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Tacrolimus (TAC) is essential for prophylaxis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HSCT). We have sometimes observed large fluctuations in TAC concentration. However, links between the variability in the concentration or the concentration/dose (C/D) ratio of TAC and clinical complications remain ambiguous. To clarify relationships between various parameters of TAC and early complications such as pre-engraftment immune reactions/engraftment syndrome, aGVHD, and transplant-associated thrombotic microangiopathy (TA-TMA), a total of 146 patients who underwent allo-HSCT were included. Intrapatient variabilities in the concentration and C/D ratio of TAC were estimated by intrapatient mean absolute deviation (iMAD). The mean concentration and C/D ratio of TAC were not significantly different between with and without complications. A strong association was observed between greater iMAD for TAC C/D ratio from days 15 to 21 and the development of TA-TMA. iMAD values for TAC C/D ratio of 11.4 or greater was a risk factor for TA-TMA and the cumulative incidence of nonrelapse mortality (NRM) was significantly higher in patients with iMAD values for TAC C/D ratio of 11.4 or greater. Intrapatient variability in the C/D ratio of TAC was associated with the incidence of TA-TMA and NRM and might be useful for predicting TA-TMA.

One major cause of treatment-related death is transplant-associated thrombotic microangiopathy (TA-TMA). Because of difficulties with diagnosis, many criteria for TA-TMA have been defined. Some patients clinically suspected as TA-TMA have been treated as TA-TMA regardless of TA-TMA criteria fulfillment (clinical-TMA). To examine sensitivities of TA-TMA criteria for clinical-TMA, we retrospectively evaluated 160 patients undergoing allogeneic hematopoietic stem cell transplantation by five major TA-TMA criteria and compared them with clinical-TMA. Cumulative incidences of TA-TMA and non-relapse mortality (NRM) were widely diverse between criteria. Thirty-eight patients fulfilled one or more TA-TMA criteria (total-TMA), and 12 of them fulfilled only one criterion. In patients with total-TMA, thrombocythemia, serum creatinine > 1.5 × baseline, and proteinuria were especially repeatedly observed among TA-TMA criteria. Ninety-two percent of clinical-TMA patients were classified as patients with total-TMA, and high NRM incidences were exhibited in patients with total-TMA even without clinical-TMA. Hematopoietic cell transplant-comorbidity index ≥ 3, nutritional risk index

Permanent impairment (PI) of vital organs is one of the transplantation-related health problems affecting the quality of life and morbidity even in patients who do not develop graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT), but no data are available on PI of multiple organs. This retrospective study aimed to estimate a novel composite endpoint of PI-free, relapse-free survival (PIRFS) in 164 allo-HCT recipients. We defined PI as26% to 30% impairment of the whole person in 6 vital organs using the whole person impairment rating. Conventional GVHD-free/relapse-free survival (GRFS) and PIRFS at 5 years were 33.8% (95% confidence interval [CI], 26.5% to 41.3%) and 40.6% (95% CI, 32.6% to 48.4%), respectively. In the whole cohort, PIRFS was higher than GRFS at any time after allo-HCT. However, PIRFS was lower than GRFS after day 397 post-transplantation in patients who underwent umbilical cord blood transplantation (UCBT). In UCBT recipients, 5-year GRFS and PIRFS were 47.6% (95% CI, 34.3% to 59.7%) and 39.2% (95% CI, 26.6% to 51.5%), respectively. The cumulative incidence of PI after 5 years was 20.9% (95% CI, 13.7% to 29.0%) in patients surviving for ≥6 months without relapse. The multivariate analysis revealed that high disease risk (hazard ratio [HR], 1.91; 95% CI, 1.26 to 2.88; P.01) and Karnofsky Performance Status score ≤90% at transplantation (HR, 1.73; 95% CI, 1.14 to 2.63; P = .01) were correlated with the lower PIRFS, whereas UCBT (HR, 2.35; 95% CI, 1.11 to 4.99; P = .03), grade III-IV acute GVHD by day 180 (HR, 3.59; 95% CI, 1.04 to 12.4; P = .04), and thrombotic microangiopathy by day 180 (HR, 2.74; 95% CI, 1.10 to 6.87; P = .03) were significantly correlated with a higher incidence of PI. More than 20% of long-term survivors had PI. Our data suggest that PIRFS is a useful endpoint for assessing long-term transplantation success from a different perspective than has been established previously.

A prospectively registered observational study was conducted to assess the significance of allogeneic hematopoietic stem cell transplantation from highly HLA-matched unrelated donors (UD) and cord blood (CB) on outcomes in adult acute leukemia (AL) and myelodysplastic syndrome (MDS). Between 2007 and 2015, 231 transplant-eligible patients were registered for a phase 2 study of alternative donor transplantation. After registration, a sufficient time period was given to find appropriate UD. Patients received CB transplantation (CBT) if an appropriate UD was unavailable. In total, 119 patients received CBT (106 AL and 13 MDS) and 91 patients received UD transplantation (UDT) (86 AL and 5 MDS). The median age was 39 years in both groups. The primary objective was overall survival (OS); secondary objectives included cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival. Diagnosis, disease status at transplantation, refined disease risk index, and hematopoietic cell transplant-specific comorbidity index did not differ between UDT and CBT. In multivariate analyses, graft source was not a significant risk factor for all objectives. In adjusted analyses, UDT and CBT showed similar OS, NRM, and relapse in this prospective study. CB can be a comparable alternative stem cell source to UD by achieving a timely transplant.

Although autologous hematopoietic cell transplantation (HCT) is an established therapy for patients with relapsed acute promyelocytic leukemia (APL) after returning to complete remission (CR), the role of allogeneic HCT remains unclear for treating relapsed APL. This study aimed to investigate allogeneic HCT outcomes in patients with relapsed APL, focusing particularly on those who underwent transplantation in non-CR and those who had relapsed after prior autologous HCT. We retrospectively analyzed Japanese nationwide transplantation registry data of patients with relapsed APL age ≥16 years who underwent allogeneic HCT between 2006 and 2020. A total of 195 patients were eligible for this analysis, including 69 who underwent transplantation in non-CR and 55 who relapsed after prior autologous HCT. The median duration of follow-up for survivors was 5.4 years. Multivariate analysis revealed that both non-CR at transplantation (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.12 to 2.71; P = .014) and prior autologous HCT (HR, 2.10; 95% CI, 1.28 to 3.44; P = .013) were associated with higher risks of overall mortality. The 5-year overall survival (OS) rates for patients who underwent transplantation in CR and non-CR were 58% and 39%, respectively (P = .085), if they did not have a history of prior autologous HCT. In the patients who had relapsed after prior autologous HCT, the 5-year OS rate was 47% for those who underwent allogeneic HCT in CR and 6% for those who did so in non-CR (P = .001). Allogeneic HCT still provides an opportunity for long-term survival for certain patients with relapsed APL for whom autologous HCT is unlikely to be effective. The dismal outcome of those with prior autologous HCT who underwent allogeneic HCT in non-CR poses a significant therapeutic challenge.

