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Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment for patients with non-remission myeloid malignancies. Although bone marrow (BM) or peripheral blood (PB) from HLA-matched related donor (MRD) have been the first choice of graft when available, true superiority of MRD over others can still be controversial especially for patients with non-remission myeloid malignancies. Cord blood (CB) has emerged as a promising alternative graft and its outcome has been encouraging over periods. Rapid availability is the advantage of MRD and CB over unrelated adult donor, which could fit to patients with non-remission myeloid malignancies who need urgent allo-SCT. So far, few studies are available comparing the outcomes of CB and MRD for adults with non-remission myeloid malignancies. We retrospectively reviewed the outcomes of patients with non-remission myeloid malignancies who underwent allo-SCT using CB or MRD at our institute from Jan. 2008 to Dec. 2015 consecutively. Patients who lacked MRD or were unable to find suitable unrelated donor within appropriate periods underwent CB transplantation. Patients who had a prior history of transplantation, were in poor performance status (ECOG PS 3 and greater), had active infections at the time of conditioning, were over 60 years, or received ATG as GVHD prophylaxis were excluded. One hundred and fifty-nine patients were included in this study. One hundred and thirty-seven patients received single CB, whereas 21 receive PB from MRD and one received both PB and BM from the same MRD. Underlying diagnoses were AML (n=125), MDS-RAEB (n=20), CML (n=11), and MPN (n=3). All patients were not in remission at the start of conditioning regimens including primary induction failure (n=47), first relapse (REL) (n=37), second REL (n=4), and CML-BC/AP after TKI failure (n=11). Fifty-six patients who were diagnosed with AML with MRC or MDS were untreated or only received agents for blast control before transplantation. One hundred and twenty-nine patients were conditioned with MAC regimens, whereas 21 patients received RIC regimens. The median interval from diagnosis to transplant was 162 days (range, 34-2774 days). Recipients of CB and MRD were comparable in terms of median age (50 years in CB, 47 years in MRD), diagnosis, disease status, conditioning regimens, median interval from diagnosis to transplant, and year of transplant. CB recipients received more HLA-mismatched grafts and received a lower number of CD34+ cells, compared to MRD recipients. Median follow-up periods of survivors were 997 days for CB and 1459 days for MRD recipients, respectively. The overall (OS) and progression-free survival (PFS) showed no statistically significant differences between CB and MRD recipients; 3-year OSs of CB and MRD recipients were 47.2% (95% CI, 37.4-56.3%) and 45.5% (24.1-64.6%) (p=0.67), respectively (Figure 1), and 3-year-PFSs of CB and MRD recipients were 40.6% (31.4-49.6%) and 35.6% (15.7-56.2%) (p=0.3), respectively. Cumulative incidence of neutrophil engraftment was almost comparable between CB and MRD recipients (91% vs 100%, p=0.1), although CB recipients showed slower neutrophil recovery (median 21 (12-39) days vs 15 (11-39) days, p Both transplant strategies have shown promising outcomes in patients with non-remission myeloid malignancies. Our analysis also shows that CB is not inferior to MRD as a source of hematopoietic stem cell grafts and may be associated with a lower relapse rate. CB could expand the possible donor pool for patients who need urgent allo-SCT and should be more considered as valuable grafts. Figure 1 Figure 1. Disclosures Izutsu: Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding.

[Background] FMS like tyrosine kinase 3 (FLT3) mutations occur in about 30% of patients with acute myeloid leukemia (AML). Patients with FLT3-mutated AML have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). So far, there is still limited data available on allo-HSCT for FLT3-mutated AML in non-remission status. [Objective and method] To assess the clinical features and outcome of allo-HSCT for FLT3-mutated AML, we retrospectively analyzed patients underwent first allo-HSCT for FLT3-mutated AML excluding acute promyelocytic leukemia (FAB M3) from January 2011 to March 2016. [Result] During the study period, 332 patients received first allo-HSCT for AML in our institute. One hundred and thirty-eight were tested for the presence of FLT3-mutation and 35 showed positive results and were subjected to the analysis. The median follow-up day of survivors was 602 (101-1867). The median age of the patients was 55 years (range, 21-72). Twenty-one patients had de novo AML, 12 had AML with myelodysplasia related changes, and 2 had therapy related AML. Eighteen had normal karyotype, 4 had complex, and 13 had others. Seven were in remission (5 in CR1, and 2 in CR2), and 28 were in non-remission (8 in primary induction failure, 13 in relapse 1, and 7 in chemo naïve status). Twenty-nine patients used unrelated cord blood, 2 did unrelated bone marrow, and 4 did related peripheral blood stem cell as grafts. All but 1 received myeloablative pretransplant conditionings. At 2 years after transplantation, overall survival (OS), disease free survival (DFS), relapse rate (RR), and non-relapse mortality (NRM) of whole studied population were 65.9%, 50.2%, 28.4%, and 21.4%, respectively. Among those in non-remission before transplantation, OS, DFS, RR, and NRM at 2 years post-transplant were 62.2% (Figure 1A), 49.9%(Figure 1B), 24.3%, and 25.8%, respectively. Only younger age ( [Conclusion] Our data indicated that allo-HSCT could overcome the poor prognosis of FLT3-mutated AML even for those in non-remission status, despite the profound chemo-resistant character of FLT3-mutated AML. Figure 1A Figure 1A. Figure 1B Figure 1B. Disclosures Izutsu: Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding.

Background & Aim: Recombinant human soluble thrombomoduline alpha (rhTM) is a novel anticoagulant agents and approved for disseminated intravascular coagulation (DIC) in Japan. Although several case reports suggested its therapeutic potential for sinusoidal obstructive syndrome/hepatic veno-occlusive disease (SOS/VOD), no information is available in large cohort. The aim of the study is to evaluate the therapeutic potential of rhTM for SOS/VOD. Patients & Methods: We retrospectively studied 878 times of allogeneic hematopoietic cell transplantation (HCT) in Toranomon Hospital from June 2008 to June 2015. We extracted the patients who used rhTM for DIC and satisfied the diagnostic criteria of SOS/VOD around the same time, because the use of rhTM for SOS/VOD alone is off-label. We excluded the patients who were already treated with rhTM before the emergence of the first symptom or sign of SOS/VOD, who used rhTM only in the short period (within 2 days), and who started rhTM over 30 days after the emergence of the first symptom or sign of SOS/VOD. To diagnose classical SOS/VOD (≤ 21 days after transplantation), we used two classical criteria of the modified Seattle (McDonald et al. Ann Intern Med 1993) and the Baltimore (Jones et al. Transplant 1987). For late-onset SOS/VOD (> day 22 of transplantation), we used the criteria which was recently published from the EBMT group (Mohty et al, Bone Marrow Transplant 2016). We considered the atrophic change of the liver in a long-term clinical course as an evidence of SOS/VOD, in a patient who was not evaluated the portal flow. We defined as severe SOS/VOD, if the patients had renal (Cr ≥ 2 times of baseline at transplant), respiratory (SpO2 ≤ 90% and/or the need for positive pressure) or central nervous system failure (confusion, lethargy and/or delirium) until 2 weeks after the diagnosis of SOS/VOD. Complete response (CR) of SOS/VOD was defined as the resolution of all the symptoms and the signs of SOS/VOD diagnostic criteria. We prioritized the date of Baltimore criteria, when we fixed the date of diagnosis. Results: A total of 39 patients used rhTM for DIC and concurrent SOS/VOD. The median age was 60 years (range, 27 - 72) and 27 patients (69%) was male. Hematologic diseases were as follows; AML (n=25), ALL (n=5), lymphoma (n=3), CML (n=2), MDS (n=2) and CMML (n=2). Donor cell sources were UCB (n=34) and UBM (n=5). Most of the prophylaxis regimen at the time of transplantation was the combination of ursodeoxycholic acid and dalteparin in 36 patients (92%). Classical SOS/VOD was diagnosed in 3 (8%) and 8 patients (21%) by the criteria of the modified Seattle and the Baltimore at the median day of 14 (range, 11 - 14) and 16 (range, 11 - 20), respectively. Twenty-eight patients (72%) were diagnosed as late-onset SOS/VOD at the median day of 44 (range, 22 - 89). In a total of 39 patients, severe SOS/VOD developed in 33 patients (85%) (renal, n=32; respiratory, n=7; central nervous system, n=15). The elevation of transaminase (2x upper limit of normal range) was observed in 18 patients (46%). The median interval from the emergence of the first symptom or sign of SOS/VOD to rhTM administration was 7 days (range, 0 - 23). The median duration of rhTM administration was 11 days (range, 3 - 63). RTM was used alone in 20 patients (51%), in combination with dalteparin in 7 (18%), with antithrombin III (ATIII) in 5 (13%), with dalteparin & ATIII in 3 (8%), with ATIII & prostaglandin E1 (PGE1) in 2 (5%), and with PGE1 in 2 (5%). Corticosteroid was used with rhTM concomitantly in 32 patients (82%). Finally, 13 patients achieved CR of SOS/VOD. The cumulative incidence of CR of SOS/VOD was 33.3 % at 1 year after the administration of rhTM (95% confidence interval, 18.5 - 48.9%) (Figure 1). The median interval from the administration of rhTM to CR of SOS/VOD was 51 days (range, 6 - 141). At 1 year after transplantation, overall survival was 25.6% (95% confidence interval, 13.3 - 69.9%) (Figure 2). From the administration of rhTM to 2 weeks after the cessation of rhTM, 23 hemorrhagic adverse events were observed. Seven out of 23 events were at grade 3-5, and 5 out of 7 events were fatal (intra-abdominal n=2, gastro-intestinal n=1, lung n=1, and brain n=1). Conclusion: We concluded that rhTM had a possible therapeutic potential for SOS/VOD. Its safety and efficacy should be evaluated in a prospective study in the future. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Izutsu: Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding.

