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We retrospectively analyzed 12 consecutive adult severe aplastic anemia patients who received unrelated umbilical cord blood transplantation after a reduced-intensity conditioning regimen (RI-UCBT). The conditioning regimen consisted of 125 mg/m2 fludarabine, 80 mg/m2 melphalan, and 4 Gy of total body irradiation. The median infused total nucleated cell number and CD34+ cell number were 2.50 × 107/kg and 0.76 × 105/kg, respectively. Eleven of the 12 patients achieved primary neutrophil and platelet engraftment. All patients who achieved engraftment had complete hematologic recovery with complete donor chimerism, except for one patient who developed late graft failure 3 years after RI-UCBT. Two of the 12 patients died of idiopathic pneumonia syndrome, and the remaining 10 patients are alive, having survived for a median of 36 months. Our encouraging results indicate that RI-UCBT may become a viable therapeutic option for adult severe aplastic anemia patients who lack suitable human leukocyte antigen-matched donors and fail immunosuppressive therapy.

Delayed engraftment or graft failure is one of the major complications after cord blood transplantation (CBT). To investigate factors impacting engraftment, we conducted a retrospective analysis of adult patients who underwent reduced-intensity CBT at our institute, in which preparative regimens mainly consisted of fludarabine, melphalan, and total body irradiation with graft-versus-host (GVH) disease prophylaxis using single calcineurin inhibitors. Among 152 evaluable patients, the cumulative incidence of neutrophil engraftment was 89%. High total nucleated cell and CD34+ cell dose were associated with the faster speed and higher probability of engraftment. In addition, the degree of human leukocyte antigen (HLA) mismatch in the GVH direction was inversely associated with engraftment kinetics, whereas no statistically significant association was observed with the degree of HLA mismatch in the host-versus-graft direction. Similarly, the number of HLA class I antigens mismatched in the GVH direction, but not in the host-versus-graft direction, showed a negative correlation with engraftment kinetics. HLA disparity did not have significant impact on the development of GVH disease or survival. This result indicates the significant role of HLA disparity in the GVH direction in the successful engraftment, raising the novel mechanism responsible for graft failure in CBT.

Background: Bloodstream infection (BSI) is one of serious complications after allogeneic hematopoietic cell transplantation (HCT). Several risk factors have been described in previous reports. They included elderly patients, myeloid malignancies, myeloablative conditioning and HLA mismatch. In recent years, the number of umbilical cord blood used as an alternative donor source is rapidly increasing. The interval between transplant and neutrophil engraftment after umbilical cord blood transplantation (UCBT) is longer than that of other stem cell sources, and bacterial infections are one of the most serious concerns after UCBT. However, studies that focus on the impact of donor source on the incidence of BSI and include sufficient number of UCBT are lacking. In the study, we aimed to analyze the impact of umbilical cord blood on the development of BSI after allogeneic HCT retrospectively. Patient and Method: We retrospectively studied the patients who received transplant as first allogeneic HCT in Toranomon Hospital between Apr 2003 and Mar 2014. We analyzed the incidence of BSI that occurred within 100 days after transplant. BSI was defined as isolation of a bacterial or fungal pathogen from at least 1 blood culture, with the exception of coagulase-negative staphylococci (CNS) and normal contaminants (Corynebacterium species, Lactobacillus species, Bacillus species and Propionibacterium species), which required 2 separate blood cultures with the same antibiogram, to be considered a true infection. BSI was considered polymicrobial, if 2 or more pathogens were isolated in a single blood culture. The patients whose blood culture was positive within 2 weeks before transplant and the patients whose performance status (PS) were 4 before transplant were excluded. Result: A total of 1032 patients were extracted. Donors were related peripheral blood stem cell and/or bone marrow (r-PB/BM) in 155 patients, unrelated BM (ur-BM) in 243, and unrelated umbilical cord blood (ur-CB) in 634. The median age of recipient was 49 years (range, 16 - 82). Underlying diseases were as follows; AML (n=458), MDS (n=83), CML (n=30), MPN (n=15), MDS/MPN (n=13), ALL/LBL (n=134), CLL (n=3), AUL (n=9), NHL (n=162), HL (n=17), ATL (n=53), MM (n=16), AA (n=35) and others (n=4). The cumulative incidence of BSI was 47.6% (95% confidence interval, 44.5 - 50.6%) at 100 days after allogeneic HCT. The median onset of first BSI was day 7 (range, 0 - 99) after transplant. In 491 patients who developed BSI, a single pathogen was isolated in 409 patients (gram-positive cocci: GPC in 257, gram-negative rod: GNR in 112, gram-positive rod: GPR in 31, fungus in 9). Of the 491 patients with BSI, two pathogens were isolated in 74 patients (two GPCs in 37, one GPC & one GNR in 20, one GPC & one GPR in 13, two GNRs in 3, one GNR & one GPR in 1) and three pathogens were isolated in 8 patients (three GPCs in 5, two GPCs & one GNR in 1, two GPCs & one GPR in 1, one GPC & two GNRs in 1). Of the 581 isolates, GPCs accounted for 66%. The most frequent isolates in GPCs and GNRs were Staphylococcus epidermidis (34% in GPCs) and Pseudomonas aeruginosa (33% in GNRs), respectively. The cumulative incidence of BSI after transplants from r-PB/BM, ur-BM, ur-CB was 31.7%, 35.0%, 56.3%, respectively (p49 vs. ≤49, p Conclusion: The study included 634 UCBT and it allowed us to clarify the impact of umbilical cord blood on the development of BSI. We concluded that umbilical cord blood was the most significant risk factor for BSI after allogeneic HCT. BSI should be recognized as a serious complication that emerges in more than a half of recipients in the early phase after UCBT. