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Bacterial meningitis is a rare but severe infectious complication after hematopoietic stem cell transplantation. However, its clinical features were previously not clear. We reviewed the cases of 7 patients diagnosed with bacterial meningitis with a positive cerebrospinal fluid culture among 1147 patients who underwent cord blood transplantation (CBT) at our institution between September 2007 and September 2020. The diagnosis was made on day + 5- + 45, and 5 patients developed bacterial meningitis before neutrophil engraftment. The causative organisms were all Gram-positive cocci: Enterococcus faecium and Enterococcus gallinarum (2 patients each), and Staphylococcus haemolyticus, Streptococcus mitis/oralis, and Rothia mucilaginosa (1 patient each). Six patients developed bacterial meningitis secondary to prior or concomitant bacteremia caused by the same bacterium. Five patients had received anti-MRSA agents at onset: vancomycin in 3, teicoplanin in 1, and daptomycin in 1. After diagnosis of bacterial meningitis, linezolid was eventually used for 6 patients. Two patients with E. gallinarum were alive at day + 1380 and + 157 after CBT, respectively, whereas 5 patients died 17-53 (median 43) days after the onset of bacterial meningitis. Breakthrough meningitis in CBT can occur even during the use of anti-MRSA drugs, and intensive antibiotic treatment is necessary.

A 72-year-old man was admitted for examination of proteinuria (9.14 g/day) and leg edema. Essential thrombocythemia (ET) was diagnosed because of thrombocytosis (platelet count, 57.9×10

A 66-year-old man with fever was diagnosed with B-cell acute lymphoblastic leukemia. He failed to achieve complete remission after initial hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) therapy and was referred to our hospital to undergo allogeneic stem cell transplantation. Bone marrow aspiration showed 97.5% lymphoblasts positive for CD19. Blood tests revealed the presence of broad antihuman leukocyte antigen (HLA) antibodies. After blinatumomab therapy, bone marrow aspiration showed 19.6% blasts. Furthermore, after additional mini-mitoxantrone, etoposide, and cytarabine (mini MEC) therapy, the patient achieved complete remission. Interestingly, after blinatumomab therapy, the blood tests revealed that the titers of anti-HLA antibodies had decreased, and cord blood transplantation was performed in complete remission. This case report revealed that chemotherapy including blinatumomab, which targets CD19-positive cells, has the potential to decrease antibody-producing cells, thus leading to a dramatic reduction of anti-HLA antibodies.

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.

Limited data are available on breakthrough fungemia, defined as fungemia that develops on administration of antifungal agents, in patients with hematological disorders. We reviewed the medical and microbiological records of adult patients with hematological diseases who had breakthrough fungemia between January 2008 and July 2019 at Toranomon Hospital and Toranomon Hospital Kajigaya in Japan.

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.

Glyoxalase I (GLO I) is a known therapeutic target in cancer. Even though TLSC702, a GLO I inhibitor that we discovered, induces apoptosis in tumor cells, exceptionally higher doses are required compared with those needed to inhibit GLO I activity in vitro. In this work, structure-activity optimization studies were conducted on four sections of the TLSC702 molecule to determine the partial structural features necessary for the inhibition of GLO I. Herein, we found that the carboxy group in TLSC702 was critical for binding with the divalent zinc at the active site of GLO I. In contrast, the side chain substituents in the meta- and para- positions of the benzene ring had little influence on the in vitro inhibition of GLO I. The CLogP values of the TLSC702 derivatives showed a positive correlation with the antiproliferative effects on NCI-H522 cells. Thus, two derivatives of TLSC702, which displayed either high or low lipophilicity due to the types of substituents at the phenyl position, were selected. Even though both derivatives showed comparable inhibitory effects as that of their parent compound, the derivative with the high CLogP value was distinctly more antiproliferative than TLSC702. In contrast, the derivative with the low CLogP value did not decrease cell viability in NCI-H522 and HL-60 cells. These findings suggested that structural improvements, such as the addition of hydrophobic moieties to the phenyl group, enhanced the ability of TLSC702 to induce apoptosis by increasing cell membrane permeability.

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.

A 46-year-old female patient underwent a cord blood transplantation (conditioning regimen: fludarabine/busulfan4/melphalan80; graft-versus-host disease (GVHD) prophylaxis: tacrolimus + mycophenolate mofetil) for acute myeloid leukemia (AML) with her 1st hematological complete response to induction therapy (idarubicin 3 days+cytarabine 7 days). She lost her consciousness due to human herpesvirus 6 (HHV-6) encephalitis on day 31, and therefore, we increased the foscarnet dosage (from 120 mg/kg to 180 mg/kg). Her consciousness level improved after treatment. However, 8 hours of sudden hypothermia occurred with hyperhidrosis, hypertension, and subsequent hyperglycemia on day 34. Her condition did not improve even after administration of anticonvulsant, steroid pulse, or intravenous immunoglobulin. A total of 75 attacks were observed until she was discharged on day 471. She has not shown chronic GVHD or relapsed AML since then. However, HHV-6 caused prolonged damage to her hypothalamus as observed through magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) using

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.

Passion fruit seed extract (PFSE), a product rich in stilbenes such as piceatannol and scirpusin B, has various physiological effects. It is unclear whether PFSE and its stilbene derivatives inhibit cancer cell proliferation via human glyoxalase I (GLO I), the rate-limiting enzyme for detoxification of methylglyoxal. We examined the anticancer effects of PFSE in two types of human cancer cell lines with different GLO I expression levels, NCI–H522 cells (highly-expressed GLO I) and HCT116 cells (lowly-expressed GLO I). PFSE and its stilbenes inhibited GLO I activity. In addition, PFSE and its stilbenes supressed the cancer cell proliferation of NCI–H522 cells more than HCT116 cells. These observations suggest that PFSE can provide a novel anticancer strategy for prevention and treatment., Highlights • Piceatannol, and scirpusin B inhibited GLO I activity. • Passion fruit seed extract suppressed proliferation and colony formation of NCI–H522 cells. • Passion fruit seed extract and piceatannol could exert anticancer activity via GLO I inhibition.

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

The evaluation of the removal efficacy during manufacturing is important for the risk assessment of plasma products with respect to possible contamination by infectious prions, as recently reported in several papers on the potential for prion transmission through plasma products. Here, we evaluated a virus removal filter which has 15 nm pores. An antithrombin sample immediately prior to nano-filtration was spiked with prion material prepared in two different ways. The removal (log reduction factor) of prion infectivity using animal bioassays was >or=4.72 and 4.00 in two independent filtrations. However, infectivity was detected in both the pellet and supernatant following ultracentrifugation of the 15 nm filtered samples, indicating difficulty in complete removal. The data supports the conclusion that a certain amount of infectious prion protein is present as a smaller and/or soluble form (less than approximately 15 nm in diameter).

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.