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INTRODUCTION: This double-blind, parallel-group, active-controlled phase III trial (NCT02260804) assessed CT-P10 and rituximab safety and efficacy in patients with previously untreated low-tumor-burden follicular lymphoma (LTBFL), including after a single switch from rituximab to CT-P10. PATIENTS AND METHODS: LTBFL patients were randomized (1:1) to receive CT-P10 or rituximab (375 mg/m(2) intravenously; day 1 of 4 7-day cycles). Patients achieving disease control entered a 2-year maintenance period. CT-P10 or rituximab were administered every 8 weeks (6 cycles) in year 1; all patients could receive CT-P10 (every 8 weeks; 6 cycles) in year 2. Secondary endpoints (reported here) were overall response rate (ORR) during the study period, progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Safety and immunogenicity were evaluated. RESULTS: Between November 9, 2015 and January 4, 2018, 258 patients were randomized (130 for CT-P10; 128 for rituximab). ORR was similar between groups over the study period (CT-P10: 88%; rituximab: 87%). After 29.2 months' median follow-up, median PFS, TTP, and OS were not estimable; 24-month Kaplan-Meier estimates suggested similarity between groups. Overall, 114 (CT-P10: 88%), and 104 (rituximab: 81%) patients experienced treatment-emergent adverse events. The single switch was well tolerated. CONCLUSION: These updated data support therapeutic similarity of CT-P10 and rituximab and support the use of CT-P10 monotherapy for previously untreated LTBFL.

This multicenter, open‐label, phase I study assessed the safety and antitumor activity of acalabrutinib in Japanese patients with relapsed/refractory (r/r) B‐cell malignancies. Parts 1 (dose confirmation) and 2 (dose expansion) of this three‐part study are reported. Treatment was a single dose of 100 mg acalabrutinib (day 1), followed by a washout period and then twice daily 100 mg acalabrutinib in part 1, or twice daily 100 mg acalabrutinib in part 2. Patients from parts 1 and 2 with r/r chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and r/r mantle cell lymphoma (MCL) were assessed as r/r CLL/SLL and r/r MCL cohorts, respectively. Twenty‐five patients received treatment (part 1, n = 6). Median age was 71.0 years. Nine (one patient from part 1) and 13 (two patients from part 1) patients were included in the r/r CLL/SLL and r/r MCL cohorts, respectively. Treatment‐related adverse events (AEs) occurred in 88% of patients (grade ≥3, 36%); the most common were headache (28%) and purpura (24%), both grade 1/2. No AEs resulted in treatment discontinuation or death. Median duration of treatment was 31, 20, and 7 months for part 1, r/r CLL/SLL cohort, and r/r MCL cohort, respectively. Overall response rate (ORR) was 89% and 62% for the r/r CLL/SLL and r/r MCL cohorts, respectively. The median progression‐free survival (PFS) was not reached for the r/r CLL/SLL cohort and was 7 months for the r/r MCL cohort. Acalabrutinib (100 mg twice daily) was generally safe and well‐tolerated in adult Japanese patients with B‐cell malignancies., This phase I study assessed the safety and antitumor activity of acalabrutinib in Japanese patients with relapsed/refractory B‐cell malignancies. Twenty‐five patients received treatment, and adverse events occurred in 88% of patients; however, most were grade 1 or 2, and no adverse event resulted in treatment discontinuation. Acalabrutinib was generally safe and well‐tolerated in adult Japanese patients with B‐cell malignancies.

Although romidepsin as monotherapy appears to be useful for treating T-cell lymphoma, combined chemotherapy with other therapeutic agents is required for improvement of the treatment outcome. To establish safer and more effective regimens, systematic screening was conducted to identify suitable drugs to be used in combination with romidepsin for T-cell malignancies, and the underlying molecular mechanisms were examined. The most effective agent was tamoxifen. The combination of romidepsin and tamoxifen had a significant synergistic effect in inducing apoptosis. The growth-inhibitory effects of the combined treatment were reversed by α-tocopherol. FOXO1 expression was greatly upregulated in MOLT-4 cells treated with romidepsin plus tamoxifen. Knockdown of FOXO1 expression by siRNA significantly reduced the cell death induced by romidepsin plus tamoxifen. The combination of romidepsin and tamoxifen might be considered for the treatment of T-cell lymphoma patients.

Mantle cell lymphoma (MCL) accounts for approximately 3% of all cases of malignant lymphoma in Japan. The CLIMBER-DBR (Treatment practices and patient burden in chronic lymphocytic leukemia and mantle cell lymphoma patients in the real world: An observational database research in Japan) study examined the clinical characteristics, treatment patterns, and healthcare resource utilization of MCL in a real-world clinical setting in Japan. Using the Japanese Medical Data Vision database, we extracted data for 1130 patients with MCL (ICD-10 code C83.1) registered between March 1, 2013 and February 28, 2018. The date of first MCL diagnosis was taken as the index date. The mean (standard deviation) age, body weight, and modified Charlson Comorbidity Index were 71.4 (10.9) years, 58.3 (11.7) kg, and 1.9 (1.6), respectively, and 24.6% were ≤65 years old. The median follow-up period was 654 days (first-third quartile 290.5 E049 days). A total of 802 patients (71.0%) underwent first-line treatment. The most common first-line treatment was bendamustine/rituximab (BR; 27.8%), followed by rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP; 15.6%) and rituximab/tetrahydropyranyl-adriamycin/cyclophosphamide/vincristine/prednisolone (R-THP-COP; 6.5%). The median (95% confidence interval) times to initial (first-line), second-line, and third-line treatments were 45 (36 E2), 687 (624 E34), and 1188 (1099 E444) days, respectively. Treatment practices for MCL in Japan are consistent with trends observed in Western countries. Our study can serve as a benchmark to assess future MCL treatments in Japan.

Background Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) developed for treatment of patients with chronic myeloid leukemia (CML). The drug has been shown to act as a potent multikinase inhibitor by blocking not only the BCR-ABL1 gene sequence but also the SRC kinase family, though unexpected adverse events such as pleural effusion have recently been reported in patients undergoing treatment with dasatinib. Hemorrhagic colitis is a unique gastrointestinal adverse events associated with dasatinib and its pathogenesis remains poorly understood. Case presentation We report here a case of dasatinib-induced asymptomatic colitis in a patient with CML, who showed no exacerbation in careful observations and maintained deep molecular response (DMR) during a 3-year period. In addition, we performed transcriptome analysis of inflamed colonic mucosa specimens to clarify the possible mechanism of colitis that develops in association with dasatinib administration. Our results demonstrated that differential gene expression, especially lymphocyte-associated genes and chemokines, is substantially involved in inflammation of colonic mucosa in affected patients. Conclusion Dasatinib induces immune-mediated colitis following lymphocyte infiltration.

