ALBERT

Description: Objectives Fever during neutropenia occurs in 〉 90% and 80% of allogeneic and autologous hematopoietic stem cell transplantation (HSCT) recipients, respectively. Current guidelines recommend the prophylaxis with fluoroquinolones (FQs) in HSCT patients. Although there is evidence that antibiotic prophylaxis improve clinical outcome in patients with chemotherapy-induced neutropenia, prophylactic antibiotic therapy has not been thoroughly evaluated in HSCT recipients. Therefore, we performed a meta-analysis to evaluate the impact of systemic antibiotic prophylaxis in HSCT recipients on mortality, incidence of infection and related adverse events. Data sources We identified reports that were not restricted to those in English and not restricted to published trials through PubMed, the Cochrane Library, and references of identified studies. Review Methods We included prospective, randomized studies on systemic antibiotic prophylaxis in HSCT recipients. The outcome measures included the all-cause mortality, infection-related mortality, febrile episodes, incidence of clinically or microbiologically documented infection, bacteremia, or related adverse events. The summarized odds ratios (ORs) were calculated using the Mantel–Haenszel method and the DerSimonian–Laird method. Results Seventeen trials with 1453 patients (842 autologous and 407 allogeneic HSCT recipients) were included. The percentage of autologous and allogeneic HSCT recipients was not specified in 2 trials. Systemic antibiotic prophylaxis was compared with placebo or no prophylaxis in 10 trials and with non-absorbable antibiotic in 2 trials, respectively. Systemic antibiotics other than FQs were evaluated in five out of these 12 trials. Four trials evaluated the effect of addition of antibiotics for gram positive bacteria to FQs. Remaining 1 trial compared the two different systemic antibiotic regimens, FQs versus trimethoprim sulfamethoxazole. As a result, systemic antibiotic prophylaxis reduced the incidence of febrile episodes (OR 0.16; 95 percent confidence interval [CI], 0.09-0.30), clinically or microbiologically documented infection (OR 0.41; 95% CI 0.30-0.57) and bacteremia (OR 0.37; 95% CI 0.26-0.53) without the significant effect on all-cause mortality or infection-related mortality (OR 0.89; 95% CI 0.48-1.66, OR 1.37; 95% CI 0.50-3.76, respectively). Impact of prophylaxis with FQs on mortality was inconclusive because of small number of clinical trials evaluated. Adverse events increased in patients with systemic antibiotic prophylaxis compared to controls (OR 3.32; 95% CI 1.45-7.63). In meta-regression, percentage of allogeneic HSCT recipients was not associated with each outcome measure. With regard to the comparison between different prophylactic regimens, addition of antibiotics for gram positive bacteria to FQs decreased the incidence of bacteremia (OR 0.44; 0.24-0.80) without significant effects on all-cause mortality, infection related death and febrile episodes. There was not significant, but consistent decrease in clinically or microbiologically documented infection (OR 0.55; 95% CI 0.30-1.01). There was significant increase of adverse events in patients receiving addition of antibiotics for gram positive bacteria to FQs (OR 6.65; 95% CI 2.15-20.54). Conclusions Systemic antibiotic prophylaxis successfully reduced the incidence of infection in HSCT recipients. However, there was no significant impact on mortality. Impact of prophylaxis with FQs on mortality in HSCT recipients was inconclusive because of small number of trials evaluated. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Empiric antifungal therapy (EAT) is recommended for persistent or recurrent febrile neutropenia based on an old randomized controlled trial, but such treatment is apparently overtreatment for the majority of patients. On the other hand, preemptive therapy triggered by positive blood tests for fungal antigens and/or imaging study findings was shown to increase the incidence of invasive fungal infection, and thus, a risk-based approach is important. The D-index, which is defined as the area over the neutrophil curve during neutropenia and hence reflects both the duration and depth of neutropenia (Figure 1A), enables real-time monitoring of the risk of invasive fungal infection. Previous studies showed that the cumulative D-index (c-D-index), which was calculated as cumulative D-index from the onset of neutropenia (Figure 1B), had high negative predictive values for invasive mold infection or pulmonary infection with cutoff values of 5,800 or 5,500 in high-risk neutropenic patients [J Clin Oncol 2009; 27: 3849-54. Biol Blood Marrow Transplant 2010; 16: 1355-61]. Methods: We investigated a novel approach, called D-index-guided early antifungal therapy (DET) and compared it to EAT