Abstract: A preemptive strategy has successfully decreased cytomegalovirus (CMV) disease after allogeneic hematopoietic cell transplantation (HCT). However, some recipients still develop CMV gastroenteritis, especially after acute graft-versus-host disease (aGVHD), and its incidence, risk factors, and prognostic impact remain to be elucidated. We retrospectively analyzed 3759 consecutive adult patients who developed grade II-IV aGVHD using a Japanese registry database. The cumulative incidence of CMV gastroenteritis was 5.7% by day 365 from the development of grade II-IV aGVHD. Advanced age (hazard ratio [HR], 1.60; 95% confidence interval [CI] , 1.16-2.22; P = .004), GVHD prophylaxis with mycophenolate mofetil and calcineurin inhibitor (HR, 1.73; 95% CI, 1.08-2.77; P = .024), lower-gut aGVHD (HR, 2.17; 95% CI, 1.58-2.98; P & lt; .001), and the use of systemic steroids (HR, 1.78; 95% CI, 1.16-2.74; P = .008) were independent risk factors for CMV gastroenteritis. Development of CMV gastroenteritis was associated with an increased risk of nonrelapse mortality (HR, 1.89; 95% CI, 1.50-2.39; P & lt; .001). Moreover, letermovir prophylaxis significantly reduced both the incidence of CMV gastroenteritis (HR, 0.50; 95% CI, 0.25-0.99; P = .047) and the risk of nonrelapse mortality (HR, 0.72; 95% CI, 0.52-0.99; P = .043). In summary, CMV gastroenteritis is a life-threatening complication that sets the need for preventive strategies with letermovir and targeted surveillance.

Abstract: Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for myelodysplastic syndrome (MDS) but is associated with high non-relapse mortality (NRM). Its use was originally limited to younger patients eligible for myeloablative conditioning (MAC). Introducing reduced-intensity conditioning (RIC), such as a combination of fludarabine with reduced doses of busulfan (Flu/Bu2), increased the number of elderly patients suitable for allo-HSCT. Additionally, a combination of fludarabine and myeloablative doses of busulfan (Flu/Bu4) was developed to retain the antitumor activity of MAC and reduce the NRM to the level of RIC. However, few published reports have compared Flu/Bu4 and Flu/Bu2 in patients with MDS. We thus retrospectively performed a nationwide study to compare the outcomes of Flu/Bu4 and Flu/Bu2 in MDS patients undergoing allo-HSCT. Methods Clinical data were obtained from the Japanese Data Center for Hematopoietic Cell Transplantation. Inclusion criteria were age ≥16 years, diagnosis of de novo MDS, first allo-HSCT between 2006 and 2018, and receiving Flu/Bu4 consisted of intravenous busulfan (12.8 mg/kg) and fludarabine (125-180 mg/m 2) or Flu/Bu2 consisted of intravenous busulfan (6.4 mg/kg) and the same dose of fludarabine. Administration of anti-thymocyte globulin and low-dose total body irradiation (TBI, total dose ≤4 Gy) was permitted. Propensity score (PS)-matched analysis was performed to minimize selection bias, and the PS was calculated by logistic regression using the following factors: age, sex, hematopoietic cell transplantation-comorbidity index, French-American-British classification at diagnosis, cytogenetic risk, International Prognostic Scoring System score at diagnosis, disease status at allo-HSCT, bone marrow (BM) blasts at allo-HSCT, days from diagnosis to allo-HSCT, stem cell source, graft-versus-host disease (GVHD) prophylaxis, administration of anti-thymocyte globulin and TBI, and year of allo-HSCT. PS matching was performed at a 1:1 ratio using the nearest neighbor-matching method; caliper width was fixed at 0.2. The primary endpoint was the 3-year overall survival (OS). Results In total, 3406 patients underwent their first allo-HSCT: 447 and 256 received Flu/Bu4 and Flu/Bu2, respectively. Among them, 202 patients were assigned to each of the Flu/Bu4 and Flu/Bu2 groups after PS matching. The PS model created comparable cohorts with balanced baseline characteristics. The median age was 61 (range, 21-75) years. At the time of allo-HSCT, BM blasts were ≥5% in 273 (67.6%) patients. Regarding stem cell source, BM, peripheral blood stem cell, and cord blood was used in 268 (66.3%), 51 (12.6%), and 85 (21.0%) patients, respectively. The median follow-up period for survivors was 1117 (range, 40-3784) days. The 3-year OS rates were 44.8% (95% confidence interval [CI], 37.1-52.1%) and 46.9% (95% CI, 39.2-54.2%) in the Flu/Bu4 and Flu/Bu2 groups, respectively (P = 0.671, Figure 1A). The 3-year GVHD- and relapse-free survival rates were 28.8% (95% CI, 22.2-35.7%) and 33.0% (95% CI, 26.2-40.0%; P = 0.357, Figure 1B); the 3-year cumulative incidence of relapse, 28.9% (95% CI, 