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To investigate the use of high-dose therapy and autologous stem cell transplantation (ASCT) for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL) between 1990 and 2007, we conducted a nationwide survey using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Of the 1222 patients in the database, 576 (47%) received ASCT in first complete remission (CR1), 140 (12%) in first partial remission, 281 (23%) in sensitive relapse, 150 (12%) in resistant or sensitivity-unknown relapse, and 75 (6%) in primary refractory status. With a median follow-up of 22 months, the 2-year overall survival (OS) and progression-free survival rates were 71% and 68%, respectively. The cumulative incidences of 2-year non-relapse mortality and relapse/progression were 6% and 26%, respectively. Relapse/progression after ASCT in the rituximab era (2002-2007) was significantly lower than that in the pre-rituximab era (1990-2001; P < 0.001). Older age, male gender, poor performance status at ASCT, non-CR1 at ASCT, ASCT performed in 1990-2001, and LEED or MCEC regimen were adverse predictors of OS. Because ASCT for newly diagnosed high-risk DLBCL has not been performed recently, a registry database study to assess the impact of ASCT for relapsed or refractory DLBCL in the rituximab era is warranted.

To investigate the use of high-dose therapy and autologous stem cell transplantation (ASCT) for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL) between 1990 and 2007, we conducted a nationwide survey using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Of the 1222 patients in the database, 576 (47%) received ASCT in first complete remission (CR1), 140 (12%) in first partial remission, 281 (23%) in sensitive relapse, 150 (12%) in resistant or sensitivity-unknown relapse, and 75 (6%) in primary refractory status. With a median follow-up of 22 months, the 2-year overall survival (OS) and progression-free survival rates were 71% and 68%, respectively. The cumulative incidences of 2-year non-relapse mortality and relapse/progression were 6% and 26%, respectively. Relapse/progression after ASCT in the rituximab era (2002-2007) was significantly lower than that in the pre-rituximab era (1990-2001; P 0.001). Older age, male gender, poor performance status at ASCT, non-CR1 at ASCT, ASCT performed in 1990-2001, and LEED or MCEC regimen were adverse predictors of OS. Because ASCT for newly diagnosed high-risk DLBCL has not been performed recently, a registry database study to assess the impact of ASCT for relapsed or refractory DLBCL in the rituximab era is warranted.

To investigate the use of high-dose therapy and autologous stem cell transplantation (ASCT) for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL) between 1990 and 2007, we conducted a nationwide survey using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Of the 1222 patients in the database, 576 (47%) received ASCT in first complete remission (CR1), 140 (12%) in first partial remission, 281 (23%) in sensitive relapse, 150 (12%) in resistant or sensitivity-unknown relapse, and 75 (6%) in primary refractory status. With a median follow-up of 22 months, the 2-year overall survival (OS) and progression-free survival rates were 71% and 68%, respectively. The cumulative incidences of 2-year non-relapse mortality and relapse/progression were 6% and 26%, respectively. Relapse/progression after ASCT in the rituximab era (2002–2007) was significantly lower than that in the pre-rituximab era (1990–2001; P

Thrombomodulin, encoded by the THBD gene, is a critical regulator of coagulation and innate immunity. Its gene variant (rs3176123, 2729A>C) in the 3′ untranslated region has been reported to be associated with vasculopathies. The present study analyzed the impact of THBD variation on transplant outcomes in a cohort of 317 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor A/C or C/C genotype vs. the donor A/A genotype resulted in a lower incidence of grades II–IV acute graft-versus-host disease [GVHD; hazard ratio (HR) 0.66; 95 % confidence interval (CI) 0.44–0.99; P = 0.05] according to a multivariate analysis. In patients with grades II–IV acute GVHD, the donor A/C or C/C genotype vs. the donor A/A genotype was associated with significantly better overall survival rates (HR 0.45; 95 % CI 0.21–0.99, P = 0.05), while this effect was absent in other patients. A functional analysis using lymphocytes obtained from healthy individuals revealed that the 2729C allele has a higher level of THBD mRNA than the 2729A allele. These findings suggest the functional relevance of the rs3176123 variation and indicate that higher thrombomodulin expression by individuals with the 2729C allele likely accounts for their decreased risk for acute GVHD development and subsequent mortality.

The prognosis for adult acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement (CNS+) who received allogeneic hematopoietic stem cell transplantation (allo-SCT) remains unclear. We retrospectively compared the outcomes of allo-SCT for patients with CNS involvement and for patients without CNS involvement (CNS−) using a database in Japan. The eligibility criteria for this study were as follows: diagnosis of ALL, aged more than 16 years, allo-SCT between 2005 and 2012, and first SCT. Data for 2582 patients including 136 CNS+ patients and 2446 CNS− patients were used for analyses. As compared with CNS− patients, CNS+ patients were younger, had worse disease status at SCT and had poorer performance status (PS) at SCT (P < 0.01). Incidence of relapse was higher in CNS+ patients (P = 0.02), and incidence of CNS relapse was also higher (P < 0.01). The probability of 3-year overall survival (OS) was better in CNS− patients (P < 0.01) by univariate analysis. However, in patients who received SCT in CR, there was no difference in the probability of OS between CNS+ and CNS− patients (P = 0.38) and CNS involvement did not have an unfavorable effect on OS by multivariate analysis. CNS+ patients who achieved CR showed OS comparable to that of CNS− patients.