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Background Invasive fungal infections (IFIs) are of great concern after allogeneic hematopoietic stem cell transplantation (HSCT), the risk of which is considered to be particularly prominent among cord blood transplantation (CBT) recipients. Patients and Methods We retrospectively analysed the records of 749 adult patients who underwent CBT or unrelated bone marrow transplantation (uBMT) for the first time at the Toranomon Hospital between 2002 and 2012, and who had neither prior history nor suspicious findings of IFIs. As prophylaxis for IFIs, fluconazole (FLCZ) or itraconazole (ITCZ) capsules were conventionally used until around 2006, which were then changed to newer mold-active agents including ITCZ oral solution, voriconazole or micafungin after their approval in Japan, the choice of which was subjected to physician's discretion. Results Engraftment achieved in 418 CBT patients and 198 uBMT patients with a significantly longer neutropenic period in CBT patients (median 20 days vs 18 days, P Four patients had 2 infectious episodes caused by different fungal species, and a total of 83 infectious episodes were documented. Eighty-one cases were breakthrough infection during antifungal prophylaxis (FLCZ/ITCZ capsules in 28, and newer mold-active agents in 53). Invasive aspergillosis (IA) was the most common, accounting for 67.9% (proven in 11, probable in 46), followed by invasive candidiasis (IC), (19.3%; candidemia in 15, encephalitis in 1). Although the incidences of IA and IC were comparable between CBT and uBMT patients, relatively rare type of IFIs caused by Trichosporon (4 cases), Mucor (2 cases) and Rodotorula (1 case) exclusively occurred in CBT patients, except one case of Fusarium infection in a patient who relapsed after uBMT. Grade II-IV acute GVHD, extensive chronic GVHD and systemic corticosteroids at ≥0.5mg/kg/day were identified as significant risk factors of IFIs for both groups (HR 1.89, P=0.01, HR 4.16, P=0.006, and HR 1.83, P=0.02). However, the impact of all these were not apparent in CBT patients (HR 1.59, P=0.16, HR 2.18, P=0.29 and HR 1.48, P=0.22), in contrast with the powerful impact in uBMT patients (HR 2.51, P=0.049, HR 10.23, P=0.03 and HR 2.87, P=0.03). Although the cessation of antifungal prophylaxis significantly increased the risk of IFIs in uBMT patients (HR 5.95, P=0.01), it showed no impact in CBT patients (HR 0.87, P=0.89). IFIs were main causes of death in 21 patients, which significantly affected non-relapse mortality in both CBT and uBMT patients (HR 3.93 and HR 6.08, both P Conclusion Unrelated cord blood did not increase an overall incidence of IFIs, because higher risk in the early post-transplant period was counterbalanced by the dramatically decreased risk due to lower frequencies of GVHD and its treatment in the later period. Particular attention might be required to the early-onset IFIs due to fungi other than Aspergillus or Candida species, in order to further decrease the risk of IFIs after CBT. Disclosures: No relevant conflicts of interest to declare.

Background Respiratory viral infections (RVI) in early phase after allogeneic stem cell transplantation (alloSCT) are associated with high morbidity and mortality and may result in institutional outbreak. So far, there have been few reports on incidence of RVI in alloSCT recipients with prospective surveillance. Methods We prospectively surveyed 247 recipients (271 transplants)who received alloSCT in Toranomon Hospital from June 2010 to May 2012. Oropharyngeal swab samples were collected weekly from each patient starting from 1 week before transplantation until 100 days after SCT. Respiratory viruses (RV) were isolated by viral culture (HHMV method). Symptoms related to RVI including fever, cough, sputum, and rhinorrhea were surveyed with patient questionnaire form. To exclude concomitant infection, culture of sputum and blood, serological tests (such as Aspergillus-galactomannan and beta-D-glucan), antigen test of influenza (Flu) and PCR of respiratory syncytial virus (RSV), parainfluenzavirus (PIV) type 3, and adenovirus (ADV) were routinely performed in symptomatic patients. RVI was defined by detection of RV from viral culture. Respiratory viral infectious disease (RVID) was defined as fulfilling both the definition of RVI and the presence of at least one of respiratory symptoms except for fever. In patients with RVID, chest X-ray and/or computed tomography were performed for the diagnosis of upper (URTID) or lower respiratory tract infectious disease (LRTID). Results One hundred and seventy-seven patients (65.3%) developed respiratory symptoms in first 100 days after alloSCT and RVs were detected from 59 patients (24.1%); PIV3 was detected in 49 patients, PIV2 in 3, PIV1 in 1, RSV in 2, FluA in 2, ADV in 1, and mumps virus in 1. There were no culture-positive patients without any symptoms. RVs were detected by PCR and antigen test from 25 culture-negative patients with respiratory symptoms; RSV was detected in 10 patients, PIV3 in 9, FluA in 1, RSV and PIV3 in 1, and PIV3 and ADV in 2. RSV was less detected by viral culture compared to PCR. All patients with RVI developed respiratory symptoms (median days of onset: 15.5 days), and symptoms presented before the detection of RVs in all of them. Radiological findings showed LRTID in 40 patients with RVI. Respiratory symptoms were improved in 39 of patients with RVI and the median duration from onset to cure of their RVID was 26 days (7-115). Although a majority of RVID was self-limited, seven patients (12.1%) died from RV-induced LRTID. Two of them developed interstitial pneumonia without other pathogens, and 5 of them had co-infection with other pathogens; Aspergillus spp. was detected in 1 patient, Pseudomonas aeruginosa in 1, Stenotrophomonas maltophilia in 1, and other RVs in 2 (RSV 1 and ADV 1) only detected by PCR. Six died patients developed RVI-induced LRTID before engraftment. Viral shedding occurred from 1 to 4 weeks (median: 1 week). Phylogenetic analysis of hemagglutinin-neuraminidase genes revealed institutional outbreak of PIV3 in 3 seasons (summer and winter in 2010, summer in 2011). Conclusion This study showed the high frequency of RV infections in early phase after alloSCT and horizontal dissemination of PIV3 in transplantation unit confirmed by genetical method. Although a majority of RVID was self-limited, patients who developed RVID before engraftment and had concomitant pulmonary infection were sometimes fatal. Thorough prophylactic strategy for respiratory viruses including early precise detection and patient isolation should be necessary to reduce the rate of RVI-induced mortality and to prevent outbreaks by RV. Disclosures: No relevant conflicts of interest to declare.

