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Recent progress in genetic analysis technology has helped researchers understand the pathogenesis of acute myeloid leukemia (AML). Considering this progress, AML karyotype is still one of the most significant prognostic factors that provides risk-adapted treatment approaches. Karyotype changes during treatment have been observed at times, but their prognostic impact is sparse, especially on allogeneic stem cell transplantation (allo-SCT). Here, we retrospectively investigated the effect of chromosomal changes between diagnosis and pretransplantation on the prognosis of allo-SCT by analyzing the outcomes of 212 consecutive patients who underwent allo-SCT for the first time at Toranomon Hospital, Tokyo, Japan, between 2008 and 2018. Cytogenetic abnormalities at diagnosis and pretransplantation were categorized based on the 2017 European Leukemia Net risk stratification. Genetic abnormalities such as FLT3-ITD and NPM1 were not considered in this study due to lack of genetic information in most patients. We defined cytogenetic evolution as chromosomal changes classified from lower category to higher category. Seventeen patients (8%) had cytogenetic evolution between diagnosis and pretransplantation, and they showed a significantly worse relapse rate than those who were categorized in the intermediate group based on the karyotype at diagnosis (3-year confidence interval [CI] of relapse, 57.4% versus 24.9%; P.01). In multivariate analysis, cytogenetic evolution before allo-SCT had a significant impact on the CI of relapse (hazard ratio [HR], 3.89; CI, 1.75 to 8.67; P.01), as well as the high score of the hematopoietic cell transplantation-specific comorbidity index (HR, 0.54; CI, 0.31 to 0.94; P = .03), but had no significant impact on overall survival or nonrelapse mortality. These results indicate that cytogenetic evolution has a significant impact after allo-SCT and should be considered during AML treatment.

The aim of this study is to clarify the characteristics of gram-negative bacteremia (GNB), including extended-spectrum β-lactamase (ESBL)-producing pathogens, among allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients on levofloxacin (LVFX) prophylaxis. A retrospective analysis on GNB at the first episode of febrile neutropenia (FN) was conducted among allo-HSCT recipients (age ≥ 20 years) on 500 mg/day of oral LVFX prophylaxis. Epidemiological and microbiological features of GNB were investigated and compared between the inappropriate and appropriate empiric therapy groups. In total, FN occurred in 414 allo-HSCT cases, and bacteremia at the first episode of FN occurred in 169 cases. Overall, 29 GNB cases were documented, and the causative organisms identified were Escherichia coli in 21 cases (including 10 ESBLs), Klebsiella pneumoniae in 2, Pseudomonas aeruginosa in 2, and other in 4. The crude 30-day mortality rate was not significantly different among cases of GNB (6.9%), gram-positive bacteremia (GPB) (7.1%), or non-bacteremia (5.4%; P = 0.78). Cefepime (CFPM) was administered in all cases in the inappropriate empiric therapy group, and all causative organisms were ESBL-producing E. coli (ESBL-EC). All patients in the inappropriate empiric therapy group had a low Pitt bacteremia score (≤ 2). Thirty-day mortality did not differ significantly between the inappropriate and appropriate empiric therapy groups (1/10 vs. 1/15, P = 0.61). In conclusion, GNB was not a significant cause of death. In LVFX breakthrough ESBL-EC bacteremia among allo-HSCT recipients, the administration of CFPM as empiric therapy did not lead to significantly poor prognosis. Empiric CFPM administration might be an acceptable strategy.

There are few reports on the clinical course of proven invasive aspergillosis (IA) due to rare/cryptic species in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. We retrospectively reviewed the electronic medical records of patients who underwent allo-HSCT between January 2012 and December 2018. Of 934 allo-HSCT recipients, 10 were diagnosed with proven IA and 61 were diagnosed with probable IA. DNA sequencing was performed in cases of proven IA, and Aspergillus could be identified to the species level in 8 of the 10 cases. Three were due to A. fumigatus, and 5 were due to rare/cryptic Aspergillus species, namely, A. turcosus, A. felis, A. viridinutans, A. nidulans, and A. calidoustus. In these 8 patients, no patients with IA due to A. fumigatus died, whereas 3 of the 5 with IA due to rare/cryptic species died within 12 weeks. The 2 surviving cases of IA due to rare/cryptic species were treated with surgical resection and antifungal treatment. Susceptibility testing for cryptic species in 4 cases showed an amphotericin B minimum inhibitory concentration (MIC) > 1 mg/L in 3 cases, itraconazole MIC > 1 mg/L in 2 cases, and voriconazole MIC > 1 mg/L in 2 cases. In conclusion, more than half of the causative pathogens of proven IA were rare/cryptic species, so it is important to accurately identify the Aspergillus species. In addition, surgical treatment might be an important option in cases of proven IA, given the possibility that the causative organisms are azole-resistant A. fumigatus or rare/cryptic species.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA-LPDs, including 36 with diffuse large B-cell lymphoma (DLBCL)-type and 19 with Hodgkin lymphoma (HL)-type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein-Barr virus positivity in DLBCL-type (P = 0·013). The 2-year overall survival and progression-free survival (PFS) at a median follow-up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2-year PFS was seen between patients with DLBCL-type and HL-type OIIA-LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour-derived DNA from 20 DLBCL-type OIIA-LPD samples, histone-lysine N-methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha-induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL-type OIIA-LPD. Cases with DLBCL-type OIIA-LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA-LPDs, especially DLBCL-types, showed favourable prognoses.