Background Pneumonia caused by Stenotrophomonas maltophilia is rare, but can be lethal in severely immunocompromised patients. However, its clinical course remains unclear. Patients and methods Patients with pneumonia caused by S. maltophilia in Toranomon Hospital (890 beds, Tokyo, Japan) were reviewed retrospectively between April 2006 and March 2010. Results During the study period, 10 cases of S. maltophilia pneumonia were identified. Seven patients had acute myeloid leukemia, 2 had myelodysplastic syndrome, and 1 had malignant lymphoma. All patients developed symptoms after allogeneic hematopoietic stem cell transplantation (HSCT). Five patients received first cord blood transplantation (CBT), 4 patients received second CBT, and 1 patient received first peripheral blood stem cell transplantation (PBSCT). The overall incidence of S. maltophilia pneumonia among 508 patients who received HSCT during the period was 2.0%. The incidence was 0% (0/95) in patients after bone marrow transplantation, 0.8% (1/133) after PBSCT, and 3.2% (9/279) after CBT. Pneumonia developed a median of 13.5 days (range, 6–40) after transplantation. At onset, the median white blood cell count was 10/μL (range, 10–1900), and the median neutrophil count was 0/μL (range, 0–1720). In all patients, S. maltophilia bacteremia developed with bloody sputum or hemoptysis. The 28-day mortality rate was 100%; the median survival after onset of pneumonia was 2 days (range, 1–10). Conclusions Hemorrhagic S. maltophilia pneumonia rapidly progresses and is fatal in patients with hematologic malignancy. Attention should be particularly paid to the neutropenic phase early after HSCT or prolonged neutropenia due to engraftment failure. A prompt trimethoprim-sulfamethoxazole-based multidrug combination regimen should be considered to rescue suspected cases of S. maltophilia pneumonia in these severely immunosuppressed patients.

Abstract 4535 Incidence and clinical features of idiopathic pneumonia syndrome and diffuse alveolar hemorrhage after unrelated cord blood transplantation. Aya Nishida 1, Atsushi Wake 1, Hisashi Yamamoto 1, Kazuya Ishiwata 1, Nobuaki Nakano 1, Masanori Tsuji 1, Yuki-Asano Mori 1, Naoyuki Uchida 1, Koji Izutsu 1, Kazuhiro Masuoka 1, Akiko Yoneyama 3, Shigeyoshi Makino 4, Shuichi Taniguchi 1. 1 Department of Hematology, Toranomon Hospital, Tokyo, Japan; 2 Department of Pathology, Toranomon Hospital, Tokyo, Japan; 3 Department of Infectious Diseases, Toranomon Hospital, Tokyo, Japan; 4 Department of Transfusion Medicine, Toranomon Hospital, Tokyo, Japan [Background] Idiopathic pneumonia syndrome (IPS) and diffuse alveolar hemorrhage (DAH) are non-infectious pulmonary complications of hematopoietic stem cell transplantation (HSCT) with unclear pathogenesis and treatment. [Objective and method] To investigate the incidence and clinical features of IPS/DAH after unrelated cord blood transplantation (uCBT), we retrospectively analyzed 370 patients underwent uCBT from January 2005 to June 2010 at Toranomon Hospital. Diagnosis of IPS/DAH was made by multilobar infiltrates on CXR or CT, clinical signs of pneumonia: cough, dyspnea, or rales, abnormal physiology: increased arterial-alveolar oxygen gradient, or the needfor supplemental oxygen support, and no evidence of respiratory tract infection. [Result:] Twenty five cases of IPS/DAH were identified, with incidence of 6.8%. The median-age was 59 years (range; 26–72). Nineteen patients underwent transplantation for leukemia, 4 for malignant lymphoma, and 2 for aplastic anemia. IPS/DAH was diagnosed at a median of 34 days (range; 8–93) after uCBT. All patients were administered mPSL therapy. Nine of 25 patients were administered etanercept combined with mPSL pulse therapy. Five of 9 had not responded, while 4 responders had worse their respiratory condition after discontinuation of etanercept therapy. Twenty four of 25 died of respiratory failure. [Conclusion] IPS/DAH after uCBT are fetal pulmonary complications. It is suggested that the incidence of IPS/DAH after uCBT appears similar to that observed after transplantation using other sources. But our results suggested that the existing treatment such as etanercept combined mPSL pulse have only limited efficacy as a therapy for IPS/DAH after uCBT. Further research is needed to characterize the condition of this syndrome and to investigate the optimal therapy and prophylaxis. Disclosures: No relevant conflicts of interest to declare.

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.

Early central nervous system (CNS) complications have been associated with significant morbidity and mortality after allogeneic stem cell transplantation (Allo-SCT). However, the incidence, etiology and clinical characteristics of early CNS complications have not been well understood. Moreover, the impact of stem cell sources on early CNS complications remains to be determined. To address these issues, we retrospectively reviewed the medical record of 723 consecutive patients who underwent first Allo-SCT at Toranomon Hospital between 2006 and 2013. Early CNS complications were defined as distinct CNS manifestations such as convulsion, change of mental state, defect of short-term memory, or focal motor or sensory symptoms, occurring within 100 days post-transplant. The etiology of CNS complications was determined by clinical, radiologic, or microbiological finding or a combination of these factors. Patients who developed transient consciousness disturbances in septic state or circulatory collapse, had a history of brain surgery, or showed change of mental status at the terminal stage of multiple organ failures, were excluded from CNS complications. CNS relapses of underlying diseases were also excluded from this analysis. Their median age was 56 years (range, 16-82). Underlying diseases were AML in 360, MDS/MPD in 76, CML in 21, ALL in 82, ATL in 30, HL in 11, NHL in 109, AA in 23 and others in 11. Four hundred ninety-nine (69%) were not in remission at the time of transplant. Three hundred ninety-five patients (54.6%) were conditioned with myeloablative regimens, whereas 328 patients received reduced-intensity regimens. Donor sources consisted of related peripheral blood /bone marrow (BM) (n=101), unrelated BM (166) or cord blood (456). One hundred thirty-seven developed CNS complications on median of 25 (3-89) days post-transplant. Cumulative incidence of CNS complications at 100 days was 19%. The etiology included human herpesvirus 6 (HHV-6) encephalitis/myelitis (n=52), Non HHV-6 viral infections (4), bacterial infections (10), cerebrovascular diseases (18), thrombotic microangiopathy (TMA) / posterior reversible encephalopathy syndrome (PRES) (10), others (3) and unknown causes (40). With median observation period of survivors of 791 (27-2919) days, overall survival at 2 years was 26% in patients who developed CNS complication and was significantly worse than in those who did not develop it (46%, p Early CNS complications are serious concerns leading to inferior survival rate after Allo-SCT. Cord blood recipients are at higher risk for developing CNS complications, particularly of HHV-6 associated. Mechanisms behind them and optimal treatment approaches need to be clarified further to improve outcome. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Relapse after allogeneic stem cell transplantation (Allo-SCT) remains a serious concern and its prognosis is poor. Although 2nd Allo-SCT is the only curative strategy for relapsed patients after Allo-SCT, it is not easy to proceed to 2nd Allo-SCT because of the next donor availability, tumor cell control, and infectious and organ complications. Cord blood (CB) is rapidly available in Japan, but its clinical efficacy is not clearly clarified yet. We retrospectively analyzed the outcome of 85 consecutive 2nd CB recipients with relapsed myeloid malignancies following allogeneic transplantation at Toranomon hospital between January 2005 and March 2014. Their median age was 52 years (range, 19-71). Donors at 1st Allo-SCT were related peripheral blood /bone marrow (BM) (n=24), unrelated BM (27) or CB (34), respectively. Underlying diseases were AML in 79, CML in 4, MDS in 1 and MPD in 1. The median duration of remission after 1st Allo-SCT was 197 (29-2586) days, and the median time from relapse to 2nd CBT and from 1st Allo-SCT to 2nd CBT were 85 (13-1667) days and 370 (56-2680) days, respectively. Twenty-three (27%) received re-induction chemotherapy after relapse after 1st Allo-SCT, whereas 42 (71%) received less intensive chemotherapy (low dose Ara-C and/or hydroxyurea (n=37), gemtuzumab ozogamicin (9), 5-azacitidine (2), and DLI (8)), and 20 (24%) did not receive any treatment. All except 5 patients (94%) were not in remission and 15 (18%) had active infections at the start of conditioning regimen of 2nd CBT. Performance status (PS) at 2nd CBT were 0 in 8 patients, 1 in 30, 2 in 29 and 3 in 7. Thirty-eight patients (45%) were conditioned with myeloablative regimens, whereas 47 patients received reduced-intensity. Calcineurin inhibitor (CI) plus mycophenolate mofetil were used in 36 cases (42%) as GVHD prophylaxis, while CI alone in 49 (58%). All patients received single CB unit with 2.84 (1.85-5.87) x 107/kg median number of total nucleated cell. Sixty-three patients achieved neutrophil recovery on median of 18 (11-39) days post-transplant with a cumulative incidence of 74.1%, and, among 22 who failed to achieve neutrophil recovery, 15 died before engraftment, 4 had early disease progression and 3 were rejected. Fifty-five patient (68%) developed infectious complications due to bacteria (n=42), virus (3), fungus (2) and unknown pathogens (8) within 30 days after 2nd CBT at median of 5 days post-transplant (range, -7 - 21). Median observation period of survivors was 734 (101-3023) days post-transplant. Cumulative incidences of NRM at 100 days and 2 years were 43.5% and 53.6%, respectively. Causes of NRM were Infections (n=19), idiopathic pneumonia syndrome (7), MOF+infections (4), VOD (2), GVHD (2), graft failure (1), and others (11). Higher age, myeloablative-conditioning at 1st Allo-SCT and active infection at 2nd CBT were negatively affected NRM in multivariate analysis. Twenty-seven patients relapsed at a median of 209 (16-2597) days. Cumulative incidences of relapse at 100 days and 2 years were 11.2% and 32.4%, respectively. Overall survival (OS) and progression free survival (PFS) at 2 years were 14.4% and 10.5%, respectively (Figure). Reduced-intensity conditioning at 1st Allo-SCT, younger age ( Although CBT has provided more opportunities of 2nd transplant for relapsed patients, high NRM was noted in this study, resulted in unsatisfactory survival. Multiple factors associated with poor outcome were identified, mostly related to patients' poor background conditions that are not easy to be ameliorated. There were, however, certain population of patients (age Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