Abstract 4573 Background: Clostridium difficile, a gram-positive sprore-forming anaerobic bacillus, associated diarrhea (CDAD) is a major cause of nosocomial antibiotic-associated diarrhea. Hematopoietic stem cell transplant (HSCT) recipients are at increased risk of developing CDAD during the early posttransplant period due to prolonged exposure to broad-spectrum antibiotics and immunosuppressive agents. The incidence of CDAD has been increasing up to as high as 20% in allogeneic bone marrow (BMT) and peripheral blood stem cell transplantation (PBSCT). Although cord blood transplant (CBT) recipients are subjected to delayed immune constitution and high incidence of infectious complications to be risk factors for CDAD, the frequency of CDAD after CBT is unclear. We therefore retrospectively investigated the incidence and clinical features of CDAD in patients receiving CBT. Objectives/Methods: During the 2-yr retrospective period (2007–2008), 201 allogeneic HSCT were performed at the Department of Hematology of Toranomon Hospital: 135 CBT, 39 BMT and 27 PBSCT. The median age of the patients was 56 yr (range, 19–82 yr). All patients with diarrhea had a minimum of one diarrheal stool sample evaluated for the presence of toxin A. A patient found to have toxigenic Clostridium difficile by ELISA was diagnosed as CDAD. The cumulative incidence of CDAD was calculated using the Gray method considering death without CDAD as a competing risk. Overall survival (OS) was estimated by the Kaplan-Meier method. The time-dependent Fine and Gray proportional hazards model was used for multivariate analysis. Results: CDAD developed within 100 days in 11 out of 135 CBT recipients at a median onset of day 18 (range, 3–56 days). The cumulative incidence of CDAD after CBT was 9% at day 100 (Fig 1), which was similar to that after BMT (6%, P= 0.55) and to that after PBSCT (16%, P=0.27). All 17 patients who developed CDAD were successfully treated with using oral metronidazole or oral vancomysin. Of the 17 patients with CDAD, 7 (41%) died within 100 days after transplant, and the direct cause of death was irrelevant to CDAD in the 7 patients. The 1-yr survival after diagnosis of CDAD was 58%, which was comparable to that in patients without developing CDAD (59%, P=0.98). The univariate analysis failed to identify any significant risk factors for CDAD as well as the multivariate analysis. Conclusions: The current study showed that CDAD developed early after CBT at the incidence similar to BMT or PBSCT, and that prompt treatment for CDAD may work in improving its prognosis. It is therefore essential to recognize CDAD as one of the differential diagnosis of diarrhea because it is treatable complication after HSCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 4563 Introduction: Cord blood transplantation with fludarabine-containing toxicity-reduced conditioning (RT-CBT) has been widely applied to adult patients who have advanced hematologic diseases and are not eligible for conventional conditioning. Severe immune-mediated reactions early after transplant (preengraftment immune reactions, PIR) have been the major cause of early non-relapse mortality particularly for elderly patients. Mycophenolate mofetil (MMF) has been administered since late December 2005 at our institute and was shown to be effective in reducing early toxicity (Transplantation 92:366,2011). However, disease relapse has been the issue hampers successful outcomes, and the optimal GVHD prophylaxis has still not been established. We conducted a retrospective analysis of those who received RT-CBT at our institute using tacrolimus + MMF focusing on the impact of MMF dosing on the outcome. Design and Methods: We retrospectively reviewed patients aged 55 and older who underwent single-unit RT-CBT and GVHD prophylaxis using tacrolimus + MMF consecutively. Median dose of MMF was 33 mg/kg recipient body weight per day, ranging from 13 to 80 mg/kg, divided by 2 or 3 times at each physician’s determination. MMF was started on day -1 and continued until neutrophil recovery (>500/μl). Patients who had prior history of transplantation, were in poor performance status (ECOG PS 4 and greater), had active bacterial or fungal infections at the time of conditioning, had diagnosed as multiple myeloma were excluded. Results: From December 2005 to April 2011, 134 patients underwent RT-CBT at our institute. Twenty-seven were excluded due to active infection at the day of transplant or poor performance status, and 107 patients were subjected to the following analysis. The diagnoses included were AML/MDS (n=87), ALL (n=2) CML/MPD (n=4), ML (n=11), and SAA (n=3). Eighty-six (80%) had high risk diseases, and 29 (27%) and 6 (6%) were in ECOG PS 2 and 3, respectively. Cumulative incidence of neutrophil recovery >500/μl were 81 %. Median follow-up time of survivors was 521 days (range, 83 – 1847). Cumulative incidences of non-relapse mortality were 21.4 % and 27.3 % at day 100 and 1 year post-transplant, respectively. Overall survival and event-free survival at 1 year post-transplant were estimated as 47.7 % and 31.7 %, respectively. The patients were subdivided into 2 groups according to MMF dosing (≥30 vs. Conclusions: These data indicated that lower MMF dosing ( Disclosures: Off Label Use: Mycophenolate mofetil is used in off-label for GVHD prophylaxis.