Objectives We report a rare case of B-lymphoblastic lymphoma (B-LBL) and low-grade follicular lymphoma (FL) identified concurrently in biopsies from different sites at the initial diagnosis in a 39-year-old man. The clonal relationship between the 2 histologic subtypes was investigated. Methods A diagnosis of FL grade 1/2 (low grade) was made by bone marrow (BM) biopsy. B-LBL was identified in biopsies from the testis and pancreas. Cytogenetic and molecular analyses were performed to investigate their clonal relationship. Results Interphase fluorescence in situ hybridization analyses and G-banding karyotype analyses identified the BCL2-IGH and MYC-IGH translocation in tumor cells from both the BM and testis. The tumor cells from the BM and testis shared the same IGH VDJ usage and a high degree of somatic mutations. These findings suggest that acquisition of MYC gene rearrangement is a critical event for lymphoblastic transformation of FL. Of note, the presence of intraclonal diversity in the B-LBL sample further suggests an earlier or concurrent event of MYC translocation than the somatic IGH mutation in the germinal center and the dedifferentiation of lymphoma cells to a precursor stage of B-cell development. Conclusions B-lymphoblastic transformation of FL can occur with MYC gene rearrangement.

We conducted a multicenter study on anti-programmed cell death-1 monoclonal antibodies (anti-PD-1 mAbs) before/after allogeneic hematopoietic cell transplantation (allo-HCT) for Hodgkin lymphoma. Anti-PD-1 mAbs were administered to 25 patients before allo-HCT and to 20 after allo-HCT. In pre-allo-HCT setting, the median interval from the last administration to allo-HCT was 59 days. After allo-HCT, 12 patients developed non-infectious febrile syndrome requiring high-dose corticosteroid. The cumulative incidences of grade II-IV acute graft-versus-host disease (aGvHD) were 47.1%. Eight patients who had GvHD prophylaxis with post-transplant cyclophosphamide (PTCy) had less frequent aGvHD (grade II-IV, 14.6% versus 58.8%; P = 0.086). The 1 year overall survival (OS), relapse/progression, and non-relapse mortality rates were 81.3%, 27.9%, and 8.4%. In post-allo-HCT setting, the median interval from allo-HCT to the first administration was 589 days. The overall and complete response rates were 75% and 40%. At 100 days after anti-PD-1 therapy, the cumulative incidences of grade II-IV aGvHD, moderate-to-severe chronic GvHD, and grade 3-4 immune-related toxicity were 15.0%, 30.0%, and 30.0%. While the 1 year relapse/progression rate was 47.4%, the 1 year OS probability was 89.7%. In conclusion, immune-related complications were frequent despite modifications of GvHD prophylaxis or anti-PD-1 mAb dosing. In anti-PD-1-mAb-pretreated patients, PTCy-based GvHD prophylaxis may be effective.

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.)

We report a retrospective analysis of 38 patients (age ≤ 30 years) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) for relapsed or refractory anaplastic large-cell lymphoma (ALCL). Median follow-up for survivors after undergoing allo-SCT was 72 months (range, 35-96 months). Eight patients received reduced-intensity conditioning (RIC) regimens, including three patients with fludarabine plus melphalan-based regimens and five patients with fludarabine plus busulfan-based regimens. The remaining 30 patients received myeloablative conditioning (MAC) regimens. Median ages in the RIC and MAC groups were 24 and 15 years, respectively. The 5-year overall survival rates in the RIC and MAC groups were 100% and 49%, respectively (P = 0.018). The 5-year event-free survival rates in the RIC and MAC groups were 88% and 43%, respectively (P = 0.039). In the RIC group, four of the eight patients showed residual disease at allo-SCT, but all eight patients survived with complete remission (CR), including one patient with relapse. This result suggests that allo-SCT using the RIC regimen may be effective for relapsed or refractory ALCL in children, adolescents, and young adults, even in non-CR cases.

There are limited real-world data on the treatment practices and healthcare resource utilization associated with chronic lymphocytic leukemia (CLL) in Japan. In this study (CLIMBER-DBR), we performed retrospective analyses of the Japanese Medical Data Vision database, and extracted data for 2562 patients with newly diagnosed CLL (CLL-1 cohort) and 930 patients receiving CLL treatment (CLL-2 cohort) registered between March 1, 2013 and February 28, 2018. The median follow-up in the CLL-1 cohort was 721 (quartile 1-3: 363-1267) days and the median time to initial (first-line) treatment was 1331 (quartile 1-3: 189-not reached) days. In the CLL-2 cohort, the most frequently used regimens were fludarabine alone (17.7%), cyclophosphamide alone (13.7%), and bendamustine/rituximab (8.2%). The median (quartile 1-3) times to second-line and third-line treatments were 1066 (273-not reached) and 1795 (631-not reached) days, respectively. The CLIMBER-DBR was the first database research study to assess current treatment practices for CLL in Japan, where the treatment patterns were driven by the approval/reimbursement status of drugs in the study period. Our study provides an important benchmark for future studies of CLL in Japan.

Alemtuzumab is the treatment choice for patients with T-prolymphocytic leukemia (T-PLL). However, patients with T-PLL have a poor prognosis, and the option of allogeneic hematopoietic cell transplantation (HCT) remains controversial in these patients. This study aimed to analyze the outcomes of allogeneic HCT among patients with T-PLL to identify the potential clinical efficacy of allogeneic HCT. We retrospectively analyzed data from 20 patients with T-PLL, including five patients with complex chromosomal abnormalities at diagnosis who received an allogeneic HCT between 2000 and 2016. The median follow-up of survivors was 51 months in allogeneic HCT from human leukemia antigen (HLA)-matched donors. All five patients with complex chromosomal abnormalities died after allogeneic HCT. Our data suggest that allogeneic HCT from an HLA-matched donor can be considered for patients with T-PLL without complex chromosomal abnormalities. New treatment strategies of allogeneic HCT are required to improve the safety and efficacy of allografting in patients with T-PLL and complex chromosomal abnormalities. Potential approaches that identify patients with T-PLL and complex chromosomal abnormalities for allogeneic HCT with better disease control may allow identification of individuals who are suitable for allogeneic HCT.

We undertook a retrospective study using the national registry data of hematopoietic stem cell transplantation (HSCT) in Japan to investigate the effect of graft source, particularly autologous or allogeneic tissue, on the treatment outcome in patients aged less than 18 years with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL). Survival analysis was conducted on 31 autologous HSCT (auto-HSCT) and 48 allogeneic HSCT (allo-HSCT) recipients between 1990 and 2013. The 5-year survival rates were significantly lower for allo-HSCT compared to auto-HSCT recipients (32% vs. 55%; P = 0.036). Multivariate analysis of survival rates identified allogeneic graft, Burkitt histology, and lack of response to chemotherapy as poor prognostic factors for survival. The cumulative incidence of treatment-related mortality (TRM) was significantly higher in allo-HSCT compared to auto-HSCT recipients (P = 0.017), explaining the difference in survival rates. In patients with Burkitt lymphoma (BL), overall survival was significantly inferior in the group of patients undergoing HSCT within 12 months from the initial diagnosis (P = 0.039). These data indicate that treatment outcomes for HSCT in children and adolescents with B-NHL were better in autograft recipients, suggesting that greater attention should be paid to the risk of TRM, especially after allografts, for patients with BL.