MUD 169 0.65 (0.57-0.72) 0.54 (0.45-0.62) 8/10 Loci 31 0.47 (0.29-0.64) 0.40 (0.23-0.57) 0.04 DFS 9/10 Loci 105 0.65 (0.55-0.74) 0.50 (0.40-0.60) Single DQB 18 0.78 (0.51-0.91) 0.72 (0 45-0.87) 0.29 Single C 26 0.56 (0.35-0.73) 0.37 (0.18-0.56) 0.14 Single DQB1 87 0.64 (0.53-0.73) 0.47 (0.36-0.58) 0.42 MUD 169 0.09 (0.04-0.14) 0.13 (0.08-0.19) 8/10 Loci 31 0.07 (0.01-0.19) 0.13 (0.40-0.28) 0.36 aGvHD (Gr 2-4) 9/10 Loci 105 0.14 (0.08-0.22) 0.21 (0.14-0.30)

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.

Introduction In reduced intensity cord blood transplantation (CBT) post transplant immune disorders, including early immune reactions (PIR) and acute GVHD, are potential complications following CBT in adult patients. Such reactions might increase the risk of organ dysfunction, leading to high rates of transplantation-related mortality, particularly in patients who do not respond to primary therapy, which usually consists of steroids. There is no consensus on the optimal salvage treatment of steroid-refractory acute GVHD. Patients and Methods We retrospectively reviewed 388 patients who underwent single-unit reduced intensity cord blood transplantation consecutively from June 2008 to October 2012 at Toranomon Hospital. Patients who were in poor performance status (ECOG PS >3), had active bacterial or fungal infections at the time of conditioning were excluded. The most frequently used conditioning regimens were fludarabine, alkylating agent (melphalan or busulfan) with total body irradination (TBI), tacrolimus plus mycophenolate mofetil for GVHD prophylaxis. Patients in whom acute GVHD developed received methylpredonisolone 1-2 mg/kg per day. If no partial or complete resolution of symptoms occurred, they were considered steroid-refractory and proceeded to salvage treatment with infliximab or ATG. The dose of infliximab was 5 mg/kg/day once weekly for at least 1 course. ATG was given at 1mg/kg/day once weekly for at least 1 course. An observational study compared response and survival rates in all consecutive patients receiving 1 of these 2 treatments. Results 52 patients among this group developed steroid refractory acute GVHD. Infliximab group (n=31) had a higher proportion of patients with grade III-IV GVHD (69% VS 59%, p=0.18). ATG group (n=21) had a higher proportion of patients with stage 3-4 liver GVHD (28% VS 5%, p Both overall response (PR+CR) were significantly higher in the infliximab group compared with the ATG group (54.8% VS 33.3%, p=0.015 ). In multivariate analysis, time from first-line therapy (days Median follow-up of surviving patients from the date of initiation of salvage treatment was 21.6 months (range, 5.5-57.9 months).Overall, median survival was 2 months after salvage treatment (95% CI, 1-3), with 25% of patients surviving at 12 months (95%CI, 11-20). Patients who achieved a CR have better survival rates. GVHD was the main cause of death (50%). When comparing survival according to salvage treatment, better OS with infliximab (33.9% VS 22.8, p=0.08) in univariate analysis was not confirmed in multivariate analysis. In multivariate analysis, grade IV GVHD at steroid refractory GVHD onset (HR,7.1; 95% CI, 1.29-38.7; P=0.021), and gut involvement with bleeding (HR, 7.65; 95% CI, 1.35-43.2; P=0.024) were significantly associated with worse survival. Conclusion We conclude that infliximab has more activity than ATG in the treatment of severe steroid-refractory GVHD, and earlier initiation of salvage therapy may give better response. But outcomes remain poor. New methods to prevent and treat GVHD are needed. Disclosures: No relevant conflicts of interest to declare.

Introduction Although cord blood transplantation (CBT) using reduced-intensity regimens has emerged as an effective therapy for elderly or patients with comorbidities, high relapse rate and non-relapse mortality (NRM) still remain to be resolved. Tointensify antitumor effects without increasing NRM, we have conducted a pilot study of a novel reduced-toxicity myeloablative conditioning for CBT in our institute. Methods The conditioning consisted of intravenous busulfan 12.8 mg/kg, fludarabine 180 mg/m2 and melphalan 80 mg/m2 followed by single CBT. Fifty-one patients with myeloid malignancies not in remission were included in this study between June 2007 and November 2012. All patients provided written informed consent, andmedical records were retrospectively reviewed. Results Their median age was 59 years (range, 19-70), with a median HCT-CI score of 3 (0-6). Underlying diseases were AML in 44, MDS (RAEB-2) in 3, and CML (AP/BC) in 4. All patients were not in remission including primary induction failure (n=19), relapse 1 (14), relapse>2 (7), and untreated (11). Tacrolimus (TAC) plus mycophenolate mofetil were used in 38 cases as GVHD prophylaxis, while TAC alone in 13. All patients received single cord blood unit with 2-mismatches (MM) to the recipient (n=47) and 1-MM (4). The median number of total nucleated cell and CD34+ cells infused at cryopreservation was 2.61 (range, 1.67-5.09) x 107/kg and 0.94 (range, 0.28-2.97) x 105/kg, respectively. Median observation period of survivors was 18.3 (range, 9-75.5) months. Overall survival (OS) and disease free survival (DFS) at 2 years were 62.4% and 55.1%, respectively (Figure 1). Eleven patients relapsed at a median of 5.2 months (range; 0.5-26.7). Cumulative incidences of relapse at 100 days and 2 years were 7.8% and 20.1%, respectively. Cumulative incidences of NRM at 100 days and 2 years were 11.8% and 21.7%, respectively. Causes of NRM were Infection (n=8), GVHD (2) and idiopathic pneumonia syndrome (1). Forty-six out of 51 achieved neutrophil engraftment at median of 19.5 days (range, 13-38) post-transplant, with a cumulative incidence of 90.2%. All patients who achieved engraftment showed complete remission with complete donor chimerism in bone marrow analysis performed at around 30 days post-transplant. Among 5 who failed to achieve neutrophil recovery, 3 experienced early disease progression and 2 died before engraftment, while no patients developed graft rejection. Cumulative incidence of grade II-IV and III-IV acute GVHD were 52.9% and 13.7%, respectively. Of the 42 patients who achieved engraftment and survived longer than 100 days post-transplant, 13 developed limited type of chronic GVHD, and 5 developed extensive type. Conclusion This study demonstrated that the novel conditioning regimen using full-dose busulfan and melphalan for CBT provides reliable engraftment without graft rejection and high OS and DFS rates without increasing NRM, even for relatively higher age population with myeloid malignancies not in remission. The promising results using the regimen deserve further evaluation in a multicenter prospective study. Disclosures: No relevant conflicts of interest to declare.

