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This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI-8000) in patients with relapsed or refractory (R/R) adult T-cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty-three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end-point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression-free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.

Bortezomib (Btz) shows robust efficacy in patients with multiple myeloma (MM); however, some patients experience suboptimal responses and show specific toxicities. Therefore, we attempted to identify specific HLA alleles associated with Btz‐related toxicities and response to treatment. Eighty‐two transplant‐ineligible patients with newly diagnosed MM enrolled in a phase II study (JCOG1105) comparing two less intensive melphalan, prednisolone, plus Btz (MPB) regimens were subjected to HLA typing. The frequency of each allele was compared between the groups, categorized based on toxicity grades and responses to MPB therapy. Among 82 patients, the numbers of patients with severe peripheral neuropathy (PN; grade 2 or higher), skin disorders (SD; grade 2 or higher), and pneumonitis were 16 (19.5%), 15 (18.3%), and 6 (7.3%), respectively. Complete response was achieved in 10 (12.2%) patients. Although no significant HLA allele was identified by multiple comparisons, several candidates were identified. HLA‐B*40:06 was more prevalent in patients with severe PN than in those with less severe PN (odds ratio [OR] = 6.76). HLA‐B*40:06 and HLA‐DRB1*12:01 were more prevalent in patients with SD than in those with less severe SD (OR = 7.47 and OR = 5.55, respectively). HLA‐DRB1*08:02 clustered in the group of patients with pneumonitis (OR = 11.34). Complete response was achieved in patients carrying HLA‐DQB1*03:02, HLA‐DQB1*05:01, and HLA‐DRB1*01:01 class II alleles. HLA genotyping could help predict Btz‐induced toxicity and treatment efficacy in patients with MM, although this needs further validation., Four factors, HLA‐B4006, female (sex), Arm A (treatment course), and bone pain, were chosen as explanatory variables using the stepwise method. The carriers of HLA‐B4006 showed the highest odds ratio for the risk of bortezomib‐induced peripheral neuropathy.

E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin‐2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single‐arm phase II study of E7777 in patients with relapsed or refractory peripheral T‐cell lymphoma (PTCL) and cutaneous T‐cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T‐cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression‐free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment., Among 36 patients with refractory peripheral T‐cell lymphoma (PTCL) and cutaneous T‐cell lymphoma (CTCL), objective response rate based on the independent review was 36% (41% in PTCL and 31% in CTCL). Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common adverse events were manageable, but increase in alanine aminotransferase / aspartate aminotransferase, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment.

Adult T‐cell leukemia/lymphoma (ATL) is a mature T‐cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983‐1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010‐2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow‐up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016‐2017. Of 770 evaluable patients, 391 (50.8%) had acute‐type, 192 (24.9%) had lymphoma‐type, 106 (13.8%) had chronic‐type, and 81 (10.5%) had smoldering‐type ATL. The initial therapy regimens used for acute/lymphoma‐type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP‐AMP‐VECP)‐like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)‐like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma‐type ATL patients. The 4‐year survival rates (the median survival time, days) for acute‐, lymphoma‐, unfavorable chronic‐, favorable chronic‐, and smoldering‐type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4‐year survival rates for acute‐ and lymphoma‐type ATL improved compared with those reported in 1991, but those for chronic‐ and smoldering‐type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan., The survival curve shows that the prognoses of patients with acute and lymphoma‐type ATL in Japan have improved modestly, but those of patients with chronic and smoldering‐type ATL have not improved.

The efficiency of upfront consolidation with high‐dose chemotherapy/autologous stem‐cell transplantation (HDCT/ASCT) for newly diagnosed high‐risk diffuse large B‐cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high‐risk DLBCL patients having an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R‐CHOP‐14 (arm A) or 3 cycles of R‐CHOP‐14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2‐y progression‐free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow‐up of 40.3 mo, 2‐y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%‐81.2%) and 66.7% (95% CI: 48.8%‐79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%‐85.7%) and 83.3% (95% CI: 66.6%‐92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non‐hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R‐CHOP‐14 showed higher 2‐y PFS and less toxicity compared with R‐CHOP‐14/CHASER in patients with high‐risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN‐CTR, UMIN000003823)., The efficiency of upfront consolidation with high‐dose chemotherapy/autologous stem‐cell transplantation (HDCT/ASCT) for newly diagnosed high‐risk diffuse large B‐cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in patients with high‐risk DLBCL who had an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3. R‐CHOP‐14 showed higher 2‐y PFS and less toxicity compared with R‐CHOP‐14/CHASER in patients with high‐risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations.