Nutritional status is an important component of cancer care, and malnutrition itself can cause death in 10% to 20% of cancer patients. A nutritional risk index (NRI) is a useful tool for nutritional assessment of cancer patients. This study aimed to evaluate the impact of pretransplant NRI values on outcomes of allogeneic hematopoietic cell transplantation (allo-HSCT). One hundred sixty patients who underwent allo-HSCT between January 2008 and July 2017 at Konan Kosei Hospital were included in this single-center, retrospective analysis. NRI was calculated at the beginning of the conditioning regimen. The patients were divided into high NRI (NRI ≥ 97.5) and low NRI (NRI97.5) groups, and overall survival (OS), nonrelapse mortality (NRM), and cumulative incidences of acute and chronic graft-versus-host disease (GVHD) were evaluated. Two-year OS rates were 76% (95% confidence interval [CI], 63% to 83%) and 50.4% (95% CI, 38% to 62%) in the high NRI and low NRI groups, respectively (P.001). One-year cumulative incidences of NRM were 7.9% (95% CI, 3.5% to 15%) and 23% (95% CI, 14% to 33%; P = .014) and 2-year cumulative relapse rates were 17% (95% CI, 10% to 26%) and 32% (95% CI, 21% to 43%; P = .10) in the high NRI and low NRI groups, respectively. The multivariate analysis indicated low NRI was a significant risk factor for OS and NRM. Conversely, high NRI was associated with increased incidences of grades II to IV acute GVHD and chronic GVHD. Additionally, the subgroup analysis according to stem cell source revealed a significant benefit of higher NRI on survival only in umbilical cord blood recipients. Overall, these results suggest that pretransplant NRI might predict OS and NRM after allo-HSCT.

The role of killer immunoglobulin-like receptor-ligand mismatch (KIR-ligand mismatch) between donors and recipients undergoing cord blood transplantation (CBT) is controversial. If each immunosuppressant differently affects natural killer (NK) cell function, the effect of KIR-ligand mismatch may be altered depending on the type of graft versus host disease (GVHD) prophylaxis. To verify this hypothesis, the difference in the effect of KIR-ligand mismatch was retrospectively assessed between patients who received CBT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia, as well as GVHD prophylaxis comprising tacrolimus plus methotrexate (MTX) or mycophenolate mofetil (MMF). In the MMF group (n = 1363), KIR-ligand mismatch augmented the incidence of non-relapse mortality (NRM; hazard ratio [HR], 1.40; P = 0.008), which worsened overall survival (OS; HR, 1.30, P = 0.0077). In the analysis of each KIR-ligand mismatch type, HLA-C2 mismatch had a favorable effect on relapse incidence (HR, 0.56; P = 0.0043) and OS (HR, 0.72; P = 0.037) only in the MTX group. In the MMF group, HLA-A3/A11 mismatch worsened NRM (HR, 1.93; P < 0.001) and OS (HR, 1.48; P = 0.014). These results imply that the effects of KIR-ligand mismatch differ with the type of GVHD prophylaxis and that assessing the KIR-ligand mismatch status is important for CBT.

Acute myeloid leukemia (AML) associated with double-minute chromosomes (dmin) is a rare condition and has a poor prognosis. A 68-year-old man with leukocytosis and thrombocytopenia was admitted to our hospital. Bone marrow aspiration showed that 79.5% of myeloblasts were positive for myeloperoxidase. The patient was diagnosed with acute myeloid leukemia (French-American-British classification: M2, World Health Organization classification: AML, not otherwise specified, AML with maturation). Chromosomal analysis revealed the presence of dmin: 45, X, -Y, 5-33 dmin. Fluorescence in situ hybridization revealed multiple MYC signals, and spectral karyotyping showed that dmin was derived from chromosome 8. These findings indicated resistance to chemotherapy alone. After the standard induction therapy with daunorubicin and cytarabine, the number of myeloblasts in the bone marrow decreased, and the amplified MYC signals disappeared. Then, the patient achieved complete remission. Reportedly, most patients with AML correlated with dmin have a complex karyotype, except for this case. Owing to the absence of a complex karyotype, the patient had good sensitivity to chemotherapy. Further studies with a larger population of patients with AML associated with dmin, but without complex karyotypes, should be conducted to accurately predict prognosis in such cases.

Blastic plasmacytoid dendritic cell neoplasm is a rare disease with difficulty in diagnosis, and clinical courses of patients with BPDCN vary widely. We report a case of a 63-year-old man with BPDCN showing severe tumor lysis syndrome (TLS). BPDCN with high tumor burden should be carefully considered to prevent TLS.

The combination of methotrexate (MTX) and a calcineurin inhibitor is widely used for GVHD prophylaxis in umbilical cord blood transplantation (UCBT). However, the optimal MTX dosage for GVHD prophylaxis in UCBT remains unclear. In the present study, we investigated the impact of MTX dosage on clinical outcomes following UCBT in a single-center retrospective study. Of 70 UCBT recipients included in this study, 37 received MTX at doses of 10 mg/m2 on day 1, and 7 mg/m2 on days 3 and 6 (low-dose MTX: LD-MTX), and 33 received MTX at doses of 15 mg/m2 on day 1, and 10 mg/m2 on days 3 and 6 (standard-dose MTX: SD-MTX), in addition to tacrolimus (TAC). Grade 3–4 acute GVHD and/or transplant-related complications with endothelial cell damage were considered severe transplant-related complications. Univariate analysis findings revealed that the risk of grade 3–4 acute GVHD was significantly lower in the SD-MTX group than in the LD-MTX group (P = 0.013). Multivariate analysis findings revealed that SD-MTX was significantly associated with a lower incidence of severe transplant-related complications (HR = 0.25; 95% CI, 0.07–0.87; P = 0.029). We conclude that SD-MTX in combination with tacrolimus is optimal for GVHD prophylaxis in UCBT.

Reduced pulmonary function is commonly observed after allogeneic hematopoietic stem cell transplantation (HSCT); however, its relationship with the development of noninfectious pulmonary complications (NIPCs) is unclear, and the impact of changes in pulmonary function test (PFT) values on HSCT outcome remains controversial. We conducted a retrospective study including 150 patients to investigate changes in PFTs and impact on clinical outcome. PFT data at around 1 year after HSCT were available in 84 patients, and showed a significant time-dependent decline in percentage predicted forced expiratory volume in 1 s and other parameters. We focused on %FEV1, calculated decline of %FEV1 from pretransplant to around 1 year after HSCT (Δ%FEV1), and divided patients into good-Δ%FEV1 or poor-Δ%FEV1 groups, using a cut-off point of 20% decline of Δ%FEV1. In the poor-Δ%FEV1 group, half of the patients developed NIPCs. In the good-Δ%FEV1 group, PFT values were maintained, whereas those of the poor-Δ%FEV1 group declined significantly. Multivariate analysis showed that busulfan use was a risk factor for %FEV1 decline, and poor-Δ%FEV1 was a risk factor for overall survival. These data indicate that decline of %FEV1 may be a useful indicator of pulmonary damage after HSCT, and is strongly associated with busulfan use.