Comparable 2-year overall and progression free survival among unrelated cord blood, unrelated bone marrow, and related peripheral blood stem cell transplantation in adult patients with standard-risk hematological diseases; A single center retrospective analysis Background Cord blood has become one of the major alternative donor sources for those who lack identical related donors in recent years. In Japan, an annual number of unrelated cord blood transplantation (uCBT) has been increasing and it reached 1179 cases in 2012, which is comparable to those of unrelated bone marrow transplantation (uBMT) and related peripheral blood stem cell transplantation (rPBSCT). So far, there is still limited data available on the comparative outcomes of adult standard risk patients receiving uCBT, uBMT and rPBSCT. Objectiv and method To compare the outcome of uCBT with those of uBMT and rPBSCT for adult patients with standard-risk hematological diseases, we retrospectively reviewed medical records of 142 patients with standard risk hematological diseases who underwent first allogeneic hematopoietic stem cell transplantation (allo-HSCT) at Toranomon Hospital from Jan 2005 to December 2011. The definition of standard risk disease is severe aplastic anemia (SAA), myelodysplastic syndrome (MDS) in refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), and refractory cytopenia with multilineage dysplasia (RCMD), acute leukemia in complete remission (CR) 1 or 2, chronic myeloid leukemia in chronic phase, non-Hodgkin lymphoma (NHL) in CR, and adult T-cell leukemia/lymphoma (ATL) in CR. Patients with active infection were excluded. Result The median follow-up day of survivors was 654 (19-2745). The characteristics of patients are summarized in Table 1. Forty-six patients performed uCBT, 66 did uBMT, and 30 did rPBSCT. The median age of the patients was 50 years (range, 16-70). There were more elderly patients in uCBT group than uBMT and rPBSCT groups (p=0.009). Cumulative incidence of neutrophil recovery at 50 days after transplantation was lowest in uCBT group and highest in rPBSCT group (uCBT= 87.1%, uBMT= 94.7%, rPBSCT=100%; P Conclusion Clinical outcomes of uCBT, uBMT and rPBSCT groups for adult standard-risk hematological diseases were comparable. Early death is prominent in uCBT, but the increase of late relapse and GVHD-related complications in rPBSCT offset it. Although immune cells in CB are primarily immature, comparable incidence of relapse with other donor sources indicate sufficient anti-tumor effect of uCB for longterm. uCB can now be considered as a promising donor source almost equivalent to uBM or rPB for adult standard-risk hematological diseases. Disclosures: No relevant conflicts of interest to declare.

Background EBV-associated post-transplant lymphoproliferative disorder (EBV-PTLD) is uncommon but one of serious complications after allogeneic stem cell transplantation (SCT). However, there has been little literature published on clinicopathological feature of it. Method We retrospectively investigated 825 cases of allogeneic SCT (unrelated bone marrow (uBM) 159, related peripheral blood (rPB) 94, cord blood (CB) 572) at Toranomon Hospital between January 2006 to November 2012. EBV-PTLD was defined as histologically confirmed Epstein-Barr virus (EBV) positive lymphoproliferative disorder developed after allogeneic SCT. Results We identified 12 cases of EBV-PTLD in our cohort. Cumulative incidence of EBV-PTLD at 2 years was 1.5%. Median time from allogeneic SCT to the diagnosis of EBV-PTLD was 6.4 (2.5-26) months. Eight patients were male and median age at the diagnosis of EBV-PTLD was 58.5 years (28-66). Underlying diseases were acute myeloid leukemia (n=5), myelodysplastic syndrome (1), acute lymphoblastic leukemia (2), adult T cell leukemia-lymphoma (1), aplastic anemia (2) and chronic myeloid leukemia in blastic phase (1). Conditioning regimens were fludarabine-based (n=10) and TBI/CY (n=2). None had an antithymocyte globulin-containing regimen. Donor sources were uBM (n=1) and CB (11). EBV serology before allogeneic SCT was tested in 11 and all were positive. Patients who received CB showed higher incidence of EBV-PTLD compared to those in non-CB cohort (2.2% vs 0.6%, p < 0.01), although patients characteristics was different between them. One patient developed PTLD after third allogeneic SCT. All but one patients had a history of acute graft-versus-host disease (aGVHD) of grade I (n=2), grade II (6) and grade III (3), respectively. Chronic GVHD was observed in 6 patients. Eight patients were on immunosuppressive therapy (IST) with calcineurin inhibitors and/or steroids when EBV-PTLD was suspected for the first time. Although lymphadenopathy was detected by CT scan in 7 patients, surface lymph nodes were swollen in only 3 patients. Initial manifestations were fever in 8, and diarrhea in 5 patients. EBV-PTLD was diagnosed from lymph nodes (n=3), skin (3), bone marrow (2), stomach/duodenum (1), colon (2), and lung (1), respectively. Histological feature was monomorphic (n=4), polymorphic (2), early lesion (4), and unknown (2), respectively. LMP1 and EBNA2 was positive in 40% (4/10) and 30% (3/10), suggesting latency status of I in 50% (6/12), II in 8.3% (1/12), III in 25% (3/12), and unknown in 16.7% (2/12). EBV DNA of 100 copies/microL or above was detected in peripheral blood in all of the EBV-PTLD cases. The treatment for EBV-PTLD were rituximab alone (n=3), rituximab plus reduction of IST (6), rituximab plus cytotoxic chemotherapy (1), and observation alone(2). Although 8 patients achieved response, 2 patients suffered a relapse of EBV-PTLD. With a median follow up of 27.5 (4.1-47.7) months, 2-year overall survival was 46.9% after diagnosis of EBV-PTLD. Eight patients died and 4 are alive without relapse of EBV-PTLD. Causes of death were EBV-PTLD (n=2), relapse of underlying disease(3), infectious disease(2), and aGVHD(1). Conclusion Twelve cases of EBV-PTLD were identified in 825 transplants. Cumulative incidence of EBV-PTLD at 2 years was 1.5%. The incidence of EBV-PTLD after CB transplant was higher than that after non CB transplant, although we have to take into consideration that patients feature was different between them. Response to rituximab and/or reduction of IST was observed in 8 patients with a 2-year overall survival rate of 46.9%. Patients with prior aGVHD and with longer duration of immunosuppressive therapy may have an increased risk of developing EBV-PTLD. Since the initial manifestations were often equivocal, and survival rate after diagnosis is not high, having EBV-PTLD in mind as one of the possibilities is critical for prompt diagnosis. Disclosures: No relevant conflicts of interest to declare.

Abstract 4498 Background: Unrelated cord blood transplantation (uCBT) using reduced-intensity conditioning (RIC) is increasingly used for older and medically unfit patients. Data on the efficiency of hematopoietic stem cell transplantation (HCT) after RIC in younger and standard-risk patients are limited relative to myeloablative conditioning (MAC). Objective and method: To compare the outocomes of RIC to MAC in uCBT for adult patients with standard-risk hematological diseases, we retrospectively reviewed medical records of 57 standard risk hematological disease patients who underwent first uCBT at Toranomon Hospital from Jan. 2005 to December.2011. The definition of standard risk disease is severe aplastic anemia (SAA), myelodysplastic syndrome (MDS) in RA, RARS, and RCMD, acute myeloid or lymphoid leukemia (AML, ALL) in complete remission (CR) 1 or 2, chronic myeloid leukemia (CML) in chronic phase, malignant lymphoma (ML) and adult T-cell leukemia (ATL) in CR. RIC and MAC are defined according to previously reported criteria. Result: The median age of the studied patients was 55 years (range; 26–70). Twenty nine of patients received RIC and 28 MAC. Eleven patients of SAA, 7 MDS, 17 AML, 12 ALL, 5 CML, 2 ML, and 3 ATL were included in this study. Median follow-up days of survivors was 299 (11–2522). Cumulative incidence of neutrophil engraftment was 89.2% and the median days of engraftment is 20 days (11–51). Cumulative incidence of grade 2 to 4 acute graft versus host disease (aGVHD) was 42.9%. The 5-year disease-free and overall survival (DFS and OS) rates were 49.1% and 42.6%, respectively. The 5-years OS was comparable between MAC and RIC (RIC= 52.1% versus MAC= 44.2%; P=0.90). The 5-years OS of the elderly patients >54 years (n=27, 47%) were significantly lower than that in the younger patients (n=30, 53%) (35.1% versus 63.7%; P=0.042). The 5-years transplant-related mortality (TRM) was comparable between MAC and RIC (RIC= 35.0% versus MAC= 28.6%; P=0.56). The relapse rate was also comparable in two groups (RIC=11.9% versus MAC=33.6%; P=0.2) Conclusion: This study showed that uCBT with RIC for standard risk disease patients with median age of 55 years old had the similar results as MAC regimens in the 5-years OS, DFS, TRM and relapse rate. Disclosures: No relevant conflicts of interest to declare.

