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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.

Little is known about stem cell transplantation in solid organ transplantation (SOT) recipients. We conducted a nationwide retrospective survey of Japan Society for Hematopoietic Stem Cell Transplantation centers. A total of 19 patients who underwent 22 hematopoietic stem cell transplantations (HSCTs) after SOT were identified: 5 autologous HSCTs and 17 allogeneic HSCTs were performed. Patients who underwent autologous HSCT received a liver (n = 4) or kidney (n = 1) transplant. All 5 patients achieved neutrophil engraftment, and 2 of 3 patients with hepatoblastoma were alive at 1 year after HSCT. Allogeneic HSCT was performed in 16 patients (7 liver transplant recipients and 9 kidney transplant recipients). Among these, 2 donors were identical for both transplantations. All but 1 patient achieved neutrophil engraftment. The 5-year overall survival rate was 41.7%, but that in patients with malignant disease (n = 13) was much lower than the overall rate (23.1%). Only 1 patient with malignant disease underwent allogeneic HSCT in nonremission. In allogeneic HSCT after kidney transplantation, post-transplantation (1 year) kidney function in 5 evaluable patients was significantly lower than that before allogeneic HSCT, and 3 patients experienced renal rejection. However, no severe hepatic rejection was noted. In SOT recipients, HSCT is a potentially curable treatment for hematologic disorders, but it must be performed with caution, especially in patients with malignancy.

Almost comparable transplantation outcomes have been reported with HLA-matched unrelated donor transplantation (UDT) and cord blood transplantation (CBT). We conducted a prospective phase 2 study to assess the efficacy and safety of single-unit myeloablative CBT in adult leukemia and myelodysplastic syndrome. Because the day 180 survival of UDT was approximately 80%, we determined the alternative hypothesis of expected day 180 survival with a successful engraftment rate of 80% and set the null hypothesis of threshold rate at 65%. Sixty-two patients (median age, 37 years) were registered, including 28 with acute myelogenous leukemia, 25 with acute lymphoblastic leukemia, and 9 with myelodysplastic syndrome. Of 61 eligible patients, 52 were successfully engrafted and survived at day 180 (85%; 95% confidence interval, 74% to 93%). Single-unit CBT was judged to be effective because the null hypothesis was rejected (P.001). Furthermore, neutrophil engraftment was observed in 57 patients (92%); the incidences of grade II-IV acute and chronic graft-versus-host disease were 30% and 32%, respectively; and the cumulative incidences of nonrelapse mortality and relapse at 2 years were 18% and 13%, respectively. The present study showed favorable survival outcomes with single-unit CBT. Therefore, this method may be considered if a well-HLA-matched UDT cannot be obtained.

Background Despite recent progress in blood systems, transfusion errors can occur at any time from the moment of collection through to the transfusion of blood and blood products. This study investigated the actual statuses of blood transfusion errors at institutions of all sizes in Aichi prefecture. Materials and methods We investigated 104 institutions that perform 98 % of the blood transfusions in Aichi prefecture, and investigated the errors (incidents/accidents) that occurred at these facilities over 6 months (April to September, 2017). Incident/accident data were collected from responses to questionnaires sent to each institution; these were classified according to the categories and risk levels. Results Ninety-seven of the 104 institutions (93.3 %) responded to the questionnaire; a total of 688 incidents/accidents were reported. Most (682 cases; 99.2 %), were classified as risk level 2; however, 6 were level 3 and over, which included problems with autologous transfusion and inventory control. Approximately one-half of the incidents/accidents (394 cases; 57.3 %), were related to verification and the actual administration of blood products at the bedside; more than half of these incidents/accidents occurred at large-volume institutions. Meanwhile, a high frequency of incidents/accidents related to transfusion examination and labeling of blood products was observed at small- or medium-sized institutions. The reasons for most of these errors were simple mistakes and carelessness by the medical staff. Conclusions Our results emphasize the importance of education, operational training, and compliance instruction for all members of the medical staff despite advances in electronic devices meant to streamline transfusion procedures.

Ganciclovir (GCV) and foscarnet (FCN) are effective anti-cytomegalovirus (CMV) preemptive therapies; however, the impact of the 2 agents on various clinical outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) remains unclear. We retrospectively analyzed data on 532 patients undergoing allogeneic HSCT from unrelated donors and administered FCN (n = 86) or GCV (n = 446) as first-line anti-CMV preemptive therapy. Overall survival, relapse, and nonrelapse mortality (NRM) did not differ between the FCN and GCV groups, whereas the GCV group had a higher risk of chronic graft-versus-host disease (cGVHD) (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.28 to 4.39; P = .006) and extensive cGVHD (HR, 3.94; 95% CI, 1.43 to 10.9; P = .008). All 13 patients with cGVHD in the FCN group survived. Switching to the other agent was done mainly due to hematologic adverse events in the GCV group and mainly due to insufficient efficacy in the FCN group. The incidence of end-organ CMV disease was similar in the 2 groups. Selection of FCN or GCV as first-line preemptive anti-CMV therapy did not affect survival, relapse, or NRM. Physicians can select either of the agents, depending on the clinical situation; however, the selection may influence the cGVHD-related clinical course in HSCT recipients.

Little is known regarding the chimerism status after reduced-intensity conditioning transplantation when bone marrow is used as a stem cell source. We prospectively analyzed lineage-specific chimerism and retrospectively evaluated clinical outcomes in 80 adult patients who underwent unrelated donor bone marrow transplantation (URBMT) with fludarabine plus melphalan (FM) as the conditioning regimen. Mixed donor chimerism (MDC) was seen in 43 and 10 % of patients at days 14 and 28, respectively. Melphalan at ≤130 mg/m(2) was associated with an increased incidence of MDC at day 28 (P = 0.03). Patients with MDC at day 14 showed a marginally increased risk of primary graft failure and a marginally decreased risk of graft-versus-host disease. In multivariate analysis, MDC at day 14 was associated with higher overall mortality (hazard ratio (HR) = 2.1; 95 % confidence interval (CI), 1.1-4.2; P = 0.04) and relapse rate (HR = 3.0; 95 % CI, 1.2-7.5; P = 0.02), but not with non-relapse mortality (HR = 1.8; 95 % CI, 0.70-4.6; P = 0.23). Thus, the FM regimen yields prompt complete donor chimerism after URBMT, but the melphalan dose significantly impacts the kinetics of chimerism. Chimerism status evaluation at day 14 may be instrumental in predicting relapse after URBMT with the FM regimen.

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.

Summary What is known and Objective: Although new thrombopoietin (TPO) receptor agonist drugs, such as romiplostim and eltrombopag, are highly effective and well tolerated for patients with immune thrombocytopenia (ITP) refractory to first-line treatments such as prednisolone, the cross-resistance of these two TPO receptor agonists is still unknown. Case summary: An 84-year-old Japanese female patient with steroid-refractory ITP received eltrombopag with a gradually increasing dose schedule from 12·5 to 25 mg/day, 37·5 mg/day and finally 50 mg/day. As no increase in platelet count was observed even at the maximum dose of 50 mg/day, and eltrombopag-related grade 3 elevation of aspartate aminotransferase was observed, another TPO receptor agonist, romiplostim, was administered at 1 μg/kg/week subcutaneously. A rapid increase in platelet count was observed 1 week after the first injection. The dose of romiplostim was escalated to 4 μg/kg according to the platelet count and a complete response was achieved 7 weeks after the first injection without any adverse events. What is new and Conclusion: The successful treatment of ITP refractory to eltrombopag with romiplostim strongly suggests that the absence of cross-resistance between these two approved TPO receptor agonists and possible differences in mechanism of action. Further study of the mechanisms of action of TPO receptor agonists is called for along with further exploration of the potential of romiplostim in refractory ITP.