The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) has been recently proposed to predict the probability of nonrelapse mortality (NRM) and overall survival (OS) in allogeneic hematopoietic stem cell transplantation (HSCT). However, the usefulness of the HCT-CI in single-unit umbilical cord blood transplantation (UCBT) remains unclear. We investigated the impact of the HCT-CI on the clinical outcomes of allogeneic HSCT in a single-center retrospective study including 53 recipients of UCBT (UCBT group) and 90 recipients of other HSCT (non-UCBT group). In the non-UCBT group 2-year OS rates for HCT-CI score 3 and ≥3 were 67% (n = 74; 95% confidence interval [CI], 54% to 78%) and 26% (n = 16; 95% CI, 7% to 51%), respectively (P = .001). In the UCBT group these rates were 66% (n = 39; 95% CI, 48% to 79%) and 69% (n = 14; 95% CI, 36% to 87%), respectively (P = .73). In the non-UCBT group 1-year NRM rates for HCT-CI score 3 and ≥3 were 14% (95% CI, 6.4% to 22%) and 37% (95% CI, 14% to 61%), respectively (P = .02). In the UCBT group these rates were 6.1% (95% CI, 3.4% to 24%) and 7.7% (95% CI, .4% to 29%), respectively (P = .78). Using multivariate analysis we showed that HCT-CI score ≥ 3 was significantly associated with lower OS (hazard ratio, 3.06; 95% CI, 1.47 to 6.38; P = .003) and higher NRM (hazard ratio, 2.87; 95% CI, 1.18 to 6.96; P = .02) for the non-UCBT group. UCBT showed good OS with low incidence of NRM, even in patients with high HCT-CI scores. Altogether, we propose single-unit UCB to be a promising stem cell source for improving survival in patients with multiple comorbidities.

A 64-year-old man with acute myeloid leukemia underwent umbilical cord blood transplantation (UCBT). After 11 months of complete remission (CR) following UCBT, the bone marrow showed 7.5% myeloblasts. CR was obtained after a single course of azacitidine monotherapy, but the myeloblasts gradually increased in the blood. We made a diagnosis of acute megakaryoblastic leukemia derived from donor cell with a fluorescence in situ hybridization (FISH) analysis of the sex chromosomes and an immunophenotypic analysis. Azacitidine was administered again and produced a therapeutic effect of stable disease. This case suggests that azacitidine may be a useful therapy for patients with acute megakaryoblastic leukemia in situations in which intensive chemotherapy and transplantation are not indicated.

Cryptogenic organizing pneumonia (COP) after allogeneic hematopoietic stem cell transplantation (HSCT) is characterized by frequent recurrence. Few studies have examined onset and recurrence patterns of COP after HSCT. We investigated the clinical features of COP after HSCT in a single-center retrospective study including 165 consecutive patients who underwent allogeneic HSCT. Eighteen patients (11%) developed COP after HSCT. Hypoxemia and pleural effusion at the onset of COP were significantly associated with umbilical cord blood transplantation (P = 0.002 and P = 0.002, respectively). Recurrence of COP was observed in six patients and significantly associated with the presence of chronic graft-versus-host disease (cGVHD; P = 0.013) and stem cell sources other than umbilical cord blood (P = 0.038). Four patients with COP died of pulmonary failure after recurrence of COP. No patients who underwent umbilical cord blood transplantation experienced recurrence of COP. These findings suggest that the clinical features at the onset of COP may depend on stem cell sources. Moreover, both stem cell source and the absence or presence of cGVHD may affect COP recurrence, indicating the need to develop treatment strategies against COP according to stem cell source and risk of cGVHD.

Introduction The combination of methotrexate (MTX) and a calcineurin inhibitor is widely used for GVHD prophylaxis in umbilical cord blood transplantation (UCBT). However, the optimal MTX dosage for GVHD prophylaxis in UCBT remains unclear. Methods We investigated the impact of the MTX dosage on clinical outcomes of UCBT. We retrospectively analyzed a cohort of 70 patients who received first UCBT between October 2002 and December 2017 in our hospital. Of the 70 recipients, 37 received MTX at doses of 10 mg/m2 on day 1, and 7 mg/m2 on days 3 and 6 (low-dose MTX: LD-MTX), and 33 received MTX at doses of 15 mg/m2 on day 1, and 10 mg/m2 on days 3 and 6 (standard-dose MTX: SD-MTX), in combination with tacrolimus (TAC).The following conditions within day 180 were considered to be transplant-related complications with endothelial cell damage: sinusoidal occlusive syndrome, systemic transplant-associated microangiopathy (TAM), intestinal TAM, capillary leak syndrome, idiopathic pneumonia syndrome, and diffuse alveolar hemorrhage. We defined grade 3-4 acute GVHD and/or transplant-related complications with endothelial cell damage as severe transplant-related complications in this study. Results The characteristics of patients and transplantation procedures were comparable between the two groups. T-cell depletion was not used as GVHD prophylaxis in our study. The median follow-up period for surviving patients was 1504 days (range, 302-3864). The cumulative incidence of neutrophil engraftment by day 42 was 97.3% (95% CI, 71.5%-99.8%) for the LD-MTX group and 93.9% (95% CI, 73.1%-99.8%) for the SD-MTX group (P = 0.36). The cumulative incidence of platelet engraftment by day 60 was 78.4% (95% CI, 60.6%-88.8%) for the LD-MTX group and 87.9% (95% CI, 69.0%-95.6%) for the SD-MTX group (P = 0.40). Univariate analysis findings revealed that the risk of grade 3-4 acute GVHD was significantly lower in the SD-MTX group than in the LD-MTX group (P = 0.013). Multivariate analysis findings revealed that SD-MTX was significantly associated with a lower incidence of severe transplant-related complications (HR = 0.25; 95% CI, 0.07-0.87; P = 0.029). Non-relapse death was not observed in patients with standard-risk disease in the SD-MTX group (n = 22). There was no significant difference between the two groups in the 2-year incidence of relapse: 27.0% (95% CI, 13.9%-42.0%) for the LD-MTX group and 15.3% (95% CI, 5.4%-29.7%) for the SD-MTX group (P = 0.55). Conclusion Our study demonstrated that the GVHD prophylaxis consisting of SD-MTX and TAC led to a significantly lower incidence of severe acute GVHD and/or TRC-EC than the combination of LD-MTX and TAC without increasing the risk of graft failure and relapse. Thus, while our findings need to be further verified by multicenter studies with larger cohorts of patients, for now SD-MTX is optimal in combination with TAC for GVHD prophylaxis in UCBT.