Limited data are available on Stenotrophomonas maltophilia bloodstream infections (SM-BSIs) and the therapeutic efficacy of trimethoprim–sulfamethoxazole (SXT) against SM-BSI in umbilical cord blood transplant (uCBT) recipients. Medical and microbiological records of adult patients who received uCBTs between December 2008 and December 2015 at Toranomon Hospital (Tokyo, Japan) were reviewed. The efficacy and safety of SXT were evaluated only for recipients who were treated with ≥7 days of intravenous SXT for SM-BSI (evaluation cohort). Of 561 uCBT recipients, 34 developed SM-BSI. Diabetes mellitus (P = .005) and age ≥ 60 years (P = .013) were significant independent risk factors for SM-BSI. Moreover, SM-BSI was identified as an independent risk factor for all-cause mortality up to 100 days following uCBT (P = .025). Of the 34 recipients with SM-BSI, 24 were treated with an intravenous SXT-containing regimen (iSXT-CR). Septic shock (P = .0021), pneumonia (P = .011), neutropenia (P = .0015), and systemic steroid administration (P = .018) were identified as significant independent risk factors for 7-day crude mortality. The evaluation cohort included nine recipients. Doses of SXT were 2.4 to 6.9 mg/kg/day of the trimethoprim component. Of the nine recipients, five developed SM-BSI during the pre-engraftment phase. The 30-day crude-mortality rate and clinical cure rate of the cohort were 22% and 67%, respectively. Only one of the nine recipients experienced significant neutrophil toxicity. In this study, the epidemiology of SM-BSI in uCBT recipients was determined and its negative impact on survival was demonstrated. A low- to moderate-dose iSXT-CR appeared to be a tolerable and important therapeutic option for SM-BSI in the uCBT setting, including during the pre-engraftment phase.

Background Factors affecting the safety of bronchoscopy in patients with malignant hematologic disorders have not been well described. We evaluated the safety of bronchoscopy and describe factors affecting its complication rate in such patients. Methods Between January 2009 and December 2018, 316 bronchoscopies in 282 patients with malignant hematologic disorders and pulmonary infiltrates were performed at our institution. The bronchoscopic procedure used and its complications were evaluated. Results The most common underlying disease was acute myeloid leukemia (134/282 patients, 47.5%). Platelet transfusion was performed the day before or the day of bronchoscopy in 42.4%, supplemental oxygen was administered before the procedure in 23.1%, and midazolam was used in 74.4%. Thirty-five bronchoscopies (11.1%) were complicated by hemoptysis and 7 patients developed pneumothorax, 4 of whom required thoracic drainage. Two patients (0.6%) were intubated within 48 h of the procedure and prolonged oxygen desaturation (> 48 h) occurred in 3.8%. Multivariate analysis showed that only use of midazolam significantly reduced the risk of prolonged oxygen desaturation (hazard ratio 0.28, 95% confidence interval 0.09–0.85, p = 0.03). Transbronchial lung biopsy significantly increased the risk of hemoptysis (hazard ratio 10.40, 95% confidence interval 4.18–25.90, p = 0.00), while use of midazolam significantly reduced the risk (hazard ratio 0.31, 95% confidence interval 0.14–0.73, p = 0.01). Conclusions Bronchoscopy is relatively safe in patients with malignant hematologic disorders. Caution and judicious use of sedatives may improve the patient’s procedural tolerance and lower complications.

Bloodstream infection (BSI) is a major infectious complication after allogeneic hematopoietic cell transplantation (HCT). To clarify the impact of graft cell source on the incidence of BSI after transplantation, we retrospectively examined 782 adult patients receiving their first allogeneic HCT: 122 recipients of related peripheral blood stem cells or bone marrow, 215 recipients of unrelated bone marrow, and 445 recipients of unrelated umbilical cord blood (U-CB). The cumulative incidence of BSI was 42.5% at 100 days after transplantation (95% confidence interval, 39.0-46.0). Gram-positive cocci were present in 64.2% of detected isolates. Among the pre-transplant factors including age, performance status, primary disease, disease status, graft cell source, sex and ABO blood type matching, and the intensity of conditioning regimen, U-CB use was identified as the most significant risk factor for BSI by multivariate analysis (hazard ratio, 1.76; 95% confidence interval, 1.40-2.22; p < 0.00001). Among the U-CB recipients, those who are not in remission at the time of transplantation were at the greatest risk of BSI (hazard ratio, 1.69; 95% confidence interval, 1.14-2.50; p < 0.01). The study makes it clear that graft cell source has an impact on BSI development after allogeneic HCT.