Abstract 1954 Backgrounds: Viral infections remain serious complications after hematopoietic stem cell transplantation (HSCT), despite a remarkable progress of the prophylactic and treatment strategies. Detection of the early stage of viral reactivation and infection was extremely important as CMV antigenemia monitoring and pre-emptive therapy. In this study, we performed a prospective PCR-guided viral monitoring for 13 species and evaluate the association with actual onset of viral disease. Patients and methods: Adult patients aged ≥ 16 years old who were scheduled for allogeneic or autologus HSCT were eligible for this study. Informed consent was obtained from all patients. From a week before transplantation to the 8 weeks after, the DNA quantity of 13 viral species was weekly measured using in-house multiplex PCR assays, which enable to simultaneously determine the amount of herpes simplex virus-1 (HSV-1), human simplex virus-2 (HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) humanherpesvirus 6 (HHV-6), humanherpesvirus 7(HHV-7), humanherpesvirus 8 (HHV-8), parvovirus B19, hepatitis B virus (HBV), JC virus (JCV), BK virus (BKV), and adenovirus (ADV). As antiviral prophylaxis for HSV/VZV and HHV-6 diseases, oral acyclovir and intravenous foscarnet in all recipients and exclusively in those receiving unrelated cord blood, respectively, whereas antigenemia-guided preemptive therapy against CMV disease with ganciclovir or foscarnet was performed in allo-transplant settings. Results: A hundred patients who underwent HSCT at Toranomon Hospital from May to December 2010 were enrolled for this study. Median age was 52 (16–71) years old. Six patients who underwent autologous transplantation were included. In a total of 821 peripheral specimens obtained during the study period, HHV-6 was detected in 69.6%, CMV in 37.7%, BK in 13.2% and ADV in 7.7% of 471 PCR positive samples, and the detection rate of other virus was lower than 3.1%. The cumulative incidences of positive viral load due to HHV-6, CMV, BKV, ADV during the study period were 88.5%, 54.3%, 24.1%, and 11.6%. During the study period, 31 patients developed any viral infections with a cumulative incidence of 34.0%, at a median of 18 (-1-56) days after HSCT. Ten patients had 2 or more episodes of different viral infections, and a total of 45 infectious episodes were documented. HHV-6 encephalitis accounted for 33.3% of all viral infections during prophylactic foscarnet administration. Other common viruses included ADV 22.2 % (dissemination in 8, hemorrhagic cystitis (HC) in 2), and BKV 35.6 % (HC in all 22 patients). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were analyzed for common virus such as ADV, BKV and HHV-6. CMV was excluded CMV antigenemia-guided pre-emptive therapy successfully suppressed the onset of diseases. The sensitivity, specificity, PPV, and NPV for diagnosing ADV infections were 85.7%, 100.0%, 100.0% and 98.9%. These data suggest ADV monitoring is a useful strategy for predicting the onset of disease. The sensitivity, specificity, PPV, and NPV for diagnosing BKV associated HC were 61.1%, 86.6%, 50.0% and 91.0%, whereas those of the PCR assay with use of a threshold of 10000 copies/ml were 46.6%, 71.8%, 29.1% and 88.4% for diagnosing HHV-6 encephalitis. Conclusion: Our multiple viral monitoring system using multiplex PCR assay was useful for detecting viral load kinetics for 13 species early after HSCT. As for ADV, viral load in blood detected in our assay had a high sensitivity and specificity for developing ADV infectious diseases. The sensitivity and specificity level for HHV-6 and BK was not as high as ADV because definite threshold level was not determined yet and HHV-6 encephalitis might be suppressed due to prophylactic foscarnet, these findings suggested that the multiplex PCR assay could be applied to the routine monitoring for viral infections in the early period after HSCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 1162 Poster Board I-184 Backgrounds Umbilical cord blood can be an alternative stem cell source for the patients of hematological diseases. However, little is known about chronic GVHD (cGVHD) and graft versus leukemia/lymphoma (GVL) effect in reduced-intensity cord blood transplantation (RICBT). We had been demonstrated that cGVHD in CBT is tolerable compared with that in BMT and that the occurrence of cGVHD could result in good prognosis. Here, we analyzed the clinical picture of chronic GVHD following RICBT and the GVL effect. Methods We reviewed medical records of 192 patients with hematological diseases who had received CBT between Jan. 2004 and Dec. 2008 who had been free from disease progression for more than 100 days after RICBT at Toranomon Hospital, Tokyo, Japan. Median age was 54 years (17-82). Most of them had diseases in advanced status (n=168). Most of the pre-transplant conditioning were reduced intensity consisted of fludarabine, melphalan and TBI 4Gy (n=157). GVHD prophylaxis were tacrolimus (Tac) alone (n=99) and Tac plus mycophenolate mofetil (MMF) (n=93). HLA disparities were as follows; 6/6 (n=9), 5/6 (n=38), 4/6 (n=142), and 3/6 (n=3). Underlying diseases