Peripheral T cell lymphomas are an aggressive group of non-Hodgkin lymphomas with poor outcomes for most subtypes and no accepted standard of care for relapsed patients. This study evaluated the efficacy and safety of forodesine, a novel purine nucleoside phosphorylase inhibitor, in patients with relapsed peripheral T cell lymphomas. Patients with histologically confirmed disease, progression after ≥ 1 prior treatment, and an objective response to last treatment received oral forodesine 300 mg twice-daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Forty-eight patients (median age, 69.5 years; median of 2 prior treatments) received forodesine. In phase 1 (n = 3 evaluable), no dose-limiting toxicity was observed during the first 28 days of forodesine treatment. In phase 2 (n = 41 evaluable), the ORR for the primary and final analyses was 22% (90% CI 12–35%) and 25% (90% CI 14–38%), respectively, including four complete responses (10%). Median PFS and OS were 1.9 and 15.6 months, respectively. The most common grade 3/4 adverse events were lymphopenia (96%), leukopenia (42%), and neutropenia (35%). Dose reduction and discontinuation due to adverse events were uncommon. Secondary B cell lymphoma developed in five patients, of whom four were positive for Epstein-Barr virus. In conclusion, forodesine has single-agent activity within the range of approved therapies in relapsed peripheral T cell lymphomas, with a manageable safety profile, and may represent a viable treatment option for this difficult-to-treat population.

Aggressive NK-cell leukemia (ANKL) has a fulminant clinical course with a poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment. Using the Japanese transplant registry data, the outcomes of 59 ANKL patients who underwent first allo-HSCT were analyzed. Twenty-nine patients received stem cells from cord blood (CB), 18 from peripheral blood, and 12 from bone marrow. At the time of transplant 21 patients had complete response (CR), and 7 partial response (PR), but 31 without response. The 1-year and 5-year overall survival (OS) were 33.9% and 27.3%, respectively. The 1-year cumulative incidences of relapse or progression was 55.5%, and that of non-relapse mortality was 12.1%. The OS was significantly better for patients with CR or PR at the time of allo-HSCT (P = 0.046), which was equivalent to that for patients who experienced primary induction failure at the time of allo-HSCT but achieved CR afterwards (40.6% versus 32.0% at 5 years; P = 0.95). Patients receiving CB had a significantly better OS than those receiving stem cells from others (37.3% versus 16.2% at 5 years; P = 0.04). Patients achieving event-free survival at 12 months after allo-HSCT had good outcomes with 5-year OS of 85.2%.

CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) −/+ rituximab (R) is the standard chemotherapeutic regimen for aggressive lymphoma, but is insufficient for aggressive lymphoma with adverse prognostic factors. Dose-adjusted (DA)-EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisolone) −/+ R demonstrates excellent efficacy against some aggressive lymphoma. Thus, we conducted a retrospective study to evaluate the feasibility and efficacy of this therapy in clinical practice. We enrolled 149 patients from 17 institutions diagnosed between 2007 and 2015. The median follow-up period for survivors was 27 months (range 0.2–123). The complete response (CR) rate of newly diagnosed patients was 79% (95% CI 68–87%). All patients were hospitalized to receive this therapy and 94% of patients also received granulocyte-colony-stimulating factor support. There were no treatment-related deaths. Febrile neutropenia (FN) and grade 3 or 4 infection occurred in 55% and 28% of patients, respectively. There were no significant differences in FN or infection between young (≤ 65 years) and elderly patients (> 65 years). In newly diagnosed diffuse large B-cell lymphoma-not otherwise specified patients (n = 46), the CR rate was 80% (95% CI 64–91%) and the 2-year OS rate was 81% (95% CI 66–90%). In the present study, DA-EPOCH −/+ R exhibited excellent efficacy and feasibility for aggressive lymphoma.

Advances in the molecular biology of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and development of molecularly targeted therapies have resulted in treatment innovations. Therapeutic approaches for previously untreated CLL/SLL patients are changing from chemoimmunotherapy (CIT) to molecularly targeted drugs. The aim of therapy for CLL patients has been to control the disease; however, FCR (fludarabine, cyclophosphamide, rituximab) has improved outcomes and reduced the high incidence of undetectable minimum/measurable residual disease (MRD) in previously untreated CLL patients with no 17p deletion/TP53 disruption and mutated immunoglobulin heavy chain gene (IGHV). Patients achieving undetectable MRD in the bone marrow are expected to be cured. BTK inhibitors and BCL-2 inhibitors are effective for CLL/SLL patients. However, atrial fibrillation and bleeding are associated with the BTK inhibitor, ibrutinib, while tumor lysis syndrome is an adverse event (AE) of the BCL-2 inhibitor, venetoclax. Although these novel targeted drugs are very useful, they are also expensive. Emergence of resistant clones of CLL cells must also be addressed. Therefore, treatments of indefinite duration until progression have been replaced by fixed-duration treatments. This review introduces advances in the treatment of previously untreated CLL/SLL patients in Europe and the United States.

Although allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to provide prolonged remission of relapsed/refractory mycosis fungoides (MF) and Sezary syndrome (SS), its role has not been fully evaluated. Here, the outcomes of allogeneic HSCT for patients with MF/SS were retrospectively evaluated by using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Forty-eight patients were evaluable and enrolled in the analysis. Median age was 45.5 years. Eighteen patients (38%) received myeloablative conditioning, and 33 (69%) received HSCT from an alternative donor. Disease status was complete or partial response in 25% of the patients and relapsed or refractory in the others. At the time of analysis, 18 patients were alive, with a median follow-up of 31.0 months (range, 3.8-31.1). Three-year overall survival (OS) and progression-free survival (PFS) were 30% (95%CI, 16-45%) and 19% (95%CI, 9-31%), respectively. Disease progression was not observed later than 17 months after transplantation. Both disease status and performance status at transplant significantly affected OS and PFS. Although our findings suggest that allogeneic HSCT provides long-term PFS in patients with MF/SS, the timing of transplantation should be decided carefully based on the disease status and the patient's condition in order to improve the outcome.

