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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.

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.

Delayed neutrophil engraftment (NE) has been reported in cord blood transplantation (CBT) compared with other stem cell transplantation methods. The numbers of total nucleated cells (TNCs), CD34+ cells (generally ≥ 1 × 105/kg), and granulocyte/macrophage colony-forming units (CFU-GM) significantly impact NE. Splenomegaly exerts negative effects on NE, but the appropriate cell dose for the patients with splenomegaly has not yet been determined, especially in CBT. We retrospectively investigated the effect of splenomegaly and number of CD34+ cells infused on NE through the analysis of outcomes of 502 consecutive patients who underwent single CBT for the first time at Toranomon Hospital between 2011 and 2018. Spleen index, Lmax × Hvert (SI Lmax × Hvert), was defined as maximal length at any transverse section, (Lmax) × vertical height (Hvert), and splenomegaly was defined as SI Lmax × Hvert ≥ 115 cm2. Our results show that splenomegaly (hazard ratio [HR], .60; P

With increasing focus on the importance of long-term survivorship care after allogeneic hematopoietic cell transplantation (allo-HCT), more institutions have been establishing long-term follow-up (LTFU) clinics. Currently, however, with varying volumes of HCT procedures and resources, there is no standardized operation of these clinics in HCT centers. We conducted a nationwide questionnaire survey to characterize the current operation of LTFU clinics in Japan. We targeted 271 HCT centers (189 adult and 82 pediatric) that registered allo-HCT cases to the national transplant registry database. The response rate was 69%, and 117 of the 188 participating centers (62%) had an established LTFU clinic. The most frequent reason cited for not operating an LTFU clinic was a "lack of human resources," especially nurses. Most centers with an LTFU clinic targeted allo-HCT recipients, although autologous HCT survivors were followed up at 18% of adult centers and 48% of pediatric centers. Ninety-two percent of centers did not terminate LTFU at a specific time point, and 56% recommended that patients visit the LTFU clinic beyond 5 years after HCT. Fifteen of 20 pediatric centers indicated that they did not routinely refer survivors who underwent HCT at a young age to an adult HCT center for their adulthood LTFU. We found that staffing and standard practices varied widely among centers, and that most centers continued to see long-term HCT survivors at their own outpatient clinics. The development of common LTFU tools may help standardize LTFU practices and facilitate efficient transitions.

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.

We evaluated cases of esophageal squamous cell carcinoma (ESCC) that developed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our institution. Allo-HSCT was performed in 1534 patients (1776 cases) at our institution from 2001 to 2016. Overall, 602 patients were confirmed to have survived for 2 or more years and 154 underwent upper gastrointestinal endoscopy at least 1-year post-transplantation. ESCC was discovered in 17 patients (1.1%), 15 of whom had 31 lesions discovered at our institution (ESCC group). A retrospective comparative study was conducted with the remaining 137 patients for whom no ESCC was noted (non-ESCC group), and we also evaluated the clinicopathological characteristics of the ESCC group. History of TBI (total body irradiation) and bone marrow transplant was significantly higher in the ESCC group. The mean time from transplantation to detection of ESCC was 82.3 months. Localization was upper thoracic in 12 cases, middle thoracic in 10, cervical in 4, lower thoracic in 3, and upper to lower thoracic in 2. Treatment comprised endoscopic submucosal dissection in 23 cases, surgery in 4, untreated due to worsening primary disease in 3, and chemoradiotherapy in 1. In this study, lesions were located in the cervical to upper thoracic esophagus in approximately 60% of all secondary ESCC cases after allo-HSCT. History of TBI and bone marrow transplantation are high risk of ESCC, and proactive screening endoscopy is desirable.

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.

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.