were AML (n=58), myelodysplastic syndrome (n=36), ALL (n=23), lymphoma (n=64) and others (n=11). Results The Median observation period after the transplantation was 924 days (range, 109–1944). Chronic GVHD was admitted in 114 patients (59.4%) consisted of limited type 88 (45.8%) and extensive type 26 (13.5%) in classical criteria, and mild type 96 (50.0%), moderate type 15 (7.8%), and severe type 3 (1.6%) in NIH consensus criteria of cGVHD. The target organs of cGVHD were skin 87.5%, liver 40.6%, and mouth mucous membranes 32.8 %, eye 23.4%, and the lungs only 7.8% (COP3 and BOS2). Except 21 cases ( 10.9%) required systemic steroid or MMF therapy. The median of Karnofsky score of cGVHD was 90%(40-100). During observation period, no patients except one patient caused by heart failure were died of cGVHD. In multivariate analysis, high-risk disease (p=0.019) and preceding acute GVHD (p=0.026) are related to the occurrence of cGVHD, and cGVHD increased overall survival (p Conclusion Although the frequency of cGVHD was not low, the severity was mild, and the death related to cGVHD is rare in RICBT. NIH consensus criteria is useful for the evaluation of cGVHD severity. Some effect of GVL may play a role on better survival and lower relapse rate in RICBT. Disclosures No relevant conflicts of interest to declare.

Abstract 1153 Poster Board I-175 Introduction Systemic corticosteroid has been used as initial treatment for gastrointestinal tract acute graft-versus-host disease (GI-aGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). However, the response remains far from satisfactory, and adverse events caused by prolonged immunosuppression are significant problem. Oral beclomethasone dipropionate (BDP) is a topically active corticosteroid with low bioavailability. Although several studies demonstrated that BDP as monotherapy or in combination with systemic corticosteroid is safe and effective for treatment of GI-aGVHD, there has been not much data available regarding this issue in unrelated cord transplantation (UCBT). Design and Methods This study was approved by the institutional review board and started since January 2006. BDP was administered as a single agent in patients who developed stage 1-2 GI-aGVHD following UCBT, were able to swallow the drug, and gave written informed consent. BDP was administered orally as one enteric-coated cellulose capsule and an aqueous suspension every 6h for a total daily dose of 8mg. Response was evaluated on days 3, 7, 14, 21, and 28 after the beginning of BDP treatment. Patients who had worsening GI symptoms at day 3, or who had no improvement at day 7 were classified as nonresponders, and systemic corticosteroid was started. Results Forty patients were included in this analysis from Jan 2006 through April 2009. Median age was 53.5 years (range 22-82). Twenty-eight (70%) had advanced disease (relapse or refractory disease), and 12 (30%) had history of prior transplantation. All but one patient received fludarabine-based preparative regimen. GVHD prophylaxis consisted of tacrolimus plus mycophenolate mofetil in 27, and tacrolimus alone in 13. Single cord blood units, matched at 4/6 in 35, 5/6 in 3, and 6/6 in 2, were infused. GI-aGVHD developed at a median of 32.5 days (range, 8-80 days) post-transplant. Twenty-five (62.5%) had stage 1 and 15 had stage 2 GI-aGVHD. Twenty (50%) had only GI involvement and the others had mild skin involvement. BDP was started at a median of 36 days (range, 8-86 days) post-transplant. Thirty-three (82.5%) responded to BDP treatment. Response occurred at a median of 4 days (range, 2-7 days) after BDP treatment. Response rate was suggestively higher in patients with stage 1 GI-aGVHD (88%) compared with those with stage 2 (73%), although not statistically significant (P=0.1). The median duration of BDP treatment was for 51 days (range, 7-343 days). Three patients progressed and 4 patients did not respond. Twenty-seven (67.5%) developed infectious episodes during BDP treatment; bacterial sepsis in 9, CMV reactivation in 10, CMV gastroenteritis in 2, Fungal pneumonia in 3, and others in 3 patients. Two patients developed symptomatic adrenal insufficiency during BDP treatment, and required systemic steroid hormone replacement. Transplant-related mortality was 15% at 100 days post-transplant. Three patients died due to sepsis associated with GVHD, 2 died from idiopathic pneumonia syndrome, and 1 died from invasive fungal infection. At median follow-up of 475 days (range, 132-1368 days), overall survival at 2 years was 35.7%. Conclusions: In this study, we evaluated the efficacy and safety of BDP as a single agent in a series of patients with stage 1-2 GI-aGVHD following UCBT. The response rate was 82.5%, which compares favorably with previously reported response rate using BDP as monotherapy or in combination with systemic corticosteroid after allogeneic HSCT. Furthermore, BDP treatment was not associated with the increased risk of severe opportunistic infections. We conclude that BDP as a single agent could become an ideal therapeutic approach for stage 1-2 GI-aGVHD following UCBT Disclosures No relevant conflicts of interest to declare.

