TDT on EG provide a rational for sufficient evaluation of comorbidity and functional impairments to select appropriate initial treatment. Disclosures Kim: Takeda: Research Funding; ILYANG: Consultancy, Honoraria, Research Funding; Sun Pharma.: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kim:Abbvie: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Honoraria; SL VaxiGen: Consultancy, Honoraria; Yuhan: Consultancy, Honoraria; AML Global Portal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astella: Consultancy, Membership on an entity's Board of Directors or advisory committees; BL&H: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: Relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains an area of high unmet patient need and no curative options are currently available. Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human IgG4-based bispecific antibody that binds to CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity independent of T-cell receptor recognition. The safety, tolerability, and anti-tumor activity of odronextamab monotherapy was evaluated in a global, multicenter, Phase 1 study in heavily pretreated patients with R/R B-NHL (NCT02990951; Bannerji et al, ASH 2019). Intravenous infusion of odronextamab has demonstrated an acceptable safety profile at doses up to 320 mg weekly (QW), and the maximum tolerated dose was not reached. Broad and durable anti-tumor responses were observed in both indolent and aggressive lymphomas, including in patients who progressed after prior CAR T-cell therapy. An assessment of pharmacokinetics, efficacy and safety data from the Phase 1 study informed the recommended Phase 2 dosing regimens. METHODS: This global, Phase 2, open-label, multi-cohort study (R1979-ONC-1625; NCT03888105) is designed to assess the anti-tumor activity and safety of odronextamab in patients with B-NHL. There are five disease-specific cohorts, each with independent parallel enrollment. The study includes patients with: (1) R/R follicular lymphoma (FL) Grade 1-3a after ≥2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent; (2) R/R diffuse large B-cell lymphoma (DLBCL) after ≥2 lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent; (3) R/R mantle cell lymphoma (MCL) following or with failure to tolerate Bruton's tyrosine kinase inhibitor therapy; (4) R/R marginal zone lymphoma (MZL) after ≥2 lines of systemic therapy; (5) other R/R B-NHL subtypes, excluding Waldenström macroglobulinemia, after ≥2 lines of systemic therapy (Fig. 1). Estimated total enrollment is 481 patients. Key eligibility criteria are: age ≥18 years; not appropriate for other approved therapy with established benefit; ≥1 bi-dimensionally measurable nodal lesion of ≥1.5 cm; Eastern Cooperative Oncology Group performance status ≤1; and adequate bone marrow, renal, and hepatic function. Key exclusion criteria are: prior anti-CD20 x CD3 bispecific antibody therapy; prior CAR T-cell therapy; primary central nervous system (CNS) lymphoma or known involvement by non-primary CNS NHL; and history of allogeneic hematopoietic stem cell transplantation. Odronextamab is administered using a step-up dose schedule consisting of an initial dose at Week (W)1, an intermediate dose at W2, and thereafter, a fixed weekly dose until W12 followed by maintenance Q2W dosing until progression or discontinuation (Fig. 2). The dose for indolent B-NHL is 80 mg QW followed by 160 mg Q2W, and for aggressive B-NHL is 160 mg QW followed by 320 mg Q2W. All patients with durable complete responses of 9 months will transition from Q2W to Q4W dosing. The primary endpoint for each cohort is objective response rate (ORR) by independent central review, as assessed from first dose until completion of 28 weeks of study treatment, or study withdrawal. Secondary endpoints include complete response (CR) rate, progression-free survival, duration of response, disease control rate (DCR), overall survival, incidence and severity of treatment-emergent adverse events, pharmacokinetics, immunogenicity, and patient-reported outcomes. ORR, CR rate and DCR with a two-sided 95% confidence interval (CI) will be summarized. Time-to-event endpoints will be summarized by median and corresponding 95% CI using the Kaplan-Meier method. The study is actively accruing patients at sites across North America, Europe, and Asia-Pacific. Disclosures Kim: AstraZeneca: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Voronoi: Consultancy; Boryung: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding. Stevens:Amgen, MorphoSys: Consultancy. Poon:Astrazeneca, Pfizer, Takeda, Janssen, Roche, Novartis: Honoraria. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. Carpio:Takeda, Regeneron: Consultancy. Keating:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Adriaens:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Dosing regime that mitigates cytokine release syndrome for therapeutic antibodies (status: pending). Ufkin:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Sabir:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Li:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Jankovic:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Zhu:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Brouwer-Visser:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Leng:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Sirulnik:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Chaudhry:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Ambati:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Won Seog:Roche, Takeda, J&J, Kyowa-Kirin, Celltrion ,Pfizer, Donga: Research Funding. OffLabel Disclosure: The Trial in Progress abstract will report on use of odronextamab in a Phase 2 clinical trial of patients with B-NHL