Abstract 461 Background: Human herpes virus 6 (HHV-6) encephalitis is a growing concern after cord blood transplantation (CBT), which leads to permanent neurological sequelae that do not allow patients to get back into society. The pathogenic mechanism remains unknown and appropriate preventative strategies have not been established. Patients and methods: To evaluate incidences, risk factors and outcomes of HHV-6 encephalitis after CBT, we reviewed the medial records of 496 adult patients who underwent CBT for the first time at the Toranomon Hospital between 2002 and 2011, and who survived more than 7 days. Over the entire period, routine prophylaxis with acyclovir against reactivation of herpesviruses and pre-emptive therapy with ganciclovir or foscarnet (FCV) against cytomegalovirus disease were performed. From January 2006, prophylactic administration of FCV with monitoring of serum HHV-6 viral load against HHV-6 disease was introduced, the indication of which was decided at a physician's discretion. Plasma HHV-6 DNA copy numbers were measured using real-time PCR method, and the detection limit was 200 copies/mL. Immune reaction prior to neutrophil engraftment characterized by unexplained fever in the absence of documented infection with skin eruption, peripheral edema and body-weight gain was defined as pre-engraftment immune reaction (PIR), which was categorized as mild and severe, according to the degree of concomitant organ dysfunctions. HHV-6 encephalitis was defined as the neurological symptoms with positive PCR results for HHV-6 in cerebrospinal fluid (CSF) and the absence of other identified etiologies of encephalitis. Results: Forty-two patients developed HHV-6 encephalitis with a cumulative incidence of 8.5%. The incidence was significantly higher in the period from 2006 to 2011 compared to the period from 2002 to 2005 in spite of the introduction of prophylactic FCV after 2006 (11.1% vs. 4.3%, P=0.01), probably owing to more vigorous investigation. Among the 308 patients who received CBT after 2006, engraftment was achieved in 239 at a median of 20 (10–66) days after CBT, and PIR occurred in 133 patients at a median of 10 (4–24) days, the severity of which was classified into mild in 114 and severe in 19. 132 patients developed grade II-IV acute graft-versus-host disease (GVHD) at a median of 31 (9–91) days, and 182 received high-dose corticosteroids at >= 0.5mg/kg with a median starting point of 19.5 (0–1363) days. Serum HHV-6 PCR measurement was performed in 280 patients, 122 of who showed positive test results at a median of 20 (8–193) days. Prophylactic FCV was given in 234 patients from a median of 11 (0–35) days, with a median duration of 23 (2–79) days. HHV-6 encephalitis occurred in 34 of the 308 patients at a median of 22 (11–49) days, with a cumulative incidence of 11.2%. The median peak level of HHV-6 DNA was 20,000 (200–400,000) copies/mL in CSF, in contrast with 200 (0–89,300) copies/mL in plasma. PIR was identified as an independent significant risk factor for HHV-6 encephalitis (HR 3.13(1.52–6.44), P=0.002), which occurred more frequent in patients with severe PIR compared to those with mild one (HR 2.82(1.11–7.18), P=0.029). Another significant risk factor was high-level of HHV-6 DNA in plasma at >=10,000 copies/mL (HR 3.29(1.17–9.30), P=0.024), which was, however, observed in only 7 of the 34 patients with encephalitis. Neither grade II-IV acute GVHD nor the use of high-dose steroids influenced an incidence of the encephalitis (HR 2.2(0.90–5.37), P=0.083, and HR 0.98(0.47–2.03), P=0.95). Prophylactic FCV at >=60mg/kg showed a significant benefit in preventing HHV-6 encephalitis (HR 0.27(0.09–0.77), P=0.015), which substantially reduced the incidence to 1.6% if PIR was completely suppressed, whereas the incidence reached 23.4% in the presence of PIR if the FCV was not given (P Conclusions: PIR seems to bring at least similar or more risk for HHV-6 encephalitis compared to high-level HHV-6 viral load. Prophylaxis with FCV at >=60mg/kg combined with the optimal suppression of PIR might provide a further reduction of HHV-6 encephalitis after CBT. Disclosures: No relevant conflicts of interest to declare.

Abstract 4144 Hepatitis B virus (HBV) reactivation is a serious complication for allogeneic stem cell transplant (alloSCT) recipients which sometimes results in lethal hepatic failure. Lamivudine has widely been used as a prophylaxis, but the virus tends to acquire resistance to lamivudine by its long-term use. Entecavir is another nucleoside analogue with selective activity against HBV, and is known to induce less resistance to itself. Although there are several reports about lamivudine, anti-HBV immunoglobulin, and donor vaccination as prophylaxis for HBV reactivation in alloSCT recipients, only few reports about entecavir available so far. We retrospectively analyzed 191 alloSCT recipients (227 transplants) having chronic or resolved HBV infection from January 2005 to December 2011 in Toranomon Hospital. One hundred and forty (64%) cases were male, disease status of 170 (78%) cases was in high risk, and reduced-intensity conditioning regimens were selected in 177 (80%) cases. Related PBSCT, unrelated BMT, and unrelated CBT were 28 cases, 50 cases, 149 cases, respectively, and all the donors were free of HBV infection. Chronic HBV infection (18 cases) was defined as HBsAg-positive, and resolved HBV infection (209 cases) was defined as HBsAg-negative and positive for HBsAb and/or HBcAb before alloSCT without history of HBV vaccination. In recipients with chronic HBV infection, 12 cases had high serum HBV-DNA levels (more than 3 log copies/mL) before alloSCT. Antiviral agents were administered as prophylaxis for HBV reactivation in all cases with chronic HBV infection (entecavir 18 cases) and 140 (67%) cases with resolved HBV infection (lamivudine 12 cases and entecavir 128 cases). The dose of entecavir was 0.5 mg/day, and that of lamivudine was 100 mg/day. Antivirals were started before conditioning therapy, and were continued as long as the patients tolerated oral medication. Cumulative incidence of neutrophil engraftment was 90%. Two-year overall survival was 42%. About OS and neutrophil engraftment, there were no significant difference between entecavir, lamivudine, and non-prophylaxis group. Liver damages (transaminase more than 3 × upper normal limits) occurred in 80 cases, and cumulative incidence of sinusoidal obstructive syndrome was 2.2%. HBV was reactivated in 4 cases with resolved HBV infection and no cases with chronic HBV infection. The median duration of HBV reactivation from alloSCT was 326 days (250–1855). All 4 cases received unrelated RIC-CBT and had received no prophylactic antivirals, while none of those received prophylaxis developed viral reactivation. Immunosuppressants had been discontinued in all of them at the time of HBV reactivation. Two cases developed acute hepatitis, and successfully treated with entecavir and steroids. In other 2 cases, reversed sero-conversion occurred, but they did not develop hepatitis by starting entecavir. In conclusion, entecavir as prophylaxis for HBV reactivation in alloSCT recipients is considered to be safe and effective in this analysis. When to stop entecavir administration is the next issue to be investigated. Disclosures: No relevant conflicts of interest to declare.

Abstract 3043 Introduction HLA-mismatched unrelated cord blood transplantation (UCBT) is feasible and, in retrospective comparative analyses, allows survival rates similar to conventional unrelated HLA-matched adult-derived grafts. Although it is clear that the degree of UCB HLA mismatch in patients has a negative effect on outcomes, the biologic implications of HLA haplotype itself have not been explored for UCBT. In unrelated bone marrow transplantation, an effect of HLA haplotype matching on GVHD has been clarified. (S.Morishima. et al. Blood 2010). This study was conducted to determine the impact of HLA haplotype matching in reduced intensity UCBT. Patients and Methods To determine the impact of HLA haplotype matching with outcomes after UCBT, We retrospectively reviewed patients with hematologic malignancies who underwent reduced intensity CBT at Toranomon Hospital from August 2006 and December 2010 consecutively. Patients who had prior history of transplantation, were in poor performance status (ECOG PS >3), had active bacterial or fungal infections at the time of conditioning were excluded. Then, the remaining 164 consecutive patients were reviewed. The most frequently used conditioning regimens were fludarabine, alkylating agent (melphalan or busulfan) with total body irradination (TBI), tacrolimus plus mycophenolate mofetil for GVHD prophylaxis. DNAs of 164 pairs were analysed for HLA-A, -B, and -DRB1 based on High Resolution typing, and we have determined the HLA haplotype based on Japanese common HLA haplotypes referred from the previous reports. Results For A, B, DR based on high resolution typing the following mismatch occurred: no mismatch 3(2%), one mismatch 12(7%), two mismatch 58(35%), three mismatch 60(37%), four mismatch 28(17%), five mismatch 3(2%) in the GvH direction, and: no mismatch 2(1%), one mismatch 16(10%), two mismatch 55(34%), three mismatch 56(34%), four mismatch 32(20), five mismatch 3(2%) in the HvG direction. Then 37 among 164 pairs were defined as the HLA haplotype matched group. The number of total nucleated cells and CD34+ cells were not significantly different between HLA haplotype matched group and non-matched group. The cumulative incidence of neutrophil recovery was higher in HLA haplotype matched group than in non-matched group.( 94.6% vs. 80.3% up to day 60, p=0.0027). Lower incidence of pre-engraftment immune reaction(PIR) and acute GVHD were observed in haplotype matched group (37.8 % vs. 47.9 % up to day 60 post-transplant, P = 0.32), III to IV acute GVHD( 18.9% vs. 27.7% up to day 100 post-transplant, p=0.29). The cumulative incidences of relapse tended to be lower in haplotype matched group than in non-matched group (21.5% vs. 31.5%, P=0.28).Overall survival (OS) was estimated as 36.0 % at 3 years post-transplant. There were no significant differences between mathed and non-matched group in the cumulative incidence of OS (36.8 % vs. 34.3% at 3 years post-transplant, P = 0.84). Conclusion HLA haplotype matching in UCBT was found to have a significant impact on engraftment in this analysis. Disclosures: No relevant conflicts of interest to declare.