Although unrelated cord blood transplantation (UCBT) has become a viable therapeutic option widely applicable for adult patients with hematological diseases, UCBT for severe aplastic anemia (SAA) remains to be controversial due to higher incidence of graft failure (GF) relative to the other stem cell sources. To evaluate the feasibility of UCBT for SAA, we retrospectively analyzed results for 11 adult patients with SAA who received first UCBT after reduced-intensity conditioning regimen (RI-UCBT) in Toranomon Hospital. Median age was 49 years (range, 20–70). Nine of them were non-responders to intensive immunosuppressive therapy and were multiply transfused, and two patients were fulminant type with no neutrophils in peripheral blood at diagnosis. The conditioning regimen consisted of fludarabine 125mg/m2, melphalan 80mg/m2, and 4 Gy of total body irradiation. Graft-versus-host disease prophylaxis was composed of cyclosporine alone (n=2), tacrolimus alone (n=2), and tacrolimus plus mycophenolate mofetil (n=7). Median total nucleated cell number and median CD34+ cell number were 2.65 × 107/kg (range, 1.83–4.39) and 0.70 × 105/kg (range, 0.27–1.52), respectively. Serological HLA disparities were as follows; 6/6 (n=3), 5/6 (n=2), and 4/6 (n=6). Ten of the 11 patients achieved primary neutrophil and platelet engraftment. Median time to an absolute neutrophil count > 0.5×109/liter and an unsupported platelet count > 20×109/liter were 18 days (range, 12–28) and 42.5 days (range, 26–64) respectively. All patients who achieved engraftment resulted in complete hematological recovery with complete donor chimerism, except for one patient who developed late GF at three years after UCBT. All 2 who experienced GF (1: primary GF, 1: late GF) were rescued by second RI-UCBT. Two of the 11 patients died from IPS (n=2), and remaining 9 patients are alive, having survived for 18.7 months (range, 2–71 months). Six out of 7 patients who survived more than 6 months were free from immunosuppressant. The probabilities of overall survival and event-free survival at 2 years after UCBT were 77.8% and 68.2%, respectively. Our results here strongly indicated feasibility and effectiveness of RI-UCBT for adult SAA patients with high engraftment rate and low treatment-related mortality. RI-UCBT could be considered as a viable therapeutic option for those who lack suitable HLA-matched sibling donors and failed immunosuppressive therapy.

Umbilical cord blood transplantation with reduced-intensity conditioning (RICBT) has been widely applied to various diseases. However, little information on long-term outcome of RICBT in advanced mature or immature lymphoid malignancies has been available so far. We retrospectively reviewed patients who had lymphoid malignancies and underwent RICBT as the first allogeneic transplant at our institute from Jan. 2002 to Apr. 2008 consecutively, excluding those who had active infection before RICBT. This study includes 110 CB recipients who diagnosed as lymphoblastic lymphoma (LBL)/acute lymphoblastic leukemia (ALL) (n=26, including 12 Ph positive) and mature lymphoid malignancies (n=84, 29 DLBCL, 6 FL/CLL, 16 peripheral T-cell lymphoma, 5 HL, 6 MM, and 22 adult T-cell leukemia (ATL)). Median age was 53 (range 26–79). The numbers of HLA-A, B and DR antigen mismatches were 0 (1.8%), 1 (8.1%) and 2 (89.1%). Median number of total nucleated cells (TNC) and CD34 positive cells infused were 2.68 x 107/kg and 0.87 x 105/kg, respectively. Majority (81.8%) had advanced disease (relapse or refractory disease), 36 cases (32.7%) had poor performance status (ECOG PS≥ 3), and 27 cases (24.5%) had prior autologous transplant. Conditioning regimen consisted mainly of fludarabine 125mg/m2, melphalan 80–140 mg/m2, and 0–8 Gy TBI. Cyclosporine A or taclolimus±mycophenolate mofetil were used as GVHD prophylaxis. Eighty five percent of the cases who survived longer than 28 days showed neutrophil recovery (median 19 days (11–44)). The incidence of grades II–IV acute GVHD and chronic GVHD among evaluable patients were 42.3% and 37.6%, respectively. Median follow-up time of survivors was 1422 days (109–1896). Overall survival (OS) and progression-free survival (PFS) were 36.9%(27.8–46.0) and 30.6%(22.0–39.3) at 1 year, and 25.3%(17.0–33.6) and 22.8%(14.9–30.8) at 3years, respectively. Treatment related mortality (TRM) and relapse mortality (RM) at 500days were 41.9% and 28.6%, respectively. The diagnosis-based PFS at 3 years were 33.8% for ALL, 20.7% for DLBCL, 33.3% for FL/CLL, 25.5% for PTCL, 40.0% for HL, 20.0% for MM, and 9.1% for ATL. In univariate analyses, factors significantly associated poor PFS were the diagnosis of ATL, high disease risk, poor PS (≥ 2), high HCT-CI (≥ score 2), and high LDH level (high tumor burden). Factors associated higher TRM were poor PS (≥ 2) and lower TNC infused (4Gy), although Ph chromosome was not associated with OS or PFS. In multivariate analyses of all patients, poor PS (≥ 2) was the only significant factor associated with lower OS (RR 2.63, p=0.0093), PFS (RR2.13, p=0.0338) and not only higher TRM (RR 2.30, p=0.0148),but higher RM (RR 2.94, p=0.0081), suggesting poor PS group have highly advanced disease. Interstingly, higher LDH level, not poor PS, was found to be the only significant factor associated with lower OS and PFS in multivariate analysis of mature lymphoid malignancies. Although the high TRM should be improved, these data indicate RICBT to have sufficient potential to achieve long-term durable remission for both immature and mature lymphoid malignancies except ATL in advanced status. Lower tumor burden (low LDH level) in mature lymphoid malignancies and higher dose of TBI in ALL may be the keys to further improve long-term outcome.