Some HLA alleles have been shown to be associated with susceptibility to cytomegalovirus (CMV) disease incidence in vitro. The objective of this study was to identify correlations between donor HLA allotypes and CMV disease incidence in patients with acute myeloid leukemia who had undergone allogeneic hematopoietic stem cell transplantation (HSCT). Methods and materials we retrospectively analyzed the medical records of 613 donors and recipients with acute myeloid leukemia who had received an allogeneic HSCT from matched sibling (n = 260), unrelated (n = 168), or haploidentical (n = 186) donors, from 2012 to 2017. The HLA-A, -B, -C, and -DRB1 allotypes in the donors were determined using sequence-based typing. Overall, CMV disease incidence was significantly associated with three genotype alleles, HLA-A*30:04:01G, -B*51:01:01G, and -DRB1*09:01:02G. In the donor CMV IgG seropositive subgroup, CMV disease incidence was significantly associated with HLA-B*51:01:01G and -DRB1*09:01:02G. In the IgG seropositive donors in the unrelated allo-HSCT subgroup CMV disease incidence was also significantly associated with HLA-B*51:01:01G. In the CMV seropositive donors in the haploidentical allo-HSCT subgroup, the incidence of CMV disease was significantly associated with HLA-A*24:02:01G and -DRB1*09:01:02G. HLA-DRB1*13:02:01G was a protective marker among IgG seropositive donors in the unrelated allo-HSCT recipient category. Discussion and conclusions The incidence of CMV disease among HSCT recipients varies according to donor HLA alleles and the donor CMV IgG serostatus. Certain donor HLA alleles can be considered to be risk or protective markers. Donors' HLA types and CMV IgG serostatus should be considered in donor selection.

BACKGROUND Mesenchymal stem cells (MSCs) are an attractive tool to treat graft-versus-host disease because of their unique immunoregulatory properties. Although human bone marrow-derived MSCs (BM-MSCs) were the most widely used MSCs in cell therapy until recently, MSCs derived from human umbilical cords (UC-MSCs) have gained popularity as cell therapy material for their ethical and noninvasive collection. AIM To investigate the difference in mechanisms of the immunosuppressive effects of UC-MSCs and BM-MSCs. METHODS To analyze soluble factors expressed by MSCs, such as indolamine 2,3-dioxygenase, cyclooxygenase-2, prostaglandin E2 and interleukin (IL)-6, inflammatory environments in vitro were reconstituted with combinations of interferon-gamma (IFN-γ), tumor necrosis factor alpha and IL-1β or with IFN-γ alone. Activated T cells were cocultured with MSCs treated with indomethacin and/or anti-IL-10. To assess the ability of MSCs to inhibit T helper 17 cells and induce regulatory T cells, induced T helper 17 cells were cocultured with MSCs treated with indomethacin or anti-IL-10. Xenogeneic graft-versus-host disease was induced in NOG mice (NOD/Shi-scid/IL-2Rγnull) and UC-MSCs or BM-MSCs were treated as cell therapies. RESULTS Our data demonstrated that BM-MSCs and UC-MSCs shared similar phenotypic characteristics and immunomodulation abilities. BM-MSCs expressed more indolamine 2,3-dioxygenase after cytokine stimulation with different combinations of IFN-γ, tumor necrosis factor alpha-α and IL-1β or IFN-γ alone. UC-MSCs expressed more prostaglandin E2, IL-6, programmed death-ligand 1 and 2 in the in vitro inflammatory environment. Cyclooxygenase-2 and IL-10 were key factors in the immunomodulatory mechanisms of both MSCs. In addition, UC-MSCs inhibited more T helper 17 cells and induced more regulatory T cells than BM-MSCs. UC-MSCs and BM-MSCs exhibited similar effects on attenuating graft-versus-host disease. CONCLUSION UC-MSCs and BM-MSCs exert similar immunosuppressive effects with different mechanisms involved. These findings suggest that UC-MSCs have distinct immunoregulatory functions and may substitute BM-MBSCs in the field of cell therapy.

Although the antimyeloma effect of lenalidomide is associated with activation of the immune system, the exact in vivo immunomodulatory mechanisms of lenalidomide combined with low-dose dexamethasone (Len-dex) in refractory/relapsed multiple myeloma (RRMM) patients remain unclear. In this study, we analyzed the association between immune cell populations and clinical outcomes in patients receiving Len-dex for the treatment of RRMM. Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len-dex therapy. Peripheral blood CD3(+), CD4(+), and CD8(+) cell frequencies were significantly decreased by 3 cycles of therapy, whereas NK cell frequency was significantly increased after the 3rd cycle. For the myeloid-derived suppressor cell (MDSC) subset, the frequency of granulocytic MDSCs transiently increased after the 1st cycle, whereas there was an increase in monocytic MDSC (M-MDSC) frequency after the 1st and 3rd cycles. Among 81 evaluable patients, failure to achieve a response of VGPR or greater was associated with a decrease in CD8(+) cell frequency and increase in M-MDSC frequency after 3 cycles of Len-dex treatment. A high proportion of natural killer T (NKT)-like cells (CD3(+)/CD56(+)) prior to Len-dex treatment might predict a longer time to progression. In addition, patients with a smaller decrease in the frequency of both CD3(+) cells and CD8(+) cells by 3 cycles exhibited a longer time to the next treatment. These results demonstrated that early changes in immune cell subsets are useful immunologic indicators of the efficacy of Len-dex treatment in RRMM.