The risk of invasive fungal infections (IFIs) is extremely high in patients with hematological malignancies due to the prolonged and profound neutropenia and immunosuppression after chemotherapy and hematopoietic stem cell transplantation. There has been increasing interest in mucormycosis despite its relatively uncommon occurrence, because occasional breakthrough infections have been observed under anti-Aspergillus prophylaxis. The aggressive nature of mucormycosis easily leads to high mortality because of delays in diagnosis and incorrect treatment decisions, which are due in part to lack of adjunctive diagnostic tools and having similar clinical and radiological features with invasive aspergillosis. The only currently available antifungals against Mucorales in Japan are amphotericin B formulations. Thus, comprehensive therapeutic strategies, including surgery, should be considered to achieve a successful outcome.

The risk of invasive fungal infections (IFIs) is extremely high in patients with hematological malignancies due to the prolonged and profound neutropenia and immunosuppression after chemotherapy and hematopoietic stem cell transplantation. There has been increasing interest in mucormycosis despite its relatively uncommon occurrence, because occasional breakthrough infections have been observed under anti-aspergillus prophylaxis. The aggressive nature of mucormycosis easily leads to high mortality because of delays in diagnosis and incorrect treatment decisions, which are due in part to lack of adjunctive diagnostic tools and having similar clinical and radiological features with aspergillosis. The only currently available antifungals against Mucorales in Japan are amphotericin B formulations. Thus, comprehensive therapeutic strategies, including surgery, should be considered in order to achieve a successful outcome.

Cytomegalovirus (CMV) infection is a major infectious complication after allogeneic hematopoietic cell transplantation (allo-HSCT). Recently, it was reported that CMV reactivation is associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). The aim of this study was to evaluate the impact of early CMV reactivation on the incidence of disease relapse after allo-HSCT in a large cohort of patients. The Japan Society for Hematopoietic Cell Transplantation's Transplantation-Related Complication Working Group retrospectively surveyed the database of the Transplant Registry Unified Management Program at the Japan Society for Hematopoietic Cell Transplantation. Patients with AML (n = 1836), acute lymphoblastic leukemia (ALL, n = 911), chronic myeloid leukemia (CML, n = 223), and myelodysplastic syndrome (MDS, n = 569) who underwent their first allo-HSCT from HLA-matched related or unrelated donors between 2000 and 2009 and who survived without disease relapse until day 100 after transplantation were analyzed. Patients who received umbilical cord blood transplantation were not included. Patients underwent surveillance by pp65 antigenemia from the time of engraftment, and the beginning of preemptive therapy was defined as CMV reactivation. Cox proportional hazards models were used to evaluate the risk factors of relapse, nonrelapse, and overall mortality. CMV reactivation and acute/chronic graft-versus-host disease (GVHD) were evaluated as time-dependent covariates. CMV reactivation was associated with a decreased incidence of relapse in patients with AML (20.3% versus 26.4%, P = .027), but not in patients with ALL, CML, or MDS. Among 1836 patients with AML, CMV reactivation occurred in 795 patients (43.3%) at a median of 42 days, and 436 patients (23.7%) relapsed at a median of 221 days after allo-HSCT. Acute GVHD grades II to IV developed in 630 patients (34.3%). By multivariate analysis considering competing risk factors, 3 factors were significantly associated with a decreased risk of AML relapse and 1 factor with an increased risk of AML relapse: CMV reactivation (hazard ratio [HR], .77; 95% confidence interval [CI], .59 to .99), unrelated donor compared with related donor (HR, .59; 95% CI, .42 to .84), development of chronic GVHD (HR, .77; 95% CI, .60 to .99), and pretransplantation advanced disease status compared with standard disease status (HR, 1.99; 95% CI, 1.56 to 2.52). However, CMV reactivation was associated with increased nonrelapse mortality (HR, 1.60; 95% CI, 1.18 to 2.17) and overall mortality (HR, 1.37; 95% CI, 1.11 to 1.69). A beneficial effect of CMV reactivation on subsequent risk of relapse was observed in patients with AML but not in those with other hematological malignancies. However, this benefit was nullified by the increased nonrelapse mortality. The underlying mechanism is unclear; however, immunological activation against CMV reactivation plays an essential role in this association. Thus, immune augmentation treatment options, including vaccination and adoptive T cell transfer, may be useful to take advantage of the efficacy of CMV reactivation with minimal increase in nonrelapse mortality.