Endothelial cell damage has been reported to be associated with noninfectious transplant-related complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among these, noninfectious transplant-related complications with endothelial cell damage (TRC-EC) include sinusoidal occlusive syndrome, transplant-associated microangiopathy, intestinal transplant-associated microangiopathy, capillary leak syndrome, idiopathic pneumonia syndrome, and diffuse alveolar hemorrhage. Because angiopoietin-2 (ANG2) plays an essential role in the endothelial cell damage of various inflammatory disorders, we hypothesized that ANG2 may also play a critical role in TRC-EC. We retrospectively estimated the incidence of TRC-EC and evaluated the association with ANG2 level at transplant. We studied 153 consecutive adult patients who underwent allo-HSCT at our institution between 2000 and 2012. Median patient age was 49 years (range, 16 to 68 years). With a median follow-up of 55 months, 3-year overall survival for all patients was 55%. The incidence of TRC-EC at day 100 was significantly higher in the high-ANG2 group (≥2000 pg/mL; n = 36) than in the low-ANG2 group (

Background: Among HLA-well-matched unrelated donor (UD) and umbilical cord blood (CB), HLA-8/8 allele-matched UD transplantation (UDT) showed superior overall survival (OS) to 7/8 allele-matched UDT and CBT, while a similar OS has been demonstrated between the HLA-7/8 allele-matched UDT and the CBT. However, a fair comparison between UDT and CBT is difficult, because graft availability and time required for donor-search is completely different. Once patients relapsed during UD-search period, most of those patients would choose immediate CBT. This means that patients who maintained CR in UD group may have more favorable characteristics, because those patients have been longer in remission and selected as a group of patients who maintained CR. Thus we thought that the factor of "donor-search duration" is important upon conducting a comparative study between UDT and CBT. We planned a clinical study that also taken "donor-search duration" into consideration to compare CBT outcomes with HLA well-matched UDT in a prospective trial setting. Purpose: The purpose of the current study is to compare the transplant outcomes of HLA-well-matched UDT with those of CBT in a prospective trial. Patients and Methods: From 2007 to 2015, 231 patients were provisionally registered for a single-arm phase 2 study of CBT (manuscript submitted). All provisionally registered patients were subjects of current study (Figure 1). After provisional registration, we attempted to find appropriate UD within a decent time period. After approximately 180 days of donor-search, patients received CBT if an appropriate UD was not available. In total, 91 patients received UDT, and 119 patients received CBT. Six patients withdrew and three died before transplantation. Twelve patients did not receive either UDT or CBT, but five received HLA-mismatched SCT from family donor (seven chose not to receive allogeneic SCT). Of 119 CBT recipients, 62 patients were eligible and registered to a phase 2 clinical trial reported elsewhere. Herein we analyzed transplant outcomes of 91 UDT and 119 CBT (UDT group; 49 AML, 37 ALL, 5 MDS: CBT group; 68 AML, 38 ALL, 13 MDS). Risk factors were analyzed by cox proportional hazard model, and survival estimates were depicted by Kaplan-Meier estimation and tested by log-rank test. Results: Patient age was median 39 yrs in both UDT and CBT (p=0.80). Patient body weight was median 59kg (37-90kg) in UDT, and median 55kg (35-90kg) in CBT (p=0.10). Sixty-six of 91 (72.5%) in UDT and 114 of 119 (95.8%) in CBT received myeloablative conditioning. More than 90% of patients received Tacrolimus and short-term methotrexate as GVHD prophylaxis in both UDT and CBT. Days from provisional registration to transplant were median 126 days (range, 77-261 days) in UDT, and median 99 days (8-286 days) in CBT (p Conclusion: Taken donor-search period into consideration, OS after UDT and CBT were similar in a prospective clinical study. CB may be the comparable alternative donor source to UDT. Disclosures Terakura: Novartis: Honoraria; Astellas Pharma Inc.: Honoraria; Amgen Astellas BioPharma K.K.: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Yakult Honsha, Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria. Nishida:Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; MSD K.K.: Consultancy, Honoraria; Amgen Astellas BioPharma K.K.: Honoraria. Sawa:Mundi Pharma: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanofi: Honoraria; Astellas Pharma Inc.: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Otsuka Pharmaceutical: Honoraria; Kyowa-Hakko Kirin: Honoraria; Novartis: Honoraria; Shire: Honoraria; Eisai: Honoraria; Mochida: Honoraria; Pfizer Japan Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku: Honoraria; MSD: Honoraria; Asahi-Kasei: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Miyao:Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria; Novartis: Honoraria. Ozawa:Pfizer Japan Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria; Astellas Pharma Inc.: Honoraria; Novartis: Honoraria. Goto:Celgene Co., Ltd.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria. Onishi:Sumitomo Dainippon Pharma: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Nippon Shinyaku: Honoraria; Kyowa-Hakko Kirin: Honoraria; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma: Honoraria; Takeda Pharmaceutical Co., Ltd.: Research Funding; MSD: Honoraria, Research Funding. Fukuhara:Janssen Pharma: Honoraria; Eisai: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; AbbVie: Research Funding; Celgene Corporation: Honoraria, Research Funding; Zenyaku: Honoraria; Bayer: Research Funding; Nippon Shinkyaku: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Mundi: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Fujii:Novartis Pharma Co., Ltd.: Honoraria; Kyowa-Hakko Kirin Co., Ltd.: Honoraria. Iida:Chugai Pharmaceutical Co., Ltd.: Research Funding. Endo:Ono: Research Funding. Onizuka:Sumitomo Dainippon Pharma: Research Funding; Astellas: Research Funding; Novartis: Research Funding; pfizer: Research Funding; Chugai Pharma: Research Funding; Bristol-Myers Squibb: Research Funding. Iyama:Otsuka Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Factory: Honoraria; Astellas Pharma: Honoraria; Daiichi Sankyo: Honoraria; Allexion Pharma: Honoraria; CSL Behring: Honoraria. Nakamae:Japan Blood Products Organization: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Nippon Shinyaku: Honoraria; Bristol-Myers Squibb: Honoraria; Shire Japan KK.: Honoraria; Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Inc.: Research Funding; Alexion: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria. Nagata:Janssen Pharmaceutical K.K.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Novartis Pharma K.K.: Honoraria; Celgene K.K.: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kurahashi:Novartis Pharma Co., Ltd.: Honoraria; Bristol-Myers Squibb, Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria. Suzuki:Celgene: Honoraria; Eisai: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Honoraria; Meiji Seika: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Atsuta:Mochida Pharmaceutical Co. Ltd: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Miyamura:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria; Kyowa-Hakko Kirin Co., Ltd: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria. Murata:Bristol-Myers Squibb, Ltd.: Honoraria; Kyowa-Hakko Kirin Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Consultancy, Honoraria; GSK Co., Ltd.: Consultancy; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; MSD Co., Ltd.: Honoraria.

We herein present the case of a 30-year-old man who developed recurrent pancreatitis and chronic graft-versus-host disease following unrelated bone marrow transplantation for acute myeloid leukemia (AML) with t(16;21)(p11;q22). Autoimmune pancreatitis was initially suspected due to the radiological findings and lack of response to gabexate mesilate and antibiotics. An examination of specimens successfully obtained via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) demonstrated invasion of AML cells in the pancreatic tissue. EUS-FNA is a less invasive method and a particularly useful diagnostic tool in severely ill patients.

We describe the case of a 70-year-old male with acromegaly who developed colon carcinoma and myelodysplastic syndrome (MDS) during the course of acromegaly. MDS progressed to acute myeloid leukemia, but was refractory to chemotherapy. Acromegaly is a rare disorder caused by excessive amounts of growth hormone (GH) primarily secreted by pituitary adenomas. Patients with acromegaly are more prone to develop various malignancies, but there are few reports of hematological malignancies in such patients. In the present case, excessive endogenous GH and insulin-like growth factor-I levels may have altered cell proliferation and thereby affected the oncogenesis and chemosensitivity of both malignancies.