Abstract 3132 Introduction: In year 2008 version of WHO classification for myeloid malignancies, a category of AML with myelodysplasia-related changes (AML-MRC) was defined which included both de novo AML with dysplasia and AML secondary to MDS. It is characterized by poor chemosensitivity for which allogeneic transplantation (allo-SCT) has been a viable option to cure. Umbilical cord blood transplantation (UCBT) is a possible treatment strategy that can be performed for those who lack suitable donors due to rapid availability and less stringent HLA matching required. So far, there have been sparse reports available on UCBT for those with AML-MRC. This study was conducted to see the current update in our institute and to see whether the presence of induction chemotherapy before transplant is better for the outcome. Design and Methods: We retrospectively reviewed patients diagnosed as AML-MRC who underwent UCBT at our institute from Mar. 2002 to Mar. 2011 consecutively. Patients who lacked appropriate adult PB/BM donors underwent UCBT. Patients who had prior history of transplantation, were in poor performance status (ECOG PS >3), had active bacterial or fungal infections at the time of conditioning were excluded. Results: Eighty-one patients were included. 52 (64%) were males, and median age was 61 years (range, 17–72). 35 (43%) were de novo AML, and 46 (57%) were AML secondary to MDS. Median time from diagnosis to transplantation was 346 days (range, 42–7997). 39 (48%) did not receive induction chemotherapy before transplant. 76 (94%) were not in remission, 29 (36%) were in high, and 52 (64%) were in very high WPSS risk group, just before transplant. 54 (67%) received reduced-intensity conditionings. 65 received GVHD prophylaxis of tacrolimus-based, while 16 did cyclosporine alone. Median observation time for survivors was 646 days (range 32–2456). Median days of neutrophil recovery (> 500/ul) was 20 days (range, 11–45), and cumulative incidence of engraftment was 76.5 % up to day 50 post-transplant. Cumulative incidences of relapse and non-relapse mortality at 2 years post-transplant were 37.8 % and 33.3 %, respectively. Higher incidence of relapse was observed in those with prior history of MDS in univariate analysis (51.8 % vs. 21.2 % at 2 years post-transplant, P = 0.004), which was the only significant factor associated with higher relapse rate in multivariate analysis (P = 0.020). More NRM was observed in those received transplant early period from 2002 to 2005 vs. those who did from 2006 to 2010 (45.1 % vs. 25.5 % at 2 years post-transplant, P = 0.001), and in those received GVHD prophylaxis using CsA alone vs. others (72.0 % vs. 24.8 % at 2 years post-transplant, P = 0.0002). In multivariate analysis, higher degree of HLA mismatch (2 antigens vs. less than 2) and GVHD prophylaxis using CsA alone were associated with higher incidence of NRM (P = 0.024 and P = 0.00047, respectively). Overall survival (OS) was estimated as 42.1 % at 2 years post-transplant. Better OS was observed in those who received conditioning containing 12.8mg/kg of iv busulfan (60.8% vs. 32.4% at 2 years post-transplant, P = 0.0337), in those received tacrolimus-based GVHD prophylaxis vs CsA alone (47.9 % vs. 17.0 % at 2 years post-transplant, P = 0.0024), and in those received transplant in recent period from 2006 to 2010 vs. those who did from 2002 to 2005 (52.1 % vs. 26.1 % at 2 years post-transplant, P = 0.0248). In multivariate analysis, GVHD prophylaxis using CsA alone and poor WPSS risk category just before transplant were the factors significantly asssociated with poor OS (P < 0.0001 and P = 0.001, respectively). There were no significant differences between presence or absence of prior induction chemotherapy in terms of cumulative incidence of neutrophil recovery (71.4 % vs. 82.1% up to day 50 post-transplant, P = 0.88), relapse (38.0 % vs. 36.1%, P = 0.94), NRM (30.7 % vs. 35.4 %, P = 0.87), and OS (47.7 % vs. 36.2%, P= 0.72) at 2 years post-transplant. Conclusions: These data indicate that CBT is a feasible and promising treatment approach for those with AML-MRC, including elderly patients. More intensive GVHD prophylaxis was beneficial in reducing NRM and improving OS for the population studied. Presence of prior induction chemotherapy before transplant was not associated with higher rate of engraftment or better OS, suggesting tumor reduction before pre-transplant conditioning may not be necessary for successful outcome in our transplant settings. Disclosures: No relevant conflicts of interest to declare.

Abstract 4705 [Background] Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by abnormal accumulation of alveolar surfactant protein within alveoli. Acquired PAP has been sub-classified into autoimmune and secondary PAP according to the presence of serum anti-granulocyte macrophage colony-stimulating factor (GM-CSF) autoantibody. Hematological diseases including myelodysplastic syndrome (MDS) are the most frequent causes for secondary PAP with unclear pathogenesis independent of anti-GM-CSF antibody.[Objective and method] To assess the clinical effect of HSCT for PAP, we retrospectively analyzed 4 patients with MDS who received allogeneic transplantation at Toranomon Hospital. [Case report] Case 1 is a 35-year-old male with pancytopenia. He was diagnosed with MDS-RA with trisomy 8 abnormality in January 2008. In January 2009, he had productive cough and chest X-ray and CT revealed opaque consolidation in the bilateral lower lung fields. The diagnosis of PAP was made by transbronchial lung biopsy findings. In April 2010, he underwent unrelated bone marrow transplantation (BMT). But idiopathic pneumonia syndrome as a transplant-related complication developed and died on day 55. Case 2 was a 42-year-old female who had a history of aplastic anemia with normal karyotype from March 2007. In March 2009, she had cough and abnormal chest X-ray and CT findings. The diagnosis of PAP was made by bronchoalveolar lavage (BAL) findings. At this time, the diagnosis of MDS-RAEB with trisomy 8 was made. In September 2009, she underwent unrelated cord blood transplantation. But she died by sepsis and pneumonia of Stenotrophomonas maltophilia on day 12. Case 3 was a 58-year-old female with stomatitis who was diagnosed with Behcet's disease in 2001. In May 2001, she developed fever and productive cough. She was diagnosed with PAP by abnormal chest X-ray and BAL findings. In July 2009, she developed pancytopenia, and the diagnosis of MDS-RAEB with trisomy 8 was made. In March 2010, she underwent unrelated BMT. After transplantation, PAP was gradually improved. Case 4 was a 47-year-old male with dyspnea who was diagnosed with PAP by CT and BAL findings. At the same time, he was diagnosed with MDS-RCMD with trisomy 8. In June 2011, he underwent peripheral blood stem cell transplantation from a HLA-identical brother. His transplant clinical course was uneventful and PAP was completely improved by day 42 in CT findings.[Discussion &Conclusion] Case 1 and 2 died of pulmonary complication developed after HSCT, one is pneumonia and another was idiopathic pneumonia syndrome. In case 3 and 4, both transplant clinical course was relatively uneventful and PAP disappeared with the improvement of MDS after HSCT. It is suggested that HSCT might be the effective treatment of secondary PAP with hematological disease, but secondary PAP itself may be the risk of pulmonary complication after HSCT. As we reported the possible association of trisomy 8 MDS with PAP development in 3 cases1, all 4 MDS cases presented here revealed trisomy 8 abnormality of bone marrow cells. Disclosures: Off Label Use: Mycophenolate mofetil was off-lable use for GVHD prophylaxis.