The choice of conditioning regimen before allogeneic stem cell transplantation (SCT) in patients with acute lymphoblastic leukemia (ALL) is important. We retrospectively compared outcomes of medium-dose VP-16/cyclophosphamide/total body irradiation (VP/CY/TBI) regimen and CY/TBI. Five hundred and twenty-nine patients (VP/CY/TBI: n = 35, CY/TBI: n = 494) who met all of the following criteria were compared: first time for SCT, aged 15-59 years; first or second complete remission at SCT; bone marrow or peripheral blood as stem cell source; and HLA phenotypically matched donor. Median age of the patients was 34 years, and patients who received VP/CY/TBI were younger (28 years vs. 34 years, P = 0.02). Cumulative incidences of relapse and non-relapse mortality (NRM) were higher for patients who received CY/TBI (P = 0.01 for relapse, P < 0.01 for NRM). After a median follow-up period of 36.9 months, 5-year overall survival (OS) rates were 82.2% in the VP/CY/TBI group and 55.2% in the CY/TBI group. OS, and disease-free survival (DFS) in the VP/CY/TBI group were shown to be significantly better by multivariate analysis [hazard ratio: 0.21 (95% confidence interval: 0.06-0.49) for DFS, hazard ratio: 0.25 (95% confidence interval: 0.08-0.59) for OS]. VP/CY/TBI was associated with a lower relapse rate and no increase in NRM, resulting in better survival than that in CY/TBI for adult ALL patients.

Members of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family participate in the innate immune system, exerting widespread effects on cytokine secretion, autophagy, and apoptosis. Recent studies in Caucasians revealed the association between mutants of NOD2, a member of the NLR family, and severity of acute graft-versus-host disease (GVHD). NOD2 polymorphism screening has been recommended for donor selection and risk assessment at bone marrow transplantation. To investigate whether NOD2 plays a role in the pathogenesis of GVHD in a Japanese population, we examined DNA from 142 bone marrow transplant patient/donor pairs to detect genetic variation in the NOD2 gene. No genetic variants of NOD2 were associated with the severity of acute GVHD in our patients. However, a weak association between a single nucleotide polymorphism in the NOD2 gene (R471C) and acute myeloid leukemia in the bone marrow patients (p = 0.029, odds ratio 4.08, 95% CI 1.22-13.67) was detected. This polymorphism was not prevalent in 479 Crohn's disease (CD) patients in Japan. These results suggest that, in the Japanese population, unlike the Caucasian, NOD2 is not a major contributor to susceptibility to severe acute GVHD.

The Japan Clinical Oncology Group conducted two multicenter phase II trials in 200 patients with advanced Hodgkin lymphoma (HL) in the 1990s. Among 181 patients whose histopathological specimens were available and reviewed by 6 hematopathologists, 167 (92.3%) were diagnosed with HL. Five-year overall survival (OS) among these 167 patients was 88.3%, including 89.2% among nodular sclerosis and 82.2% among mixed cellularity cases. International prognostic score was not closely associated with OS. Seven unfavorable prognostic factors for OS on univariate analysis were male, B symptoms, clinical stage of III or IV, elevated serum LDH, elevated alkaline phosphatase, elevated beta2-microglobulin, and pathological subtype (mixed cellularity and lymphocyte depletion). On multivariate analysis, male [HR 3.30 (95% CI 1.15-9.52, p = 0.027)] and elevated serum LDH [HR 2.41 (95% CI 1.07-5.43, p = 0.034)] were independent factors for OS. Based on these prognostic factors, the 5-year OS was 95.7% in the low-risk group (no adverse factor), 87.9% in the intermediate-risk group (1 adverse factor) and 73.3% in the high-risk group (2 adverse factors). This simple prognostic model for HL warrants further validation studies.

A phase 1/2 study was conducted to assess the safety and efficacy of dasatinib in Japanese patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) resistant or intolerant to imatinib. In phase 1, 18 patients with chronic phase (CP) CML were treated with dasatinib 50, 70, or 90 mg twice daily to evaluate safety. Dasatinibor= 90 mg twice daily was well tolerated. In phase 2, dasatinib 70 mg was given twice daily to CP-CML patients for 24 weeks and to CML patients in accelerated phase (AP)/blast crisis (BC) or Ph(+) ALL for 12 weeks. In the CP-CML group (n = 30) complete hematologic response was 90% and major cytogenetic response (MCyR) 53%. In the AP/BC-CML group (n = 11) major hematologic response (MaHR) was 64% and MCyR 27%, whereas in the Ph(+) ALL group (n = 13) MaHR was 38% and MCyR 54%. Dasatinib was well tolerated and most of the nonhematologic toxicities were mild or moderate. Dasatinib therapy resulted in high rates of hematologic and cytogenetic response, suggesting that dasatinib is promising as a new treatment for Japanese CML and Ph(+) ALL patients resistant or intolerant to imatinib.