Noninfectious transplantation-related complications (TRCs), such as graft-versus-host disease or TRC with endothelial cell damage (TRC-EC), remain as the major obstacle for successful allogeneic hematopoietic cell transplantation (allo-HCT). However, the diagnosis and prognosis for the emergence of these complications are difficult to define during the early post allo-HCT period. Here, we tried to generate a novel diagnostic system for TRC-EC by analyzing 188 adult patients who received allo-HCT. Our study found that the peripheral blood levels of angiopoietin 2 (ANG2), C-reactive protein (CRP), D-dimer, and thrombomodulin (TM) at the onset of TRCs were significantly associated with the development of TRC-EC. We next developed a composite biomarker panel incorporating the risk values of ANG2, CRP, D-dimer, and TM at the onset of TRCs, which classified these patients into 3 risk groups: low, intermediate, and high risk. As a result, the panel was useful not only for the diagnosis of TRC-EC with high specificity and sensitivity, but also for the prediction of the patients' long-term outcome. The 5-year overall survival (OS) rates of patients in the low-, intermediate-, and high-risk groups since the occurrence from TRCs were 76.2%, 54.9%, and 26.9%, respectively, and the high-risk score was significantly associated with both poor OS (hazard ratio [HR], 5.60; 95% confidence interval [CI], 2.81 to 11.20; P .01) and frequent nonrelapse mortality (HR, 19.75; 95% CI, 5.59 to 69.77; P .01). Thus, the composite panel proposed in this study provides a powerful tool for the diagnosis of TRC-EC and for the prediction of survival for patients with TRC-EC after allo-HCT.

The Rho family of small GTPases, including Rho, Rac and Cdc42, has been well characterised as a molecular switch that transduces signals from plasma membrane to the downstream effectors. RhoH gene, a member of the Rho family, is specifically expressed in haematopoietic cells. The known function of RhoH is antagonising Rac and mediating activation of ZAP-70 in T lymphocytes; however, biological roles of RhoH in myeloid cells remain unknown. Here, we analysed the prognostic implication of the expression level of the RhoH gene transcript in bone marrow samples from 90 newly diagnosed acute myeloid leukaemia (AML) patients using a real-time fluorescence detection method. Kaplan-Meier analysis demonstrated that low expression of the RhoH transcript was a predictor of worse prognosis in both overall and disease-free survival. Multivariate analysis demonstrated that low expression of RhoH was an independent unfavourable prognostic factor for both overall and disease-free survival of AML patients. Overexpression of RhoH leads to dephosphorylation of Bad at Serine 75 residue possibly through deactivation of Rac. It is possible that low expression of RhoH (i.e. high GTP-Rac) contributes to chemotherapy resistance in leukaemia cells. Our result suggests that inhibition of Rac and its signalling components might provide a useful anti-leukaemic strategy.

Purpose: The aim of this study was to evaluate the antileukemia activity of a novel FLT3 kinase inhibitor, FI-700. Experimental Design: The antileukemia activity of FI-700 was evaluated in human leukemia cell lines, mutant or wild-type (Wt)-FLT3–expressing mouse myeloid precursor cell line, 32D and primary acute myeloid leukemia cells, and in xenograft or syngeneic mouse leukemia models. Results: FI-700 showed a potent IC50 value against FLT3 kinase at 20 nmol/L in an in vitro kinase assay. FI-700 showed selective growth inhibition against mutant FLT3-expressing leukemia cell lines and primary acute myeloid leukemia cells, whereas it did not affect the FLT3 ligand (FL)–driven growth of Wt-FLT3–expressing cells. These antileukemia activities were induced by the significant dephosphorylations of mutant FLT3 and STAT5, which resulted in G1 arrest of the cell cycle. Oral administration of FI-700 induced the regression of tumors in a s.c. tumor xenograft model and increased the survival of mice in an i.v. transplanted model. Furthermore, FI-700 treatment eradicated FLT3/ITD-expressing leukemia cells, both in the peripheral blood and in the bone marrow. In this experiment, the depletion of FLT3/ITD-expressing cells by FI-700 was more significant than that of Ara-C, whereas bone marrow suppression by FI-700 was lower than that by Ara-C. Conclusions: FI-700 is a novel and potent FLT3 inhibitor with promising antileukemia activity.

Recently, somatic mutations of the nucleophosmin gene (NPM1), which alter the subcellular localization of the product, have been reported in acute myeloid leukemia (AML). We analyzed the clinical significance of NPM1 mutations in comparison with cytogenetics, FLT3, NRAS, and TP53 mutations, and a partial tandem duplication of the MLL gene (MLL-TD) in 257 patients with AML. We found NPM1 mutations, including 4 novel sequence variants, in 64 of 257 (24.9%) patients. NPM1 mutations were associated with normal karyotype and with internal tandem duplication (ITD) and D835 mutations in FLT3, but not with other mutations. In 190 patients without the M3 French-American-British (FAB) subtype who were treated with the protocol of the Japan Adult Leukemia Study Group, multivariate analyses showed that the NPM1 mutation was a favorable factor for achieving complete remission but was associated with a high relapse rate. Sequential analysis using 39 paired samples obtained at diagnosis and relapse showed that NPM1 mutations were lost at relapse in 2 of the 17 patients who had NPM1 mutations at diagnosis. These results suggest that the NPM1 mutation is not necessarily an early event during leukemogenesis or that leukemia clones with NPM1 mutations are sensitive to chemotherapy.

To clarify the role of fragile histidine triad (FHIT) in hematological malignancies, we examined the methylation status and the expression level of the FHIT gene in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells in comparison with the methylation of the p15(INK4B) gene. The FHIT methylation was found in 13 of 94 (13.8%) AML and 22 of 40 (55.0%) MDS cases, but not in normal mononuclear cells (MNCs). Both the frequency and density of methylation increased in the advanced-stages MDS and the relapsed AML cases. Although FHIT and p15(INK4B) methylations were not correlated in MDS and AML, increased FHIT methylation at the relapse in AML was associated with p15(INK4B) methylation. The median expression level in AML was significantly higher than in normal MNCs, although the median expression level in those with methylation was significantly lower than in those without methylation. Furthermore, the methylation level at relapse was significantly higher than at diagnosis in AML. These results suggested that FHIT methylation was accumulated through the disease progression of MDS and AML, and the role of the FHIT gene as a tumor suppressor seemed different in AML and MDS.

Unmanipulated hematopoietic stem cell transplantation from haploidentical family donors is frequently associated with graft failure and severe graft-versus-host disease (GVHD). We employed a myeloablative conditioning regimen consisting of 125 mg/m2 of fludarabine, 140 mg/m2 of melphalan and TBI of 10 to 12 Gy for three patients. The donor in each case was a haploidentical two-loci HLA mismatch mother or son. Engraftment failure was observed in one patient. In the other two patients, engraftment was confirmed within 15 days after transplantation. Acute and chronic GVHD was observed, but was controllable in both cases. HLA mismatched transplantation based on feto-maternal tolerance may provide an alternative option for patients who do not have HLA-matched donors.