Antihuman T-lymphocyte immune globulin (ATG) was shown to lower the incidence of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor. The type, dose, and duration of ATG treatment is a matter of ongoing controversy in allo-HSCT. Furthermore, there has been no phase 3 study to explore the role of ATG-thymoglobulin for the prevention of cGVHD in allo-HSCT from matched siblings, whereas results from a recent randomized trial of ATG-Fresenius was reported (NEJM 2016). We performed a prospective, single-center, open-label, randomized trial of ATG-thymoglobulin as a part of the conditioning regimen. The primary endpoint was the cumulative incidence (CI) of cGVHD at a 2-year evaluation. A total of 126 patients with acute leukemia were planned to be enrolled and assigned randomly at a 1:1 ratio to receive ATG-thymoglobulin (1.25 mg/kg at three and two days before allo-HSCT) or receive no ATG-thymoglobulin stratified according to the refined Disease Risk Index and conditioning intensity. Both groups were well balanced for NCCN risk, disease type, disease status, and MRD status at HSCT. The current study finally enrolled 120 patients with a median of 560 days of follow-up (range 52 - 1257). The CI of cGVHD in the ATG group (n=60) and non-ATG (n=60) group at 2 years after allo-HSCT was 37.2% and 82.7%, respectively (p In conclusion, the current study revealed that the use of ATG-thymoglobulin, even at a relatively low dose (2.5 mg/kg), decreases the occurrence of cGVHD at a cost of an increased risk for relapse in the setting of allo-HSCT from matched sibling donors for acute leukemia. The optimal dose, timing, and duration of ATG-thymoglobulin should be investigated further. Disclosures Kim: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding; ILYANG: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AML Global Portal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL&H: Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy, Honoraria; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Yuhan: Consultancy, Honoraria; SL VaxiGen: Consultancy, Honoraria; AbbVie: Honoraria; Sanofi-Genzyme: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background The aim of this study is to evaluate the prognostic impact of myeloid-derived suppressor cells (MDSCs) in multiple myeloma (MM) in the context of autologous stem cell transplantation (ASCT). Methods Peripheral blood samples were collected for measuring monocytic (M-) MDSCs (CD14posHLA-DRlow/neg) and early-stage (E-) MDSCs (LinnegHLA-DRnegCD33posCD11bpos) before and after ASCT. Clinical outcomes following ASCT differed according to the frequency of each MDSC phenotype. Results In the pre-ASCT analyses, lower M-MDSCs (

Oral mucositis (OM) is a common complication in cancer patients undergoing anticancer treatment. Despite the clinical and economic consequences of OM, there are no drugs available for its fundamental control. Here we show that high-mobility group box 1 (HMGB1), a “danger signal” that acts as a potent innate immune mediator, plays a critical role in the pathogenesis of OM. In addition, we investigated treatment of OM through HMGB1 blockade using NecroX-7 (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholin-4-yl)methyl-1Hindole-7-yl]amine). NecroX-7 ameliorated basal layer epithelial cell death and ulcer size in OM induced by chemotherapy or radiotherapy. This protective effect of NecroX-7 was mediated by inhibition of HMGB1 release and downregulation of mitochondrial oxidative stress. Additionally, NecroX-7 inhibited the HMGB1-induced release of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and macrophage inflammatory protein (MIP)-1β, as well as the expression of p53-upregulated modulator of apoptosis (PUMA) and the excessive inflammatory microenvironment, including nuclear factor-kB (NF-kB) pathways. In conclusion, our findings suggest that HMGB1 plays a key role in the pathogenesis of OM; therefore, blockade of HMGB1 by NecroX-7 may be a novel therapeutic strategy for OM.