Although cord blood (CB) transplantation with reduced-intensity conditioning (RICBT) has been widely applied to those who lack available related or unrelated donors and are not eligible for conventional conditioning, the optimal pre-transplant conditioning has not been established yet. Intravenous busulfan (ivBu) has been incorporated in conditioning regimens before bone marrow or peripheral blood stem cell transplantation, but the feasibility in cord blood transplantation has been controversial. In order to address this issue, we retrospectively reviewed patients who underwent RICBT including ivBu. Twenty-one patients, who were at ECOG performance status of 2 or less and received RICBT at our institute from June 2007 to April 2008 consecutively, were included in this study. Median age was 56 years (range, 21–71). Seventeen were AML, 3 were ALL, and 1 was MDS RA. All but 2 (MDS RA and ALL in CR2) were not in remission, 5 had CNS involvement, and 9 had history of prior transplantation. Seventeen had HCT-specific comorbidity index score ≥1, including 8 ≥2, and 6 ≥3. Fludarabine phosphate 125–180mg/m2 and ivBu 6.4–12.8mg/kg were used in all patients. All but 2 received additional melphalan (Mel) or total body irradiation (TBI); Mel 80–140mg/m2 for 10, 2–8Gy of TBI for 8, and Mel 40mg/m2 plus 4Gy of TBI for 1. Graft-versus-host disease prophylaxis consisted of tacrolimus plus mycophenolate mofetil in 11, tacrolimus alone in 8, and cyclosporine alone in 1. Single cord blood units, matched at 4/6 in 20 and 5/6 in 1, of 2 x 107/kg of recipient body weight at minimum were infused. Seventeen achieved neutrophil recovery ≥500/μl on day 19 post-transplant at medium (range, 12–30). Among 4 who failed to achieve neutrophil recovery, 2 experienced early disease progression, 1 showed rejection, and 1 died before engraftment due to interstitial pneumonia. All 17 patients who achieved neutrophil engraftment and 1 who died before engraftment showed complete donor-type chimerism on 13 days post-transplant at medium (range, 8–35). Median follow-up time of survivors was 398 days (range, 162–532) post-transplant. Cumulative incidence of non-relapse mortality at day 100 and day 365 post-transplant were both 19%. No VOD/SOS was observed. Disease-free survival and overall survival (OS) at 1 year post-transplant were 40±11% and 61±9%, respectively. Thus, ivBu can be safely administered, and have potential to achieve successful engraftment as well as sufficient disease control, indicating possible benefit of incorporating this drug in pre-transplant conditioning of RICBT. The optimal dosing schedule or combination with other therapeutic modalities needs further investigation in prospective clinical trials.