An 80-year-old woman was diagnosed with primary cutaneous B cell lymphoma. She had multifocal cutaneous tumors, but no nodal lymphadenopathy or bone marrow involvement. Histopathological examination of a biopsy specimen showed diffuse large B cell lymphoma without a bcl-2 expression. Complete resolution of hypercalcemia and disappearance of tumors were achieved with CHOP therapy, but a rapidly progressive skin lesion was observed soon after the completion of the therapy. The clinical manifestation of primary cutaneous diffuse large B cell lymphoma is diverse and the treatment strategy is not entirely clarified. This case represents another example of this rare lymphoma.

Cord blood (CB) is becoming an increasingly attractive alternative stem cell source for allogeneic hematopoietic stem cell transplantation (HSCT), but the outcomes of CB transplantation (CBT) are inconsistent. In the present study, we compared non-infectious transplantation-related complications (NITRCs) post-CBT in patients with acute myeloid leukemia (AML) with those following related bone marrow and peripheral blood transplantation and unrelated BM transplantation. We analyzed 108 patients with AML who received HSCT at the Konan Kosei Hospital between 1992 and 2013. After a median follow-up of 74 months, the 3-year overall survival (OS) rate was 49.4 % with no differences between graft sources. The cumulative incidence of total NITRCs was 36 % at day 100. After adjusted analyses, patients with NITRCs showed significantly decreased OS [relative risk (RR) 3.51; p < 0.001) and increased non-relapse mortality (NRM) (RR 6.49; p < 0.001) compared with patients without NITRCs. Although the cumulative NITRC incidence did not differ among transplantation groups, NRM in patients with NITRCs was significantly lower in CB recipients than in other graft recipients (11.2 versus 68.4 %, p = 0.015). These data suggest that NITRCs contribute significantly to the outcome of HSCT and that the low virulence of NITRCs favored CBT for adult AML.

金沢大学理工研究域物質化学系, A gas-jet transport system has been coupled to the RIKEN gas-filled recoil ion separator GARIS to startup superheavy element (SHE) chemistry at RIKEN. The performance of the system was appraised using an isotope of element 104, 261Rf, produced in the 248Cm(18O,5n) 261Rf reaction. Alpha-particles of 261Rf separated with GARIS and extracted to a chemistry laboratory were successfully identified with a rotating wheel apparatus for α spectrometry. The setting parameters such as the magnetic field of the separator and the gas-jet conditions were optimized. The present results suggest that the GARIS/gas-jet system is a promising approach for exploring new frontiers in SHE chemistry: (i) the background radioactivities of unwanted reaction products are strongly suppressed, (ii) the intense beam is absent in the gas-jet chamber and hence high gas-jet efficiency is achieved, and (iii) the beam-free condition also allows for investigations of new chemical systems. © 2010 American Institute of Physics.

KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. In this study, we examined its possible modes of action for antileukemic effects on FLT3-activated, FLT3 wild-type, or imatinib-resistant leukemia cells. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G1 arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wild-type human leukemia, it induced the reduction of phosphorylated histone H3, G2/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as α1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations.

Decay properties of an isotope $^{266}$Bh and its daughter nucleus $^{262}$Db produced by the $^{248}$Cm($^{23}$Na, 5\textit{n}) reaction were studied by using a gas-filled recoil separator coupled with a position-sensitive semiconductor detector. $^{266}$Bh was clearly identified from the correlation of the known nuclide, $^{262}$Db. The obtained decay properties of $^{266}$Bh and $^{262}$Db are consistent with those observed in the $^{278}$113 chain, which provided further confirmation of the discovery of $^{278}$113., Accepted for publication in J. Phys. Soc. JPN., to be published in Vol.78 No. 6

A 49-year-old male developed recurrent acute myeloid leukemia 27 months after allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical brother. The immunophenotype of the blastic cell population was incompatible with that of the pre-transplant blast cells; a mutation in C/EBPA gene was found in the pre-transplant blast cells that was not present in the post-transplant blast cells, and short tandem repeat analysis of marrow cells, which included 71% blasts, showed complete donor chimera. Thus, this recipient developed donor cell leukemia (DCL). The donor was healthy when DCL developed in the recipient as well as before donation of the peripheral blood stem cells. Only five cases of DCL after PBSCT have been reported in the literature. As a mechanism for the development of DCL, a vigorous proliferative demand on the donor cells, which often correlates with a higher likelihood of replication error or mutation, has been proposed. Peripheral blood stem cells might have an advantage in that they are associated with a low incidence of DCL development because PBSCT recipients receive a higher total cell dose than recipients of bone marrow or cord blood cells.

Proton knockout reactions on carbon isotopes, p(9–16C,2p)8‐15B, at 250MeV/A were performed for systematic information on weakly to strongly bound 1p valence protons and deeply bound 1s protons. Various information such as energy gap between 1s and 1p orbits, widths of momentum distributions for 1s and 1p orbits, relative (p,2p) yields are obtained.

Background: Non-infectious transplant-related complications (TRCs) after allogeneic hematopoietic cell transplantation (allo-HCT) are associated with an unfavorable prognosis. Despite several proposed biomarkers, it remains difficult to predict survival outcomes before transplantation. Here we tested clinically available serum markers to identify patients at high risk of poor survival. Patients and methods: Patients (median age, 45 years; range, 16-68 years) who received allo-HCT at 2 institutions between May 2000 and August 2014 were included in the analysis. A total of 383 patients [203 patients from Konan Kosei Hospital (KKH) and 180 patients from Japanese Red Cross Nagoya First Hospital (RCH)] were evaluated. TRCs within 100 days were categorized as complications with endothelial damage (TRC-ED), acute graft-versus-host disease (GVHD), and other complications. TRC-ED was defined as sinusoidal obstruction syndrome, transplant-associated microangiopathy, capillary leak syndrome, and idiopathic pulmonary syndrome. C-reactive protein (CRP), albumin (Alb), ferritin, cholinesterase (ChE), and uric acid (UA) were selected as candidate biomarkers based on the literature. The above biomarkers were evaluated for their associations with the TRC incidence and probabilities of overall survival (OS) and non-relapse mortality (NRM). Results: Patient characteristics were comparable between the 2 hospital cohorts, except for a lower unrelated donor bone marrow transplant rate (38% vs. 58%) and a longer follow-up duration (5.6 years vs. 2.6 years) in the KKH cohort. Overall, 68% patients received allo-HCT for acute myeloid leukemia or myelodysplastic syndrome, and 37% patients had a high disease risk (non-remission). The graft source was cord blood in 24% patients, and 73% patients received a myeloablative conditioning regimen. The cumulative TRC-ED incidence was 21.7% at day 100. Acute GVHD occurred in 38.1% patients (n = 147) with grade III/IV seen in 41 patients. Low serum Alb (0.5 mg/dL) and ferritin (>2000 ng/mL) levels before pre-conditioning were significantly associated with inferior OS in a univariate analysis (log-rank test). All markers except ferritin and UA were statistically significant prognostic factors for NRM (Gray test). Low Alb and high CRP, which had the lowest p-values, were chosen as risk markers for a combined panel. The 5-year OS was 60% for patients with neither risk marker, 48% for those with either marker, and 20% for those with both markers. When patients were divided into low-risk (high Alb and low CRP) and high-risk combinations (low Alb and/or high CRP), the high-risk combination was identified as a strong prognostic factor for NRM [hazard ratio (HR): 2.27; 95% confidence interval (CI), 1.48-3.47; p = 0.00016; Fine-Gray test] and OS (HR: 1.60; 95% CI, 1.16-2.22; p = 0.0045; Cox regression hazard model) in a multivariate analysis with clinical confounders. Disease risk was another risk factor for OS, but not NRM. The high-risk combination also predicted TRC-ED occurrence. The cumulative TRC-ED incidence at day 100 was 31% and 17% in patients with high-risk and low-risk combinations, respectively (p = 0.00165). Substituting low ChE for low Alb as a marker yielded a combination of high CRP and low ChE, which was a better predictor for TRC-ED. Both combined markers were independently associated with a higher TRC-ED incidence in a multivariate analysis. No significant differences were observed in the cumulative incidence of grade III/IV acute GVHD at day 100 between the high-risk and low-risk groups for any biomarker. Conclusions: A combined panel comprising Alb and CRP provided significant power for pre-transplant TRC-ED occurrence and survival predictions. Independent cohort confirmations and further investigations of underlying mechanisms are warranted in future studies. Disclosures No relevant conflicts of interest to declare.