Bone marrow transplantation from unrelated donors (UR-BMT) has been considered to be effective for patients with hematological malignancies who have no suitable related donor. However, disparities of HLA between a recipient and a donor increase the risk of severe acute graft-versus-host disease (GVHD). We evaluated GVHD prophylaxis using tacrolimus and methotrexate for HLA-A, B, or DRB1 genotypically mismatched UR-BMT. Fifty-five patients were enrolled in this study. The incidence of grade III to IV acute GVHD was 23.6% for all patients. No significant difference in the incidence of grade III to IV acute GVHD was observed between HLA-A or B 1 locus mismatch transplantation (18.8%) and HLA-DRB1 1 locus mismatch transplantation (16.7%) (P = 0.96). The incidence of chronic GVHD was 71.7%. Disease-free survival at 5 years was 53.2% for patients with standard risk disease and 24.5% for patients with high-risk disease. Patients with chronic GVHD exhibited better disease-free survival than those without chronic GVHD (53.2 vs. 30.9%, P = 0.011). Twenty patients (36.4%) had a relapse of leukemia and 14 of them died of recurrent leukemia. This study indicates tacrolimus and methotrexate can lower the risk of severe acute GVHD after HLA-A, B, or DRB1 genotypically 1 locus mismatched UR-BMT.

We describe the clinical outcome of autologous bone marrow transplantation (ABMT) for patients with Philadelphia chromosome —positive acute lymphoblastic leukemia (Ph-ALL). Between 1985 and 2000, 14 patients in first complete remission underwent transplantation. In all cases, harvested marrow was purged with a cocktail of complement and monoclonal antibodies to common acute lymphoblastic leukemia antigen (CALLA). Eight patients died following BMT: 2 patients from interstitial pneumonia and 6 from disease recurrence. For the 6 surviving patients in continuous remission, the median follow-up period was 96 months. The probability of disease-free survival and the rate of relapse at 5 years were 41.7% and 51.4%, respectively. Minimal residual disease (MRD) was assayed quantitatively with patient-specific D-JH probes in 6 of 14 cases. A higher residual tumor burden at marrow harvest was associated with subsequent relapse. Efforts to reduce the MRD burden before harvesting stem cells should improve the clinical outcome of ABMT.

This nationwide, retrospective study compared the efficacy of cyclosporine and tacrolimus with methotrexate (CsA/MTX and TAC/MTX) for acute graft-versus-host disease (aGVHD) prevention and transplant-related outcomes. Data were obtained from the Transplant Registry Unified Management Program of the Japan Society for Hematopoietic Cell Transplantation for ≥ 16-year-old leukemia patients who received CsA/MTX or TAC/MTX after bone marrow transplantation and peripheral blood stem cell transplantation from serological HLA-matched related donors (MRD), HLA 8/8 allele-matched, or one allele-mismatched unrelated bone marrow (UBM), or 0-2 antigen-mismatched unrelated cord blood (UCB) transplantation between January 2005 and December 2009. Separate analyses were performed for each cohort. Adjusted multivariate analyses indicated that in the MRD (n = 1524) and the UBM (n = 1466) cohorts, TAC/MTX significantly reduced grade II-IV aGVHD risk (HR 0.58, P = 0.006 and HR 0.77, P = 0.015, respectively) without affecting the other transplant-related outcomes. In the UCB cohort (n = 925), TAC/MTX significantly reduced the risk of non-relapse mortality (HR 0.63, P = 0.027) and chronic GVHD (HR 0.60, P = 0.02) without significant effects on grade II-IV aGVHD (HR 0.83, P = 0.21). Our results may provide the most up-to-date data regarding GVHD prevention in Japan.

A nationwide survey of hematopoietic cell transplantation (HCT) was started in Japan in 1991, and the analyzed survey data have been presented as the annual report of the Japan Society for Hematopoietic Cell Transplantation. The 10-year overall survival (OS) rates after HCT for each disease are as follows: acute myelogenous leukemia, 44.2%; acute lymphocytic leukemia, 33.7%; adult T-cell leukemia, 24.6%; chronic myelogenous leukemia, 53.3%; myelodysplastic syndrome, 37.3%; non-Hodgkin's lymphoma, 41.5%; Hodgkin's lymphoma, 50.8%; aplastic anemia, 72.5%; breast cancer, 37.1%; germ cell tumor, 52.6%; and ovarian cancer, 44.2%. The 5-year OS rates for multiple myeloma and lung cancer were 40.6% and 23.6%, respectively. Except in cord blood transplantation, engraftment was accomplished in more than 90% of patients. The respective frequencies of acute graft-versus-host disease (GVHD) and chronic GVHD were 41.1% and 34.9% for related bone marrow transplantation (BMT), 66.8% and 34.5% for unrelated BMT, 52.9% and 36.0% for allogeneic peripheral blood stem cell transplantation, and 53.3% and 32.1% for allogeneic cord blood transplantation. OS for each disease was analyzed by patient age, stem cell source, donor type, disease status, and disease type. These data provide objective and valuable information for hematologists as well as for patients who need HCT.