Hairy cell leukemia (HCL) is a rare B-cell lymphoid malignancy that is difficult to distinguish from other morphological variants. The frequency of HCL has not been determined accurately in Japan. Recent studies revealed that the BRAF V600E mutation is the causal genetic event in HCL. We assessed the BRAF mutation in Japanese patients with HCL and related diseases using the quenching probe (QP) method, a single-nucleotide polymorphism detection system, and evaluated the incidence rate of HCL among Japanese patients with chronic lymphocytic leukemia, and related diseases. We identified 18 cases (33.3%) harboring the BRAF mutation among 54 patients diagnosed with, or suspected of having HCL. Of BRAF V600E-positive patients, 7 were only detected using the QP method, not by direct sequencing, whereas 11 were positive using both tests. In a larger cohort of Japanese patients diagnosed with chronic lymphoid leukemia or related diseases, the frequency of HCL was 4%. Patients with the BRAF V600E mutation had a significantly higher frequency of neutropenia, thrombocytopenia, and elevated soluble interleukin-2 receptor and common B-cell surface markers than patients without the mutation. Our results confirm that BRAF V600E-positive HCL is a relatively rare disorder in the Japanese leukemia patient population.

Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epigenetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies., Article, NATURE COMMUNICATIONS.9:1567(2018)

Adult T-cell leukemia-lymphoma (ATL) has been divided into 4 clinical subtypes: acute, lymphoma, chronic, and smoldering. The aim of this study is to develop a novel prognostic index (PI) for chronic and smoldering ATL. We conducted a nationwide retrospective survey on ATL patients, and 248 fully eligible individuals were used in this analysis. In the univariate analysis, sex, performance status, log10 (soluble interleukin-2 receptor [sIL-2R]), neutrophils count, and lymphadenopathy showed values of P < .05 in training samples. A multivariate analysis was performed on these factors, and only log10 (sIL-2R) was identified as an independent prognostic factor in training samples. Using a regression coefficient of this variable, a prognostic model was formulated to identify different levels of risk: indolent ATL-PI (iATL-PI) = 1.51 × log10 (sIL-2R [U/mL]). The values calculated by iATL-PI were divided into 3 groups using a quartile point. In the validation sample, median survival times (MSTs) were 1.6 years, 5.5 years, and not reached for patients in the high-, intermediate-, and low-risk groups, respectively (P < .0001). To make the scoring system clinically practicable, we simplified iATL-PI according to trichotomizing sIL-2R at 1000 and 6000 U/mL, using a quartile point. Patients with more than 6000 U/mL sIL-2R were categorized into the high-risk group, less than and equal to 1000 U/mL into the low-risk group, and the others into the intermediate-risk group, and MSTs were 1.6 years, not reached, and 5.5 years, respectively (P < .0001). iATL-PI has potential as a novel tool for a risk-adapted therapeutic approach.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P

A Phase II, multicenter clinical trial of bendamustine plus rituximab (BR) regimen was conducted in previously untreated patients with high-tumor-burden indolent B-cell non-Hodgkin lymphoma (B-NHL) and previously untreated elderly patients with mantle cell lymphoma (MCL) in Japan. Bendamustine 90 mg/m2/day on days 1 and 2, as well as rituximab 375 mg/m2 on day 1 were administered intravenously up to six cycles. The primary endpoint was the complete response (CR) rate as assessed by the International Workshop Response Criteria (1999). Sixty-nine patients (59 with indolent B-NHL and 10 with MCL) were treated. The median number of delivered cycles was six (range 1–6). The CR rates were 67.8% [95% confidence interval (CI) 54.4–79.4%] and 70.0% (95% CI 34.8–93.3%) for indolent B-NHL and MCL, respectively. Estimated progression-free survival at 30 months was 72.1% (95% CI 58.5–82.0%) in indolent B-NHL and was 67.5% (95% CI 29.1–88.2%) in MCL. Major grade 3/4 toxicities were hematologic and included lymphopenia (97%), CD4 lymphopenia (91%), neutropenia (86%), and leukopenia (83%). No treatment-related death was found. The BR regimen showed high efficacy as evidenced by the expected CR rate and durable response, as well as an acceptable safety profile for the study populations.

Background Patients with relapsed or refractory lymphoblastic lymphoma (LBL) have a poor prognosis. The efficacy of allogeneic blood stem cell transplantation for treatment of this disease remains unclear in terms of transplantation-related toxicity. Acute and chronic graft-versus-host diseases (GVHD) are both harmful to patients after allogeneic transplantation, but may have some positive effects through a substitute graft-versus-lymphoma effect. Methods To investigate the effect of GVHD on the survival of patients with refractory LBL, we retrospectively studied the outcomes of 213 patients with LBL who underwent first allogeneic stem cell transplantation before the age of 18 years, between 1990 and 2015 in Japan. Results The five-year overall survival (OS) and event-free survival rates after stem cell transplantation were 50.3% (95% confidence interval [CI], 43.2-56.9) and 47.8% (95% CI, 40.8-54.4), respectively. In univariate landmark analyses, the probability of OS was significantly better in patients with aGVHD than in those without (P = 0.002, five-year OS 58.1% vs 39.0%). The probability of OS was also better in patients with cGVHD than in those without (P = 0.036, five-year OS 72.2% vs 54.7%). Multivariate analysis demonstrated that only aGVHD was associated with better OS (hazard ratio, 0.63; 95% CI, 0.42-0.94, P = 0.024). Progression and recurrence statuses at SCT were associated with poor prognosis. The patients with grade II aGVHD showed the best prognosis (five-year OS: 65.6%). Conclusion Our results suggest that the occurrence of aGVHD may be associated with better outcomes in patients with relapsed/refractory LBL who undergo allogeneic transplantation.

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.

Conditioning regimens for stem cell transplantation (SCT) involving total body irradiation (TBI) are generally preferred over busulfan (BU)-based ones for lymphoid malignancies. However, reports of favorable results using BU against lymphomas have recently emerged. This study sought to compare the effectiveness of BU and TBI regimens for SCT against lymphomas. We retrospectively analyzed 893 lymphoma patients who underwent primary SCT in Japan between 1980 and 2015. The median age of all patients was 18 years (range, 0-30 years) with 589 males, 303 females, and 1 patient whose sex was unknown. Overall survival (OS) was not different between those receiving BU and TBI (P = 0.672). OS in patients receiving autologous SCT was significantly better with BU over TBI regimens (P = 0.038), particularly in children (0-15 years) (P = 0.024). Conversely, OS in adolescents and young adults (AYAs; 16-30 years) receiving allogeneic SCT was significantly worse with BU over TBI regimens (P = 0.035). Overall, BU regiments had comparable effectiveness to TBI conditioning regimens, and, although less effective for AYAs with allogeneic SCT, were particularly more effective than TBI regimens for children who received autologous SCT.