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: Follicular lymphoma is the most common indolent non-Hodgkin lymphoma, but has heterogeneous clinical behavior. PET-CT scan has the central role of determining of clinical staging and its five-point Deauville scale to grade response has been widely accepted in the management of follicular lymphoma. PET-CT scan also plays a significant role of predicting transformation of follicular lymphoma by considering high uptake of standardized uptake value (SUV). Recently, the total metabolic tumor volume (TMTV) measured by PET-CT scan and histological grades are prognostic factors of FL. But TMTV is not easily measured as everyday medical care, more simplified marker such as SUV value is desired. Methods: We retrospectively analyzed 275 patients who were diagnosed as follicular lymphoma including transformed form in our hospital between January 2008 and November 2018. One patient had also been diagnosed as rectal cancer as well as follicular lymphoma, aso we excluded this patient from our study. Results: We first investigated the relationship between histological grade and SUV value on FDG PET/CT. One hundred and ninety-eight biopsies were conducted at the same time of PET-CT. The median SUVmax value was 6.6 (range, 0-34.1) in FL grade 1 patients (n=89), 7.4 (0-23.9) in FL grade 2 patients (n=59), 12.1 (4.6-26.5) in FL grade 3a patients (n=33), and 14.8 (6.5-34.4) in FL grade 3b (n=17) (p We then analyzed clinical impact of SUVmax value on follicular lymphoma grade 1-3a. Patients with follicular lymphoma grade 3b, or lack of information were excluded, so we finally analyzed 164 patients. Median follow-up of survivors was 47.5 (0.4-10989) months. The median age at diagnosis was 62 (31-90) years. Ninety patients were male. Thirty-two patients were diagnosed as duodenum follicular lymphoma. Ninety-four patients were advanced clinical stage (III/IV). Using FLIPI2 score, 32 patients (20%) were in the low risk group, 105 (64%) in the intermediate group, and 27 (16%) in the high risk group. Thirty-six patients had high tumor burdens defined by GELF criteria. The median SUVmax value was 7.5 (range, 0-34.1). As first line treatment strategy, 83 patients (51%) received watch and wait strategy, 38 (23%) received R-CHOP, 3 patients (2%) received R-CVP, 14 (9%) received R-Benda, 20 (12%) received RIT, and 6 (4%) received others. High uptake value (SUV max ≧ 10 vs. SUV max < 10) correlated with high tumor burden and sIL2-R (p Conclusion: Uptake value of SUVmax correlated with histological grade of FL and high tumor burden, but did not affect OS and TNT. Disclosures No relevant conflicts of interest to declare.

Delayed immune reconstitution after allogeneic transplantation increases the risk of treatment-related mortality, and chronic GVHD. Previous reports showed that absolute lymphocyte count at day 30 (ALC30) was a significant prognostic factor of transplantation, and lower numbers of total CD4+ T cells and naïve CD4+ T cells in particular were associated significantly with higher mortality. However, there is little knowledge about the factors associated with low lymphocyte recovery, especially in cord blood transplantation (CBT). The cut-off value of lymphocyte recovery for statistical significance has not been determined yet. We retrospectively analyzed the outcome of 579 consecutive patients who underwent single cord blood transplantation (CBT) for the first time at Toranomon Hospital between January 2011 and 2018. Patients with active infection at transplantation (n=40), in poor ECOG PS (3 or more) (n=36), or lacked information about CT before CBT (n=1) were excluded from this study. Five hundred and two patients (n=317 male; n=185 female) were included in this study. The median age at transplantation was 57 years (range, 16-77), with a median HCT-CI score of 2 (0-10). Underlying diseases were AML (307), MDS (43), MPN (20), ALL (50), mature lymphoid malignancies (54), and others (28). Median spleen index (SI) before transplantation was 60.2 (16.5-319.7). Three hundred and ninety eight patients (79%) were not in remission at transplant. MAC regimens were selected in 400 (80%). TAC alone was used in 132 (26%) as GVHD prophylaxis. Median number of TNC and CD34+ cells infused were 2.62 (1.57-6.85) x 107/kg and 0.86 (0.29-3.77) x 105/kg, respectively. 194 (39%) were positive for anti-HLA antibodies, but none had donor-specific. With a median follow-up of 32 (range, 3-99) months, cumulative incidence of neutrophil engraftment (NE), the 3-year probabilities of overall survival (OS), relapse rate (RR) and non-relapse mortality (NRM) for entire population were 92.8%, 40.6%, 23.5%, and 35.3%, respectively. Underlying disease (myeloid malignancy), disease status at SCT (non-CR), poor PS (PS=2), GVHD prophylaxis (TAC+MMF), low CD34-positive cell dose ( We analyzed the relationship between ALC30 and transplantation outcome. Median number of ALC30 was 231 (3.5-1503), and the 25th percentile was 144. We divided the cohort into two groups, ALC30 low group ( This retrospective study demonstrated that low ALC30 after CBT had negative impact on survival because of higher NRM rate. High CD34-positive cell dose was the only factor associated with high ALC30. Not CD34-positive cell dose, but ALC30 had significant impact on OS in multivariate analysis, so we need to take lymphocyte recovery into account, in an attempt to improve transplantation outcome. Figure Disclosures No relevant conflicts of interest to declare.