This report concerns the clinicopathologic features of 4 patients with CD56/neural cell adhesion molecule (NCAM)-positive Langerhans cell sarcoma (LCS). Three of the patients were elderly, between 59 and 62 years of age at presentation, and the other was 35 years old. The presenting symptoms included fever, bone pain, and weakness. The patients shared some clinical findings, such as multiorgan involvement of lymph nodes, skin, lung, bone marrow, and spleen. LCS carries a poor prognosis, and 3 of the patients died of the disease within several years of presentation despite multiagent chemotherapy and radiotherapy. Of special interest is that all of the cases showed CD56 expression on the tumor cells in addition to expression of CD1a, S100beta, and langerin, the presence of which suggests derivation from Langerhans cells. For control, CD56 was also examined in 8 cases of Langerhans cell histiocytosis (LCH), a single-system unifocal or multifocal disease, and the results of staining of the tumor cells were negative. Our findings indicated that CD56 may be a clinically relevant biologic marker for predicting an intractable course of Langerhans cell neoplasms, although it is often difficult to draw a definite morphologically-based distinction between LCS and LCH.

We conducted a phase II study to evaluate the efficacy and safety of cladribine (2-chlorodeoxyadenosine [2-CdA]) for patients with refractory or relapsed indolent B-cell lymphoma or mycosis fungoides. Forty-five patients were enrolled, and 43 patients, including 34 with follicular lymphoma, were eligible. 2-CdA was given by continuous intravenous infusion at a dose of 0.09 mg/kg daily for 7 consecutive days, and this schedule was repeated every 4 weeks up to a maximum of 6 cycles. The overall and complete response rates were 58.1% (25/43; 90% confidence interval, 44.5%-70.9%) and 14.0% (6/43), respectively. The disease progression-free proportions of all 43 eligible and all 25 responding patients at 2 years were 30.3% and 48.1%, respectively. Neutropenia and thrombocytopenia of grade 3 or 4 were observed in 53.3% and 37.8% of patients, respectively, with prolonged cytopenia observed in patients with increased numbers of treatment cycles. Nonhematologic toxicities of grade 3 or greater included diarrhea, arrhythmia, malaise, and gastrointestinal bleeding in 1 patient each, an increase in glutamic-pyruvic transaminase level in 2 patients, and infection in 5 patients. Two treatment-related deaths were observed. Four patients developed myelodysplastic syndrome (MDS) at 13 months to 2 years after completion of the 2-CdA treatments. 2-CdA is an active agent with acceptable toxicity for refractory or relapsed indolent lymphoma; however, prolonged myelosuppression and the potential development of MDS should be carefully monitored.

Imatinib mesylate is a relatively new drug that targets the BCR-ABL chimeric protein, the molecular basis of chronic myeloid leukemia (CML). A phase II clinical trial in 39 Japanese patients in the first chronic phase of CML was conducted with imatinib mesylate at a dose of 400 mg/day. Hematologic complete response was obtained in 92.3% of the patients, complete cytogenetic response (CR) was obtained in 43.6%, and major partial CR was obtained in 20.5% of the patients. Although 29 of 39 patients required an adjustment of dosing because of grade 3 or 4 adverse events, most of the events were reversible, and 25 of the 29 patients were able to resume therapy. Between day 15 and day 35, grade 3 or 4 neutropenia and/or leukocytopenia occurred in 13 patients, and grade 3 thrombocytopenia occurred in 5 patients. Overall, nonhematologic grade 3 adverse events occurred in 28.2% of the patients. These data support the use of imatinib mesylate as the treatment of choice for chronic-phase CML patients.

A pilot phase I/II study was conducted as a single-institute trial for evaluation of the feasibility and efficacy of a new salvage chemotherapy, CHASE, for patients with refractory or relapsed lymphoma . The CHASE regimen, consisting of cyclophosphamide, cytosine arabinoside, etoposide, and dexamethasone, was administered every 3 weeks in a maximum of 5 courses. A total of 16 patients were eligible and registered for this study. Myelosuppression was the major toxicity. Although grade 4 leukopenia and grade 3 thrombocytopenia were identified in 15 and 16 patients, respectively, duration of the nadir was brief (median, 3 days). Nonhematological grade 4 toxicity was not observed, and transient elevations of bilirubin and grade 3 aspartate aminotransferase/alanine aminotransferase (AST/ALT) were observed in 2 and 3 courses, respectively, in a total of 57 courses. Complete and partial response rates were 71.4% (10/14) and 7.1% (1/14), respectively. The median percentage of maximal CD34+ cells was 6.1% on day 15, and a median number of 1.88 x 10(6) CD34+ cells/kg per apheresis were obtained. Thirteen patients received high-dose chemoradiotherapy followed by autologous peripheral blood stem cell transplantation. With a median follow-up time of 36 months from the start of CHASE, the overall survival rate for the 16 patients was 66.6%. These results indicated that CHASE is a safe and effective salvage regimen for malignant lymphoma, has sufficient mobilizing effect on peripheral blood stem cells, and warrants further phase II study.