Background: HHV6 reactivation has been increasingly recognized in allogeneic haematopoietic stem cell transplant recipients, particularly in umbilical cord blood transplantation. In adult recipients, HHV6 has been associated with limbic encephalitis (HHV6-LE), which causes anterograde amnesia and epilepsy. The CNS disorder confined to the hippocampal regions; the presence of abnormal MRI signals involving the hippocampus, and detection of HHV6 DNA inCSF. However, the clinical features of the syndrome have not been well characterized. Methods: In this study we retrospectively reviewed the medical records of 139 umbilical cord blood transplantation recipients with reduced-intensity conditioning between January 2006 and December 2007 at Toranomon Hospital in Japan to determine the incidence of HHV6-LE among these patients. The diagnosis was based on the acute development of retrograde amnesia, confusion, coma and seizures accompanied by charascteristic MRI findings of abnormal high signal intensity on flair and T2 weighted images in the hippocampus and mesial temporal lobes, and the detection of HHV6 DNA in CSF. Eighty-six were received foscarnet before the onset of HHV6-LE as prophylaxis. All the patients who manifested suspicious symptoms of HHV6-LE were treated with foscarnet. Results: HHV6-LE was diagnosed in 11/139 for a cumulative incidence of 7.2%. The median age was 49 years (range 36–82), 3 were female. Diseases treated were AML/MDS (8), ALL (1), diffuse large B-cell lymphoma (1), and aplastic anemia (1). All 11 were conditioned with fludarabine-based reduced-intensity regimen, and tacrolimus alone (5) or tacrolimus+mycophenolate mofetil (6) were used as GVHD prophylaxis. Five of them had started foscarnet before the onset of HHV6-LE as a prophylaxis. Median symptom onset was on day +20 (range, 12–50). Initial symptoms included confusion in 9, retrograde amnesia in 8, and seizures in 5. MRI demonstrated hyppocampal and mesial temporal lobe FLAIR/T2 high signal intensity in 8/11. Initial CSF analysis demonstrated a median WBC count was 7 (range, 1–21)/μl, median protein was 49 (range, 44–337) mg/dl, median glucose was 107 (range, 62–269) mg/dl. No positive results of bacterial or viral cultures were observed in any of the patients. Median HHV6 DNA levels in the CSF was 20000 (range, 200–80000) copies/ml. Median HHV6 DNA levels in peripheral blood was 200 (range, 0–300000) copies/ml. Remarkably, 7 patients were negative for HHV6 in peripheral blood even within 6 days prior to the onset of CNS symptoms. All were treated with foscarnet at 50–100mg/kg of body weight, and clinical symptoms improved in 9 evaluable patients (2 were not evaluable due to severe pulmonary complications). The virus was cleared in the CSF successfully in 7 patients evaluated. Seven died with the median survival of 32 days (range, 7–346) from diagnosis of limbic encephalitis. HHV6-LE was not a direct cause of death in any of them (2 were from infection, 2 from IP, 2 from relapse, and 1 from MOF). Four were alive as of July 31, 2008, and what is of extreme interest is that all were those who received foscarnet as a prophylaxis. None of the factors analysed failed to reach statistical significance regarding the impact on the onset of HHV6-LE. Conclusions: High incidence of HHV6-LE as well as reactivation of the virus was observed in CB recipients. HHV6 DNA monitoring in peripheral blood may not be sufficient to predict the development of HHV6-LE. Although clinical manifestations were severe in some cases, foscarnet therapy was effective in all evaluable cases. Possible positive impact of prophylactic foscarnet therapy on better survival was suggested, which needs further evaluation by prospective study.

Objective: Cord blood is widely used as a third possible stem cell source for allogeneic transplantation following bone marrow and peripheral blood. CBT has unique characteristics such as allowing 2 loci mismatch and emergency use or ready to use transplantation. Reduced-intensity transplantation also has been widely accepted to offer opportunities for allogeneic transplant for older and poor overall status patients. We previously showed the feasibility of reduced-intensity cord blood transplantation (RI-CBT) in 30 patients with advanced hematological diseases. Then performed more than 300 time RI-CBT to those whom needed urgent transplantation without suitable HLA matched donors. Methods: We retrospectively analyzed medical records of 318 times and 287 cases of RI-CBT from 1/1/2004 to 5/7/2008 in Toranomon Hospital. Disease distribution of 287 studied patients was as follows; acute myeloblastic leukemia/myelodysplastic syndrome was 136 cases, malignant lymphoma 58, acute lymphoblastic leukemia 42, adult T cell leukemia/lymphoma 25, severe aplastic anemia 8 and others 18. A mean age was 56 ranging from 19 to 79 years old. The number of high risk and standard status patients were 243 and 44, respectively. High risk disease status is defined as residual uncontrolable tumor cells despite of chemotherapy such as primary refractory and beyond CR1 and standard risk is as in remission in a meaning of tumor control. MDS and SAA patients who need frequent transfusions and intensive care for infection are defined as standard risk. Preparative regimen mainly composed of fludarabine 25 mg/m2 on days -7 to -3, melphalan 80 mg/m2 on day -2, and 4 Gy total body irradiation on day -1. Some patients were contiditioned with iv-busulfan without TBI. Graft-versus- host disease prophylaxis was composed of cyclosporine or tacrolimus alone. Results: We analyzed the association of various factors on engraftment in possible 158 patients. Eighty eight % (95% CI, 83%–93%) of patients were engrafted on a median days of 20 (range, 11–55 days) after transplant. Multivariate analysis revealed 5 to 6 antigen match in GVH direction was a significant independent factor for engraftment as well as CD34 dose, while HLA in HVG direction did not significantly influence on engraftment. Three-year estimated overall survival (OS) in total 287 cases was 39.6% (95% CI: 33.5–45.8%). Standard risk patients (n=44) showed 3-year OS of 53.8% (95% CI: 38.3–69.2%) and high risk (n=243) was 26.3% (95% CI:20.2–32.5%). Tacrolimus GVHD prophylaxis group (n=159) had superior 3y-OS of 33.8%(95% CI: 25.9–41.8) to cyclosporine alone with 3yOS of 22.4 % (95% CI: 14.2–30.7). We previously reported pre-engraftment immune reaction characterized by high-grade fever and weight gain and developed on a median of day 9. More intensive immune suppression after RI-CBT using tacrolimus decreased the incidence and severity of PIR and increased OS. Conclusion: RI-CBT is a feasible approach even for relatively aged patient population (Mean age=56) with advanced hematological malignancies.