Cytomegalovirus (CMV)-reactivation is associated with graft-vs-leukemia (GVL) effect by stimulating natural-killer or T-cells, which showed leukemia relapse prevention after hematopoietic stem cell transplantation (HSCT). We enrolled patients with acute myeloid leukemia (n = 197) and acute lymphoid leukemia (n = 192) who underwent allogeneic-HSCT in first remission. We measured RQ-PCR weekly to detect CMV-reactivation and preemptively used ganciclovir (GCV) when the titer increased twice consecutively, but GCV was sometimes delayed in patients without significant graft-vs-host disease (GVHD) by reducing immunosuppressive agents. In the entire group, CMV-reactivation showed poor overall survival (OS). To evaluate subsequent effects of CMV-reactivation, we excluded early relapse and deaths within 100 days, during which most of the CMV-reactivation occurred. Untreated CMV-reactivated group (n = 173) showed superior OS (83.8% vs. 61.7% vs. 74.0%, p < 0.001) with lower relapse rate (10.1% vs 22.1% vs. 25.5%, p = 0.004) compared to GCV-treated CMV-reactivated group (n = 122) and CMV-undetected group (n = 42). After excluding chronic GVHD, untreated CMV-reactivated group still showed lower relapse rate (9.4% vs. 24.1% vs. 30.2%, p = 0.006). Multivariate analysis showed adverse-risk karyotype and patients in other than untreated CMV-reactivated group were independent factors for relapse prediction. Our data showed possible GVL effect of CMV-reactivation and minimizing antiviral therapy may benefit for relapse prevention in acute leukemia.

Interleukin (IL)-21, a proinflammatory cytokine, has been developed as an immunotherapeutic approach due to its effects on various lymphocytes, including natural killer (NK) cells and T cells; however, the clinical success in cancer patients has been limited. Recently, mesenchymal stem cells (MSCs) have emerged as vehicles for cancer gene therapy due to their inherent migratory abilities toward tumors. In the present study, we hypothesized that MSCs, genetically modified to express high levels of IL-21 (IL-21/MSCs), can enhance antitumor responses through localized delivery of IL-21. For tumor induction, BALB/c mice were injected intravenously with syngeneic A20 B-cell lymphoma cells to develop a disseminated B-cell lymphoma model. Then, 6 days following tumor induction, the tumor-bearing mice were treated with IL-21/MSCs weekly, four times. Systemic infusion of A20 cells led to hind-leg paralysis as well as severe liver metastasis in the control group. The IL-21/MSC-treated group showed delayed tumor incidence as well as improved survival, whereas the MSC- and recombinant adenovirus-expressing IL-21 (rAD/IL-21)-treated groups did not show significant differences from the untreated mice. These therapeutic effects were associated with high levels of IL-21 delivered to the liver, which prevented the formation of tumor nodules. Furthermore, the infusion of IL-21/MSCs led to induction of effector T and NK cells, while potently inhibiting immune suppressor cells. Our findings demonstrate that IL-21-expressing MSCs have the therapeutic potential to induce potent antitumor effects against disseminated B-cell lymphoma through localized IL-21 delivery and induction of systemic antitumor immunity.

Aim Current guidelines recommend all patients scheduled to receive chemotherapy should be screened for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B virus core antigen (anti-HBc) status. However, still, more research is needed to identify the risk factors for hepatitis B virus (HBV) reactivation. We retrospectively investigated the incidence, risk factors and outcome of HBV reactivation in HBsAg negative patients with hematological malignancies. Methods Seven hundred and thirty-eight HBsAg negative patients with hematological malignancies were included in the study. HBV reactivation was defined as reverse seroconversion of HBsAg (HBsAg reappearance). Risk factors, cumulative incidence and overall survival of HBV reactivation were analyzed. Results Reactivation occurred in 23 of the 738 (3.1%) enrolled patients. As expected, the reactivation rate of the anti-HBc positive group was significantly higher than that of the anti-HBc negative group (5.4% vs 0.8%). Multivariate analysis indicated that loss of antibody to the hepatitis B surface antigen (anti-HBs) was an independent risk factor. Patients with acute lymphoblastic leukemia and multiple myeloma showed significantly higher reactivation rate than those with other diseases. The cumulative incidence of HBV reactivation after starting chemotherapy in the anti-HBc positive subgroup was 0.3% at 1 year, 1.7% at 2 years and 10.5% at 3 years. Conclusion Close monitoring of HBV markers, including anti-HBs, should be performed for longer than 24 months. Further study is needed to establish a strategy to prevent HBV reactivation after chemotherapy in HBsAg negative patients with hematological malignancies.

Graft-versus-host disease (GVHD) is a major complication associated with allogeneic hematopoietic stem cell transplantation. Despite the prominent role of the adaptive immune system, the importance of controlling the innate immune system in the pathogenesis of GVHD has recently been rediscovered. High-mobility group box 1 (HMGB1) is a crucial damage-associated molecular pattern signal that functions as a potent innate immune mediator in GVHD. In the present study, we investigated treatment of experimental GVHD through HMGB1 blockade using the compound cyclopentylamino carboxymethylthiazolylindole (NecroX)-7. Treated animals significantly attenuated GVHD-related mortality and inhibited severe tissue damage. These protective effects correlated with the decrease in HMGB1 expression and lower levels of reactive oxidative stress. Additionally, NecroX-7 inhibited the HMGB1-induced release of TNF and IL-6, as well as the expression of TLR-4 and receptor for advanced glycation end products. We also observed increased regulatory T cell numbers, which may be associated with regulation of differentiation signals independent of HMGB1. Taken together, these data indicate that NecroX-7 protects mice against lethal GVHD by reciprocal regulation of regulatory T/Th1 cells, attenuating systemic HMGB1 accumulation and inhibiting HMGB1-mediated inflammatory response. Our results indicate the possibility of a new use for a clinical drug that is effective for the treatment of GVHD.