Background: To evaluate the safety of bronchoscopy and describe factors affecting its complication rate in patients with hematologic disorders. Methods: Between January 2009 and December 2018, 316 bronchoscopies in 282 patients with hematologic disorders and pulmonary lesions were performed at our institution. The bronchoscopic procedure used and its complications were evaluated. Results: The most common underlying disease was acute myeloid leukemia (134/282 patients, 47.5%). Platelet transfusion was performed the day before or the day of bronchoscopy in 42.4%, supplemental oxygen was administered before the procedure in 23.1%, and midazolam was used in 74.4%. Two patients (0.6%) were intubated within 48 hour of the procedure and prolonged oxygen desaturation (>48 hour) occurred in 3.8%. Multivariate analysis showed that only use of midazolam significantly reduced the risk of prolonged oxygen desaturation ( p = 0.01, hazard ratio 0.23, 95% confidence interval 0.07–0.75). Conclusions: Bronchoscopy is relatively safe in patients with hematologic disorders. Sedation with midazolam may reduce the risk of prolonged oxygen desaturation.

Hairy cell leukemia (HCL) is a rare B-cell lymphoid malignancy that is difficult to distinguish from other morphological variants. The frequency of HCL has not been determined accurately in Japan. Recent studies revealed that the BRAF V600E mutation is the causal genetic event in HCL. We assessed the BRAF mutation in Japanese patients with HCL and related diseases using the quenching probe (QP) method, a single-nucleotide polymorphism detection system, and evaluated the incidence rate of HCL among Japanese patients with chronic lymphocytic leukemia, and related diseases. We identified 18 cases (33.3%) harboring the BRAF mutation among 54 patients diagnosed with, or suspected of having HCL. Of BRAF V600E-positive patients, 7 were only detected using the QP method, not by direct sequencing, whereas 11 were positive using both tests. In a larger cohort of Japanese patients diagnosed with chronic lymphoid leukemia or related diseases, the frequency of HCL was 4%. Patients with the BRAF V600E mutation had a significantly higher frequency of neutropenia, thrombocytopenia, and elevated soluble interleukin-2 receptor and common B-cell surface markers than patients without the mutation. Our results confirm that BRAF V600E-positive HCL is a relatively rare disorder in the Japanese leukemia patient population.

Infection caused by Cunninghamella bertholletiae carries one of the highest mortality rates among mucormycosis, and there are no reported cases that survived from the infection in allogeneic hematopoietic stem cell transplantation recipients occurring before neutrophil engraftment. Here, we present two cases of pulmonary mucormycosis caused by C. bertholletiae occurring before neutrophil engraftment after cord blood transplantation. Both were successfully treated with high-dose liposomal amphotericin B (10 mg/kg/day) combined with micafungin, which was then followed by neutrophil recovery, reduction in immunosuppressive agents, and a subsequent lobectomy. The intensive antifungal therapy immediately administered upon suspicion of mucormycosis greatly suppressed the infection in its early stage and was well tolerated despite its prolonged administration and simultaneous use of nephrotoxic agents after transplantation. Although the synergic effect of micafungin remains unclear, these cases highlight the importance of prompt administration of high-dose lipid polyene when suspecting mucormycosis in highly immunocompromised patients, which enables subsequent diagnostic and therapeutic interventions, resulting in a favorable outcome.

We report a case of simultaneous macroamylasemia and macrolipasemia complicated with mucosa-associated lymphoid tissue (MALT) lymphoma. A 78-year-old man presented with hyperamylasemia and hyperlipasemia for 2 years and was misdiagnosed with chronic pancreatitis at another hospital. However, his other pancreatic enzymes were normal, his amylase-creatinine clearance ratio was low, and no definite findings of pancreatic disease were evident. Immunological analyses revealed that both amylase and lipase were bound to immunoglobulin (Ig) A-κ, and that serum IgA was high (827.1 mg/dL). He was diagnosed with simultaneous macroamylasemia and macrolipasemia. Since these diseases are associated with malignancy, an additional investigation was performed which revealed the complication of MALT lymphoma, and polymerase chain reaction analysis showed monoclonal immunoglobulin light chain gene rearrangement (κ >> λ). In this case, macroamylasemia and macrolipasemia may have developed due to the formation of macroenzymes resulting from excess IgA-κ secreted by the MALT lymphoma. Simultaneous macroamylasemia and macrolipasemia are very rare and difficult to diagnose and can lead to diagnostic and therapeutic errors. When encountering atypical clinical features associated with hyperamylasemia and hyperlipasemia, the possibility of macroenzymes and underlying diseases such as lymphoproliferative disorders should be considered.