Prophylactic granulocyte-colony stimulating factor(G-CSF)is necessary for some cancer patients receiving anti-cancer drugs. However, it is difficult for cancer patients in rural areas to receive G-CSF as outpatients because of inconvenient official transport, lack of public support, and low activity levels due to age. To resolve this problem, we began conducting a critical path(G-path)with regional medical institutions from 2011.We retrospectively surveyed the clinical records of cancer patients receiving prophylactic G-CSF using G-path at our hospital.Eighty-two patients who were administered a total of 254 cycles of chemotherapy were examined between January 2011 and December 2016. Diseases included malignant lymphoma(n=64), pancreatic cancer(n=7), soft tissue sarcoma(n=5), and others(n=6). The median age of the patients was 70(range: 24-94)years. Fifty-three patients visited medical offices, and 31 patients visited regional hospitals. In 245 of 254(96%)cycles, planned G-CSF administration was performed. In 37 of 254(15%)cycles, infectious episodes developed, but patients needed hospitalization for only 5 cycles(2%).Cooperation between clinics and hospitals using G-path reduced ambulatory burden and prevented severe infection. Cooperation in supportive care may allow for equal accessibility to cancer treatment.

FF-10501 is a novel inhibitor of inosine monophosphate dehydrogenase (IMPDH). Clinical trials of FF-10501 for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are currently being conducted in the United States. Although it has been shown that FF-10501 induces apoptosis in hematological malignant cells, the intracellular mechanisms of this effect have not been characterized. We conducted an in vitro study to elucidate the mechanisms of FF-10501-induced cell death using 12 hematological malignant cell lines derived from myeloid and lymphoid malignancies. FF-10501 suppressed the growth of each cell line in a dose-dependent manner. However, the clinically relevant dose (40 μM) of FF-10501 induced cell death in three cell lines (MOLM-13, OCI-AML3, and MOLT-3). Investigation of the cell death mechanism suggested that FF-10501 induces both apoptotic and necrotic cell death. FF-10501-induced apoptosis was mediated by caspase-8 activation followed by activation of the mitochondrial pathway in MOLM-13 and MOLT-3 cells. FF-10501 induced necrotic cell death via endoplasmic reticulum stress in OCI-AML3 cells. The present study is the first to identify intracellular pathways involved in FF-10501-induced cell death.

The Japan Study Group for Cell Therapy and Transplantation (JSCT) organized a phase II study to evaluate the efficacy and safety of a treatment protocol (JSCT-MM12) for multiple myeloma (MM) patients who were previously untreated and transplantation-eligible. Since bortezomib-based therapy is known to be effective for MM, the protocol is intensified more than the previous protocol (JSCT-MM10) and comprised the subsequent treatments: bortezomib + cyclophosphamide + dexamethasone (VCD) induction; bortezomib + high-dose-melphalan (B-HDM) conditioning with autologous stem cell transplantation (ASCT); bortezomib + thalidomide + dexamethasone (VTD) consolidation; and lenalidomide (LEN) maintenance. Sixty-four symptomatic patients aged between 20 and 65 years were enrolled for treatment and received three cycles of VCD, followed by cyclophosphamide administration for autologous stem cell harvest and B-HDM/ASCT, and subsequently two cycles of VTD, after that LEN for 1 year. Complete response (CR)/stringent CR (sCR) rates for induction, ASCT, consolidation, and maintenance therapies were 20, 39, 52, and 56%, respectively. The grade 3/4 toxicities (≥ 10%) with VCD treatment included neutropenia (27%), anemia (19%), and thrombocytopenia (11%). There was no treatment-related mortality. After median follow-up of 41 months, estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 64% and 88%, respectively. The high-risk group revealed lower CR/sCR, PFS, and OS than the standard-risk group. The study revealed that the treatment protocol consisting of VCD induction, B-HDM/ASCT followed by VTD consolidation, and LEN maintenance could produce highly beneficial responses and favorable tolerability in newly diagnosed MM. However, future study is required for improving treatment in the high-risk group.

High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) has been shown to improve the prognosis of patients with central nervous system (CNS) lymphoma. We queried the Japan Society for Hematopoietic Cell Transplantation Registry for 2006 to 2015 to analyze the outcomes of 102 patients with primary CNS lymphoma (PCNSL) who underwent first HDT/ASCT. The median patient age was 54 years (range, 20 to 74 years), and 65 patients were treated in an upfront setting. With a median duration of follow-up of 44 months, the 5-year overall survival (OS) and progession-free survival (PFS) were 54.9% and 38.4%, respectively. There were no significant differences in OS and PFS between upfront and salvage HDT/ASCT. Because thiotepa, a key agent in HDT/ASCT for PCNSL, has been unavailable since 2011 in Japan, the HDT regimens used were not uniform. Thiotepa-containing HDT was received by 16 out of 32 patients before 2010, but by only 2 of 70 patients after 2011. Thiotepa-containing HDT was associated with better PFS (P = .019), lower relapse (P = .042), and a trend toward a survival benefit. In multivariate analysis, noncomplete remission at HDT/ASCT was an independent predictor for OS (hazard ratio [HR], 2.40; 95% confidence interval [CI], 1.25 to 4.58; P = .008) and thiotepa-containing HDT remained significant for PFS (HR, .42; 95% CI, .19 to .95; P = .038). These results confirm the activity of thiotepa-containing regimens.

All-trans retinoic acid (ATRA) is valuable in differentiation therapy for acute promyelocytic leukemia (APL). However, ATRA has had limited success as a single agent, due to the development of resistance. We found that tamoxifen effectively enhanced the differentiation-inducing effect of ATRA. Tamoxifen alone inhibited the proliferation of myeloid leukemia cell lines while only slightly increasing morphologic differentiation. Tamoxifen effectively enhanced the growth-inhibiting actions of various differentiation-inducing agents. ATRA in the presence of tamoxifen increased NBT reduction and the expression of CD11b in HL-60 cells more effectively than ATRA alone. Tamoxifen also enhanced the differentiation induced by the other inducers tested. ATRA induced the differentiation of APL cell lines NB4 and HT93 and APL cells in primary culture, and this differentiation was also enhanced by tamoxifen. Tamoxifen is one of the most widely used drugs for the treatment of cancer and has few side effects. The combination of ATRA and tamoxifen might be considered for the treatment of APL patients in whom it can be difficult to apply arsenic trioxide or anthracyclines.