Extranodal NK/T-cell lymphoma (ENKTCL) is associated with latent Epstein-Barr virus (EBV) infection and frequent relapse even after complete response (CR) to intensive chemotherapy and radiotherapy. The expression of EBV proteins in the tumor provides targets for adoptive immunotherapy with antigen-specific cytotoxic T cells (CTL). To evaluate the efficacy and safety of EBV latent membrane protein (LMP)-1 and LMP-2a-specific CTLs (LMP1/2a CTLs) stimulated with LMP1/2a RNA-transferred dendritic cells, we treated 10 ENKTCL patients who showed complete response to induction therapy. Patients who completed and responded to chemotherapy, radiotherapy, and/or high-dose therapy followed by stem cell transplantation (HDT/SCT) were eligible to receive eight doses of 2 × 10(7) LMP1/2a CTLs/m(2). Following infusion, there were no immediate or delayed toxicities. The 4-year overall survival (OS) and progression-free survival (PFS) were 100%, and 90% (95% CI: 71.4 to 100%) respectively with a median follow-up of 55·5 months. Circulating IFN-γ secreting LMP1 and LMP2a-specific T cells within the peripheral blood corresponded with decline in plasma EBV DNA levels in patients. Adoptive transfer of LMP1/2a CTLs in ENKTCL patients is a safe and effective postremission therapeutic approach. Further randomized studies will be needed to define the role of EBV-CTLs in preventing relapse of ENKTCL.

CD161 is a type II transmembrane glycoprotein with characteristics of the C-type lectin superfamily, which has recently been shown to promote T cell expansion. In this study, the role of T cells expressing CD161 as a predictor for the occurrence of acute graft-versus-host disease (aGVHD) after allogeneic stem cell transplantation (SCT) was investigated. Sixty-one patients who underwent first allogeneic SCT were enrolled. At engraftment, the expression of CD3, CD4, CD8, CD161, CD16, and CD56 was analyzed by flow cytometry. After adjusting for potential variables by univariate analysis, we performed a multivariate analysis, which revealed a low frequency of CD8(+)CD161(+) cells (P = .034) and a high ratio of CD4(+)CD161(+) to CD8(+)CD161(+) cells (P = .001) were associated with the occurrence of aGVHD with a grade of ≥ II. Moreover, the frequency of CD8(+)CD161(+) T cells was negatively correlated with aGVHD grade. A separate analysis for visceral aGVHD showed similar results, with a low frequency of CD8(+)CD161(+) T cells (P = .031) or a high ratio of CD4(+)CD161(+) to CD8(+)CD161(+)cells (P.001), indicating a high risk. Also, the predictive role of serum IL-17 levels for the occurrence of aGVHD was identified, and RORγT was more highly expressed in CD4(+)CD161(+) T cells than in CD8(+)CD161(+) T cells after allogeneic SCT (P = .032). Although our study was limited by the heterogeneity and small number of patients, these results suggest that the CD8(+) subset of CD161(+) T cells may have regulatory effects and that they provide a basis for predicting the occurrence of aGVHD after allogeneic SCT.

Emerging molecular studies have identified a subgroup of patients with unfavorable core-binding factor-positive (CBF)-AML who should be treated by intensified post-remission treatments. We analyzed 264 adults with CBF-AML from 2002 to 2011, and focused on 206 patients who achieved CR after standard '3+7' induction chemotherapy. Patients who achieved CR with an available donor were treated with allogeneic hematopoietic SCT (allo-HSCT, n=115) and the rest were treated with autologous (auto) HSCT (n=72) or chemotherapy alone (n=19). OS was not significantly different between CBFβ/MYH11 (n=62) and RUNX1/RUNX1T1 (n=144), and auto-HSCT showed favorable OS compared with allo-HSCT or chemotherapy alone. Cytogenetic analysis identified that inv(16) without trisomy had a favorable OS and t(8;21) with additional chromosomes had an unfavorable OS, but multivariate analysis revealed those were NS. Patients with c-kit mutation showed inferior OS. For transplanted patients, residual post-transplant CBF-minimal residual disease quantitative PCR with higher WT1 expression at D+60 showed the worst OS with a higher incidence of relapse. Conclusively, we found that unfavorable CBF-AML can be defined with risk stratification using cytogenetic and molecular studies, and a careful risk-adapted treatment approach using frontline transplantation with novel therapies should be evaluated for this particular risk subgroup.