Limited data are available on micafungin breakthrough fungemia (MBF), fungemia that develops on administration of micafungin, in patients with hematological disorders. We reviewed medical and microbiological records of patients with hematological disorders who developed MBF between January 2008 and June 2015. A total of 39 patients with MBF were identified, and Candida (30 strains) and non- Candida (9 strains) fungal species were recognized as causative strains. Among 35 stored strains, Candida parapsilosis (14 strains), Trichosporon asahii (7 strains), Candida glabrata (5 strains), and other fungal species (9 strains) were identified by sequencing. Neutropenia was identified as an independent predictor of non- Candida fungemia ( P = 0.023). T. asahii was the most common causative strain (7/19) during neutropenia. The 14-day crude mortality rate of patients treated with early micafungin change (EMC) to other antifungal agents was lower than that of the patients not treated with EMC (14% versus 43%, P = 0.044). Most of the stored causative Candida strains were susceptible (80%) or showed wild-type susceptibility (72%) to micafungin. The MICs of voriconazole for T. asahii were low (range, 0.015 to 0.12 μg/ml), whereas the MICs of amphotericin B for T. asahii were high (range, 2 to 4 μg/ml). MBF caused by non- Candida fungus should be considered, especially in patients with neutropenia. EMC could improve early mortality. Based on epidemiology and drug susceptibility profiling, empirical voriconazole-containing therapy might be suitable for treating MBF during neutropenia to cover for T. asahii .

The impact of anti-HLA antibodies, except for donor-specific anti-HLA-A, -B, -DRB1 antibodies, on engraftment was retrospectively evaluated in 175 single cord blood transplantations (CBT). Patients and donors had been typed at HLA-A, -B, and -DRB1 antigens, and anti-HLA antibodies had been screened before transplantation to avoid the use of cord blood (CB) units with corresponding antigens. The median age was 59 (range, 17 to 74) years. Overall, 61% were male, 89% had high-risk disease status, 77% received myeloablative conditioning regimens, and over 80% were heavily transfused patients. Sixty-nine of the 175 (39.4%) were positive for anti-HLA antibodies. Thirty-nine patients had antibodies only against HLA-A, -B, or -DRB1, 13 had antibodies only against HLA-C, -DP, -DQ, or -DRB3/4/5, and 17 had antibodies both against HLA-C, -DP, -DQ, or -DRB3/4/5 and against HLA-A, -B, or -DRB1. Because CB units had not been typed at HLA-C, -DP, -DQ, or -DRB3/4/5, it was possible that antibodies against them were unrecognized donor-specific antibodies. Patients with antibodies only against HLA-A, -B, or -DRB1 showed comparable neutrophil engraftment rates to those without antibodies (89.7% versus 83%, P = .65), whereas patients having antibodies against C, DP, DQ, or -DRB3/4/5 showed lower engraftment rate (66.7%, P = .12), which became statistically significant in a subgroup of HLA-mismatched donor-recipient pairs (50%, P = .01). Our results demonstrated that the presence of donor nonspecific anti-HLA-A, -B, -DRB1 antibodies had no significant influence on engraftment, whereas anti-HLA-C, -DP, -DQ, or -DRB3/4/5 antibodies adversely affect engraftment, possibly because of unrecognized donor-specific anti-HLA antibodies against them, especially in HLA-mismatched CBT.

Cord blood transplantation (CBT) has now become one of the alternative stem cell sources for patients with a wide variety of hematological diseases. Considering that cord blood (CB) grafts contain T cells with an immunologically naïve phenotype, concerns have been raised regarding the capability of CB-derived lymphocytes to mediate sufficient graft-versus-leukemia (GVL) effects. However, the incidence of relapse after CBT is reportedly comparable to that after other stem cell sources. Moreover several recent studies have shown even lower relapse rate in CBT compared to the others, despite a lower incidence of GVHD. We and others have reported a unique clinical manifestation, termed pre-engraftment immune reactions (PIR), that develop early after CBT and before engraftment. The unique immune-mediated manifestation may have the potential to cause GVL effect from very early time point after CBT besides GVHD. We conducted a retrospective study of 551 CB recipients to investigate the GVL effect of the PIR after CBT. Patients who underwent single CBT at our institute from 2004-2017 were included. Only those in non-remission status were included. Patients who had a prior history of allogeneic transplant, who had active infections, who had poor PS, and who received ATG or short-term MTX as GVHD prophylaxis were excluded. The diagnosis of PIR was made when patietns showed a high fever (=>38℃) and at least 2 of the following 5 symptoms (skin eruptions, diarrhea, jaundice, weight gain, and peripheral edema) developed six or more days before neutrophil engraftment. Patients who presented with severe organ damage, such as lung, kidney, or liver dysfunction, were classified as severe type. This study was approved by the institutional review board. The median age was 57 (range, 16-77) years. All patients had hematological malignancies and all were in non-remission status. Sixty-five percent of these patients received MAC regimens, 63% received tacrolimus plus MMF as GVHD prophylaxis, and 86% received a CB unit with 2 or 3 antigen-mismatch, and the median numbers of TNC and CD34-positive cells were 2.59x107/kg and 0.89x105/kg, respectively. The cumulative incidences of total PIR and severe PIR were 69.3% and 20.0%, respectively, with a median onset of 8 days (range, 5-19) post-CBT. Patients who developed PIR were treated with systemic corticosteroids at the discretion of the primary physicians. Younger age ( Our data clearly showed that development of PIR after single CBT reduces relapse rate without increasing NRM and contributes to superior survival rate in advanced hematological malignanicies. PIR is one of the clinically important factors associated with unique GVL effects after single CBT. Figure 1 Disclosures No relevant conflicts of interest to declare.