[Background] Patients treated with immunosuppressive drugs for autoimmune diseases may suffer "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" (OIIA-LPD). Some OIIA-LPDs regress after drug withdrawal but others need cytotoxic chemotherapy. However, the factors associated with a response to drug cessation remain unknown. [Methods] We collected clinical data on OIIA-LPD diagnosed between 2009 and 2018 at the University of Tsukuba Hospital and Toranomon Hospital in Japan. Clinicopathological features were retrospectively analyzed. The probability of overall survival (OS) and progression-free survival (PFS) was calculated using the Kaplan-Meier method. OS was defined as the time between the date of diagnosis of OIIA-LPD and the date of death or last follow-up. PFS was defined as the time from the date of diagnosis of OIIA-LPD to the date of commencing chemotherapy or the date of death or last follow up. [Results] Fifty-four cases of OIIA-LPD were identified, of which 25 were diagnosed at the University of Tsukuba Hospital and 29 at Toranomon Hospital. The male to female ratio was 1:3.5 and the median age at diagnosis was 70 years (range, 35-85). Thirty-four patients (63%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Most patients (n=50 [93%]) had rheumatoid arthritis (RA). The remaining 4 patients had systemic lupus erythematosus (SLE), myasthenia gravis (MG), polymyalgia rheumatica (PMR), and polymyositis (PM), respectively. Methotrexate (MTX), tacrolimus, and biological agents were used in 49, 17, and 16 cases, respectively. Histological diagnoses of OIIA-LPD type were diffuse large B-cell lymphoma (DLBCL) (n=24), composite lymphoma of DLBCL and follicular lymphoma (FL) (n=1), Hodgkin lymphoma (HL) (n=18), MALT lymphoma (n=2), peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) (n=2), angioimmunoblastic T-cell lymphoma (AITL) (n=1), B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic HL (n=1), extranodal NK/T-cell lymphoma (ENKTL) (n=1), Burkitt lymphoma (n=1), and not specified (n=3). Epstein-Barr virus (EBV) was detected in 61% of cases tested (31/51) by in situ hybridization for EBER. At diagnosis of OIIA-LPD, 44 cases (81%) were under MTX treatment. MTX was discontinued in all of these, after which spontaneous regression was observed in 27 (61%). There was no clinical response in 5 patients (11%) within 2 months of MTX cessation, and 12 patients (27%) received chemotherapy without confirming whether stopping MTX would have been sufficient intervention. In 27 cases with spontaneous regression after cessation of MTX, 18 achieved complete remission without chemotherapy, but 9 needed chemotherapy due to re-initiation of LPD. Regarding the histological diagnosis, spontaneous regression was observed in OIIA-LPD patients with DLBCL in 12 of 24 cases (50%) and those with HL in 8 of 18 (44%). After achieving spontaneous regression, patients with DLBCL (10/12 cases, 83%) did not require any form of chemotherapy more often than those with HL (4/8 cases, 50%). Neither EBV positivity nor histology were associated with spontaneous regression. With a median follow-up of 26.1 months (range, 1-120.7), 2-year OS and PFS was 91.9% and 30.1%, respectively. The 2-year PFS of DLBCL and HL was 33.1% and 17.5%, respectively (p=0.533). Only four patients died due to the progression of OIIA-LPD. [Conclusion] Fifty-four cases of OIIA-LPD were retrospectively analyzed. Spontaneous regression after MTX discontinuation was observed in approximately 60% of these patients. No factors associated with response to drug cessation were associated with histological features or EBV positivity, but patients with DLBCL remained in complete remission more frequently than those with HL. Despite the fact that 2-year PFS is low, our retrospective analyses revealed favorable OS of OIIA-LPD because chemotherapy resulted in a good response regardless of whether MTX discontinuation was effective. 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.