Mesenchymal stem cells (MSCs) have been considered to be an ideal cellular source for graft-versus-host disease (GVHD) treatment due to their unique properties, including tissue repair and major histocompatibility complex (MHC)-unmatched immunosuppression. However, preclinical and clinical data have suggested that the immunomodulatory activity of MSCs is not as effective as previously expected. This study was performed to investigate whether the immunomodulatory capacity of MSCs could be enhanced by combination infusion of regulatory T (Treg) cells to prevent acute GVHD (aGVHD) following MHC-mismatched bone marrow transplantation (BMT). For GVHD induction, lethally irradiated BALB/c (H-2d) mice were transplanted with bone marrow cells (BMCs) and spleen cells of C57BL/6 (H-2b) mice. Recipients were injected with cultured recipient-derived MSCs, Treg cells, or MSCs plus Treg cells (BMT + day 0, 4). Systemic infusion of MSCs plus Treg cells improved clinicopathological manifestations and survival in the aGVHD model. Culture of MSCs plus Treg cells increased the population of Foxp3+ Treg cells and suppressed alloreactive T-cell proliferation in vitro. These therapeutic effects were associated with more rapid expansion of donor-type CD4+CD25+Foxp3+ Treg cells and CD4+IL-4+ type 2 T-helper (Th2) cells in the early posttransplant period. Furthermore, MSCs plus Treg cells regulated CD4+IL-17+ Th17 cells, as well as CD4+IFN-γ + Th1 cells. These data suggest that the combination therapy with MSCs plus Treg cells may have cooperative effects in enhancing the immunomodulatory activity of MSCs and Treg cells in aGVHD. This may lead to development of new therapeutic approaches to clinical allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) preconditioning intensity, donor choice, and graft-versus-host disease (GVHD) prophylaxis for advanced myelofibrosis (MF) have not been fully elucidated. Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling (n=16) followed by matched (n=10) or mismatched (n=5) unrelated and familial mismatched donors (n=4). Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation≤ 400cGy. All showed engraftments, but four (11.4%) showed either leukemic relapse (n=3) or delayed graft failure (n=1). Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III-IV acute GVHD was higher with HLA-mismatch (70% vs. 20%, p=0.008). Significant hepatic GVHD was observed in nine patients (5 acute, 4 chronic), and six of them died. Multivariate analysis revealed inferior OS with HLA-mismatch (HR=6.40, 95%CI 1.6-25.7, p=0.009) and in patients with high ferritin level at post-HCT D+21 (HR=7.22, 95%CI 1.9-27.5, p=0.004), which were related to hepatic GVHD and high NRM. RIC allo-HCT can be a valid choice for advanced MF. However, HLA-mismatch and high post-HCT ferritin levels related to significant hepatic GVHD should be regarded as poor-risk parameters. Disclosures Kim: Handok: Honoraria; Amgen: Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Background: Hemophagocytic lymphohistiocytosis (HLH) can be life-threatening if not detected and treated appropriately. Diagnosing HLH can be confusing due to other similar febrile diseases that present with cytopenia. Although a decrease in natural-killer cell (NK)-cytotoxicity is an important diagnostic parameter for primary HLH, the role in adult HLH has not been well-defined. Aim: To identify the diagnostic relevance and the significant cut-off values for NK cytotoxic function, we focused on patients that presented with fever with either cytopenia or evidence of hemophagocytosis. NK cytotoxicity was calculated at the time of diagnosis and we tried to identify significant differences between the causes of disease. Finally, the overall treatment response and survival outcomes were also evaluated based on the level of NK cytotoxicity in several subgroup analyses. Methods: We prospectively enrolled 123 adult patients that presented with fever accompanied by either cytopenia in at least two lineages or marrow hemophagocytosis. A diagnosis of HLH was based on HLH-2004 criteria and treated based on HLH-94 protocol. HLH-suspected patients were initially treated with 10mg/BSA of dexamethasone, and etoposide was considered if clinical improvement was not observed within 7 days after dexamethasone. Patients other than HLH were treated with disease-specified therapy. NK-cytotoxicity was calculated at diagnosis by K562-cell direct lysis using flow-cytometry. Results: HLH (n=60) was determined to be caused by Epstein-Barr virus (EBV, n=11), infection other than EBV (n=16), malignancies (n=19), and unknown (n=14). Febrile diseases other than HLH (n=63) were diagnosed as rheumatologic disease (n=22), malignancies (n=21), infection (n=12), non-malignant hematological diseases (n=6), and unknown (n=2). The results revealed that an HLH diagnosis was significantly correlated with lower NK-cytotoxicity, compared to other diseases (12.1% vs. 26.2%, p Conclusion: We determined that decreased NK-cytotoxicity is a relevant marker that can be used for diagnosis of adult HLH compared with several similar febrile diseases and is also related to poor OS in non-malignant febrile diseases. Based on these results and other prospective studies, we hope that additional relevant diagnostic criteria for adult HLH can be identified in the near future. Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Introduction: Recent data emerges that transplantation with reduced intensity conditioning (RIC) seems to be effective as myeloablative conditioning (MAC). However, relapse is a major concern with RIC, and identification of patients at equivalent probability of relapse irrespective of conditioning intensity is needed. Method: A total of 567 AML patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) betwene June 2012 and Jan 2018. For this study, we selected 287 patients who fulfilled i) intermediate or poor risk group by NCCN (2017.Version 3), ii) CR or CRi at HSCT, iii) received either MAC (BuCy or CyTBI) or RIC (FluBu2TBI400) peripheral blood stem cell transplant from 8/8 matched sibling donor (MSD) or matched unrelated donor (MUD), and iv) having bone marrow Wilms tumor gene 1 (WT1) expression results before transplant. The association between conditioning intensity, WT1 level at HSCT and post-transplant clinical outcomes involving overall survival (OS), disease free survival (DFS), cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) were evaluated first. And then we attempted to compare post-tranpslant outcomes between MAC and RIC groups in pre-transplant WT1low patients only. Results: Among the total 287 patients, 232 (80.8%) and 55 (19.2%) patients received MAC and RIC transplant. The median WT1 gene expression level at diagnosis (assessable in 255 patients) was 2310.0 copies/104ABL. When ≥ 250 copies/104ABL were classified as high expression of WT1 (WT1high), 77.3% (n=197) showed WT1high at AML diagnosis. In multivariate analysis, older age and WT1high before HSCT were designated as independent prognostic factor for inferior OS, DFS and higher CIR, and NCCN risk group at diagnosis was significantly associated with incidence of relapse; whereas, conditioning intensity or WT1 level at diagnosis were not prognostic for post transplant outcomes. After excluding patients without available information on initial WT1 level (n=32), whose WT1 levels were not overexpressed at diagnosis (n=58), and whose WT1 level ≥ 250 copies before transplant (n=45), we finally selected 152 pre-trasnplant WT1low patients for further analysis. Older age was still a significant independent factor for poor OS, DFS and higher NRM, whereas NCCN risk stratification at diagnosis was no longer prognostic for post-transplant outcomes in pre-trasnplant WT1low patients only. There was no significant difference in these outcomes between MAC (n=123) and RIC (n=29) patients, and pre-HSCT WT1 level as continuous variable remain significant for predicting relapse even if the level was below 250 copies. Conclusion: Post-transplant survival or relapse did not differ by conditioning intensity in AML CR1 patients whose WT1 level was below 250 copies per 104 ABL at transplant. Figure Disclosures Kim: BMS: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding; Novartis: Research Funding; Takeda: Research Funding. Lee:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Achillion: Research Funding. Kim:Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding.