Inotuzumab ozogamicin (CMC-544), an antibody-targeted chemotherapeutic agent composed of an anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic antibiotic, specifically targets the CD22 antigen present in >90% of B-lymphoid malignancies, rendering it useful for treating patients with B-cell non-Hodgkin lymphoma (B-NHL). This phase I study evaluated the safety, tolerability, efficacy, and pharmacokinetics of inotuzumab ozogamicin in Japanese patients. Eligible patients had relapsed or refractory CD22-positive B-NHL without major organ dysfunction. Inotuzumab ozogamicin was administered intravenously once every 28 days (dose escalation: 1.3 and 1.8 mg/m(2)). All 13 patients had follicular lymphoma, were previously treated with > or =1 rituximab-alone or rituximab-containing chemotherapy, and were enrolled into two dose cohorts (1.3 mg/m(2), three patients; 1.8 mg/m(2), 10 patients). No patient had dose-limiting toxicities, and the maximum tolerated dose, previously determined in non-Japanese patients (1.8 mg/m(2)), was confirmed. Drug-related adverse events (AEs) included thrombocytopenia (100%), leukopenia (92%), lymphopenia (85%), neutropenia (85%), elevated AST (85%), anorexia (85%), and nausea (77%). Grade 3/4 drug-related AEs in > or =15% patients were thrombocytopenia (54%), lymphopenia (31%), neutropenia (31%), and leukopenia (15%). The AUC and C(max) of inotuzumab ozogamicin increased dose-dependently with pharmacokinetic profiles similar to non-Japanese. Seven patients had complete response (CR, 54%) including unconfirmed CR, four patients had partial response (31%), and two patients had stable disease (15%). The overall response rate was 85% (11/13). Inotuzumab ozogamicin was well tolerated at doses up to 1.8 mg/m(2) and showed preliminary evidence of activity in relapsed or refractory follicular lymphoma pretreated with rituximab-containing therapy, warranting further investigations. This trial was registered in ClinicalTrials.gov (NCT00717925).

Graft failure and nonrelapse mortality (NRM) are major obstacles after the first unrelated-donor bone marrow transplantation (UD-BMT) with reduced-intensity conditioning. We evaluated UD-BMT with fludarabine (5 x 25 mg/m2) and melphalan (2 x 90 mg/m2) treatment combined with short-term methotrexate and tacrolimus (n = 20) or cyclosporine (n = 2) therapy for 22 patients with hematologic malignancies who were ineligible for conventional conditioning. Only 9 patients were in remission at transplantation. Seventeen patients underwent HLA-matched or DRB1 allele-mismatched transplantation, and 5 patients underwent HLA-A allele-mismatched or serologically HLA-DR-mismatched transplantation. Regimen-related toxicities were tolerable, although transient oral mucositis, hepatobiliary enzyme elevation, and diarrhea were observed frequently. All evaluable patients achieved sustained neutrophil engraftment, and all patients tested showed complete donor chimerism on day 28. With a median follow-up of 16 months, NRM and overall survival rates at 1 year were 19% and 81%, respectively, among the patients who underwent HLA-matched or DRB1 allele-mismatched transplantation. Acute graft-versus-host disease (GVHD) of grades II to IV occurred in 26% of the patients. The cumulative incidence of chronic GVHD was 44%. Despite the small number of patients and the short follow-up period, this reduced-intensity regimen enabled satisfactory engraftment and achievement of rapid complete donor chimerism with tolerable toxicities in the patients, including those who underwent HLA-mismatched UD-BMT.

We analyzed donor-type chimerism in CD3+, CD14.15+ and CD56+ cells from 36 patients who had undergone conventional-intensity allogeneic stem cell transplantation (CST) and 34 patients who had undergone non-myeloablative allogeneic stem cell transplantation (NST) for hematological malignancies. On day 28 after transplantation, all fractions in NST patients and CD3+ cells in CST patients who received a non-total body irradiation (TBI) regimen showed more frequent mixed chimerism (

We conducted a nationwide survey to define incidence of deep fungal infections and fungal prophylaxis practices after HSCT. In all, 63 institutions responded. Total number of in-patient transplantations was 935: 367 autologous, 414 allogeneic myeloablative, and 154 allogeneic reduced-intensity (RIST) (n=154). Number of patients who were cared for in a clean room at transplant was 261 (71%) in autologous, 409 (99%) in conventional and 93 (66%) in RIST, respectively. All patients received prophylactic antifungal agents; 89% fluconazole. Number of patients who received the dosage recommended in the CDC guidelines (400 mg/day) was 135 (42%) in conventional transplant and 34 (30%) in RIST (P=0.037). Number of patients who received fluconazole until engraftment and beyond day 75 in conventional transplant vs RIST was, respectively, 324 (100%) vs 109 (97%), and 39 (12%) vs 18 (16%), with no significant difference between the two groups. A total of 37 patients (4.0%) were diagnosed with deep fungal infections; autologous transplantation (0.03%), conventional transplantation (6.0%) and RIST (7.1%). Wide variations in antifungal prophylaxis practice according to the type of transplant and the institutions, and deep fungal infection remain significant problems in RIST.

A reduced incidence of graft versus host disease (GvHD) has been documented among Japanese allogeneic bone marrow transplantation (BMT) patients, as the Japanese are genetically more homogeneous than western populations. To clarify whether this ethnic difference affects the results of allogeneic peripheral blood stem cell transplantation (PBSCT), we conducted a nationwide survey to compare clinical outcomes of allogeneic PBSCT (n = 214) and BMT (n = 295) from a human leucocyte antigen-identical-related donor in Japanese patients. The cumulative incidence of grades II-IV acute GvHD was 37.4% for PBSCT and 32.0% for BMT. The cumulative incidence of extensive chronic GvHD at 1 year was significantly higher after PBSCT than BMT (42% vs. 27%; P < 0.01). The organ involvement patterns of GvHD were different between the two groups. By multivariate analyses, the incidence of chronic GvHD was significantly increased in PBSCT, whereas the stem cell source did not affect the incidence of acute GvHD, transplant-related mortality, relapse or survival. We concluded that Japanese PBSCT patients have an increased risk of chronic GvHD compared with BMT patients, but the incidence of acute GvHD was still lower than in western populations. Thus, the choice of haematopoietic stem cell source should be considered based on data for individual ethnic populations.