INTRODUCTION: Allogeneic hematopoietic cell transplantation provides an opportunity for a cure of myeloproliferative neoplasms (MPNs). Although several studies showed its efficacy even for leukemic transformation (LT) from MPNs, no direct evidence exists which compared the long-term outcome of patients in chronic phase (CP) and LT in a same cohort. METHODS: We retrospectively studied allogeneic hematopoietic cell transplantation for MPNs between 1999 and 2017 in Toranomon Hospital. LT was defined according to the WHO classification in 2016. Risk stratification was according to the dynamic international prognostic scoring system (DIPSS). The spleen index was defined as the measurement of spleen on CT scan. The day of neutrophil and platelet engraftment was defined as the first 3 consecutive days on which the patient's absolute neutrophil and platelet count was >0.5 x 109/L and >20 x 109/L without platelet transfusion, respectively. The study was approved by the ethics committee of Toranomon Hospital (research number #1796), and conducted in accordance with the Declaration of Helsinki. RESULTS: A total of 36 patients were extracted. At transplantation, the disease status of MPN was CP in 16 patients (44%) and LT in 20 (56%). Median spleen index was significantly lower in LT than CP (104 cm2 vs. 150 cm2, p < 0.01), and more CP patients received splenic irradiation before transplantation (p = 0.04). At the start of conditioning regimen, a half of the patients in LT was not in remission even after chemotherapy. Most patients in CP used bone marrow or peripheral blood stem cells, whereas umbilical cord blood (U-CB) was preferred for patients in LT (p < 0.001). Among these 2 cohorts, the cumulative incidence of neutrophil and platelet engraftment was comparable at day 60 and at 1 year after transplantation, respectively (neutrophil engraftment: 87.5% in CP vs. 80.0% in LT, p = 0.11; platelet engraftment: 68.8% in CP vs. 65.0% in LT, p = 0.70). Overall survival (OS) was significantly superior for patients in CP to ones in LT (p = 0.02) (Figure). OS rate at 5 and 10 years after transplantation for patients in CP and LT were 56.2% (95% confidence interval [CI], 1.0 - 35.4) vs. 11.2% (95% CI, 29.5 - 76.2), and 45.0% (95% CI, 17.8 - 69.1) vs. 0%, respectively. Median survival was 7.5 and 0.9 years for patients in CP and LT, respectively. Median follow up of survivors in CP and LT was 1652 days (range, 980 - 5395) and 906 days (range, 522 - 1014), respectively. At 10 years after transplantation, the cumulative incidence of relapse was significantly higher for patients in LT than ones in CP (6.2% in CP vs. 38.0% in LT, p = 0.04). In LT patients, disease recurrence occurred within 3 years after transplantation and 7 out of 17 patients (41%) died of relapse after transplantation. CONCLUSION: To achieve a long-term relapse-free survival, it is crucial for MPN patients to undergo transplantation in chronic phase, not after the development of LT. Delayed decision to transplant may be critical for patients who are at high risk for LT. Figure Disclosures No relevant conflicts of interest to declare.

A 57-year-old Japanese woman with a 5-year history of rheumatoid arthritis (RA) was admitted to our hospital for an evaluation of nephrotic range proteinuria (4.8 g/day). A renal biopsy led to the diagnosis of amyloidosis according to strong positivity for Congo red staining and the detection of microfibrillar structures on electron microscopy that were negative for AA and positive for kappa light chain. Combination therapy with high-dose melphalan and autologous stem cell transplantation was performed according to the regimen for AL amyloidosis. Her proteinuria and RA subsided, but relapsed after 3 years. This is the first report regarding kappa light chain amyloidosis in an RA patient.

Few data on breakthrough candidemia (BC), defined as candidemia that develops on administration of antifungal agents (AFAs), in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are available. The medical and microbiological records of recipients of an allo-HSCT obtained between December 2008 and December 2014 were reviewed. Of 768 allo-HSCT cases, 26 developed BC. Among the 26 causative strains, 22 strains were stored and identified by sequencing. The following species were isolated: Candida parapsilosis (9 strains), C. glabrata (4 strains), C. guilliermondii (3 strains), and other Candida species (6 strains). The AFAs being used when BC developed were micafungin (17 cases), liposomal amphotericin B (5 cases), itraconazole (2 cases), and voriconazole (2 cases). All 17 cases who developed BC during micafungin administration were administered 150 mg/day of micafungin. The susceptibilities of the causative Candida species to the administered AFAs when breakthrough occurred ranged from susceptible to resistant. Especially, 85% of the Candida species that caused BC during micafungin administration were susceptible to micafungin. Additionally, 75% of the strains were wild type for susceptibility to the administered AFAs when breakthrough occurred. Systemic steroid administration and a longer severe neutropenic phase (≥5 days) were independent risk factors for BC ( P = 0.016 and P = 0.015, respectively). BC developed in allo-HSCT recipients even when they received a sufficient dose of AFA, including micafungin, to which the causative Candida species were susceptible and/or had wild-type susceptibility in vitro . Systemic steroid administration and a longer severe neutropenic phase were host-based factors associated with BC.