Background The comprehensive geriatric assessment (CGA) typically refers to a multidimensional assessment designed to evaluate an older person's functional ability, physical health, cognition, psychological health, nutritional status, and social support. There is a significant heterogeneity in terms of their underlying health and resilience to the burden of disease and treatments in elderly AML (eAML). To date, a few have evaluated the predictive value of CGA among newly diagnosed eAML. The purpose of this study is to investigate the potential clinical value of CGA as a screening test for frailty in eAML. We designed a comprehensive CGA battery with measures which previously validated, standardized, and widely used. This study is a single-center prospective observational cohort study focused on discriminating between those older patients who are fit for intensive therapies and those who are vulnerable and may experience excess toxicity. Patients and method This prospective cohort study is to investigate the predictive values of each domain of CGA to discriminate vulnerable patients in eAML fit for intensive chemotherapy. Between November 2016 and July 2019, we enrolled newly diagnosed eAML patients aged ≥60 years considered fit for intensive chemotherapy, who had adequate performances and organ functions. All the enrolled patients were administered various questionnaires for an initial CGA and functional evaluation divided into 3 categories; (1) Social and Nutritional support (OARS and MNA), (2) Psychological (MMSE-KC, SGDS-K, PHQ-9, NCCN distress thermometer, MADRS, and KNU-DESC), and (3) Physical function (ECOG, KIADL, SPPB, Handgrip strength, and PTA by professional ENT evaluation). Results Seventy-seven patients were enrolled, in whom the median age of 64 years (range, 60-74), 58.4% were males, and 93.5% and 77.9% of patients had on ECOG score of 0~1 and HCT-CI score of 0~2, respectively. All enrolled patients were treated with intensive chemotherapy, and 62.3% achieved the first complete remission. Three patients experienced early death within 60 days (3.9%). During induction chemotherapy, the median recovery period for neutrophil and platelet counts was 26 (range, 24-29) and 30 (range, 27-33) days, respectively. The median hospitalization days for induction chemotherapy were 32 days (range, 21-104), and infection and GI complications (NCI-CTC-AE based any grade 79.2% and 67.5% respectively) were the most common complications primarily affecting tolerance to the initial chemotherapy. The grade III to IV infection, GI complications, hepatopathy, and acute kidney injury developed in 67.5%, 42.9%, 37.7%, and 16.9% of patients, respectively. Physical impairments were significantly associated with a higher incidence of infection (intact vs. any impairments; 46.4% vs. 79.6%, p=0.003), of which handgrip strength was most accurate tool to predict infection risk (p =0.032), and a trend of more GI complications (intact vs. any impairments; 28.6% vs. 51.0%, p=0.056), resulting in prolonged hospitalization (intact vs. any impairments; 32.2±1.7 days vs. 37.5±2.1 days, p=0.088) for the period of induction chemotherapy. Psychological impairment (intact vs. any impairments; 30.9±1.3 days vs. 38.2±2.1 days, p=0.005), particularly cognitive dysfunction measured by MMSE-KC (p=0.033), was also significantly associated with prolonged hospitalization. Conclusions This data demonstrates that a significant proportion of eAML fit for intensive chemotherapy based on performance status and comorbidity had social, nutritional, physical, psychological impairments by initial CGA assessments. These interim data focusing on early events suggest that impaired physical and/or psychological functions would be useful to identify eAML with intolerance to intensive chemotherapy. This ongoing exploratory prospective study will enroll more eAML patients (targets number=100) and further follow up currently enrolled patients, which will give us invaluable data to develop practical frailty marker and a new model for fitness for intensive chemotherapy. Disclosures Kim: Takeda: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Kim:Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding.