Background: The aim of the study was to determine factors affecting the toxicity and efficacy of rituximab monotherapy in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma (MCL). Patients and methods: A total of 90 patients were enrolled and treated with rituximab infusions at 375 mg/m 2 once weekly for 4 weeks. Central pathology review revealed that histologically, 81 patients had indolent B-cell lymphoma or MCL: 59 with follicular lymphoma, 17 with MCL, four with marginal zone lymphoma and one with lymphoplasmacytoid lymphoma. Of these, four were ineligible due to violation of other eligibility criteria. Pre-treatment variables affecting toxicities were analyzed for all 90 patients, and those affecting response and progression-free survival (PFS) were analyzed for 77 eligible patients with confirmed indolent B-cell lymphoma or MCL. The relationship between serum rituximab levels and efficacy was also analyzed for 66 eligible patients. Results: Hematological toxicities (grade ≥3) occurred more frequently in females (P

Introduction The prognosis of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) has been dramatically improved since the introduction of tyrosine kinase inhibitors (TKIs). Although allogeneic hematopoietic cell transplantation (allo-HCT) is a major treatment option, the role of autologous peripheral blood stem cell transplantation (auto-PBSCT) has been reconsidered, especially in patients who achieved early molecular remission. Methods and analysis This is a multicenter exploratory study for Ph + ALL patients aged between 55 and 70 years who achieved complete molecular remission within 3 cycles of chemotherapy. The target sample size is 5, and the registration period is 2 years. The primary endpoint is Day100- mortality after transplantation, and the secondary endpoints are survival, relapse rate, nonrelapse mortality, and adverse events.This study is divided into 3 phases: peripheral blood stem cell harvest, transplantation, and maintenance. Chemomobilization is performed using a combination of cyclophosphamide (CPM), doxorubicin, vincristine (VCR), and prednisolone (PSL). As a preparative regimen, the LEED regimen is used, which consists of melphalan, CPM, etoposide, and dexamethasone. Twelve cycles of maintenance therapy using a combination of VCR, PSL, and dasatinib are performed.In association with relapse, the minimal residual disease (MRD) of BCR-ABL chimeric gene and T-cell subsets are analyzed both before and after auto-PBSCT. Ethics and dissemination The protocol was approved by the institutional review board of Nagoya University Hospital and all the participating hospitals. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. Trial registration Trial registration number UMIN000026445.

We established a real-time PCR method that can simultaneously detect 10 different fusion transcripts (major, minor and micro BCR/ABL, AML1/MTG8, PML/RARalpha, CBFbeta/MYH11, TEL/AML1, E2A/PBX1, MLL/AF4, and MLL/AF9) together with Wilms' tumor gene (WT1) transcripts. This screening method allowed the processing of six specimens concomitantly and required only one working day from RNA extraction to final results. Fifty-seven bone marrow (BM) samples from patients with acute leukemia were retrospectively screened for the presence of fusion and WT1 transcripts without knowledge of the cytogenetic data, and the fusion transcripts were detected in 20 of 57 samples (35.1%). The concordance between the present method and cytogenetic analysis was examined in 38 samples in which the cytogenetic data were available. In 12 of 38 samples, the PCR results agreed with the cytogenetic data, whereas in 4 of the remaining 26 samples, the translocations were detected by real-time PCR alone because of the insufficient number of metaphases obtained and presumably the submicroscopic or masked translocations. The WT1 levels ranged from 400 to 690,000 copies/microg RNA in BM from leukemia patients, whereas 0-470 copies/microg RNA were found in BM cells from BMT donors. This real-time PCR method enables rapid and efficient characterization of acute leukemia in addition to subsequent evaluation of minimal residual diseases.

High-dose chemotherapy with autologous hematopoietic stem cell transplantation has been expected to result in a promising outcome in high risk aggressive non-Hodgkin's lymphoma (NHL). However, it remains unknown what type of initial chemotherapy is optimal, especially regarding progenitor cell mobilization. Sixty-three untreated patients with aggressive NHL in a high risk group were randomized to either a biweekly arm with 8 cycles of standard CHOP or 6 cycles of the dose-escalated CHOP arm with cyclophosphamide 1.5 g/m2 and doxorubicin 70 mg/m2. Lenograstim (glycosylated rHuG-CSF 2.0 microg/kg/day) was administered daily from day 3 to patients in both arms. The mobilization effect of the two regimens on circulating CD34+ cells was evaluated. Twenty-seven of 29 patients in the biweekly CHOP arm and 33 of 34 patients in the dose-escalated CHOP were assessable. Dose-escalated CHOP yielded a significantly higher number of circulating CD34+ cells in the first cycle compared with biweekly CHOP (p=0.05). The peak number of circulating CD34+ cells with biweekly CHOP did not significantly change from cycle to cycle; however, in dose-escalated CHOP, the peak number of circulating CD34+ cells mobilized after the fifth and sixth cycle was lower than after the first cycle (p=0.07 and 0.009, respectively). Routine conventional-dose chemotherapy and low-dose G-CSF can mobilize sufficient CD34+ cells in patients with aggressive NHL. The mobilization kinetics of circulating progenitor cells in patients with aggressive NHL is dependent on the dosage and schedule of CHOP.

Multiple myeloma (MM) developing after renal transplantation is rare. From January 1972 to December 2011, a total of 1,485 patients underwent renal transplantation in Nagoya Daini Red Cross Hospital; 14 (0.9%) of these recipients developed post-transplantation lymphoproliferative disorders (PTLDs) including two plasma cell neoplasms. Here, we report the clinical course of a 35-year-old male with immunoglobulin G k-type MM of recipient origin that developed 5 years after renal transplantation from a human leukocyte antigen (HLA)-haploidentical female sibling donor, which was performed to address dialysis-dependent chronic glomerulonephritis. Cytogenetic analysis revealed significant del(17p) abnormalities in myeloma cells. After non-response to bortezomib treatment, the patient achieved partial response with a thalidomide-containing salvage regimen and underwent successful tandem autologous/reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated male donor matched for seven of eight HLAs. At the 8-month follow-up time point, the patient's performance status remained good, and the transplanted kidney remains functional without rejection. To the best of our knowledge, this is the first report of a successful use of allogeneic HSCT for a patient who developed MM as a PTLD after renal transplantation. This patient has a transplanted kidney and transplanted hematopoietic cells that currently coexist without rejection.

The management of myelodysplastic syndrome (MDS) remains challenging. We performed a phase I/II study to evaluate the safety and efficacy of decitabine in patients with MDS in Japan. Patients with MDS with red cell transfusion dependence or 5-30% blasts in marrow and with an International Prognostic Scoring System score of intermediate-1 or higher were eligible. Patients received intravenous decitabine at 15 or 20 mg/m(2) daily for 5 days every 4 weeks. A total of 37 patients were enrolled. Three patients received 15 mg/m(2) and experienced no dose limiting toxicity during the first cycle. Thirty-four patients received 20 mg/m(2) . Grade 3 or greater non-hematologic toxicities included cerebral infarction (n = 1), subdural hematoma (n = 1), elevated blood glucose (n = 1), and pulmonary hypertension (n = 1). At 20 mg/m(2) , complete response, partial response, and hematologic improvement were observed in 7 (20.6%), 2 (5.9%), and 7 (20.6%) patients, respectively. Complete cytogenetic response was observed in 30% of evaluable 20 patients. The median number of cycles to clinical response was 4 (range 4-8), and duration of remission was 474+ days (range 294-598+). The 2-year rate of acute myeloid leukemia-free survival was 52%. Correlative studies revealed hypomethylation in multiple genes in peripheral blood cells after treatment. Hypomethylation was generally more profound in CD15 + peripheral blood cells, which reflects myeloid cells, than in peripheral blood mononuclear cells. In summary, decitabine was safe and demonstrated efficacy in Japanese patients with high-risk MDS. This trial was registered at ClinicalTrials.gov (NCT00796003).