This multicenter, open‐label phase 1/2 study evaluated single‐agent carfilzomib in 50 heavily pretreated Japanese patients with relapsed/refractory multiple myeloma (median of five prior treatments). In phase 1, patients were dosed at three levels: 15, 20, or 20/27 mg/m2. Maximum tolerated dosage was not reached at the tolerability evaluation. Patients in phase 2 were treated with 20/27 mg/m2 carfilzomib. Median duration of exposure to carfilzomib in the 20/27 mg/m2 group at this final analysis was 4.7 months (range: 0.3‐39.4). Overall response rate in the 20/27 mg/m2 group, primary endpoint of the study, was 22.5% (n = 9) (95% confidence interval, 12.3‐37.5) with 2.5% (n = 1) stringent complete response. Median progression‐free survival and overall survival in the 20/27 mg/m2 group were 5.1 months (95% CI, 2.8‐13.6) and 22.9 months (95% CI, 14.1‐not estimable), respectively. Frequently occurring grade ≥3 adverse events in the 20/27 mg/m2 group included lymphopenia (72.5%), neutropenia (40.0%), and leukopenia (32.5%). Giving long‐term carfilzomib monotherapy led to long‐term overall survival for heavily pretreated multiple myeloma patients with a favorable safety profile. Carfilzomib monotherapy can be a good option for heavily pretreated multiple myeloma patients.

This open‐label multicenter phase 1 study evaluated the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of weekly carfilzomib and dexamethasone (Cd) in Japanese patients with relapsed or refractory multiple myeloma (RRMM). Carfilzomib was administered by 30‐minute intravenous infusion on Days 1, 8 and 15 in a 28‐day cycle starting at 20 mg/m2 on Day 1/Cycle 1 and 70 mg/m2 thereafter until progressive disease or unacceptable toxicity. Dexamethasone 40 mg was administered on Days 1, 8, 15 and 22 in Cycles 1‐9 and on Days 1, 8 and 15 thereafter. Six patients were enrolled between March 2015 and June 2015. Patients had received a median of 4.5 (range, 4‐8) prior regimens; all patients had previous therapies with bortezomib and immunomodulatory drugs. Of the 6 patients, 1 had a dose‐limiting toxicity (DLT), and tolerability was confirmed. The DLT was grade 3 thrombotic microangiopathy, which was considered serious and occurred on Day 11/Cycle 1. All 6 patients (100%) experienced at least 1 grade ≥3 adverse event (AE). Two patients (33.3%) experienced AE (also considered adverse drug reactions) leading to study discontinuation: thrombotic microangiopathy (Day 11/Cycle 1) and thrombotic thrombocytopenic purpura (Day 6/Cycle 2). The overall response rate was 83.3% (95% confidence interval, 43.6‐97.0). The weekly Cd regimen at a carfilzomib dose of 20/70 mg/m2 was well‐tolerated among Japanese patients with RRMM. Our results could be the basis for the further development of carfilzomib treatment considering safety profiles including microangiopathy‐related events and efficacy.

A randomized phase II selection design study (JCOG0904) was carried out to evaluate the more promising regimen between bortezomib (Bor) plus dexamethasone (Dex; BD) and thalidomide (Thal) plus Dex (TD) in Bor and Thal-naive patients with relapsed or refractory multiple myeloma (RRMM). Patients ≥20 and

In this multicenter, single-arm, phase II study, the efficacy and safety of ibrutinib were examined in Japanese patients with relapsed or refractory mantle cell lymphoma (MCL). Patients (age ≥20 years) with relapsed or refractory MCL who had progressed after receiving at least one prior treatment regimen, were enrolled. Patients were treated with oral ibrutinib (560 mg once daily; 28-day cycle) until disease progression (or relapse), unacceptable toxicity, or study end. The primary end-point was overall response rate. Secondary end-points included duration of response (DOR), time to response, progression-free survival (PFS), overall survival, and safety. Of the 16 patients who received treatment, 5 patients discontinued the study (progressive disease, 4; sepsis, 1). Median duration of ibrutinib exposure was 6.5 months (range, 2.8-8.3 months). The overall response rate was 87.5% (90% confidence interval, 65.6-97.7; complete response = 2 [12.5%]; partial response = 12 [75.0%]). Median time to response for all responders (n = 14) was 1.8 months (range, 0.7-5.3 months). The median DOR and PFS were not estimable due to censoring (range: DOR, 1.1-6.4+ months; PFS, 2.8-8.0+ months). Overall survival data were immature due to the limited observation period. A total of 8/16 patients (50%) had at least one grade 3 adverse event (AE), and 5 (31.3%) patients reported serious AEs. The most commonly reported AEs were diarrhea and stomatitis (37.5% each), platelet count decrease (31.3%), and anemia (25%). Overall, orally administered single agent ibrutinib was efficacious with an acceptable safety profile in Japanese patients with relapsed or refractory MCL. Clinical trial registration NCT02169180 (ClinicalTrials.gov).