A pilot study of a novel, reduced-toxicity, myeloablative conditioning regimen using intravenous busulfan 12.8 mg/kg, fludarabine 180 mg/m2, and melphalan 80 mg/m2 for single cord blood transplantation (CBT) was conducted at our institution. Fifty-one patients with myeloid malignancies not in remission were included in this study. Their median age was 59 years (range, 19 to 70 years), with a median hematopoietic cell transplantation–specific comorbidity index score of 3. With a median observation period of 39.6 months (range, 24.3 to 90.8 months) among the survivors, overall survival and progression-free survival at 2 years were both 54.9%. Forty-six of 51 achieved neutrophil engraftment at a median of 19.5 days (range, 13 to 38 days) after transplantation, with a cumulative incidence of 90.2%. No patient developed graft rejection in this study. All patients who achieved engraftment showed hematological complete remission with complete donor chimerism. Eleven patients relapsed at a median of 4.9 months (range, .5 to 26.7 months). Cumulative incidences of nonrelapse mortality (NRM) at 100 days and 2 years were 11.8% and 25.5%, respectively. In conclusion, the present results show that the novel conditioning regimen for single CBT provided durable engraftment and remission with acceptable NRM leading to excellent survival, even for a relatively older population with myeloid malignancies not in remission.

I.v. BU/fludarabine plus melphalan or TBI in unrelated cord blood transplantation for high-risk hematological diseases

BACKGROUND: Cord blood is an established alternative donor cell source for allogeneic hematopoietic cell transplantation. However, engraftment failure is still a major concern after transplantation, especially for patients transplanted lower doses of donor cells. Higher CD34+ cell dose leads to a secure and fast engraftment, and the units of cord blood which contain CD34+ cells of 1.0 - 1.7 x 105 /kg at freezing or 1.0 - 1.2 x 105 /kg at thawing are recommended (Thomas' Hematopoietic Cell Transplantation, 5th Edition). Actually, most adult patients cannot obtain such sufficient cell dose-containing cord bloods and the feasibility of single-unit cord blood transplantation (CBT) containing lower CD34+ cell dose than 1.0 x 105 /kg is unclear. METHODS: To investigate the lower threshold of CD34+ cell dose, we studied the patients who received single-unit CBT as the first transplantation between 2009 and 2017. The patients whose ECOG performance status was 0 or 1, and who do not have donor-specific anti-HLA antibody (DSA) were analyzed. Institutional review board of Toranomon Hospital approved the study (research number #1666). RESULTS: A total of 421 patients were studied. The median age and body weight of patients was 57 years (range, 16 - 74) and 56.4 kg (32.2 - 94.6), respectively. Myeloid diseases accounted for 78% of the patients, and 83% were not in remission. Myeloablative conditioning regimens were used in 80% of the patients. All patients used Tac (26%) or Tac plus MMF (74%) as GVHD prevention. The median numbers of total nucleated cells and CD34+ cells were 2.61 x107 /kg (range, 1.57 - 5.85) and 0.86 x 105 /kg (0.29 - 3.77) at freezing, respectively. The cumulative incidence of neutrophil engraftment was 90.7% at 60 days after transplantation (95% confidence interval, 87.5 - 93.1). The median day of neutrophil engraftment was day 21 (range, 5 - 45). Multivariate analysis identified higher CD34+ cell dose, less HLA mismatch, and lymphoid disease as significant favorable factors for neutrophil engraftment (p < 0.05), and CD34+ cell dose was most significant among the following pre-transplant factors (HR 1.57, p < 0.00001): age (≤ 57 vs. >57 years), body weight (≤ 56.4 vs. > 56.4 kg), ECOG performance status (0 vs. 1), disease (myeloid vs. lymphoid), disease status (in CR vs. not in CR), anti-HLA antibody (not DSA) (positive vs. negative), total nucleated cell dose (≤ 2.61 vs. > 2.61 x 107 /kg), CD34+ cell dose (≤ 0.86 vs. >0.86 x 105 /kg), HLA antigen match (≤4/6 vs. ≥5/6), ABO match (match vs. mismatch), sex match (match vs. mismatch), GVHD prevention (Tac vs. TAC plus MMF), and the intensity of conditioning regimen (MAC vs. RIC). Then, we compared the cumulative incidence of neutrophil engraftment between 4 groups as follows: 90.2% for group A (> 1.5 x 105 /kg, n = 41); 91.7% for group B (1.0 - 1.5 x 105 /kg, n = 109); 91.4% for group C (0.5 - 1.0 x 105 /kg, n = 255); 75.0% for group D (< 0.5 x 105 /kg, n = 16) (p < 0.01). The median day of neutrophil engraftment was faster for the patients transplanted more CD34+ cell doses: day 17 for group A; day 19 for B; day 21 for C; day 26.5 for D (p < 0.0001). Next, we focused on group C transplanted lower CD34+ cell dose than the recommendation (0.5 - 1.0 x 105 /kg, n = 255).The patients were divided into 5 groups according to their CD34+ cell doses, and we compared their cumulative incidence of neutrophil engraftment as follows: 96.0% for group C1 (0.9 - 1.0 x 105 /kg, n = 50); 89.7% for group C2 (0.8 - 0.9 x 105 /kg, n = 39); 88.1% for group C3 (0.7 - 0.8 x 105 /kg, n = 67); 92.2% for group C4 (0.6 - 0.7 x 105 /kg, n = 51); 91.7% for group C5 (0.5 - 0.6 x 105 /kg, n = 48) (p = 0.03). The median day of neutrophil engraftment was significantly faster for the patients transplanted more CD34+ cell dose: day 20 for group C1; day 21 for C2; day 21 for C3; day 23 for C4; day 24 for C5 (p < 0.01). Overall survival was not significantly different between group A vs. B vs. C vs. D, nor group C1 vs. C2 vs. C3 vs. C4 vs. C5, respectively. DISCUSSION & CONCLUSION: Significantly faster neutrophil engraftment was demonstrated for patients transplanted more CD34+ cells after single-unit CBT. On the other hand, the cumulative incidences of neutrophil engraftment at day 60 were comparable among the patients who used > 0.5 x 105 /kg of CD34+ cells to be around 90%. The cord blood units containing 0.5 - 1.0 x 105 /kg at freezing could be alternative donor candidates for cord blood selection, if delayed engraftment was clinically acceptable for recipients. Disclosures Yamamoto: Bristol-Myers Squibb: Honoraria.