in high-risk neutropenic patients. In the EAT group, empiric antifungal therapy was started for persistent (〉=4 days) or recurrent febrile neutropenia. For patients with persistent or recurrent febrile neutropenia in the DET group, preemptive antifungal therapy was applied until c-D-index reached 5,500, but antifungal agent was initiated after c-D-index exceeded 5,500, even if there was no significant finding in serum fungal makers or imaging studies, to prevent excessive invasive fungal infection. Micafungin at 150 mg/day was administered as EAT or DET in this study. We randomized 423 patients who underwent chemotherapy or hematopoietic stem cell transplantation for hematological malignancies, in which predicted period of neutropenia exceeded 7 days, into the EAT group or the DET group, and 413 were eligible for intent-to-treat analyses (201 patients in the EAT group, 212 patients in the DET group). The prophylactic use of fluconazole or itraconazole was allowed. Primary endpoint was the development of proven/probable invasive fungal infection. Results: Backgrounds of the patients were similar between the 2 groups (Table 1). Invasive fungal infection (proven/probable/possible) was observed in 12 patients (6.0%) of the EAT group and 5 patients (2.4%) of DET group, respectively. Proven/probable invasive fungal infection was identified in 5 patients (2.5%) of the EAT group and 1 patient (0.5%) of DET group, which fulfilled the predetermined criteria of non-inferiority of the DET group. Regarding the pathogens, the EAT group included 1 case of candidemia and 4 cases of invasive pulmonary aspergillosis, and the DET group included one fusariosis. The survival rate of the EAT and DET group was 98.0% vs. 98.6% at day 42 and 96.4% vs. 96.2% at day 84, respectively. During the observation period, 31 patients died due to disease progression (n=19), infection (n=5) or other causes (n=7). Causes of infection related mortality included Pseudomonas aerginosa infection (n=2), fusariosis (n=1), toxoplasmosis (n=1) and septic shock by unknown pathogen (n=1). The frequency of micafungin use was significantly lower in the DET group than the EAT group (32.5% vs. 60.2%, P

Description: [Background] CD34-positive monocytes (CD34+mono) have recently been identified following mobilization by granulocyte-colony stimulating factor (G-CSF), and have been suggested to have a potential to modulate immune functions in animal models. However, the biological feature of CD34+mono in humans still remains unclear. Thus, we explored the difference between CD34+mono, CD34+cells, and monocytes through the analyses of gene expression profiles (GEP). [Methods] CD34+mono　(Lin-CD34+CD33+CD14+CD11b+, Figure1), CD34+cells (Lin-CD34+CD33-CD14-CD11b- ), and monocytes (Lin-CD34-CD33+CD14+CD11b+) were directly sorted into tubes from cryopreserved grafts from three healthy donors. After the extraction of total RNA, microarray analyses were performed with GeneChip™ 3' IVT Pico Kit and analyzed according to the algorithm of Transcriptome Analysis Console (Thermo Fisher Scientific). Condition false discovery rate (FDR) F-test was used for filtering genes, and the threshold was

Description: [Background] Macrophages are known to play a crucial role in chronic graft-versus-host disease (cGVHD). Recent studies revealed that increased expression and secretion of Galectine-3 (GAL3) were associated with macrophage activation and fibrosis, and Mac 2-Binding Protein (M2BP), which was known as GAL3 ligand, induced the secretion of IL-1, IL-6, and other cytokines by monocytes and macrophages. Meanwhile, Mac 2-Binding Protein Glycan Isomer (M2BPGi) has been developed as a reliable biomarker of liver fibrosis through glycoproteomic biomarker screening using lectin microarray technologies. We hypothesized that GAL3, M2BP, or M2BPGi could be associated with cGVHD and non-relapse mortality (NRM) in allogeneic hematopoietic cell transplant (HCT) recipients. [Patients & Methods] Patients gave written consent allowing blood sample collection. We retrospectively reviewed the medical records of consecutive adult patients who underwent their first allogenic HSCT at our center from January 2010 to December 2016. The plasma levels around day +180 were measured in 110 patients who survived for 〉180 days without disease relapse after allogeneic HCT, and the predictive potential of 3 markers for NRM was assessed using the discovery (n=55) and validation (n=55) cohorts. Samples were obtained at a median of 178 days (range, 133 to 274 days) after HCT. Among the 110 patients in total, the median age at HCT was 47 years (range 18 to 66 years). GVHD prophylaxis consisted of calcineurin inhibitors and short-term methotrexate. In vivo T-cell depletion with anti-thymocyte globulin or alemtuzumab was performed in HCT for aplastic anemia or