Abstract 1961 Objectives: Invasive fungal infections (IFIs) are considered as important problems especially in the early period after allogeneic cord blood transplantation (CBT), because of the significantly prolonged neutropenia compared to bone marrow or peripheral blood stem cell transplantations. Antifungal prophylaxis should be therefore carefully selected to assure definite effects with less toxicity, without being affected by drug interactions, and patient's compliance and situation. The object of this study was to evaluate antifungal prophylactic efficacy and safety of micafungin (MCFG) at 150mg with monitoring of the plasma concentrations in high-risk CBT recipients. Patients and Methods: The study was a prospective, one-institution, single-arm trial of MCFG administered during neutropenic phase of CBT. Adult patients aged >= 20 years who were scheduled for CBT were eligible for this study, if they had no history of or symptoms consistent with IFIs. Approval for the study protocol was obtained from the ethical committee of Toranomon Hospital, and written informed consent was obtained from each patient. MCFG at a once daily dose of 150 mg as a 1-h infusion was initiated at the beginning of the transplant-related conditioning regimens. Although the study treatment was principally continued beyond 3 days after engraftment up to a maximum of 50 days after transplantation, it was ceased earlier in cases of the followings; development of proven, probable, or suspected IFIs; development of unacceptable drug toxicity; receipt of a re-transplant; death; withdrawal of study participation by patient' decision; or discontinuation of the study treatment by physician's decision. Trough and peak plasma concentrations of MCFG were measured on the day of transplantation and a week after by using high-performance liquid chromatography. The primary end point was treatment success, which was defined as the absence of proven, probable, or suspected IFIs through the end of therapy and as the absence of proven and probable IFIs through the end of the 50-day period after treatment. Results: A total of 73 patients with advanced or high-risk hematologic diseases were enrolled for this study between May, 2010 and June, 2011. The median age was 55 (20–73) years old, and 67 patients who received reduced-intensity conditioning were included. Sixty-four patients achieved engraftment at a median of 18.5 (9–36) days during the study period. The median duration of MCFG administration from transplantation was 33 (2–50) days. No patients discontinued use of the study drug because of an adverse event. In 70 patients who received at least 7 doses of study drug, median trough levels were 3.46 (0.63-7.81) μg/mL on the day of transplantation and 2.88 (0.30-8.25) μg/mL a week after, which were not influenced by body weight, creatinine clearance or serum levels of albumin, bilirubin and hepatobiliary enzymes. Median peak levels of MCFG in the first 10 patients were 12.99 (10.27-18.74) μg/mL and 12.40 (9.46-15.64) μg/mL, respectively, which were fairly constant over time in each individual. The treatment success rate at 50 days after transplantation was 76.7% and the Kaplan-Meier estimate of the treatment success was 75.6%. Seven breakthrough infections occurred at a median of 29 (8–38) days, with a cumulative incidence of 10.0%. There were 4 cases of invasive pulmonary aspergillosis (IPA) and three caused by Candida species recovered from the bloodstream. One probable IPA and two candidemia due to Candida parapsilosis and Candida krusei developed during prophylactic treatment, whereas three probable IPA and one candidemia due to Candida parapsilosis developed during the post-treatment follow-up period. There were 10 patients with suspected IFIs on the basis of abnormality in CT scan, in whom MCFG was switched to a different class of mold-active agents (liposomal amphotericin B in 7 and voriconazole in 3). Nine patients died during the study, one of who died of IPA associated with graft failure at 32 days after transplantation. Conclusions: Daily administration of MCFG at 150mg appears to be an effective and generally well-tolerated antifungal prophylaxis during neutropenic phase in high-risk CBT recipients. Prophylactic use of MCFG in the early period after transplantation might also be an appropriate approach to easing concerns about drug interactions and variability of drug concentrations. 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 651 Backgrounds: Engraft failure remains a critical issue to be solved especially after cord blood transplantation (CBT). The factors such as limited doses of infused total nucleated (TNC) and CD34+ cells, HLA disparity, and anti-HLA antibodies are considered to induce engraftment failure. We studied the patterns and mechanisms of engraftment failure for patients who failed engraftment after CBT. Patients/methods: Medical charts on 429 transplant recipients of single unit CB with hematological diseases as the first allogeneic HSCT at Toranomon Hospital between January 2002 and May 2011 were retrospectively reviewed. Patients who did not meet the criteria of engraftment were subjected to the following analysis. Engraftment was defined when the neutrophil counts exceeded 0.5 × 109/L for 3 consecutive tests. Patients who died or had progressive disease before day 28 post-transplant were excluded. Result: Among 429 recipients, 67 were excluded due to early death before day 28 (n=52) and disease progression (n=15). In remaining 362 patients, 31 were diagnosed as engraftment failure. Median age was 62 years (range, 17–71). Underlying diseases were AML (n=16), ALL (n=5), MDS (n=2), NHL (n=6), and SAA (n=2). Twenty-three (74%) were in high risk disease status (MDS RAEB and beyond, or AL, NHL not in remission). Conditioning regimens mainly comprised of purine analogue-based reduced-toxicity regimens with fludarabine phosphate (125-180 mg/m2), melphalan (80-140 mg/m2) or busulfan (8-16 mg/kg) and 0–4 Gy of total body irradiation (TBI), and others. Graft-versus-host disease (GVHD) prophylaxis comprised of tacrolimus (TAC) (n=13) or cyclosporine alone (n=8), and TAC + mycophenolate mofetil (MMF) (n=10). Median number of total nucleated cells (TNC) and CD34+ cells were 2.45×106 /kg (range, 1.94 – 4.20), and 0.76×105 /kg (range, 0.21 – 1.35), respectively. Three had 1 antigen mismatch and 28 had 2 antigen mismatches in serological HLA typing, and 15 had allelic mismatches in more than 3 loci between host and graft. Twenty-two (71%) showed recipient-dominant chimerism (donor type 90%), designated as poor graft function. Anti-HLA antibodies were present in 7 of the 13 patients tested (54%), including 2 (28%) who had a donor-specific antigen that targeted against UCB unit used. All these 7 patients who had anti-HLA antibody showed the graft rejection pattern. T-cell donor-recipient chimeric status was assessed in 14 patients. Nine who showed complete recipient dominant chimerism in T-cell fraction (donor type Discussion: These data demonstrated that the graft rejection pattern comprised 70% of engraftment failure. Presence of anti-HLA antibody showed close correlation with graft rejection, suggesting antigen-mediated graft rejection mechanism following CBT. Recipient dominant T-cell chimerism at early transplant phase (around day 15) strongly indicates impending graft rejection. All patients who showed poor graft function pattern accompanied by severe infection and/or HPS. This pattern is rarely seen in HSCT of other stem cell sources, suggesting unique characteristics of immune cells in CB graft as we reported. Disclosures: No relevant conflicts of interest to declare.

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 4553 Introduction Acute graft versus host disease (GVHD) remains the most frequent complication after allogeneic hematopoietic stem cell transplantation (SCT). In reduced intensity cord blood transplantation (CBT) previous studies have reported a lower incidence of severe acute GVHD compared with conventional allo-SCT. However, in these studies the incidences of grade II-IV acute GVHD varied widely from 26% to 51% (H.Narimatsu Stem cell int. 2011: 607569). In particular, post transplant immune disorders, including early immune reactions (PIR) and acute GVHD, are potential complications following CBT in adult patients. Such reactions might increase the risk of organ dysfunction, leading to high rates of transplantation-related mortality, particularly in patients who do not respond to primary therapy, which usually consists of steroids. Infliximab, a chimeric monoclonal antibody against tumor necrosis factor alpha, has shown activity against steroid refractory acute GVHD. Patients and Methods We retrospectively reviewed 275 patients who underwent single-unit reduced intensity cord blood transplantation consecutively from March 2007 to December 2011 at our institute. Patients in whom PIR or acute GVHD developed received methylprednisolone 1–2 mg/kg per day. If no partial or complete resolution of symptoms occurred, they were considered steroid-refractory and proceeded to infliximab treatment. The dose of infliximab was 5 mg/kg/day once weekly for at least 1 course. An antifungal drug, itraconazole or micafungin or voriconazole was used until all immunosuppressive drus were withdrawn. Results In this study we retrospectively evaluated 54 patients who had steroid refractory acute GVHD. Of these, 21 who received infliximab were analyzed. GVHD prophylaxis was with only tacrolimus(n=15) and mycophenolate mofetil+tacrolimus(n=6). All of them developed grade III to IV GVHD. Median follow-up time of survivors was 548 days (range, 222–1152). The overall response rate was 62% (n=13), and 9 patients (43%) experienced complete response (CR). 5 patients (24%) did not respond and 3 (14%) had progressive GVHD. The Kaplan-Meier estimate of overall survival was 31%, with no signs of chronic GVHD (n=2). Four patients who responded subsequently died, one of exacerbation of GVHD, three of infections. All the 8 unresponsive patients died of GVHD or infections. Five patients (21%) had non-Candida invasive fungal infections. Sixteen patients(79%) had bacterial infections. Conclusion Infliximab was well tolerated and active for the treatment of steroid-resistant acute GVHD even following reduced intensity cord blood transplantation. However, it is associated with a high rate of infections. Controlled studies to assess the pharmacokinetics and most effective dosing regimen of infliximab for the treatment of steroid refractory acute GVHD are warranted. Disclosures: No relevant conflicts of interest to declare.

Abstract 1295 Disease relapse following allogeneic hematopoietic stem cell transplant (allo-HSCT) remains a major cause of treatment failure, often with a poor outcome. Some recent reports have demonstrated successful treatment receiving 2nd allo-HSCT with bone marrow (BM) and peripheral blood (PB) following relapse. However, there are few reports about unrelated cord blood transplant (UCBT). Therefore, we retrospectively analyzed the results of 2nd allo-HSCT using UCB for 34 adult patients with acute myeloid leukemia (AML) / myelodysplastic syndrome (MDS), who relapsed after 1st HSCT. We reviewed medical records of 130 adult patients with AML/MDS who received 1st HSCT between March 2006 and May 2009 at Toranomon Hospital, Tokyo, Japan. Fifty-three of these patients relapsed after 1st allo-HSCT including 12 recipients of related peripheral blood (RPB), 13 unrelated bone marrow (UBM) and 28 UCB. In these relapsed patients, 34 proceeded to 2nd transplant with UCB. The remaining 19 patients did not receive 2nd transplants because of severe organ dysfunction or uncontrolled active infection and continued complete remission by donor lymphocyte infusion. The median age at 2nd UCBT was 54 years (18-69) and interval between 1st allo-HSCT and 2nd UCBT was 9 months (1-54). Diagnoses include de novo AML (n=21) and MDS overt AML (n=13). Disease status at 1st allo-HSCT were as follows; 4 patients in CR, 25 patients in chemo-refractory and 5 patients in progressive desease without chemotherapy. All patients at 2nd UCBT were in progressive disease. All patients received a single cord blood unit with median TNC/CD34 cell dose of 2.8×107/kg (range, 1.4–4.8) and 0.7×105/kg (range, 0.2–2.2), respectively. HLA disparities were 3/6 match (n=4), 4/6 (n=25), 5/6 (n=4) and 6/6 (n=1). Conditioning regimen consisted of fludarabine and alkylating agent. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (Tac) alone in 15, Tac plus mycophenolate mofetil in 11, and cyclosporine alone in 8. Ten patients died by day 28 because of progressive disease (n=5) and transplant related mortality (n=5) and 21 of 24 patients, who survived more than 28 days, were engrafted with complete donor type chimerism (median 19 days). Acute GVHD developed in 14, and chronic GVHD in 4 of these 21 engrafted patients. Estimated 3-year over all survival (OS), transplant related mortality rate and relapse mortality rate were 16%, 32%, and 52%. In univariate analysis, a variable associated with worsened survival were early relapse within 100 days after 1st allo-HSCT (0 vs 21% in late relapses; P=0.01), while other factors were not significant. Eighteen of 19 patients who did not undergo 2nd UCBT died of progressive disease or multiple organ failure. 3 year-OS of 16% with 2nd UCBT following relapsed AML/ MDS was comparable with that of 2nd BMT or PBCST. Considering that all patients in this study were in non-remission and in relatively higher age (median age 54 years), 2nd UCBT following relapse of AML/MDS could be a viable therapeutic option. Disclosures: No relevant conflicts of interest to declare.