In acute myeloid leukemia (AML), karyotype at diagnosis is one of the most powerful independent prognostic factors after allogeneic stem cell transplantation (Allo-SCT) but this was based on the data of patients mostly in remission. There has been little consensus about the impact of karyotypic abnormalities on All-SCT in non-remission, especially monosomal karyotype (MK) and complex karyotype (CK). We retrospectively analyzed the outcome of 515 consecutive AML patients not in remission who underwent Allo-SCT for the first time at Toranomon Hospital between January 2008 and 2018. Patients with therapy-related AML (n=32) and transformed AML from ET/PMF (n=15), with active infection at transplantation, in poor condition as ECOG PS of 3 or more (n=38), and lacked karyotype information at diagnosis (n=59) were excluded from this study. Patients in remission at transplantation (n=77) were also excluded. Cytogenetic abnormalities at diagnosis were categorized based on 2017 ELN risk stratification, but genetic abnormalities such as FLT3-ITD, NPM1 were not considered in this study, because of lack of genetic information in most of the patients. Two hundred and ninety-four patients (n=197 male; n=97 female) were included in this study. The median age at transplantation was 60 years (range, 17-77), with a median HCT-CI score of 2 (0-7). Underlying diseases were AML-NOS in 91, AML with recurrent genetic abnormalities in 31, and AML-MRC in 172. Transplanted cell origins were cord blood in 252 (86%) patients, related bone marrow (BM) or peripheral blood (PB) in 22 (7%), and unrelated BM in 20 (7%). Patients were categorized into three groups according to the cytogenetic abnormalities at diagnosis: favorable (n= 17 (6%)), intermediate (n=192 (65%)), and adverse (n=85 (29%)). With a median follow-up of 35 (range, 1-122) months, the 3-year probabilities of overall survival (OS), progression free survival (PFS), relapse rate (RR) and non-relapse mortality (NRM) for entire population were 40.3%, 36.3%, 31.7%, and 32.0%, respectively. Patients in adverse group showed a higher RR and a lower PFS compared with those in intermediate/favorable group (42.0% vs 27.7% in RR (P = 0.02), 29.1% vs 39.1% in PFS (P = 0.04), both of which were also confirmed in multivariate analysis. Among adverse group (n=85), patients with both MK and CK (n=42) showed a higher RR, and a lower PFS compared with those without MK or CK (HR 2.29 (1.13-4.65), p=0.02 in RR, HR 1.91 (1.11-3.27), p=0.02 in PFS), in multivariate analysis. Among adverse group except for the patients with both MK and CK (n=43), 3-year PFS and RR were 44.5%, and 30.4%, which were comparable to intermediate group (35.7%, and 29.4%) (Fig. 1), indicating Allo-SCT overcomes negative impact of adverse cytogenetic abnormalities other than MK or CK in PFS and RR. Among patients with both MK and CK, no factors were identified to have an impact on PFS. Of particular interest is that CBT was the only factor associated with decreased RR compared with other source (HR 0.41 (0.17-0.99), p=0.048) in multivariate analysis. Among those with both MK and CK receiving CBT in our cohort, the 3-year PFS, RR, and NRM were 16.1%, 45.9%, and 38.0%, respectively, which were almost comparable to previously reported outcome of those with both MK and CK in remission. This retrospective study demonstrated that cytogenetic classification based on 2017 ELN risk stratification well predicted PFS, and RR for those in non-remission. The presence of both MK and CK is a poor prognostic factor on Allo-SCT in AML adverse group patients, while, for those in adverse group without MK or CK, Allo-SCT reduced relapse rate to the level of intermediate group. Disclosures Yamamoto: Bristol-Myers Squibb: Honoraria.