Although high-dose chemotherapy with autologous peripheral blood stem cell transplantation (autoPBSCT) has been shown or confirmed to be an effective treatment for high-risk and relapsed non-Hodgkin's lymphoma (NHL), relapse after autoPBSCT remains a serious problem. In a clinical trial to overcome relapse, we adopted a treatment plan in which PBSCs purified in vitro to CD34+ cells to deplete tumor cells (CD34+ autoPBSCT), total body irradiation (TBI) of 1200 cGy, and melphalan, 180 mg/m2, were used as a preconditioning regimen. Eighteen patients with relapsed or high-risk NHL participated in the study. This study compared the incidence of complications following CD34+ autoPBSCT preconditioned with the TBI regimen (n = 10): the TBI group; CD34+ autoPBSCT with the non-TBI regimen (n = 8): the non-TBI group; and unselected autoPBSCT with the non-TBI regimen (n = 19): the unselected autoPBSCT control group. After day 30 posttransplantation, 6 of 10 patients treated with the TBI regimen developed 11 infectious complications in total, compared with only 1 of 8 patients treated with the non-TBI regimen and 4 of 19 patients given unselected autoPBSCT. Two fatal complications occurred in the TBI group, but none occurred in the other 2 groups. The CD4+ lymphocyte count at 1 month posttransplantation was significantly lower in the TBI group than in the unselected autoPBSCT group. These findings suggest that the addition of TBI to the preconditioning regimen for CD34+ autoPBSCT is associated with an increased incidence of severe infectious complications after transplantation.

The purpose of this study was to investigate the toxicity and the efficacy of re-treatment with rituximab, a chimeric mouse human anti-CD20 monoclonal antibody, in relapsed patients with indolent B-cell non-Hodgkin's lymphoma (NHL) who responded to rituximab in the previous phase I or phase II study. Thirteen patients with relapsed B-cell NHL, each of whom was confirmed to have Revised European-American Lymphoma Classification type II, 1-6 histology (indolent B-NHL), enrolled in this re-treatment study. All were re-treated with rituximab at 375 mg/m2 weekly for 4 consecutive weeks. Rituximab re-treatment was well tolerated with no grade 3/4 nonhematological toxicities, similar to that of the initial treatment. No patients developed detectable human anti-chimeric antibody. Partial responses were observed in 5 of 13 patients (38%; 95% confidence interval [CI], 14% to 68%); 6 patients showed stable disease and 2 showed progressive disease. Overall survival rate was 93% at 19 months of median follow-up after rituximab re-treatment. Median progression-free survival (PFS) after the re-treatment was 5.1 months (95% CI, 4.1 to 5.6 months), and the median PFS after the initial treatment was 8.2 months (95%CI, 5.9 to 11.3 months). Although rituximab re-treatment induced prolonged depletion of normal peripheral blood B cells in all patients, no significant decrease in serum immunoglobulin or complement level was observed. In conclusion, rituximab re-treatment was well tolerated, and it may produce a prolonged PFS in some patients with indolent B-cell NHL who showed initial response to rituximab.

We retrospectively compared transplant outcomes for related bone marrow transplantation (rBMT), related peripheral blood stem cell transplantation (rPBSCT), unrelated bone marrow transplantation (uBMT), and unrelated cord blood transplantation (CBT) in 1,062 patients with chronic myeloid leukemia (CML) aged 20 years or over between January 1, 2000 and December 31, 2009 in Japan. The disease status was as follows: chronic phase 1 (CP1, n = 531), CP 2 or later including accelerated phase (CP2-AP, n = 342) and blastic crisis (BC, n = 189). Graft sources (GS) were rBMT (n = 205), uBMT (n = 507), rPBSCT (n = 226) or CBT (n = 124). In multivariate analysis in CP1, lower overall survival (OS) (relative risk [RR]: 6.01, 95 % confidence interval [CI]: 1.20–29.97, P = 0.029) and leukemia-free survival (LFS) (RR: 4.26, 95 % CI: 1.24–14.62, P = 0.021) were observed in uBMT compared with those in rBMT. For patients in the advanced phase of CML beyond CP1, GS had no significant impact on OS or LFS. Our results support the use of rBMT for adults with CML in CP1, but in contrast to previous reports, the superiority of rPBSCT in advanced stage of CML was not confirmed in our cohorts.