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 .

As the number of long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT) has increased owing to advances in transplantation and supportive care techniques, the health and welfare of these survivors have come into focus. However, they are still at risks for various complications, including chronic graft-versus-host disease, infectious diseases, and secondary cancers even in the late period, which can not only interfere with the patient's quality of life (QOL) but also lead to death. The importance of long-term follow-up (LTFU) and management have been recently recognized, and nationwide systems to promote LTFU care in patients receiving HSCT, such as medical fee revision, publication of a LTFU guideline unique to Japan, and preparation of patient pocketbook, is under consideration. The number of medical facilities at LTFU outpatient clinic is also increasing; therefore, an optimal comprehensive support system may be established sooner or later. However, self-management by patients is essential to overcome late complications as well as to improve QOL after HSCT. Healthcare professionals should collaborate and continue to make the greatest possible efforts to educate patients regarding the risks of late complications and their prevention.

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.

Invasive fungal infections (IFIs) are one of the most serious complications developing after allogeneic hematopoietic stem cell transplantation (allo-HSCT). They are difficult to treat once present and usually have a fatal course in profoundly immunosuppressed patients. Upfront prevention therefore plays an important role in overcoming this threat. The combination of a protected environment and antifungal prophylaxis against Candida spp. is conventionally applied to prevent IFIs during the neutropenic period after HSCT, whereas mold-active agents are recommended for prophylaxis against Aspergillus spp. in the later period when high-dose steroids are frequently used for the treatment of graft-versus-host disease (GVHD). However, advances in transplantation technology have made the risk of IFIs more diverse and complex. Preventive strategies should be planned using the patient's background and surrounding environment as a guide for accurate evaluation of individual risks, and should also be revised to fit time-dependent changes in the patient's immune status and condition after HSCT. Sufficient knowledge of the properties of antifungal agents is also essential for maintaining the balance between the efficacy and the toxicity of the prophylaxis over time.

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.

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

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.

Background The optimal graft-versus-host disease (GVHD) prophylaxis after umbilical cord blood transplantation has not been established. Our previous observation using single calcineurin inhibitors revealed a high incidence and severity of early immune-mediated complications, especially for older patients or those with poor performance status. Methods We conducted a single institute pilot study assessing the safety and effectiveness of mycophenolate mofetil (MMF) and tacrolimus (FK) combination as a GVHD prophylaxis for 29 patients (FK+MMF), and the results were compared with matched-pairs extracted from our historical database who received FK alone as GVHD prophylaxis (control). Results FK+MMF group showed superior engraftment rate compared with control group (cumulative incidence until day 60 posttransplant; 90%±0% vs. 69%±1%, P=0.02). A cumulative incidence of severe type preengraftment immune reactions was significantly decreased in FK+MMF group (16%±1%) compared with that of control group (52%±2%, P=0.03), and, remarkably, there was no nonrelapse mortality (NRM) observed up to day 30 posttransplant in FK+MMF group, whereas 21%±1% of NRM was observed in the control group. However, the incidences of acute and chronic GVHD, estimated overall and progression-free survivals were comparable between two groups. Conclusions MMF and FK in combination was well tolerated and decreased early NRM possibly by better control of preengraftment immune reactions. Subsequent NRM or disease progression needs to be overcome to further improve survival.