The response criteria proposed by European Leukemia Net are useful to predict the prognosis of de novo chronic myeloid leukemia (CML) patients in the chronic phase (CP) treated with imatinib. However, the clinical significance of late suboptimal response, which is defined as the achievement of CCgR without MMR after 18 months, is controversial. In this study, we retrospectively analyzed the clinical courses of 16 CML-CP patients, who satisfied the criteria for late suboptimal response. The median duration of imatinib treatment was 62 (25∼87) months. The median starting dose of imatinib was 400 mg/day. Imatinib dose was escalated to 600∼800 mg/day in 10 patients for various reasons. Among 4 patients who continued high-dose imatinib for late suboptimal response, 2 patients subsequently achieved MMR, and BCR-ABL mRNA transcript levels were decreasing in 2 patients. However, imatinib was kept at 300 or 400 mg/day in 6 patients. Among these six patients, 4 patients achieved MMR, while 2 failed to achieve MMR. None of 16 patients progressed to the acute phase or blast phase. Imatinib dose escalation was effective for late suboptimal response. Furthermore, a second tyrosine kinase inhibitor such as nilotinib may be more potent to reduce the risk of disease progression by achieving earlier MMR.

To identify factors to improve the outcomes of related and unrelated allogeneic stem cell transplantations (allo-SCT) for Philadelphia chromosome–negative acute lymphocytic leukemia (Ph− ALL) in the first complete remission (CR1), we retrospectively analyzed 1139 Ph− ALL patients using the registry data, particularly the details of 641 patients transplanted in CR1. Overall survival was significantly superior among patients transplanted in CR1, but no significant difference was observed between related and unrelated allo-SCTs (related vs unrelated: 65% vs 62% at 4 years, respectively; P = .19). Among patients transplanted in CR1, relapse rates were significantly higher in related allo-SCT compared with unrelated allo-SCT, and multivariate analysis demonstrated that less than 6 months from diagnosis to allo-SCT alone was associated with relapse. On the other hand, nonrelapse mortality (NRM) was significantly higher in unrelated allo-SCT compared with related allo-SCT, and multivariate analysis demonstrated that 10 months or longer from diagnosis to allo-SCT, human leukocyte antigen mismatch, and abnormal karyotype were associated with NRM. In conclusion, our study showed comparable survival rates but different relapse rates, NRM rates, and risk factors between related and unrelated allo-SCTs. After a close consideration of these factors, the outcome of allo-SCT for adult Ph− ALL in CR1 could be improved.

Bendamustine is a cytotoxic agent with a novel mechanism of action. This phase I, dose-escalation study evaluated the safety, tolerability, efficacy, and pharmacokinetics of bendamustine in Japanese patients with relapsed/refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) or mantle cell lymphoma (MCL) without major organ dysfunction. Bendamustine 90 or 120 mg/m(2) (dose escalation) was administered intravenously over 60 min on days 1 and 2 every 3 weeks for up to three cycles. Nine patients (eight indolent B-NHL and one MCL) received per-protocol treatment, three at 90 mg/m(2) and six at 120 mg/m(2) . No dose-limiting toxicities were observed; thus, the maximum-tolerated dose was not reached. Grade 3/4 hematologic toxicities were neutropenia (33%) and leukopenia (33%). Non-hematologic toxicities were grade 1/2 and included gastrointestinal events and fatigue. Peak plasma concentrations of bendamustine occurred near the end of infusion in both dose groups and were equivalent to therapeutic concentrations observed in vitro. Bendamustine was rapidly eliminated, with a mean elimination half-life (t(1/2) ) of 29 min. Plasma concentrations of active metabolites M3 and M4 were approximately 4 and

We have analysed the expression of HLA-G in 40 leukaemia samples of various subtypes [seven cases of acute lymphoblastic leukaemia (ALL), 28 cases of acute myelogenous leukaemia (AML), three cases of chronic myelogenous leukaemia (CML) and two cases of chronic lymphocytic leukaemia (CLL)] by flow cytometry using HLA-G-specific monoclonal antibody. No leukaemia samples expressed HLA-G without incubation with interferon (IFN)-gamma. However, six out of 28 (21%) AML samples expressed HLA-G upon incubation with IFN-gamma. These six samples derived from one out of seven M2, two out of eight M4 and three out of five M5. The results indicated that AML cells, especially myelomonocytic leukaemia samples, are capable of expressing the HLA-G molecule.

To clarify the clinical and hematologic features of a rare numerical chromosome abnormality, we searched for trisomy 10 in acute myelogenous leukemias (AMLs) using the database of the Japan Adult Leukemia Study Group (JALSG) AML 92 and 95. Among the sequentially registered patients of JALSG-AML 92 (655 patients) and JALSG-AML 95 (531 patients), chromosome results were obtained in 1,074 patients (90.6%), and we found 3 patients with trisomy 10 as a sole abnormality. The first patient had an AML-M1 morphology with CD7 antigen; the patient obtained complete remission (CR) with the first course of chemotherapy. The second patient had an AML-M1 morphology without expressing CD7 antigen; this patient obtained CR, but relapsed 3 months later, and underwent allogeneic bone marrow transplantation. He suffered from chronic graft-versus-host disease and expired 38 months after the AML diagnosis. The third patient had AML-M0 with CD7 positivity. He obtained CR; however, brain abscess and cerebral hemorrhage occurred. In the literature, the mean age of patients with trisomy 10 AML is 57.8 years, the gender ratio is M/F = 1.5, and the frequency of M0/M1/M2 is 85.7%. A high incidence (81.8%) of CD7 expression of leukemia cells is notable. About 73% of patients survived for greater than 12 months.

We retrospectively analyzed the results of 707 adult patients who underwent myeloablative peripheral blood stem cell transplantation (PBSCT) (n = 365) and myeloablative bone marrow transplantation (BMT) (n = 342) for leukemia from HLA-identical sibling donors between 2000 and 2005 using the propensity score method. The results were obtained from the Japan Society for Hematopoietic Cell Transplantation registry. Multivariate Cox analysis showed that PBSCT was associated with lower overall survival (OS) in standard-risk patients [adjusted hazard ratio (aHR) = 1.83; 95% confidence interval (CI) 1.04–3.23; P = 0.036], but not in high-risk patients (aHR = 1.11; 95% CI 0.76–1.61; P = 0.599). Hematopoietic recovery was significantly faster after PBSCT. The risk of acquiring grade III–IV acute graft-versus-host disease (GVHD) (aHR = 2.23; P = 0.040) and extensive chronic GVHD (aHR = 1.93; P = 0.001) were significantly higher after PBSCT. PBSCT was associated with higher non-relapse mortality in standard-risk patients (aHR = 2.30; 95% CI 1.08–4.88; P = 0.030), but not in high-risk patients (aHR = 1.29; 95% CI 0.65–2.54; P = 0.468). Relapse after transplantation did not differ between PBSCT and BMT either in standard-risk group or in high-risk group (aHR = 1.17; 95% CI 0.55–2.52; P = 0.684 and aHR = 0.81; 95% CI 0.52–1.28; P = 0.370, respectively). In this retrospective analysis, OS was significantly lower after PBSCT in standard-risk patients, but not in high-risk patients. PBSCT was associated with significant risks of grade III–IV acute GVHD and extensive chronic GVHD.