We hypothesized that reducing the dosage of prophylaxis for graft-versus-host disease (GVHD) would reduce the risk of relapse and toxicity after bone marrow transplantation (BMT) from human leukocyte antigen (HLA)-identical siblings. In a prospective phase II trial, 21 patients with leukemia and myelodysplastic syndrome underwent BMT from HLA-identical siblings and received GVHD prophylaxis consisting of low-dose (1.5 mg/kg per day) cyclosporin A (CSP) with short-term methotrexate (MTX) treatment. This low-dose group was compared with a group of retrospective control patients (n = 22) who received a standard CSP dosage (3.0 mg/kg per day) and MTX. One patient died of transplantation-related causes within 100 days. The regimen-related toxicity was quite tolerable. Although acute GVHD of grades II to III was more frequent in the low-dose group (47.6%) than in the control group (22.7%), the increase in acute GVHD did not significantly contribute to morbidity or mortality. There were no differences between the groups in the incidence and severity of chronic GVHD. The probabilities of relapse and survival of the groups were similar according to the risk for relapse at the time of transplantation. A prospective randomized study is required to determine whether low-dose or standard-dose CSP in combination with MTX is optimal for Japanese patients who undergo allogeneic BMT from HLA-identical siblings.

We established a leukemia cell line derived from therapy-related acute myeloid leukemia with the t(11;19) by xenotransplantation into the NOD/SCID mouse with IL-2Rgamma(c)-/- (NOG mouse). The cell line, TRL-01, could be serially transplanted from mouse to mouse and also grown in an adherence-dependent manner on a murine bone marrow stroma cell line, HESS-5. TRL-01 had the same immunophenotype as the original leukemia cells: positive for CD13, CD33, CD11a, CD18, CD29, CD49d, CD49e, CD54, CD62L, and CD117, and negative for CD3, CD4, CD8, CD19, CD34, CD41a, CD41b, CD135, and myeloperoxidase. Translocation (11;19)(q23;p13) in both the original sample and TRL-01 generated MLL-ENL chimeric transcripts joining exon 6 and exon 4, respectively, which has a novel isoform. In cultures of TRL-01, addition of GM-CSF, SCF, and G-CSF and adhesion to fibronectin-coated plates promoted transient proliferation and survival, although they did not support long-term culture. Subcutaneous injection caused a tumor to form only when HESS-5 was coinjected at the same site. These results suggest that TRL-01 is a useful cell line for studying not only the leukemia-related biology of MLL-ENL but also the intercellular association between leukemia and stroma.

Although FLT3 mutations are essentially found in myeloid-lineage leukemia cells, a high level of FLT3 expression was recently observed in MLL gene-rearranged acute lymphoblastic leukemia without FLT3 mutations. Here, we analyzed the biologic and clinical significance of the FLT3 transcript level in comparison with several gene alterations in 181 de novo acute myeloid leukemia (AML) cases. The mean expression level in AML was higher than that in normal mononuclear cells, whereas the range varied widely. A high level of FLT3 is related to internal tandem duplication of the FLT3 gene (FLT3/ITD), the mutations within the activation loop of FLT3 (FLT3/D835Mt), and tandem duplication of the MLL gene (MLL-TD) but not to p53 or N-RAS gene mutations. Furthermore, a high expression level in AML cases with FLT3 mutations was not related to MLL-TD. Overexpressed FLT3 revealed autophosphorylation and had the same sensitivity to the FLT3 inhibitor as FLT3/ITD. Overexpression of FLT3 (more than 200,000 copies/microgRNA) was an unfavorable prognostic factor for overall survival in 91 AML cases without FLT3/ITD. These results indicated that FLT3 overexpression may distinguish a novel disease entity in AML without FLT3 mutations and serve as a therapeutic target for FLT3 inhibitors.

Background: Non-infectious transplant-related complications (TRCs) following allogeneic hematopoietic cell transplantation (allo-HCT) are associated with unfavorable prognosis, but it's difficult to predict the severity at the beginning of clinical symptoms. Inflammatory endothelial injury and hemostatic abnormality were found to play a critical role in the development of severe TRCs. This study aimed to explore plasma markers that could serve as independent predictors for dismal TRCs. Patients and methods: Patients who received allo-HCT between 2000 and 2013 and had available blood samples within 3 days after the initial symptoms of TRCs were included in the analysis. Patients who had undergone any prior transplantation within 6 months were excluded. A total of 185 patients were evaluated and the median age of patients was 46 years (range:16-68). TRCs within 100 days were categorized into three groups; complications with endothelial damage (ED), acute GVHD, and the other complications (OC). ED was defined as sinusoidal obstruction syndrome (SOS), transplant-associated microangiopathy (TAM), capillary leak syndrome (CLS) and idiopathic pulmonary syndrome (IPS). OC included pre-engraftment immune reaction, engraftment syndrome, hemophagocytic syndrome and organ dysfunction. If a patient experienced multiple TRC episodes, we analyzed the episode that developed first. Plasma angiopoietin-2 (ANG2), VEGF, thrombomodulin (TM), D dimer, plasmin-α2 plasmin inhibitor complex (PIC) and C-reactive protein (CRP) were measured. Multiple characteristics including plasma markers were evaluated for their association with overall survival (OS) and non-relapse mortality (NRM). Results: Median follow-up duration of surviving patients after transplant was 4.5 years. Sixty-five percent of the patients received allo-HCT for acute myeloid leukemia or myelodysplastic syndrome and the disease risk was high (not in remission) in 40% of the patients. The source of graft was bone marrow from unrelated donor in 38%, cord blood in 30% of the patients. Eighty-six percent of the patients received myeloablative conditioning regimen. Accumulative incidence of total non-infectious TRCs was 78.9% at day 100. ED was observed in 56 patients SOS (n=17), TAM (n=26), CLS (n=10) and IPS (n=3). These include 16 patients who also experienced grade III to IV GVHD in their post-transplant course. One-year NRM in patients with ED (45.8%) was significantly high compared to 13 patients with grade III-IV GVHD in the absence of ED (16.2%), 52 patients with grade I-II GVHD (10.3%), 26 patients with OC (4.8%), and 18 control patients who never experienced any TRCs or relapse within 100 days after transplant (0%). All candidate biomarkers except for VEGF and PIC at the onset of ED were significantly higher compared to the peak levels of the control patients by Kruskal-Wallis rank sum test. ANG2 and D dimer were significant for SOS, TAM and CLS, whereas CRP was significant for SOS, and TM was significant for SOS and TAM. Any biomarkers were not significantly elevated at the onset of GVHD or OC. Receiver operating characteristic curves for ANG2, D dimer, CRP and TM distinguished ED from the others with AUC of 0.92, 0.83, 0.76 and 0.74, respectively. ANG2 at the concentration of 4.8ng/ml provided a positive predictive value (PPV) of 77% and a negative predictive value (NPV) of 91% for ED. PPV and NPV reached 91% and 89% with a specificity of 97% by combining ANG2 positivity with either high D dimer (>4.3μg/ml) or high CRP (>4.3mg/dl). Additional biomarkers provided no further increased diagnostic accuracy. With adjusted analysis in 134 patients who developed non-infectious TRCs, the combined marker was independent risk factor for NRM (HR: 4.2; 95%CI, 2.2-7.9; p Conclusions: Combination of ANG2, D dimer and CRP had significant powers for confirming the diagnosis of dismal TRCs at the onset of clinical symptoms. The high diagnostic accuracy would make them useful for real-time clinical judgment and early intervention. Disclosures No relevant conflicts of interest to declare.