Varicella zoster virus (VZV) disease is a frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). We carried out a trial of 1-year low-dose valacyclovir (VCV) prophylaxis against VZV disease to evaluate its efficacy and safety. Patients received oral acyclovir (ACV) 1000mg/day until day 35 after HSCT. Oral VCV 500mg/day, 3 times a week, was started on day 36 and continued until 1 year after HSCT. The development of VZV disease was monitored until 2 years after HSCT. A total of 40 patients with a median age of 43 years were enrolled. VCV was well tolerated in all but 1 patient who discontinued it on day 224 because of thrombocytopenia of unknown cause. Seven patients developed VZV disease at a median of 479 days (range 145-651) after HSCT, with a cumulative incidence of 18.5%. Two patients developed breakthrough disease during VCV prophylaxis. The other 5 patients developed VZV disease after the discontinuation of VCV, and 3 of these had developed extensive chronic graft-versus-host disease. Visceral involvement and serious complications were completely eliminated. All patients responded to the therapeutic dose of VCV or ACV. One-year low-dose VCV can be safely and effectively administered for the prevention of VZV disease after allogeneic HSCT.

Addition of in vivo alemtuzumab to the conditioning regimen enabled 2- or 3-locus-mismatched hematopoietic stem cell transplantation with an acceptable incidence of graft-versus-host-disease. However, the procedure was associated with a high incidence of cytomegalovirus (CMV) reactivation. Although preemptive therapy with ganciclovir prevented successfully severe CMV diseases and CMV-related mortality, a patient developed persistent positive CMV antigenemia for more than 1 year after transplantation and CMV disease, despite the use of ganciclovir and foscarnet. The in vitro susceptibility assay showed that the clinical isolate was resistant to foscarnet, moderately resistant to ganciclovir, but sensitive to cidofovir. Therefore, cidofovir was administered. CMV antigenemia became negative within 2 weeks and never developed again. Nucleotide sequence of the UL54 and UL97 of the clinical isolate showed 4 amino acid substitutions (V11L, Q578H, S655L, and G874R) in UL54 and 2 mutations (A140V and A594V) in UL97 compared with the Towne and AD169 strains. Ganciclovir resistance was suspected to be caused by both A594V of UL97 and Q578H of UL54, whereas foscarnet resistance was due mainly to Q578H of UL54. In conclusion, the in vitro susceptibility assay as well as nucleotide sequence of clinical isolate is important to choose appropriate antiviral agents for patients who have persistent CMV reactivation after stem cell transplantation.

Varicella-zoster virus (VZV) infection remains a common complication after hematopoietic stem cell transplantation (HSCT). The introduction of long-term prophylaxis with low-dose acyclovir against VZV reactivation has been investigated, because VZV-related complications including post-herpetic neuralgia and secondary infection significantly affect the patient’s quality of life. We started long-term oral acyclovir at 200 mg/day in July 2001. Acyclovir was continued until the end of immunosuppressive therapy and at least one year after transplantation. To evaluate the efficacy of this long-term prophylaxis with ultra low-dose acyclovir against VZV reactivation, we analyzed the records of 242 Japanese adult patients who underwent allogeneic HSCT for the first time from June, 1995 to November, 2006 at University of Tokyo Hospital. Sixty-six patients developed VZV reactivation at a median of 248 days after HSCT, with a cumulative incidence of 34.7%. There was no VZV-related death. Only one breakthrough reactivation occurred during long-term acyclovir, responding well to the therapeutic dose of valacyclovir. The use of long-term acyclovir was the only independent determinant that significantly decreased the overall incidence of VZV reactivation (20.4% vs 50.5%, P Figure Figure