Background: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a recently recognized high-risk subgroup of T-cell ALL. T-cell ALL is characterized by poorer survival outcomes compared to B-cell ALL, but the optimal treatment strategies are not well elucidated yet. Aim: We performed integrative genetic analyses and tried to find important genetic events in T-cell ALL. We also identified clinical outcomes of T-cell ALL including ETP-ALL subgroup, which were treated with myeloid-suppressive chemotherapy followed by allogeneic hematopoietic cell transplantation (allo-HCT) for post-remission therapy. Methods: We enrolled 40 adult patients with T-cell ALL for analyses of gene mutations and treatment outcomes. Integrative genetic analyses were performed with massive parallel sequencing for NOTCH1, FBXW7, DNMT3A, PHF6, RUNX1, KRAS, NRAS, PTEN, GATA3, EZH2 and SH2B3, and multiplex ligation-dependent probe amplification (MLPA) for copy number alterations of several genes. Among them, quantification of CDKN2A and CDKN2B mRNA expression was performed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). All were treated with myeloid-suppressive chemotherapy which consisted of hyper-fractionated cyclophosphamide (300 mg/BSA, every 12 h, days 1-3), vincristine (1.4 mg/BSA, maximum dose 2 mg, days 4 and 11), daunorubicin (45 mg/m2, days 4 and 11), and dexamethasone (40 mg, days 1-4 and days 11-14) for remission induction, followed by consolidation with high-dose cytarabine (2 g/BSA, every 12 h, days 1-5) and mitoxantrone (12 mg/BSA, days 1-2). Above two anthracycline-intensified regimens were alternatively used for further consolidation. For patients not in complete remission (CR), mitoxantrone (12 mg/BSA, d 1-4), cytarabine (2 g/BSA, every 12 h, d 1-4) and etoposide (100 mg/BSA, d 5-7) were used for reinduction. Our strategy for T-cell ALL in CR was to offer allo-HCT according to the donor availability. Results: We identified 16 patients with ETP-ALL presenting 1 or more stem cell or myeloid marker with absence of CD1a, CD5, and CD8 expression, and 24 patients with non-ETP-ALL. For genetic mutation profiles between ETP-ALL and non-ETP-ALL, we found DNMT3A was more frequently observed in ETP-ALL (25% vs. 12.5%), while FBXW7 (33.3% vs. 6.2%) and RUNX1 (25.0% vs. 0.0%) were more frequently observed in non-ETP-ALL. We also observed that CDKN2A expression was significantly higher in ETP-ALL (0.053 vs. 0.001, p=0.017). In total, 33 (82.5%) patients achieved CR (24 after induction, 9 after reinduction) and their estimated 5-year overall survival (OS) was 31.3% with median survival of 18.9 months. All 16 (100%) patients with ETP-ALL achieved CR (13 after induction, 3 after reinduction), while non-ETP-ALL in 17 (70.8%, 11 after induction, 6 after reinduction) patients. Estimated 5-year OS of ETP-ALL was 41.7% and non-ETP-ALL was 24.3% (p=0.135). Finally, 12 (75.0%) out of 16 ETP-ALL and 11 (45.8%) out of 24 non-ETP-ALL underwent allo-HCT in CR and their 5-year OS was 55.6% and 45.5%, respectively. Conclusion: Our data suggested different genetic predisposition between ETP-ALL and non-ETP-ALL and myeloid-suppressive chemotherapy showed a good CR rate in ETP-ALL. Myeloid-suppressive chemotherapy induced CR followed by post-remission allo-HCT can be a good solution for improving poor survival outcome of ETP-ALL. Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.