Introduction: Hepatitis B virus (HBV) reactivation during chemotherapy is a well recognized complication. Because it is often fatal, preemptive administration of entecavir and frequent monitoring of HBV DNA mRNA level are recommended for high risk patients. To date, there are few reports on HBV reactivation by tyrosine kinase inhibitors (TKI). We present the patient with chronic myeloid leukemia (CML) who developed HBV reactivation during imatinib mesylate (IM) therapy. Case report: The patient in 70s with a history of colon carcinoma and CML in chronic phase developed mechanical ileus. He had been on IM for 10 years. On preoperative examination, AST/ALT was 350/366 IU/L respectively. Since the liver abnormality could be related to either ischemic tissue damage or drugs, all medications including IM were discontinued. However, in 3 weeks, AST/ALT reached as high as 651/909 IU/L. He became icteric and had mild ascites. Virus serological/molecular test revealed positive results for HBs antigen, HBc antibody and HBV DNA mRNA. Because HBs antigen had been negative 3 years before and HBs antibody was detected on admission, it was indicated that HBV reactivation was responsible for his hepatitis (i.e. ‘de novo’ hepatitis). Entecavir was initiated, which fortunately ameliorated symptoms and normalized laboratory data in a month. HBV DNA mRNA also bacame undetectable in 2 months. CML has been maintained in complete molecular remission for more than 6 months despite he is off IM. Discussion: Hepatotoxicity is seen up to 5% of CML patients treated with IM. But HBV reactivation by TKI is a rare event. There have been less than 10 case reports of such patient in literature, and this is the first report of a Japanese patient. Besides BCR/ABL, IM can inhibit other kinase activities on various cell types and has immunomodulatory effects. Considering the potentially fatal nature of hepatitis with HBV reactivation, patients at risk should be closely monitored during TKI treatment.

An isotope of element 104, rutherfordium (261Rf), produced in the 248Cm(18O, 5n)261Rf reaction was successfully extracted to a chemistry laboratory using a gas-jet transport system coupled to the R...

Background Non-infectious transplant-related complications (TRC) early after allogeneic hematopoietic cell transplantation (allo-HCT) are associated with considerable morbidity and mortality. Recently, research interests have been focused on endothelial cell (EC) dysfunction and angiogenesis which is a common feature implicated in the pathogenesis of TRC. Angiopoiein-2 (ANG2) plays an essential role in promoting endothelial instability in the process of angiogenesis and predisposing tissue damage. Recent studies have indicated that high level of ANG2 is associated with graft-versus host disease (GVHD) but the role of ANG2 in TRC remains unclear. Thus, we evaluated the association between plasma ANG2 levels and TRC. Patients and Methods Patients who received allo-HCT between 2000 and 2012 and had available blood samples at transplant (day0) were included in the analysis. Patients who had undergone any prior transplantation within one year were excluded. A total of 153 patients were evaluated and the median age of patients was 49 years (range: 16-68). TRC was defined as sinusoidal obstruction syndrome (SOS), systemic transplant-associated microangiopathy (TAM), capillary leak syndrome (CLS) and grade III/IV acute GVHD with massive fluid retention or hemophagocytic syndrome (HPS). Plasma ANG2 levels were measured by ELISA kit and we set the cut-off value of 2.0ng/mL for ANG2 at transplant. Multiple characteristics including ANG2 were evaluated for their association with TRC, GVHD and overall survival (OS). Results Median follow-up duration of surviving patients after transplant was 5 years. Seventy percent of the patients received allo-HCT for acute myeloid leukemia or myelodysplastic syndrome and the disease risk was high (not in remission) in 38% of the patients. Sixty-five percent of the patients received allo-HCT from unrelated donor and the source of graft was HLA-matched in 53%, mismatched in 18%, and cord blood in 29% of the patients. Seventy-five percent of the patients received myeloablative conditioning regimen and 67% of the patients received GVHD prophylaxis with tacrolimus. ANG2 level at the onset of TRC was significantly higher compared to the peak levels of the patients who had no complication during the transplant (control) {median of ANG2 ng/ml (range): control, 2.5 (1.4-4.0); TRC, 6.4 (2.4-15.7), p Conclusions High plasma ANG2 at transplant was significantly associated with TRC but not with grade III/IV acute GVHD. High ANG2 at transplant could serve as a potential risk marker for latter TRC and inferior survival. Further investigations are needed for prevention strategies for TRC navigated by plasma ANG2. Disclosures: No relevant conflicts of interest to declare.

The emittance and beam intensity of highly charged heavy ions were measured as a function of the negative voltage of a biased disc. We observed that the brightness of the highly charged uranium ion beam generated by the RIKEN 28 GHz superconducting electron cyclotron resonance ion source was strongly influenced by the bias voltage.

The production and decay properties of an isotope of the 112th element, 277Cn, were investigated using a gas-filled recoil ion separator by irradiation of 208Pb targets with 70Zn beams at 347.5, 351.5, and 355.5 MeV. The excitation function for this reaction was measured for the first time. We observed one decay event assigned to the decay of 277Cn at the beam energy of 351.5 MeV. The measured production cross section was 0.078+0.179 pb. The present result gives improved half-lives of 0.61+0.46 and 0.19+0.14 ms for 277Cn and 273Ds, respectively. At the other energies, no event was observed. The measured upper cross section limits were 0.25 and 0.15 pb at the beam energies of 347.5 and 355.5 MeV, respectively.