Introduction Marginal zone lymphoma (MZL) is an indolent lymphoma, which includes extra-nodal MZL of mucosa-associated lymphoid lymphoma (MALToma), nodal MZL (NMZL), and splenic MZL (SMZL). There are currently several treatment options for patients with relapsed or refractory (R/R) MZL, including high-dose chemotherapy with autologous hematopoietic cell transplantation (HCT). Allogeneic HCT is considered to be an optional therapy for R/R MZL patients, but there is no specific data to support allogeneic HCT for R/R MZL. Objectives We retrospectively analyzed the outcomes among R/R MZL patients treated with autologous or allogeneic HCT to identify the potential clinical efficacy of allogeneic HCT. Methods Patient information was derived from the Transplant Registry Unified Management Program database, collected by the Japanese Data Center for Hematopoietic Cell Transplantation, and sponsored by the Japanese Society for Hematopoietic Cell Transplantation. The 70 patients with R/R MZL (25 MALToma, 31 NMZL, and 14 SMZL) were receiving either autologous HCT (n=56, 19 MALToma, 27 NMZL and 10 SMZL) or allogeneic HCT (n=14, 6 MALToma, 4 NMZL and 4 SMZL). Results No patients with MALToma died because of non-relapse mortality (NRM) following autologous HCT and no patients developed relapse with MALToma and NMZL at allogeneic HCT. Progression-free survival (PFS) and overall survival (OS) of R/R SMZL patients who underwent allogeneic HCT were significantly lower compared with the autologous HCT group (median PFS, 65.6% and 25.0% at 1 year after autologous and allogeneic HCT, P=0.014; median OS, 78.7% and 25.0% at 1 year after autologous and allogeneic HCT, P=0.0030). There were no significant differences in the PFS and OS of R/R MALToma and NMZL patients who underwent autologous HCT compared with allogeneic HCT. The main findings of this study indicated that both autologous and allogeneic HCT may be acceptable for patients with chemo-sensitive MALToma and NMZL, but the results of allogeneic HCT for chemo-resistant MALToma and SMZL were inconclusive. Conclusion The parameters for choosing between autologous and allogeneic HCT for R/R MZL have not been defined, and strategies aimed at improving the selection of R/R MZL patients for autologous HCT and excluding R/R chemo-resistant MALToma patients, may allow us to identify individual R/R MZL patients who are at high risk of death after both autologous and allogeneic HCT. Selecting suitable R/R SMZL patients for allogeneic HCT might reduce NRM. The introduction of novel therapies before and after receiving allogeneic HCT could improve outcomes among R/R SMZL patients.

Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in the Western countries. Although a multi-step model has been proposed for the pathogenesis of CLL as well as other malignancies, the precise mechanism underlying the development of CLL remains complicated and unclear. In addition, several studies have investigated adverse prognostic factors, including gene abnormalities and the evolution of clones with the disease progression. FCR (fludarabine, cyclophosphamide, and rituximab) has been the standard first-line therapy for "fit" younger patients without TP53 abnormality/17p deletion. Patients with CLL with TP53 abnormality/17p deletion exhibit poor prognosis because of the resistance to chemoimmunotherapy such as FCR. However, several novel targeted therapies such as B-cell receptor inhibitors including Bruton's tyrosine kinase inhibitors, PI3 kinase inhibitors, and Bcl-2 antagonists have been developed and have proven effective for high-risk patients with CLL with TP53 dysfunction. Moreover, in patients with CLL with the IGHV somatic mutation, FCR therapy offers long-term disease-free survival. These promising findings suggest the possibility of a cure. Although the aim of CLL treatment has been disease control, it is gradually changing to the possibility of a cure. Furthermore, the evaluation of minimal residual disease is important for the cure of CLL.

The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) has substantially extended patient survival. However, TKIs do not effectively eliminate CML stem cells. In fact, CML stem cells persist and cause relapse in the majority of patients upon discontinuation of the drug treatment. Transcriptomic and proteomic analyses have revealed that p53 and c-Myc play defining roles in CML stem cell survival, suggesting that the dual targeting of p53 and c-Myc may selectively eliminate stem cells in patients with CML. Since the downregulation of c-Myc and then upregulation of p21 (a target gene of p53) are commonly observed during the differentiation of acute myeloid leukemia cells induced by differentiation inducers, we hypothesized that differentiation-inducing agents may be useful in regulating c-Myc and p53 expression in CML cells. In the present study, we demonstrate that some differentiation-inducing agents effectively suppress the self-renewal ability of CML cells, and that the combination of these inducers with TKIs results in significantly greater inhibitory effects on CML cell growth compared to the use of TKIs or the inducer alone. The KU812 cells were treated with various concentrations of the inducers in the presence or absence of 30 nM imatinib for 4 days. Among the differentiation inducers we tested, cotylenin A (CN-A) was the most potent at inhibiting the self-renewal ability of the CML cells. CN-A induced the robust expression of CD38, a marker of committed progenitor and more differentiated myelomonocytic cells, and rapidly suppressed c-Myc expression and upregulated p21 expression in CML cells. Thus, these results suggest that CN-A may have potential to promote the elimination of stem cells in CML.

Background Studies in patients with rheumatoid arthritis and advanced follicular lymphoma have shown that CT-P10, a rituximab biosimilar, has equivalent or non-inferior efficacy and pharmacokinetics to rituximab. We aimed to assess the therapeutic equivalence of single-agent CT-P10 and rituximab in patients with newly diagnosed low-tumour burden follicular lytnpliorna. Methods In this ongoing, randomised, double-blind, parallel-group, active-controlled, phase 3 trial, adult patients W.8 years) with stage II-IV low-tumour-burden follicular lymphoma were randomly assigned (1:1) using an interactive web or voice response system stratified by region, stage, and age to CT-P10 or US-sourced rituximab. Patients received CT-P10 or rituximab (375 mg/m(2) intravenous) on day 1 of four 7-day cycles (induction period). Patients who had disease control after the induction period continued to a maintenance period of CT-P10 or rituximab administered every 8 weeks for six cycles and, if completed, a second year of maintenance therapy of additional CT-P10 (every 8 weeks for six cycles) was offered. The study was partially unmasked after database lock (Feb 23, 2018) for all data up to 7 months (before cycle 3 of the maintenance period). The primary endpoint was the proportion of patients who achieved an overall response by 7 months in the intention-to-treat population. Efficacy equivalence was shown if the two-sided 90% CIs for the treatment difference in the proportion of responders between CT-P10 and rituximab was within the equivalence margin of 17%. This trial is registered with ClinicalTrials.gov, number NCT02260804. Findings Between Nov 9, 2015, and Jan 4, 2018, 402 patients were assessed for eligibility, of whom 258 were randomly assigned: 130 to CT-P10 and 128 to rituximab. 108 (83%) of 130 patients assigned to CT-P10 and 104 (81%) of 128 assigned to rituximab achieved an overall response by month 7 (treatment difference estimate 1-8%; 90% CI 6-43 to 10 20). Therapeutic equivalence was shown (90% CIs were within the prespecified margin of 17%). The most common grade 3 or 4 treatment-emergent adverse events were decreased neutrophil count (two grade 3 in the CT-P10 group) and neutropenia (one in each group); all other grade 3 or 4 treatment-emergent adverse events occurred in one patient each. Six (5%) of 130 patients who received CT-P10 and three (2%) of 128 who received rituximab experienced at least one treatment-emergent serious adverse event. Interpretation CT-P10 was equivalent to rituximab in terms of efficacy and was well tolerated. CT-P10 monotherapy is suggested as a new therapeutic option for patients with low-tumour-burden follicular lymphoma. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