We retrospectively surveyed the data of 233 patients who underwent myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) for non-Hodgkin lymphoma (NHL). Donors were HLA-matched relatives in 154 patients (66%) or unrelated volunteers in 60 (26%). Ninety patients (39%) were in complete remission. One hundred ninety-three (83%) received a total body irradiation (TBI)-based regimen, and 40 (17%) received a non-TBI-based regimen. Acute graft-versus-host disease (GVHD) occurred in 155 (67%) of the 233 evaluable patients; grade II to IV in 90 (39%), and grade III to IV in 37 (16%). Treatment-related mortality (TRM) was observed in 98 patients (42%), and 68% of them were related to GVHD. In a multivariate analysis, chemoresistance, prior autograft, and chronic GVHD were identified as adverse prognostic factors for TRM. Relapse or progression of lymphoma was observed in 21%. The 2-year overall survival rates of the patients with indolent (n = 38), aggressive (n = 111), and lymphoblastic lymphoma (n = 84) were 57%, 42%, and 41%, respectively. In a multivariate analysis, chemoresistance, prior autograft, and prior radiotherapy were identified as adverse prognostic factors for overall survival. Although myeloablative allo-HSCT represents an effective therapeutic option for patients with NHL, more work is still needed to decrease TRM and relapse. (Blood. 2006;108:382-389)

Noninfectious pulmonary dysfunction (NIPD) is a common and often fatal complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). An insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene has been extensively studied in relation to cardiovascular and renal disease, and lung fibrosis. In pulmonary fibrosis, D-allele frequency is significantly higher than in the control population. We hypothesized that a similar mechanism exists between post-HSCT NIPD and pulmonary fibrosis in the absence of HSCT. We retrospectively analyzed the incidence of NIPD and the ACE genotype polymorphism in 118 Japanese patients who underwent HSCT from HLA-identical sibling donors. NIPD occurred in 17 cases. Deletion/deletion genotype carriers were more common in the NIPD group than in the other 101 patients (41.2 vs 11.9%; hazard ratio, 5.19; 95% confidence interval, 1.67-16.21). There were no significant relationships between the clinical characteristics of patients and the development of NIPD. These findings suggest that the ACE genotype is associated with the development of NIPD following HSCT. This study is the first to report the relationship between genetic background and NIPD.

We report a patient who developed chronic renal failure 11 months after an allogeneic hematopoietic stem-cell transplantation (HSCT) for Ph1(+) acute lymphocytic leukemia. Renal biopsy showed typical pathological findings compatible with a bone marrow transplant nephropathy (BMT nephropathy). The general course of BMT nephropathy is slowly progressive, eventually reaching endstage renal failure. Intervention therapy with an angiotensin-converting enzyme inhibitor (ACE-I), temocapril, was started for this patient, based on several experimental reports showing the protective effects of ACE-Is on BMT nephropathy. After the induction of ACE-I in this patient, the rate of regression of renal function was significantly reduced and his serum creatinine was maintained at almost the same level for 18 months. Although the course of observation in this patient was short, we clearly showed the effects of an ACE-I on preventing BMT nephropathy from progressing to endstage renal failure in a human rather than in an experimental model.

A reduced incidence of graft versus host disease (GvHD) has been documented among Japanese allogeneic bone marrow transplantation (BMT) patients, as the Japanese are genetically more homogeneous than western populations. To clarify whether this ethnic difference affects the results of allogeneic peripheral blood stem cell transplantation (PBSCT), we conducted a nationwide survey to compare clinical outcomes of allogeneic PBSCT (n = 214) and BMT (n = 295) from a human leucocyte antigen-identical-related donor in Japanese patients. The cumulative incidence of grades II-IV acute GvHD was 37.4% for PBSCT and 32.0% for BMT. The cumulative incidence of extensive chronic GvHD at 1 year was significantly higher after PBSCT than BMT (42% vs. 27%; P0.01). The organ involvement patterns of GvHD were different between the two groups. By multivariate analyses, the incidence of chronic GvHD was significantly increased in PBSCT, whereas the stem cell source did not affect the incidence of acute GvHD, transplant-related mortality, relapse or survival. We concluded that Japanese PBSCT patients have an increased risk of chronic GvHD compared with BMT patients, but the incidence of acute GvHD was still lower than in western populations. Thus, the choice of haematopoietic stem cell source should be considered based on data for individual ethnic populations.

The effect of graft-versus-host disease (GVHD) on relapse incidence and survival has been analyzed in several studies, but previous studies included heterogeneous patients. Therefore, we analyzed the data of 2114 patients who received unmanipulated bone marrow graft from an HLA-identical sibling donor with a GVHD prophylaxis using cyclosporin A and methotrexate. Among the 1843 patients who survived without relapse at 60 days after transplantation, 435 (24%) developed grade II-IV acute GVHD. Among the 1566 patients who survived without relapse at 150 days after transplantation, 705 (47%) developed chronic GVHD. The incidence of relapse was significantly lower in patients who developed acute or chronic GVHD, but disease-free survival (DFS) was significantly inferior in patients who developed acute GVHD. A benefit of 'mild' GVHD was only seen in high-risk patients who developed grade I acute GVHD. The strongest association between GVHD and a decreased incidence of relapse was observed in patients with standard-risk acute myelogenous leukemia/myelodysplastic syndrome. In conclusion, the therapeutic window between decreased relapse and increased transplant-related mortality due to the development of GVHD appeared to be very narrow.

Acute promyelocytic leukemia (APL) is specifically associated with a reciprocal translocation, t(15; 17)(q22; q21), leading to the formation of a fusion of the retinoic acid receptor-alpha (RARA) gene and the promyelocytic leukemia (PML) gene. However, there are several reports describing APL cases lacking the t(15; 17). Many such cases are those bearing variant translocations involving chromosomes 15 or 17, and those with no chromosomal aberrations have rarely been reported. We have studied a patient with APL showing an apparently normal karyotype which was confirmed by spectral karyotyping (SKY). A submicroscopic PML-RARA fusion was identified by reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescent in situ hybridization (FISH). All-trans retinoic acid (ATRA) was effective as the initial therapy for remission induction and as the reinduction therapy after a relapse. The present study shows the key role of the fusion of PML-RARA in the responsiveness to ATRA as well as in the leukemogenesis of APL.