22.6-35.6%) and 30.0% (95% CI, 23.6-36.6%; P = 0.471, Figure 1C); and the 3-year cumulative incidence of NRM, 28.2% (95% CI, 21.7-35.0%) and 27.1% (95% CI, 20.6-33.9%; P = 0.597, Figure 1D) in the Flu/Bu4 and Flu/Bu2 groups, respectively. The 100-day cumulative incidence of grade II-IV acute GVHD was significantly higher in the Flu/Bu4 group than in the Flu/Bu2 group (41.7% [95% CI, 34.8-48.4%] vs. 29.3% [95% CI, 23.2-35.7%], P = 0.012, Figure 1E). The 100-day cumulative incidences of grade III-IV acute GVHD were 11.4% (95% CI, 7.5-16.3%) and 6.5% (95% CI, 3.6-10.5%; P = 0.064), while the 1-year cumulative incidences of extensive chronic GVHD were 19.5% (95% CI, 14.2-25.4%) and 15.1% in the Flu/Bu4 and Flu/Bu2 groups, respectively (95% CI, 10.5-20.6%; P = 0.196, Figure 1F). According to the findings of subgroup analyses, no patient had a favorable OS when using either of the two regimens (Figure 2). Conclusion The OS did not significantly differ between the Flu/Bu4 and Flu/Bu2 groups. While the Flu/Bu4 group was at an increased risk of acute GVHD, the relapse was not significantly different between the two groups. Data from more patients are needed to determine the optimal intensity of conditioning regimens in patients with MDS. Figure 1 Figure 1. Disclosures Kanda: Sanofi: Research Funding; MSD: Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding. Kako: Novartis Pharma K.K.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Bristol-Myers Squibb/Celgene K.K.: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Fuji Pharma Co., Ltd.: Honoraria; CSL Behring K.K.: Honoraria; Amgen K.K.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria. Imada: Novartis Pharma K.K.: Honoraria; Takeda Pharmaceutical Co. Ltd.: Honoraria; Otsuka Pharmaceutical Co. Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; Celgene Co., Ltd.: Honoraria. Kanda: Astellas Pharma Inc.: Consultancy, Honoraria; Bristol-Myers Squibb Co: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; NextGeM Inc: Patents & Royalties; Novartis Pharma K.K.: Honoraria; Ono Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Astellas BioPharma: Honoraria; TEIJIN PHARMA LIMITED.: Honoraria. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria.

Abstract: Background Therapy-related myeloid neoplasms (t-MN) have a poor prognosis with conventional chemotherapy and a median survival of ≤1 year. Allogeneic stem cell transplantation (HCT) is considered the only effective treatment. EBMT and CIBMTR analyzed their registry data on HCT against t-MN and reported its outcome and developed scoring systems using identified risk factors in HCT. This study aimed to investigate outcome and risk factors in adult patients with t-MN who underwent HCT in Japan. Methods Data source For this retrospective observational study, recipients' clinical data were provided by the Transplant Registry Unified Management Program of Japan society for Hematopoietic Cell Transplantation. Definition Therapy-related myeloid neoplasms include therapy-related AML (t-AML), t-MDS, and t-MDS/MPN occurring as late complications of cytotoxic chemotherapy and/or radiation therapy administered for a prior neoplastic or non-neoplastic disorder. Cases with past history of MDS or MPN were excluded because it was not possible to clearly distinguish their neoplasms from an original myeloid neoplasm or therapy-related neoplasm. The primary outcome of the analysis was overall survival (OS), whereas the secondary endpoints included incidence of relapse and transplantation-related mortality (TRM). Cytogenetic risk groups in AML were classified according to the MRC (2010). In MDS, three risk groups were defined using the revised International Scoring System: favorable (very good and good), intermediate (intermediate), poor (poor and very poor). HLA mismatch was defined as incompatibility between the recipient and donor when at least a single allele mismatch was detected at HLA-A, -B, and -DR in related and unrelated donors. In cord blood, HLA mismatch was defined as at least two antigen mismatches detected at HLA-A, -B, and -DR. Statistical analysis OS was estimated using the Kaplan-Meier method and was compared using the log-rank test. Cox's proportional-hazards regression model was used for multivariate analysis of prognostic factors. Cumulative incidence curves were used in a competing-risk setting to calculate the probability of relapse and TRM. Relapse and therapy-related deaths were considered a competing risk event for each other and were compared using Gray's test. Results Between 1992 and 2012, 641 adult patients who had undergone HCTs for confirmed t-MN (not