One reason for the low cancer screening rate in Japan is that people are not concerned about cancer if they do not have symptoms. The authors retrospectively analyzed 18,405 cancer patients using hospital-based cancer registry data collected between 2007 and 2013 at the 13 hospitals of Shimane Prefecture, Japan. The symptomatic rates of five cancers (stomach, colorectal, lung, breast, and cervix) at each stage and the time of early diagnosis were investigated. The early detection rates of symptomatic and asymptomatic individuals were investigated. The percentages of symptomatic cases tended to increase with progressive stages. The odds ratio (OR) of stage IV compared with that of stage I was 12.23 for stomach, 7.21 for colorectal, 16.91 for lung, 10.30 for breast, and 51.62 for cervical cancer. The proportions of early symptomatic cases at the time of diagnosis were low. Compared with the percentage of early symptomatic cases of stomach cancer of 25.5%, the percentage of lung cancer was the lowest, at 8.2% (OR 0.26), and the percentage of breast cancer was the highest, at 30.2% (OR 1.26). The percentages of early symptomatic cases of colorectal and cervical cancer were 18.9% (OR 0.68) and 19.9% (OR 0.73), respectively. The early detection rates of the asymptomatic and symptomatic groups were 77.6 and 36.1%, respectively. Cancer registry data indicate that early cancers are asymptomatic, and once symptoms appear, treatment may not be effective. Policy makers should inform people of the necessity of cancer screening before they have symptoms.

Although progress has been made in chemotherapeutic strategies against pancreatic cancer, overall survival has not significantly improved over the past decade. Thus, the development of better therapeutic regimens remains a high priority. Pancreatic cancer cell lines were treated with tamoxifen, a novel antitumor fusicoccin derivative (ISIR-042), and anticancer drugs, and their effects on cell growth, signaling and gene expression were determined. Xenografts of Panc-1 cells were treated with tamoxifen, ISIR-042 and 5-fluorouracil (5FU) to determine the effects on tumor growth. The inhibition of the growth of pancreatic cancer cells induced by tamoxifen was effectively reduced by α-tocopherol, a membrane stabilizer. ISIR-042 produced synergistic effects with tamoxifen in inhibiting cell growth. Tamoxifen elevated lipid peroxidation and the release of cytochrome c, and these effects of tamoxifen were reduced by α-tocopherol. ISIR-042 significantly inhibited colony formation and the expression of stemness-related genes of pancreatic cancer cells. The triple combination of tamoxifen, ISIR-042, and 5FU or gemcitabine was effective at inhibiting cell growth and the appearance of drug-resistant cells. This combined treatment significantly inhibited the growth of Panc-1 cells as xenografts without apparent adverse effects. The triple combination of tamoxifen and ISIR-042 with 5FU or gemcitabine may be highly effective against pancreatic cancer by overcoming resistance to therapy.

Objective Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of some anti-cancer drugs. However, medical staff frequently encounter difficulties in ascertaining the severity of CIPN. We sought to develop a questionnaire in order to accurately assess CIPN. The validity of this questionnaire was compared with that of free-style interviews. Methods We developed the CIPN self-check sheet by analyzing existing self-assessment tools for CIPN and matching the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grades. From August to December 2011, 77 cancer patients participated in this study. In order to evaluate the validity of the CIPN self-check sheet compared with a free-style interview assessment, the cross-classification and κ coefficients between the CTCAE grades from each assessment and those from a comprehensive assessment were analyzed. The comprehensive assessment utilized information obtained from the medical examination, free-style interview and CIPN self-check sheet. Results Upon completion of the study, 248 CIPN self-check sheets were collected (median number of sheets per patient, 3; range, 1-14). The cross-classification analysis illustrated that the CIPN self-check sheet successfully identified all grade 3 cases. The coefficient of the CIPN self-check sheet was significantly higher than that of the free-style interviews [κ values: 0.988 (p

To evaluate haematopoietic stem cell transplantation (HSCT) in children and adolescents, we reviewed the records of 47 patients who were ≤18 years, had relapsed or refractory anaplastic large cell lymphoma, and received HSCT between 1990 and 2010. At HSCT, complete remission (CR) was less common in allogeneic HSCT recipients (n = 24) than in autologous HSCT recipients (n = 23) (P = 0·01). The autologous and allogeneic HSCT groups differed in terms of 5-year event-free survival (EFS) (38% vs. 50%, P = 0·63), cumulative incidence of progress or relapse (49% vs. 28%, P = 0·25), and treatment-related mortality (12% vs. 25%, P = 0·40). However, these differences were not significant. Patients with non-CR at autologous HSCT had a significantly lower EFS rate (14% vs. 48%, P = 0·03). Conversely, although those with non-CR at allogeneic HSCT had a lower EFS rate, this was not significant (44% vs. 63%, P = 0·26). Reduced-intensity conditioning regimens were used for three of the 16 allogeneic HSCTs received by patients with non-CR. These three patients achieved CR, surviving 32-65 months after HSCT. These results demonstrated that allogeneic HSCT might be a treatment option for patients who do not achieve CR through conventional chemotherapy.

Rituximab has been shown to improve outcomes in patients with B-cell lymphoma. However, patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) still have a poor prognosis, and the choice between high-dose therapy with autologous hematopoietic cell transplantation (HCT) and allogeneic HCT remains controversial in these patients. We retrospectively analyzed the risk factors for outcomes in 162 R/R MCL patients who received autologous (n = 111) or allogeneic (n = 51) HCT between 2004 and 2014. The median overall survival (OS) rates were 48 and 65 months in the autologous and allogeneic HCT groups, respectively (P = 0.20). Significant risk factors for overall survival in R/R MCL patients after autologous HCT were > 60 years of age at HCT (P = 0.017), higher score of HCT-specific comorbidity index at HCT (P = 0.033), and receiving MCEC (ranimustine + carboplatin + etoposide + cyclophosphamide) regimen (P = 0.017), while higher performance status at HCT (P = 0.011) and longer interval from diagnosis to HCT (P = 0.0054) were risk factors after allogeneic HCT. Strategies that carefully select R/R MCL patients for autologous HCT may allow the identification of individuals suitable for allogeneic HCT.

Aims and background MK615 is produced from Japanese apricot and contains several cyclic triterpenes, such as oleanolic and ursolic acids. MK615 was shown to strongly suppress cutaneous in-transit metastasis in a patient with malignant melanoma. The present investigation was undertaken to clarify the antitumor effects of MK615 in vitro and in vivo. Methods Several human cancer cell lines were exposed to MK615 for 7 days to examine its antiproliferative effects. The effect of MK615 on in vivo growth of human pancreatic cancer MIAPaCa-2 cells was also examined. Results MK615 inhibited the growth of several human cancer cell lines in a concentration-dependent way. Pancreatic cancer MIAPaCa-2 cells were highly sensitive to the growth-inhibiting effects of MK615. Treatment with MK615 preferentially induced cell death in human cancer cells while sparing normal cells such as human umbilical vein endothelial cells (HUVEC) and mouse bone marrow cells. When MIAPaCa-2 cells were incubated with MK615 in the presence of antioxidant, growth-inhibition was significantly reduced, and MK615 induced the accumulation of reactive oxygen species in cancer cells but not in HUVEC. MK615, in both the presence and absence of gemcitabine, significantly inhibited the growth of human pancreatic cancer cells as xenografts without apparent adverse effects. Conclusions MK615, a supplement produced from Japanese apricot, may have therapeutic value in treating human cancers through a reactive oxygen species-dependent mechanism.