Anti-T lymphocyte globulin (ATG) is commonly used as prophylaxis for graft-versus-host disease (GVHD), especially in patients who are at high risk of GVHD. The appropriate dosage of ATG in Japan has not yet been assessed. We therefore conducted a nationwide survey of patients who received ATG-Fresenius as GVHD prophylaxis for unrelated bone marrow transplantation (uBMT). A total of 86 patients were identified (median age 31 years, range 1-68). The median total dose of ATG was 10 mg/kg. The cumulative incidence of neutrophil engraftment was 90 %. The probability of 2-year overall survival (OS) was 67 %. The cumulative incidence of 2-year non-relapse mortality was 25 %. The incidences of grade II-IV and grade III-IV acute GVHD were 20 and 8 %, respectively. The incidences of chronic and extensive chronic GVHD were 19 and 8 %, respectively. In adult patients, there was a reduction of acute GVHD with high-dose ATG (>10 mg/kg), which did not reach statistical significance. In conclusion, the addition of low-dose ATG to GVHD prophylaxis in Japanese patients who received uBMT resulted in decreased incidences of both acute and chronic GVHD without compromising OS. The effects of low-dose ATG should be assessed in a prospective clinical trial.

FDG-PET scan plays an important role in response assessment in diffuse large B cell lymphoma (DLBCL). In this study, we evaluated the prognostic value of maximum standard uptake (SUVmax) on pretreatment PET scan in DLBCL. Among 169 patients with DLBCL newly diagnosed and treated with R-CHOP between 2003 and 2008, 110 patients who had undergone pretreatment PET scan in single institute using an identical protocol were reviewed and analyzed. SUVmax at the predominant lesion on PET scan and other patient characteristics were evaluated for their association with complete response (CR) rate, overall survival (OS) and progression-free survival (PFS). The median SUVmax was 18.1 (2.0–36.4). There was no significant association between high SUV and other characteristics with the exception of PS ≥ 2 and Ki-67. Multivariate analysis revealed the independent association between high SUVmax and lower CR rate. The 3-year PFS rates in patients with SUV < 30 and those with SUV ≥ 30 were 78 and 51%, respectively (p = 0.06). The 3-year OS rates were 86 and 71%, respectively (p = 0.03). Multivariate analysis revealed that high SUVmax is a significant poor prognostic factor for both PFS and OS, independent of IPI. We showed the important prognostic value of pretreatment SUVmax of PET scan in DLBCL.

Peripheral T cell lymphoma not otherwise specified (PTCL-N) and ALK-negative anaplastic large cell lymphoma (ALCL) are heterogeneous categories with poor diagnostic reproducibility. To clarify the biologic features of these categories, we investigated the expression of two chemokine receptors, type 1 (Th1/Tc1)-associated CXCR3 and type 2 (Th2/Tc2)-associated CCR4 in 110 PTCL-N and 35 ALK-negative ALCL cases, as well as the expression of cytotoxic molecules (CM). CXCR3 and CCR4 were expressed in 69 (63%) and 37 (34%) of PTCL-N, and in 12 (34%) and 6 (17%) of ALK-negative ALCL, respectively. In PTCL-N, type 1 pattern (CXCR3(+)CCR4(-)) was dominant (52%), whereas in ALK-negative ALCL, 54% were negative for both (P0.0001). CM was expressed in 38% of PTCL-N and 51% of ALK-negative ALCL. CM-positive PTCL-N consisted mostly of type 1 disease, which shows type 1 phenotype. In contrast, type 2 pattern (CXCR3(-)CCR4(+)) was recognized in the CM-negative group only. Among type 1 disease, CM-positive cases had a higher female ratio and more aggressive clinical features than CM-negative cases and a poorer prognosis (P = 0.006). Multivariate analysis confirmed that the type 1 phenotype with CM expression was an independent prognostic factor. In both PTCL-N and ALK-negative ALCL, CM-positive type 1 disease had an extremely poor prognosis.

The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of gemtuzumab ozogamicin (GO) in patients with relapsed and/or refractory CD33-positive acute myeloid leukemia (AML). Patients received 2-h infusions of GO twice with an interval of approximately 14 days. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria Version 2.0. Samples for pharmacokinetics were taken on day 1 and day 8 of the first treatment cycle. The dose was increased stepwise and, in each cohort, patients were treated at the same dose. Forty patients, median age 58 years (range 28–68) were treated; 20 and 20 patients were enrolled to the phase I and II parts, respectively. In the phase I part, dose-limiting toxicities (DLTs) were hepatotoxicities, and the recommended dose was established as 9 mg/m2 given as two intravenous infusions separated by approximately 14 days. The pharmacokinetic study revealed that Cmax and AUC were equivalent to those of non-Japanese patients. In the phase II part, complete remission was observed in 5 patients, and one patient had complete remission without platelet recovery. Four of these 6 in remission and one in the phase I are long-term survivors (alive for at least 44 months). GO is safe and effective as a single agent among Japanese CD33-positive AML patients. Remission lasted longer in a subset of patients than in non-Japanese patients in earlier studies. Further studies of this agent are warranted to establish standard therapy.