Background: Contradictory results have been reported in terms of detecting bcr/abl transcripts in patients with essential thrombocythemia. The aim of this study was to investigate whether the bcr/abl transcript could be found in patients with essential thrombocythemia (ET). Methods: The bcr/abl transcript was amplified by the RT-nested PCR method using RNA extract from leukocytes taken from 14 essential thrombocythemia patients. The amplified DNAs were electrophoresed in 1% agarose and visualized with ethidium bromide. The DNA bands associated with the bcr/abl transcript were then extracted and followed by DNA sequence analysis. Results: Major bcr/abl transcripts of the b3a2 type and minor ones of the e1a2 type were found in one and two ET patients, respectively. The incidence of bcr/abl transcripts was 21.4% (three of 14 patients). Conclusion: Our experiments confirmed that bcr/abl transcripts are present in some patients with essential thrombocythemia.

We have constructed a novel DNA expression vector based on Semliki Forest virus (SFV). SFV produces non-structural proteins (nsPs) which replicate genomic RNA and amplify the mRNA encoding the structural proteins of SFV. A recombinant cDNA genome of SFV, in which the SFV structural genes were replaced by a polylinker cassette to allow for insertion of heterologous DNA, was placed under the control of a cytomegalovirus immediate-early enhancer/promoter with a polyadenylation signal. Transfection of mammalian cells with this SFV-based plasmid vector, pSFV3-CMV-lacZ-pA, resulted in transient high-level expression of a beta-galactosidase reporter gene. The expression level of beta-galactosidase from pSFV3-CMVlacZ-pA was more than 20-fold higher than that obtained from the plasmid with deleted nsPs genes, pSFV3A5976-lacZ, demonstrating that the nsPs genes were essential for the high level of expression. Substantial beta-galactosidase activity was detected in the medium of pSFV3-CMV-lacZ-pA-transfected cells, suggesting that the overproduction of beta-galactosidase caused cell death and release of the protein into the medium. We have demonstrated a high-level expression of the exogenous beta-galactosidase gene from pSFV3-CMV-lacZ-pA constructed using an SFV replication system.

Introduction Since prognosis of patients with relapsed or refractory NHL is very poor, an effective salvage regimen is required to be investigated. We retrospectively evaluated the efficacy and safety of dose-adjusted EPOCH (DA-EPOCH) reported by Wilson et al. for relapsed or refractory NHL in our institute. Patients and methods Patients with relapsed or refractory NHL selected based on practical clinical situation were treated with DA-EPOCH. The starting dose was as follows: doxorubicin 10 mg/m2, etoposide 50 mg/m2 and vincristine 0.4 mg/m2 as a continuous infusion on days 1–4, cyclophosphamide 750 mg/m2 intravenously on day 5 and oral prednisone 60 mg/m2 twice a day on days 1–5. G-CSF was started on day 6 until neutrophil recovered to more than 5000/ml. The dose was adjusted according to hematologic toxic effects. Patients with CD20-positive B-cell NHL (B-NHL) received DA-EPOCH with rituximab (DA-EPOCH-R). Response was evaluated in patients who received three cycles or more, and toxicity was evaluated in all patients. Results A total of 22 patients (male/female = 13/9) were treated with DA-EPOCH (11 patients with T-cell NHL) or DA-EPOCH-R (11 patients with B-NHL). Median age was 61 years (range 44–81), and median number of prior therapy was 2 (range 1–4). The median dose level of DA-EPOCH was 100% (range 80–100%). The treatment was discontinued in nine patients, due to disease progression in four patients and prolonged toxic effects in five patients. Seven patients achieved CR and two patients achieved PR (40.9% of ORR). The most frequent toxicity was transient grade 4 neutropenia observed in 20 patients (91.0%). Grade 3 febrile neutropenia was observed in seven patients (31.8%). Dose reduction was required in 6 of 13 patients who received at least three cycles. No treatment-related death was observed. Conclusion DA-EPOCH(-R) regimen is effective and well tolerated, even in heavily pretreated patients with relapsed or refractory NHL. Further prospective large scaled study is warranted in Japan.

Abstract 3942 Background: Pts with FL in whom position 158 on the FcγRIIIa (CD16) gene is heterozygous for valine/phenylalanine (V/F) or homozygous for phenylalanine (F/F) (F-carriers) have natural killer cells with lower binding affinity to IgG than valine homozygote (V/V) pts. These pts showed a lower response rate and shorter time to progression compared with V/V genotype pts after initial rituximab treatment. A humanized IgG1 anti-CD20 monoclonal antibody, LY2469298, was optimized through protein engineering in the Fc region to increase affinity with FcγIIIa and is expected to increase effector function in F-carriers. This phase I study was conducted to evaluate the safety, clinical activity, and pharmacokinetics (PK) of LY2469298 in Japanese pts with relapsed or refractory FL. Methods: Japanese pts with FL who relapsed or progressed after prior treatment, but not within 120 days of prior rituximab, received four infusions of LY2469298 at weekly intervals. The dose was assessed for safety, tolerability, and immunogenicity (HAHA) in 2 cohorts of 100 and 375 mg/m2. Dose-limiting toxicity (DLT) was evaluated from the day of the first infusion until two weeks after the last infusion. Response was evaluated according to the International Workshop Response Criteria (IWRC) at 9 and 21 weeks after the last dose. The PK of LY2469298 were assessed after the first and fourth dose by means of a non-compartmental analysis. Results: Ten pts (male/female: 5/5), median age 60.4 yrs (range: 39–75), were enrolled and treated in 2 cohorts: 3 pts at 100 mg/m2 and 7 pts at 375 mg/m2. The number of pts with stage I/II/III/IV at enrollment was 1/4/1/4, respectively. All pts received 1 or more treatment of prior rituximab alone or rituximab-containing regimen; 3/10 pts were refractory to the regimen. The median number of prior regimens was 2 (range: 1–9). Follicular Lymphoma International Prognostic Index (FLIPI) identified 4 pts at low risk, 2 at intermediate risk, and 4 at high risk. There was one V/V patient in the 375 mg/m2 cohort; all other pts were F-carriers. No DLT was observed in either cohort; therefore, the recommended phase II dose was determined to be 375 mg/m2. The most common adverse events (≥40% of pts) included hematological toxicities and infusion-related reactions: lymphopenia (n=10), pyrexia (8), leukopenia (7), chills (7), and neutropenia (5). Grade 3 or 4 hematological toxicities were lymphopenia (n=7) and neutropenia (2; no G-CSF required). There were no grade 3 or 4 infusion-related reactions; most reactions were limited to the first infusion. B-cell (CD19+) depletion in peripheral blood was rapid and sustained in all pts. B-cell recovery began in the 21-week observation period. LY2469298 was eliminated in a biphasic manner from pts' blood with a elimination half-life of 10 to 14 days. Clearance, elimination half-life, and volume of distribution were similar between the 2 doses. AUC and Cmax increased with dose. Of 10 evaluable pts, responses were observed in 5 pts (3 CR, 1 CRu, and 1 PR). Conclusions: Weekly doses of LY2469298 at 100 and 375 mg/m2 were well tolerated and resulted in evidence of clinical activity in pts with relapsed or refractory FL after prior rituximab alone or rituximab-containing regimens, although 9 of 10 pts were F-carriers. The PK characteristics of clearance, elimination half-life, and volume of distribution of the 2 LY2469298 doses were similar, both of which were eliminated in a biphasic manner. The promising results of this phase I study warrant further investigation of LY2469298 in pts with FL. Disclosures: Off Label Use: LY2469298 is an investigational agent. Matsue:Eli Lilly Japan KK: Employment. Cronier:Lilly UK: Employment. Wooldridge:Eli Lilly & Company: Employment. Koshiji:Eli Lilly Japan KK: Employment.