Background Clinical features and outcomes of extranodal natural killer/T-cell lymphoma (ENKL) arising from extranasal sites are not fully understood. The purpose of this study was to study the prognosis and treatment outcome of skin/soft tissue primary ENKL. Patients and methods This multicenter retrospective study included 48 patients with skin/soft tissue primary ENKL diagnosed from 1993 to 2010. Results Patients with Ann Arbor stage I, T1–2N0M0 by International Society for Cutaneous Lymphomas–European Organization of Research and Treatment of Cancer TNM (tumour–node–metastasis) stage, International prognostic index score of 0–1, and a Korean prognostic index (KPI) score of 0–1 were associated with better survival. Four of five patients with T1–2N0M0 disease achieved complete response with radiation alone. In disseminated disease, only 6 of 13 patients responded to anthracycline-containing chemotherapy, and all the two patients receiving SMILE showed response. Conclusion In conclusion, we identified the prognostic value of KPI, and we suggest a treatment recommendation according to the TNM (tumour–node–metastasis) stage. Radiotherapy with/without chemotherapy seemed to be optimal in localized disease. In advanced stages, a more aggressive treatment regimen with newer agents should be sought.

The present study was intended to examine the efficacy and safety of bendamustine monotherapy in patients with previously untreated chronic lymphocytic leukemia (CLL) for whom treatment with fludarabine (FLU) was not suitable, and in FLU-naive patients with relapsed/refractory CLL. We intravenously administered bendamustine 100 mg/m2/day on days 1 and 2 of each 28-day cycle to 10 patients (eight previously untreated; two relapsed/refractory) up to six cycles. The primary endpoint was overall response rate (ORR: partial remission or better) according to the 2008 International Workshop on the CLL guidelines. The ORR was 60.0% (6/10), with the 95% confidence interval of 26.2-87.8%. Neither disease progression nor mortality occurred during follow-up. Therefore, the medians for progression-free survival, duration of response, and overall survival were estimated to exceed 12.6, 8.7, and 12.6 months, respectively. Adverse events (AEs) occurred in all 10 patients. Grade 3/4 hematologic AEs included lymphopenia (90%), neutropenia (80%), CD4 lymphopenia (80%), and leukopenia (70%). Nonhematologic AEs included constipation (80%), nausea (80%), malaise (50%), and anorexia (50%). There was one case each of grade 3 infection and adenocarcinoma of the stomach. Bendamustine showed high efficacy for Japanese patients with previously untreated or relapsed/refractory CLL, and its safety profile was acceptable.

Several studies of patients with acute lymphoblastic leukemia and acute myeloid leukemia who received stem cell transplantation (SCT) have reported that adolescents and young adults (AYAs) experience higher transplant-related mortality than that in younger children. However, to the best of our knowledge, there have been no reports of a similar comparison of non-Hodgkin lymphoma (NHL) patients who received SCT. We analyzed 918 patients aged 30 years and younger who received their first stem cell transplantation for NHL. Of the allogeneic transplant patients, children and AYAs did not significantly differ in survival rate, event-free survival rate, relapse rate, or transplant-related mortality. However, 5-year transplant-related mortality after autologous transplantation was significantly higher in children than in AYAs (5.1% in children vs. 0.8% in AYAs, P = 0.0043). The cause of transplant-related death in three of four children was interstitial pneumonitis. In NHL patients, transplantation results in AYAs were not inferior than those in children.

Chemotherapy-induced nausea and vomiting (CINV) is a serious problem for cancer patients receiving chemotherapy. The CHOP regimen is the standard treatment for non-Hodgkin’s lymphoma (NHL) and is categorized as highly or moderately emetogenic in the CINV guidelines. The efficacy of oral 5-HT3 receptor antagonists is equivalent to that of the intravenous form in patients with solid tumors, but there is no clear comparative data for the use of these agents NHL patients receiving CHOP. We analyzed retrospective CINV data from medical records of 72 NHL patients who received CHOP or rituximab-combined CHOP therapy (R-CHOP). All patients received 5-HT3 receptor antagonists alone for prevention of CINV; 39 of the patients received an intravenous form (mostly granisetron) and 33 an oral form (all ramosetron). Complete response (CR: defined as no vomiting and no rescue therapy) was observed in 58 of 72 patients (80.6 %) overall (0–120 h post-CHOP). The CR rate was not statistically different in patients treated with oral or intravenous 5-HT3 receptor antagonists (82.1 vs 78.8 %, P = 0.77). These findings suggest that oral 5-HT3 receptor antagonists represent a good alternative to intravenous forms in NHL receiving CHOP/R-CHOP chemotherapy. Further studies are needed to identify the optimal anti-emetic supportive therapy for NHL.

A 61-year-old Japanese woman presented with hemophagocytic syndrome (HPS) and suffered from intravascular large B-cell lymphoma (IVLBCL). After a few days of supportive care, her condition improved without any anti-cancer drugs or steroids. She experienced recurrences of HPS at 15 mon and 21 mon after first presentation, but lymphoma cells were not observed. Relapse of IVLBCL with pulmonary involvement occurred 27 mon after first presentation. She underwent R-CHOP therapy followed by autologous stem cell transplantation. She is currently alive and without lymphoma. Immunostaining by anti-ssDNA suggested that spontaneous regression may have been due to apoptosis of the lymphoma cells.

Summary Reports of non-anaplastic peripheral T-cell lymphoma (PTCL) in paediatric patients, especially results of stem cell transplantation (SCT), are relatively rare. We herein report the results of SCT using the Transplant Registry Unified Management Program system of the Japanese Society of Stem Cell Transplantation in paediatric patients with non-anaplastic PTCL. We analysed 26 patients (13 females and 13 males) aged 18 years with nonanaplastic PTCL who underwent a total of 28 SCT. Median age at transplantation was 135 years (range: 0–18 years). PTCL not otherwise specified was diagnosed in 17 patients; extranodal Natural Killer (NK)/T cell lymphoma, nasal type in nine; and subcutaneous panniculitis-like T-cell lymphoma in two. Transplantation was with syngeneic donor in one, related donor in 10; unrelated donor in 10; and auto transplantation in 7. Fiveyear overall survival rate and event-free survival rate was 6296% and 5556%, respectively. Male gender, chronic graft-versus-host disease (GVHD), and reduced intensity conditioning were good prognostic factors in all patients. In 20 patients with refractory or relapsed disease, male gender and chronic GVHD were also good prognostic factors. This study is the first report concerning transplantation in children with non-anaplastic PTCL, although the number of patients was small. Larger studies are needed to confirm these findings.