T-cell post-transplant lymphoproliferative disorder in a patient with chronic idiopathic myelofibrosis following allogeneic PBSC transplantation

BACKGROUND: The prognosis of chronic myeloid leukemia (CML) in advanced stages (accelerated phase, AP or blast crisis, BC) is still extremely poor even with tyrosine kinase inhibitors (TKIs) and allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for them. METHOD: Using our database, we retrospectively collected CML patients transplanted at Toranomon Hospital between June 2004 and March 2014, after the introduction of TKIs in Japan. RESULT: Twenty-nine consecutive patients were extracted. The median age was 52 years (range; 16-70). The disease status at diagnosis was chronic phase (CP, n=11), accelerated phase (AP, n=5) and blast crisis (BC, n=13). All the patients were treated with TKIs before transplantation, including imatinib (n=15), nilotinib (n=1), dasatinib (n=6), imatinib/dasatinib (n=4), nilotinib/dasatinib (n=1) and imatinib/nilotinib/dasatinib (n=2). All the 11 patients in CP at diagnosis progressed into AP/BC in their course and only 3 patients achieved second CP (MinorCyR, n=1; PCyR, n=1; MMR, n=1) at transplantation. On the other hand, 11 of 18 patients in AP/BC at diagnosis achieved CP (MinorCyR, n=1; PCyR, n=4; CCyR, n=3; MMR, n=3) at transplantation and the remaining 7 patients did not achieve CHR (Fig. 1). The median HCT-CI and EBMT score at transplantation was 2 (range, 0-5) and 5 (range, 0-7), respectively. Additional cytogenetic abnormalities developed until transplantation in 8 of 11 patients (73%) in CP at diagnosis and in 11 of 18 (61%) in AP/BC at diagnosis. Point mutations in ABL gene were detected in 9 of 20 patients (45%) in their course. Four of 7 patients (57%) in CP at diagnosis had ABL mutations, including T315I (n=1), E255K (n=2) and L359C (n=1). Five of 13 (38%) in AP/BC at diagnosis had ABL mutations, including T315I (n=4) and V299L (n=1). Overall, 14 of 29 (48%) patients underwent transplantation in CP stage (MinorCyR, n=2; PCyR, n=5; CCyR, n=3; MMR, n=4). The donors were related PBSC (n=6), unrelated BM (n=4) or unrelated CB (n=19). The conditioning regimens were myeloablative in 20 patients and reduced-intensity in 9. Twenty-seven patients achieved neutrophil engraftment at a median day of 19 (range, 10-34). The cumulative incidence of neutrophil engraftment was 93.1% at day 42 (patients engrafted, n=27; dead before day 19, n=2). At 3 years, the cumulative incidence of relapse and non-relapse mortality was 32.3% and 14.0%, respectively. In 15 patients who did not achieve CP before transplantation, 11 patients (73.3%) achieved CR after transplantation. With a median follow-up of survivors of 1144 days (range, 127-3705), overall survival (OS) and event free survival (EFS) at 3 years was 63.2% and 56.3%, respectively. In univariate analysis, age ( Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

Despite the recent introduction of a new class of anti-Aspergillus agents, no standard regimen for the prevention of invasive fungal disease (IFD) following allogeneic hematopoietic stem cell transplantation has been shown to be superior to fluconazole. The present prospective, single-arm study investigated the feasibility of voriconazole (VOR) administration as primary prophylaxis in 52 recipients of umbilical cord blood transplantation (CBT) with fludarabine-based conditioning, who had no previous IFD episodes. Proven or probable IFD was determined using the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group, and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria were considered as breakthrough infections. VOR was administered as prophylaxis for a total of 6884 patient-days following CBT. The mean duration of VOR administration after transplantation was 132 days (range, 1-769); 44 patients (85 %) had advanced disease, 15 (29 %) had a history of allogeneic HSCT, and 29 (56 %) received systemic corticosteroid therapy for allogeneic immune-mediated complications. Under the prophylaxis with VOR, one patient developed probable invasive aspergillosis on day 71, and the cumulative incidence of IFD was 4.5 % at day 180. None of the patients developed breakthrough candida or zygomycetes infections. Under the extensive therapeutic dose monitoring, VOR was safely administered with a calcineurin inhibitor and was well tolerated. These results suggest that VOR represents a feasible primary prophylactic agent for IFD after CBT with fludarabine-based conditioning.

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)