Abstract 4484 Background: Dasatinib is a highly potent BCR-ABL kinase inhibitor. The previous report from the global DASISION trial showed dasatinib 100 mg once daily resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib; both treatment arms were well-tolerated (N Engl J Med. 2010;362:2260-70). The objective of this subset analysis was to assess the efficacy and safety of dasatinib compared with imatinib in the Japanese population. Methods: Forty-nine Japanese patients (total 519 pts) with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg QD or imatinib 400 mg QD. Confirmed CCyR (cCCyR; CCyR on 2 consecutive assessments at least 28 days apart) was the primary efficacy endpoint with MMR as an important secondary endpoint. The safety profiles were also evaluated. Results: Minimum follow-up time and median treatment duration were 12 months and 15 months, respectively. Twenty-six patients with median age 56 (range, 21–70) years were treated with dasatinib and 23 patients with median age 52 (range, 22–77) years were treated with imatinib. Overall 89% of patients receiving dasatinib and 83% of patients receiving imatinib continue to receive treatment. The cCCyR rate by 12 months (primary endpoint), CCyR rate by 12 months and MMR rate at any time in dasatinib arm were higher than those in imatinib for Japanese patients (96% vs 70%, 96% vs 78%, and 73% vs 48%, respectively). Grade 3/4 cytopenias in dasatinib arm and imatinib arm were as follows: anemia (8% vs 4%), neutropenia (27% vs 39%), and thrombocytopenia (8% vs 9%). Non-hematologic and drug-related adverse events occurring in ≥10% of patients are shown as Table. No deaths were reported in either group. Drug-related serious adverse events were rarely reported and all events were not severe (Grade 1–2, including vomiting, hypoxia and cardiomyopathy in dasatinib arm). Conclusion: Dasatinib showed higher rates of cCCyR and MMR compared with imatinib. Both treatments were well tolerated. Given the predictive value of 12 months cCCyR, dasatinib may improve long-term outcomes in Japanese patients with newly diagnosed CML-CP. Disclosures: Ueda: Bristol-Myers K.K.: Employment. Seriu:Bristol-Myers K.K.: Employment. Bradley-Garelik:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment.

Introduction: Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapeutic agent composed of a monoclonal antibody which targets the CD22 antigen, conjugated to calicheamicin, a potent cytotoxic antitumor antibiotic. Since CD22 is expressed on more than 90% of B-lymphoid malignancies, CMC-544 may be useful for treating patients (pts) with B-cell non-Hodgkin lymphoma (B-NHL). In a phase I study in the US and EU, CMC-544 showed definite clinical activity in pts with relapsed/refractory B-NHL (both follicular and diffuse large) with clinically manageable thrombocytopenia as the main toxicity. In this phase 1 study, the safety, tolerability, efficacy and pharmacokinetics (PK) of CMC-544 was evaluated in Japanese pts with relapsed or refractory B-cell NHL. Methods: CMC-544 was administered IV once every 28 days ± 2 days (1 cycle). A dose escalation was planned using 1.3 mg/m2 and 1.8 mg/m2, the maximum tolerated dose (MTD) which was previously determined in non-Japanese pts. Pts were allowed to enroll in the study if they had relapsed or refractory CD22+ B-NHL. Tumor responses were evaluated by investigator’s assessment according to the International Workshop Criteria for NHL. Results: Enrollment for this study is complete and included 13 pts (6 women, 7 men, median age [range] of 49 yrs [43–72]). All of the 13 pts who were enrolled had follicular lymphoma and had received at least one regimen of rituximab alone or rituximab-containing chemotherapy in their prior treatments. The median number of prior treatment regimens was 1 (range: 1–13). In dose escalation, no pts had dose limiting toxicities and the tolerability in the MTD previously determined in non-Japanese pts (1.8mg/m2) was confirmed for Japanese pts. 3 pts and 10 pts were treated with 1.3 mg/m2 and 1.8 mg/m2 of CMC-544, respectively. The median number of CMC-544 treatment cycles was 3 (range: 2–8). The most common drug-related adverse events (AEs, all grades ≥ 35% pts) included thrombocytopenia (100%), leukopenia (92%), neutropenia (85%), elevated AST (85%), anorexia (85%), lymphopenia (85%), nausea (77%), elevated ALT (54%), malaise (46%), and headache (46%). Grade 3/4 AEs ≥ 15% pts were: thrombocytopenia (54%), lymphopenia (31%), neutropenia (31%), and leukopenia (15%). 7 pts discontinued treatment due to AEs; 1 pt because of grade 2 rash, 1 pt because of grade 2 urticaria and 5 pts because of AEs which required treatment delays of >3 wks (2 pts with prolonged thrombocytopenia, 1 pt with prolonged thrombocytopenia and neutropenia, 1 pt with neutropenia and elevated alkaline phosphatase, and 1 pt with prolonged neutropenia and elevated total bilirubin). PK analyses demonstrated that maximum serum concentration (Cmax) and area under the curve (AUC) of CMC-544 increased in a dose dependent manner. Both parameters increased with the second dose in the second cycle. At all dose levels, terminal half-life (t1/2) was prolonged, and total clearance (CL) was decreased in the second cycle. Overall, the PK profile was similar to that of the previous study with non-Japanese pts. 7 pts had CRs (CR + CRu), 4 pts had PRs, and 2 pts had stable disease. The objective response rate (ORR) was 85% (11/13). Conclusions: The tolerability of CMC-544 for Japanese pts with relapsed or refractory follicular B-NHL who had been pretreated with rituximab was confirmed at 1.8 mg/m2 administered once every 28 days. This is the same dose level as the MTD for non-Japanese pts. The PK profile of CMC-544 in Japanese pts was similar to that in non-Japanese pts. Based on the acceptable safety profiles and a high preliminary ORR, CMC-544 should be considered for further investigations in Japanese pts with relapsed or refractory B-NHL who have been pretreated with rituximab.