HLA mismatched HCT. [Results] In the discovery cohort, receiver operating characteristics curve analysis showed that the best cutoff of GAL3, M2BP and M2BPGi at day +180 was 18, 70 and 1.5 with an area under the curve of 0.64, 0.75, and 0.91, respectively (Figure 1). Using this threshold, elevated M2BP and M2BPGi were significantly associated with higher NRM (M2BP; 15.0% vs. 0.0% at 5 years, P = 0.038, and M2BPGi; 15.0% vs. 0.0% at 5 years, P = 0.001). In the validation cohort, although M2BP was not significantly associated with NRM (29.8% vs. 13.4% at 5 years, P = 0.101), the adverse impact of M2BPGi on NRM was confirmed (34.0% vs. 8.4% at 5 years, P = 0.014) (Figure 2). The median sample collection timing was 179 days (range, 167 to 266 days) after HCT in the higher M2BPGi group compared with 178 days (range, 133 to 274 days) after HCT in the lower M2BPGi group (P = 0.620). On the other hand, M2BPGi was not increased in healthy individuals (n = 20) nor in patients who received autologous HCT (n = 11). Samples were collected at similar times around day +180 after autologous HCT. These results suggested that increased M2BPGi might be involved in the network in allogenic immune responses. In the entire cohort (n=110), M2BPGi was well related to liver involvement of cGVHD, while there was no association with other organ involvement. At day +180, increased M2BPGi was also correlated with higher cGVHD NIH global severity score (P = 0.004) as well as liver severity score (P 〈 0.001) (Figure 3), and lower platelet counts (P = 0.005). Multivariate analysis including cGVHD NIH global severity score, liver severity score and platelet counts at day +180 demonstrated that increased M2BPGi at day +180 was an independent risk factor for NRM (HR, 1.27; P 〈 0.001). Next, we determined the impact of M2BPGi on other time points. In earlier time point at day +90, NRM did not differ significantly according to M2BPGi in the validation cohort (the discovery cohort; 20.9% vs. 2.9% at 5 years, P = 0.016, and the validation cohort; 22.7% vs. 8.5% at 5 years, P = 0.690). In contrast, high M2BPGi at day +365 remained the significant risk factor for NRM in both cohorts (the discovery cohort; 17.6% vs. 0.0% at 5 years, P = 0.007, and the validation cohort; 40.8% vs. 6.1% at 5 years, P = 0.008). Because an increase in M2BPGi early after HCT can be caused by various reasons other than cGVHD, such as acute liver GVHD, thrombotic microangiopathy and drug exposure, its implications might be different from that during later period. [Conclusion] In conclusion, M2BPGi was a powerful predictor for late NRM after HCT. Further studies are required to determine the mechanism of elevations in M2BPGi after HCT. Importantly, this study indicated that the novel glycan profiling technologies might help to identify the potential biomarkers for GVHD in near future. Disclosures Nakasone: Phizer: Honoraria; Novartis: Honoraria; Kyowa Hakko Kirin: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Kimura:Astellas: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Other: Investigator in the institute; Nippon Kayaku: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria. Kako:Takeda Pharmaceutical Company Limited.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Celgene K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Kanda:Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; MSD: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; CSL Behring: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Tanabe-Mitsubishi: Research Funding; Taiho: Research Funding; Sanofi: Research Funding; Otsuka: Research Funding; Nippon-Shinyaku: Research Funding; Asahi-Kasei: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria.

Description: Recently, a growing body of evidence has suggested that adiponectin, which is secreted by adipose tissues, plays a critical role in obesity-related and autoimmune diseases. We compared the concentrations of adiponectin among 26 normal subjects and 34 allogeneic stem cell transplantation recipients. The concentrations of adiponectin were significantly higher in recipients with chronic graft-versus-host disease (cGVHD) than those in subjects without cGVHD (21.7 ± 11.0 vs 9.1 ± 6.1 μg/mL in females, P 〈 .001; and 10.1 ± 6.8 vs 4.3 ± 2.9 μg/mL in males, P = .003). Multivariate analysis revealed that a higher concentration of adiponectin was associated with female sex (β-coefficient 8.2, P 〈 .0001) and the severity of cGVHD (β-coefficient 6.6, 12.7, and 15.6, P 〈 .01, each for mild, moderate, and severe cGVHD, respectively). In addition, adiponectin levels increased as cGVHD progressed, decreased as cGVHD improved, and did not change with stable cGVHD. In conclusion, adiponectin was associated with the severity of cGVHD and might play a role in the pathophysiology of cGVHD.