It has been shown that allogeneic hematopoietic stem cell transplantation (HSCT) can be one of the therapeutic options for patients with metastatic solid tumors, such as renal cancer. However, the development of relatively severe GVHD seems to be necessary to achieve tumor regression in the current setting. Thus, it is crucial to identify minor histocompatibility antigens (mHags) only expressed in tumor cells but not GVHD target organs. In this study, we examined whether three mHags: ACC-1 and ACC-2 encoded by BCL2A1, and HA-1 encoded by HMHA1, could serve as such targets for melanoma. Real-time PCR and immunohistochemical analysis revealed that the expression of both BCL2A1and HMHA1 in melanoma cell lines and primary melanoma cells was comparable to that of hematopoietic cells. Indeed, melanoma cell lines were efficiently lysed by cytotoxic T lymphocytes specific for ACC-1, ACC-2, and HA-1. Our data suggest that targeting mHags encoded not only by HMHA1, whose aberrant expression in solid tumors has been reported, but also BCL2A1 may bring about beneficial selective graft-versus-tumor effects in a population of melanoma patients for whom these mHags are applicable.

There are 4 registries of hematopoietic cell transplantation in Japan; the Japan Society for Hematopoietic Cell Transplantation (JSHCT), Japanese Society of Pediatric Hematology, Japan Marrow Donor Program, and Japan Cord Blood Bank Network; each play an important role in society by reporting the number and outcomes of transplantations and contributing new findings obtained from studies on individual topics. However, there have been a number of issues with the difficulty of analyzing data in overlapping registries and multiple databases at centers affiliated with each of the 4 registry organizations. JSHCT was pivotal in orchestrating the computerization and unification of hematopoietic stem cell transplantation registries for the purpose of resolving these issues and providing a more accurate awareness of hematopoietic stem cell transplantations being performed in Japan. JSHCT played a central role in developing the "Transplant Registry Unified Management Program (TRUMP)" to enable transplantation institutes to manage patient information with emphases on convenience to institutes, safety of patient information, and quality of data management. While enhancing domestic registries, the program seeks to coordinate with other hematopoietic cell transplantation registries around the world to contribute to the development of registries throughout Asia.

Between October 1981 and December 2000, 46 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) underwent allogeneic hematopoietic stem cell transplantation (HSCT) in the Nagoya Blood and Marrow Transplantation Group. The median age was 28.5 years (range, 4-51 years). All but one patient achieved engraftment. Grade II-to-IV acute graft-versus-host disease (GVHD) developed in 32.5% of patients, and chronic GVHD developed in 40.5%. The incidences of relapse and treatment-related mortality (TRM) at 5 years were 65% and 26%, respectively. The estimated overall survival rate at 5 years was 23%. Univariate analysis showed that improved disease-free survival (DFS) was independently associated with complete remission (CR) at transplantation (39%), compared with non-CR (8%) (P = .023). Non-CR at transplantation was associated with a higher risk of relapse. Donor type, acute GVHD, and time from diagnosis to HSCT all had a significant effect on TRM. In a multivariate analysis, 9 months or more from diagnosis to HSCT was the only variable statistically significant for DFS (relative risk, 3.22; P = .01). This study demonstrates that allogeneic HSCT cures a significant population of patients with Ph+ ALL. Relapse is the major obstacle limiting the success of HSCT. Early transplantation during CR from donors, including unrelated persons or mismatched relatives, may offer improved long-term DFS.

Myeloid/natural killer (NK) cell precursor acute leukemia is an entity of acute leukemia characterized by poor prognosis and a CD7+CD56+ myeloid antigen+ phenotype without light-microscopic myeloperoxidase reactivity. This disease shares several clinical characteristics with acute myeloid leukemia (AML) M0. To clarify the relationship between these 2 leukemias, we analyzed 105 cases of AML M0. Among them, 17 were CD7+ and CD56+, 77 were negative for either antigen, and 11 could not be determined. CD7+CD56+ AML M0 showed onset at significantly lower patient age (median 46 versus 63 years, P = .004). The disease localization and the hematological manifestations were significantly different: CD7+CD56+ AML showed more frequent extramedullary involvement, fewer circulating leukemic blasts, less anemia, and less thrombocytopenia than did AML M0. The cytogenetic aberrations were also unique, because no 5q abnormalities were found in CD7+CD56+ M0. The prognosis of CD7+CD56+ M0 was poor in patients younger than 46 years (P = .03). Multivariate analysis showed that the CD7+CD56+ phenotype was a significant prognostic factor for AML M0, as well as age, circulating blast percentage, and chromosome 5 abnormalities These findings suggest that AML M0 consists of heterogeneous subgroups to be managed separately, and CD7+CD56+ M0 constitutes a distinct subtype of AML M0.