Background: Since the incidence of HL in Japan is approximately one-third of that in western countries, there are few studies on validation of international prognostic score (IPS) in Japanese patients (pts) with HL. Patients and Methods: JCOG-LSG conducted 2 multicenter phase II trials for advanced HL, including ABVd (JCOG9305) and ABV followed by involved-field radiotherapy (JCOG9705). Because dacarbazine was highly emetic, and not approved for HL in Japan in those days, the dose of dacarbazine was reduced to a two-thirds (250 mg/m2) of that in original ABVD regimen in ABVd, and in ABV with increased dose of doxorubicin, dacarbazine was not utilized. Among the whole 200 enrolled pts, histopathological specimens from 181 pts were reviewed by 6 hematopathologists and consensus diagnosis of HL was made in 167 (92.3%), according to the WHO classification. Major eligibility criteria of the trials were age between 15 and 69, ECOG performance status of 0 to 3, and clinical stage of II, III or IV in JCOG9305, and IB, IIB, III or IV in JCOG 9705. Results: 5-year survival of the 167 patients was 88.3%. Histopathological distributions of 167 pts with HL were similar with those in western countries; 2 nodular lymphocytic predominance (1.2%), 115 nodular sclerosis (68.9%), 3 lymphocyte-rich (1.8%), 34 mixed cellularity (20.1%), 7 lymphocyte depletion (4.2%), and 6 unclassified (3.6%). IPS was poorly fitted for the overall survival (OS), mainly because of too good prognosis of patients with IPS-grade 6. Seven unfavorable prognostic factors for OS identified by the univariate analysis were male sex, high β2 microglobulin, B symptoms, high LDH, high alkaline-phosphatase, clinical stage of III or IV, and histopathological subtype (mixed cellularity or lymphocyte depletion). Excluding β2 microglobulin from analysis because of only 105 available data, male sex [HR 3.30 (95%CI: 1.15–9.52, p=0.027) ] and high LDH [HR 2.41 (95%CI: 1.07–5.43, p=0.034)] were significant independent risk factors in a multivariate analysis. Conclusions: Our study suggests that male sex and high LDH might be important prognostic factors in OS of pts with HL. Simple prognostic model for HL, including sex and LDH, was suggested.

Cord blood transplantation (CBT) represents an attractive alternative for patients with advanced hematological malignancy who lack matched related or unrelated donors. Adult patients receiving myeloablative or reduced-intensity CBT display a 90% chance of engraftment, but also experience a 50% rate of transplant-related mortality. Post-transplant immune disorders including early immune reactions and acute GVHD are problematic in CBT for adult patients. These reactions and/or additional immunosuppressive therapy might increase the risk of infection and organ dysfunction, leading to high rates of transplantation-related mortality. However, optimal prophylaxis and management for immune reactions have not been established in CBT. We investigated retrospectively whether intensive graft-versus-host disease (GVHD) prophylaxis has a prognostic impact on CBT. Post-CBT immune reactions were classified according to time course as pre-engraftment immune reaction (PIR), engraftment syndrome (ES) or acute GVHD. Between March 2001 and September 2003, a total of 77 patients underwent CBT at 8 centers of the Nagoya Blood and Marrow Transplantation Group (NBMTG). Median age of patients was 48 years (range, 18–69 years). Preparative regimens were myeloablative (n=31) or reduced-intensity (n=46). Acute GVHD prophylaxis included cyclosporine alone (n=23), tacrolimus alone (n=12), cyclosporine plus short-term methotrexate (n=17), tacrolimus plus short-term MTX (n=23) or cyclosporine plus methylprednisolone (n=2). Cumulative incidences of PIR, ES and grade I-IV GVHD were 38%, 12% and 29%, respectively. Short-term MTX exerted significant favorable effects on PIR in univariate analysis (hazard ratio, 0.41; 95% confidence interval, 0.19–0.89) and on non-relapse mortality (NRM) in multivariate analysis (hazard ratio, 0.36; 95% confidence interval, 0.16–0.81). On the other hand, PIR occurred in 35% of patients with cyclosporine and 37% with tacrolimus. Short-term MTX appears to offer optimal GVHD prophylaxis to reduce PIR and improve NRM. Figure Figure

HLA incompatibility between the donor and recipient is the most critical factor governing the incidence of rejection and GVHD after conventional allogeneic stem cell transplantation. But the impact of HLA disparity on GVHD and graft rejection after RICT remains to be elucidated. We retrospectively analyzed the outcomes of 437 patients who underwent bone marrow (n=95) or peripheral blood stem cell RICT (n=342). The numbers of patients who received a graft from a HLA-matched (275 from siblings, 11 from family members, and 54 from unrelated donors), one-locus-mismatched, 2- or 3-loci-mismatched donor were 340, 65, and 32, respectively. The HLA-matched group included significantly higher population of patients who received cyclosporine alone for GVHD prophylaxis. The overall cumulative incidence of grade II-IV acute GVHD was 40% for all subjects. It was 38% (95% CI; 33%–43%) in recipients of HLA-matched donors, 43% (95% CI; 31%–54%) in those of one-locus-mismatched donors, and 54% (95% CI; 37%–68%) in those of 2–3-loci-mismatched donors. A Cox regression model adjusted for potential confounders including GVHD prophylaxis demonstrated that 2-3 loci-mismatch was identified as an independent risk factor of grade II-IV acute GVHD (Table). Use of antithymocyte globulin was identified as an independent better protective factor for GVHD (HR;0.66, p=.003). Cumulative incidence of rejection was significantly higher after one-locus mismatch RICT (Table) and the risk tended to increase in relation to an increase of HLA disparity. Malignant disease was identified as an independent prognostic factor for rejection. In patients with hematologic malignancies, overall survival (OS) of recipients of 2–3-loci-mismatched RICT at 1 year (38%, 95%CI; 21%–54%) was significantly worse than that after HLA-matched RICT (65%, 95%CI; 59%–70%). By contrast, there was no statistical difference in the incidence of grade II-IV acute GVHD and OS between HLA-matched RICT and one-locus-mismatched RICT. Multivariate analysis demonstrated 2–3-loci-mismatch (Table) and high-risk disease (HR; 2.3, p=.001) as independent risk factors for OS. Thus, HLA incompatibility between the donor and recipient is an important risk factor for rejection, acute GVHD and overall survival after RICT. Therefore RICT from a one-locus-mismatched donor may represent an effective alternative approach in patients lacking HLA-matched sibling donors. multivariate analysis n acute GVHD Rejection OS HR (95%CI) p HR (95%CI) p HR (95%CI) p match 340 1.0 1.0 1.0 1-mismatch 65 1.4 (0.9–2.2) 0.20 4.5 (1.1–17.9) 0.03 1.0 (0.6–1.6) 0.88 2–3-mismatch 32 2.2 (1.2–4.1) 0.02 7.0 (0.8–64.8) 0.08 3.3 (1.8–6.2)

A simulation of pulsed photoacoustic signals using the finite elements method is demonstrated, using a hypothetical cylindrical brass sample surrounded by air, and a weak energy density laser source to prevent the sample from being destroyed. Both the distribution of temperature and also the distribution of thermal deformation and thermal stress in the sample are discussed.

The effect on PA image of the method of coupling the sample and detector was investigated experimentally. Three coupling methods, i. e. rigid coupling, coupling using liquids, and coupling using sheet materials, were tested in terms of signal intensity and image distortion. Highly viscous liquid proved to be nearly as good as the rigid combination in terms of signal intensity and distortion over the frequency range 200 Hz to 200 kHz. Taking separability into consideration, the use of viscous liquid under pressure is the most practical coupling method.

The inspections of stacking faults of Si-wafer were carried out by means of a home-made photoacoustic microscopy (PAM). The stacking faults, which are not observed by an optical microscope, could be measured non-destructively and the depth of stacking faults beneath the surface could also be estimated by PAM.