de novo myeloid neoplasms) were identified. Median age at HCT was 53 (range; 16-80) years, with a female proportion of 49%. In total, 414 (64.6%) patients had AML, 215 (33.5%) had MDS, and 12 (1.9%) had MPN. Approximately 50% of patients had a prior history of lymphoma, 14.6% had acute leukemia, and 13.3% had breast cancer. Karyotype was available in 310 cases. Favorable karyotypes were detected in 11 (3.5%) cases, whereas intermediate and poor karyotypes were detected in 122 (39.4%) and in 177 (57.1%) cases, respectively. HLA mismatched HCT was 25.7%. Bone marrow or peripheral HCT from related donors was used in 189 (28.7%) cases, whereas bone marrow HCT from unrelated donor was used in 228 (35.7%) cases, and cord blood HCT was used in 229 (35.6%) cases. Approximately 30% of patients were in remission at HCT. Overall survival was 45.3% [95% confident interval (CI) 45-48], 33% (CI 29-37), and 28% (CI 24-32) at 1, 3, and 5 years, respectively. In multivariate analysis, the significant factors for poor survival were ECOG Performance Status (PS) 2-4 (HR 1.99; CI 1.45-2.72), disease status of non-remission at the time of HCT (HR 1.82; CI 1.33-2.50), patient age of 〉 55 years (HR 1.72; CI 1.32-2.24), and poor karyotype (HR 1.54; CI 1.15-2.05). The cumulative incidence of non-relapse mortality and relapse at 3 years was 37% and 36%, respectively. In a multivariate analysis, the significant factor for non-relapse mortality was patient age of 〉 55 years (HR 1.48; CI 1.09-2.02). For relapse, poor karyotype (HR 2.29; CI 1.65-3.18) was a significant factor. Conclusions PS 2-4, non-remission, higher patient age, and poor cytogenetics were predictive of poor survival. The outcome of HCT against therapy-related myeloid neoplasms in Japan was comparable to those of EBMT and CIBMTR. Disclosures Usuki: Novartis: Other: personal fees, Research Funding; GlaxoSmithKline: Other: personal fees, Research Funding; Taiho Pharmaceutical: Other: personal fees, Research Funding; Fuji Film RI Pharma: Other: personal fees; Chugai Pharmaceutical: Other: personal fees; Sumitomo Dainippon Pharma: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Boehringer Ingelheim: Other: personal fees, Research Funding; Nippon Shinyaku: Other: personal fees, Research Funding; Shionogi: Other: personal fees; Sanofi: Other: personal fees, Research Funding; MSD: Other: personal fees, Research Funding; SymBio Pharmaceutical: Other: personal fees, Research Funding; Eisai: Research Funding; Otsuka Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Other: personal fees, Research Funding; Shire: Research Funding; Takeda Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Research Funding; Bristol-Myers Squibb: Other; Astellas: Research Funding. Miyazaki:Chugai: Honoraria, Research Funding; Sumitomo Dainippon: Honoraria; Celgene Japan: Honoraria; Kyowa-Kirin: Honoraria, Research Funding; Shin-bio: Honoraria.

Abstract: Therapy‐related myelodysplastic syndromes (t‐MDS) are generally progressive and associated with poorer outcomes than de novo MDS (d‐MDS). To evaluate the outcome of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) for t‐MDS, we conducted a propensity score matched‐pair analysis of patients with t‐MDS and d‐MDS using a nationwide database. A total of 178 patients with t‐MDS underwent allo‐HSCT between 2001 and 2018, and 178 out of 3123 patients with d‐MDS were selected. The probability of 3‐year overall survival rate was 40.0% and 50.0% in the t‐MDS and d‐MDS groups, respectively ( p  = 0.032). The 3‐year transplant‐related mortality was 30.9% and 19.0% in the t‐MDS and d‐MDS groups, respectively ( p  = 0.005). The 3‐year cumulative incidence of relapse was 32.8% and 33.0% in the t‐MDS and d‐MDS groups, respectively ( p  = 0.983). A multivariate analysis identified four adverse factors for overall survival in the t‐MDS group: age ≥ 55 years (hazard ratio [HR], 2.09; 95% CI, 1.11–3.94; p  = 0.023), the poor cytogenetic risk group (HR, 2.19; 95% CI, 1.40–4.19; p  = 0.019), performance status at allo‐HSCT 2–4 (HR, 2.14; 95% CI, 1.19–3.86; p  = 0.011), and a shorter interval from diagnosis to transplantation ( 〈 8 months; HR, 1.61; 95% CI, 1.00–2.57; p  = 0.048). The most frequent cause of transplant‐related death was the infectious complications (21.6%) in t‐MDS group and organ failure (12.5%) in d‐MDS group. In conclusion, allo‐HSCT potentially provides long‐term remission in patients with t‐MDS; however, further efforts to reduce transplant‐related death are needed.

Abstract: The Hayabusa2 metal-sealed container successfully returned extraterrestrial He and Ne as a gas phase from the asteroid Ryugu.