We performed a retrospective survey in 62 hematopoietic cell transplantation (HCT) centers in Japan in which all HCTs performed between 1986 and 1998 were reviewed, and those involving hepatitis B virus surface antigen (HBsAg)-positive donors were identified. One hundred and thirty-five patients who underwent allogeneic HCT (alloHCT) were studied for complications related to hepatitis B virus (HBV) or hepatitis C virus (HCV). The median follow-up period was 24 months. Positivity for HBsAg was observed in 32 patients (24%) throughout the study. Twenty-six of the 32 patients were HBsAg carriers before alloHCT, whereas the remaining 6 became HBsAg(+) after alloHCT. Forty-two recipients were anti-HBs antibody (HBsAb)-positive, and 58 recipients (43%) were HCV Ab(+). Eleven of 26 (42%) HBsAg(+) recipients survived between >4 and >119 months. Six of 26 cases received transplants from HBsAg(+) donors, and, although they had not developed acute graft-versus-host disease, 4 of 6 died of hepatic and renal failure within 10 months after HCT. After transplantation, 5 patients showed serologic evidence of HBV reactivation, whereas 4 patients showed evidence of an immune response to HBV. Viral reactivation occurred during the tapering of the immunosuppressive agent. However, 3 of 5 were alive at the time of this report, suggesting that reactivation is not directly correlated with severe liver dysfunction. Seventeen patients (13%) of 135 recipients developed hepatic failure. Eight (47%) of 17 were diagnosed with fulminant hepatitis and 5 (29%) with veno-occlusive disease (VOD). VOD was observed in 12% of both HBsAg(+) and HCVAb(+) patients. In this study, the relatively high incidence of HBV events occurred after alloHCT, and, therefore, we should consider a protocol for active immunization of donors and recipients against HBV. Moreover, although the presence of HBV or HCV is not a contraindication for alloHCT, we recommend a careful follow-up of recipients after transplantation, especially during immunosuppression tapering.

Prognostic factors, including clinical, biological, and histological parameters, were assessed for 94 patients with follicular lymphomas at our institute. Follicular lymphomas constituted 7.7% (94/1208) of malignant lymphomas in this study. Eighteen patients were diagnosed with stage I follicular lymphoma, 20 with stage II, 23 with stage III, and 33 with stage IV. The cases of follicular lymphoma were subclassified as: follicular small cleaved cell lymphoma (FSC) in 20 cases, follicular mixed cell lymphoma (FMX) in 59 cases, and follicular large cell lymphoma (FLC) in 15 cases. The patients comprised 49 men and 45 women with a median age of 54 years (range, 25-84 years). The complete response rate was 76.5%, and the median survival time was 13 years. The expected 10-year overall survival and event-free survival rates were 61.9% and 38.2%, respectively. Univariate analysis identified the factors associated with poor survival as elevated serum lactate dehydrogenase (LDH) level (P.0001), age of60 (P.0001), Ann Arbor stage III/IV (P.01), and Eastern Cooperative Oncology Group performance status (PS) of 2 to 4 (P = .048). Multivariate analysis showed that LDH, age, and PS were independent predictors. After application of the International Prognostic Index (IPI), the 10-year survival rates for the low-risk, low-intermediate risk, high-intermediate risk and high-risk groups were 80.4%, 48.7%, 21.9%, and 0.0%, respectively. The differences among these groups were significant at P.01. The IPI for aggressive non-Hodgkin's lymphoma was found to be applicable to survival prediction for Japanese follicular lymphoma patients.

Mantle cell lymphoma (MCL) is currently regarded as one of the most incurable lymphomas, although reliable prognostic indicators are not yet to be defined. In a previous report, it was indicated that most of the patients with immunohistochemically cyclin D1(+)-MCL pursued the lethal clinical course within 7 years, not having achieved complete remission (CR). Recently, a high dose chemoradiotherapy was carried out, this was supported by peripheral blood stem cell transplantation (PBSCT) using the CD34(+)-selection method in a 48-year-old female patient with cyclin D1(+)-MCL. The tumor cells were detected in her peripheral blood despite four courses of combination chemotherapy using CHOP regimen. Soon after the pre-conditioning of total body irradiation (TBI) and high dose melphalan, she received the PBSCT of 1.8 x 10(6)/kg CD34+ cells and showed rapid hematological recovery without life-threatening complications. The patient achieved CR and was alive, without disease, 730 days after PBSCT. Thus, CD34+ selected PBSCT appears to provide further insight into the effective treatment and possible cure of this aggressive disease, i.e. cyclin D1(+)-MCL.

Thrombopoietin (TPO) is a growth and differentiation factor for megakaryocytes and platelets. An ELISA was developed for measuring TPO concentrations in human sera. The mean +/- S.D. of TPO level obtained in 29 control subjects was 0.87 +/- 0.35 fmol/ml. We measured the TPO level in 36 patients after allogeneic bone marrow transplantation (BMT) and determined the relationship between blood levels of TPO and changes in the circulating platelet mass. In general, a reciprocal relationship was observed between TPO and platelet count (r = -0.609, P < 0.0001; n = 165). With the decrease in the platelet mass after myeloablative therapy, the TPO level increased proportionally and peaked during the platelet nadir. The peak concentration of TPO ranged from 20-50 fmol/ml. The TPO level decreased with the normalization of the platelet mass. In contrast, the TPO level decreased during acute graft-versus-host disease (GVHD) in several patients. Furthermore, the TPO level was significantly lower in the patients with hepatic veno-occlusive disease (VOD) than in the patients after BMT without GVHD and VOD in the samples of less than 50000/microliters platelets (P < 0.005). These findings suggest that in the patients given allogeneic BMT, TPO has an important role in the physiologic regulation of platelet production and that liver damage due to acute GVHD and VOD may decrease the TPO level.