Abstract 2295 Poster Board II-272 Introduction: Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning has been widely applied to those who have advanced hematologic diseases and are not eligible for conventional conditioning. Although bone marrow or peripheral blood from related donors (rBM/PB) have been the first choice of graft when available, followed by unrelated adult donor or cord blood (CB), true superiority of rBM/PB over others can still be controversial. Elderly patients have difficulty finding related donors since their siblings are also in their elderly who have higher chance of having co-morbidity relative to younger patients. Rapid availability is the advantage of rBM/PB and CB share over unrelated adult donor, which enabled adapting similar policy of performing transplant possible, especially for elderly patients, given the significantly higher treatment-related mortality for elderly. Design and Methods: We retrospectively reviewed patients aged 55 and older who underwent reduced intensity allogeneic stem-cell transplantation using CB or rBM/PB at our institute from Jan. 2004 to Dec. 2008 consecutively. Patients who were considered for allogeneic transplant and had available 6/6 or 5/6 HLA-matched relatives performed rBM/PB transplants, whereas those who lacked rBM/PB donors underwent CB transplants. Patients who had prior history of transplantation, were in poor performance status (ECOG PS 2 and greater), had active bacterial or fungal infections at the time of conditioning, had diagnosed as multiple myeloma, adult T-cell leukemia, non-malignant diseases were excluded. Results: Two-hundred and thirty-two (171 CB and 60 rBM/PB) RI transplantation were performed from Jan. 2004 to Dec. 2008 at our institute, and 82 (61 CB and 21 rBM/PB) were eventually subjected to the analysis after excluding those who were ineligible according to the above mentioned criteria. The diagnoses included were AML (n=51), MDS (n=9), ALL (n=9) CML/MPD (n=4), and ML (n=9). Fifty-eight (71%) had high risk diseases, and 24 (29%) were in ECOG PS 2. Recipients of CB and rBM/PB were comparable in terms of diagnosis, disease risk (standard vs high), ECOG PS (0-1 vs 2), and year of transplant (2004-2005 vs 2006-2008). The median age for rBM/PB recipients was slightly younger (median 60, range 55-66) than that for CB (median 62, range 55-69, P < .03). CB recipients received more serologically HLA-mismatched grafts (98% vs. 3%, P Conclusions: These data suggest that, for elderly patients, comparable results can be expected using CB, which opens more opportunity for elderly patients to undergo allogeneic transplants who generally have difficulty finding healthy related donors compared to younger patients. However, before CB become the first choice of graft, higher rate of engraftment failure and non-relapse mortality, particularly during early period post-transplant, need to be overcome, and, at this moment, rBM/PB is still the optimal graft of choice when available over CB. Disclosures: No relevant conflicts of interest to declare.

Although cord blood (CB) transplantation with reduced-intensity (RI) conditioning (RICBT) has been widely applied to those who lack available related or unrelated donors and are not eligible for conventional conditioning, indication of RICBT to elderly patients relative to other stem-cell sources is still controversial due to higher early mortality post-transplant and undefined long-term outcome. Since there has been not much data available regarding this issue, we retrospectively reviewed patients aged 55 and older who underwent RI allogeneic stem-cell transplantation at our institute from Nov. 2000 to Dec. 2006 consecutively. The study includes 121 recipients of CB (n=42), unrelated bone marrow (UBM, n=41), and related mobilized peripheral blood (RPB, n=38) for AML / MDS (n=66), ALL (n=11), CML (n=4), ML (n=31), MF (n=3), and AA (n=6). The median age for CB, UBM, and RPB recipients were 61 (range 56–69), 60 (55–70), and 60 (55–66), respectively. CB recipients had more serologically HLA-mismatched grafts (98% vs. 24% vs. 5%, P < .05), were conditioned more frequently with melphalan (90% vs. 34% vs. 32%, P < .05) and with total body irradiation (88% vs. 71% vs. 16%, P < .05), used more tacrolimus (100% vs. 71% vs. 18%, P < .05) and less methotrexate (0% vs. 76% vs. 74%, P < .05) for GVHD prophylaxis, had shorter duration of donor search (median 41 days (14–151) vs. 166 (93–345) vs. 130 (41–311), P < .05), and were transplanted more recently (2005–2006: 71% vs. 56% vs. 37%, P < .05). CB recipients tended to have high-risk disease status (76%) relative to UBM (59%) and RPB (66%) recipients, although not statistically significant. Other characteristics such as sex, diagnosis, and body weight were balanced among three groups. Median follow-up time of survivors was 554 days (25–1132), 667 days (315–1794), and 703 days (57–2214) for CB, UBM, and RPB recipients, respectively. CB recipients tended to show slower neutrophil recovery (median 19 days (12–36) vs. 16 (10–27) vs. 13 days (10–21)), and lower rate of myeloid engraftment (86% vs. 90% vs. 100%), although not statistically significant. The incidence of grades II–IV acute GVHD among evaluable CB recipients (61%) was lower than that of UBM (83%, P < .05) and comparable to that of RPB recipients (50%). The incidences of chronic GVHD for evaluable CB, UBM, and RPB recipients were 45%, 71%, and 71%, respectively (N.S.). The disease-free survival and overall survival (OS) at 2 years post-transplant were 23+/–7% and 33+/–8% for CB, 42+/–8% and 47+/–8% for UBM, and 35+/–9% and 40+/–9% for RPB recipients, respectively (N.S.). Within those who had standard risk diseases, 2-year OS were 67+/–15.7%, 48+/–13%, and 59+/–14% for CB (n=10), UBM (n=17), and RPB (n=13) recipients, respectively (N.S.). These data suggest that CB could be a viable stem-cell source for elderly patients as UBM or RPB, not just expanding opportunity of transplant. A larger-sized, randomized study is needed to further define the position of CB for this population of patients.

Background Breakthrough viridans streptococcal bacteremia (VSB) in patients with hematological malignancy receiving levofloxacin prophylaxis is a major blood stream infection (BSI) occurring during febrile neutropenia. However, clinical data focused on VSB in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are lacking. Methods The medical records of allo-HSCT recipients who received oral levofloxacin prophylaxis between January 2011 and August 2013 at Toranomon Hospital were reviewed to evaluate breakthrough VSB. Stored viridans streptococcal (VGS) species were identified by using sodA gene sequencing, and were assessed for drug susceptibility. Results Among the 184 allo-HSCT recipients on levofloxacin prophylaxis, 28 (15.2 %) experienced breakthrough VSB. All of the 28 recipients with VSB were treated with a cefepime-based or piperacillin/tazobactam-based regimen. The susceptibility rates of the VGS strains for levofloxacin, cefepime, piperacillin/tazobactam, meropenem, and vancomycin were 0 %, 95 %, 100 %, 100 %, and 100 %, respectively. Both the MIC50 (minimum inhibitory concentration) and the MIC90 of ceftazidim (0.5 μg/mL and 2 μg/mL, respectively) were higher than the MIC90 of all the other anti-pseudomonal beta-lactams (APBLs). Only 1 VGS strain had a penicillin MIC ≥ 2 μg/mL by the Etest (3.6 %). There were no cases with acute respiratory distress syndrome (ARDS) that was associated with VSB, although the rate of viridans group streptococcal shock syndrome was high (26 %). The crude 30-day mortality rate in the VSB group (10.7 %) did not differ significantly from that in the BSI without VSB group (9.3 %) or non-BSI group (7.0 %) (P = 0.77). Also, VSB was not a risk factor for all-cause mortality up to 60 days following allo-HSCT (P = 0.43). Conclusions APBL with increased anti-VGS activity (APBL-VA) monotherapy would typically be optimal for treating the VGS strains in this setting. Indication of adding an empiric anti-gram-positive agent to APBL-VA for treating VSB should depend on local factors, such as the susceptibility results. In addition, breakthrough VSB is probably not a major cause of death in allo-HSCT settings, where beta-lactam non-susceptible VGS and the ARDS are rare. Electronic supplementary material The online version of this article (doi:10.1186/s12879-016-1692-y) contains supplementary material, which is available to authorized users.