B-cell activating factor (BAFF) promotes the survival and adhesion of multiple myeloma (MM) cells. Tabalumab (LY2127399) is an anti-BAFF monoclonal antibody. This phase 1, multicenter, open-label, nonrandomized, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory MM (RRMM). Sixteen patients received intravenous i.v. tabalumab 100 mg (Cohort 1, n = 4) or i.v. tabalumab 300 mg (Cohort 2, n = 12) in combination with oral dexamethasone 20 mg/day and i.v. or s.c. bortezomib 1.3 mg/m(2) . All patients had treatment-emergent adverse events (TEAE) possibly related to study treatment; the most common TEAE were thrombocytopenia (81.3%), lymphopenia (43.8%) and increased alanine aminotransferase (43.8%). Two (20.0%) dose-limiting toxicities were observed, both in Cohort 2 (tabalumab 300 mg), which was below the predefined cutoff for tolerability (

This study analysed incidence, patient outcome, immunophenotype and prognostic factors of histological transformation (HT) from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) to diffuse large B-cell lymphoma (DLBCL) in 467 patients (median age, 61 years). The primary sites of MALT lymphoma were the stomach (43%), ocular adnexa (25%), lung (8%), systemic (8%) and other tissues (16%). HT occurred in 8% of MALT lymphomas. Risk of HT by 15 years was 5%: 4% in limited-stage diseases (n = 385) and 16% in advanced-stage diseases (n = 56) (P = 0·02). The median time to HT was 48 months (range, 4-139). Five-year progression-free survival (PFS) and overall survival (OS) rates after HT were 80% and 94%, respectively. Immunohistochemical results of DLBCL were as follows: germinal centre B-cell (GCB)/non-GCB, 37%/63%; CD10, 9%; BCL6, 59%; MUM1, 38%; MYC, 42%; BCL2, 35%; Ki67 ≥ 90%, 23%; and CD5, 3%. The majority (75%, 9/12) of GCB-type DLBCLs exhibited CD10(-) , BCL6(+) and MUM1(-) immunophenotypes; the remainder had CD10(+) immunophenotypes. Multivariate analysis revealed that only advanced stage at HT was a significant adverse factor for PFS (P = 0·037). Thus, overall risk of HT was low and prognosis after HT was favourable; however, in advanced-stage cases, risk of HT was relatively high and prognosis was unfavourable.

This phase 1, open-label, dose-escalation study investigated the tolerated dose (recommended dose), safety, efficacy, and pharmacokinetics of pomalidomide alone or pomalidomide plus low-dose dexamethasone in Japanese patients with refractory or relapsed and refractory multiple myeloma. Twelve patients were enrolled. Patients received pomalidomide 2 mg (Cohort 1) or 4 mg (Cohort 2) orally on day 1 and days 3-21 of a 28-day cycle. The tolerated dose of pomalidomide was determined to be 4 mg given on days 1-21 of a 28-day cycle. Efficacy outcomes with pomalidomide plus low-dose dexamethasone were consistent with those of previous studies. Responses (partial response or better) were achieved by three patients (25%; 1 [17%] in Cohort 1 and 2 [33%] in Cohort 2), and the median time to response was 6.4 months overall (9.0 months for Cohort 1 and 4.2 months for Cohort 2). The median progression-free survival was 5.5 months overall (5.1 months for Cohort 1 and not reached for Cohort 2). The most frequently occurring grade ≥3 adverse events were neutropenia (67%), anemia (25%), lymphopenia (25%), and pneumonia (25%), consistent with previous studies of pomalidomide plus low-dose dexamethasone in refractory or relapsed and refractory multiple myeloma. Further investigation of pomalidomide is recommended for Japanese patients with refractory or relapsed and refractory multiple myeloma. This study was registered with ClinicalTrials.gov (NCT01568294).

The aim of the present study was to investigate the feasibility of measuring metabolic tumor burden using [F-18] fluorodeoxyglucose ((18) F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with bendamustine-rituximab. Because the standardized uptake value is a critical parameter of tumor characterization, we carried out a phantom study of (18) F-FDG PET/CT to ensure quality control for 28 machines in the 24 institutions (Japan, 17 institutions; Korea, 7 institutions) participating in our clinical study. Fifty-five patients with relapsed or refractory DLBCL were enrolled. The (18) F-FDG PET/CT was acquired before treatment, after two cycles, and after the last treatment cycle. Treatment response was assessed after two cycles and after the last cycle using the Lugano classification. Using this classification, remission was complete in 15 patients (27%) and incomplete in 40 patients (73%) after two cycles of therapy, and remission was complete in 32 patients (58%) and incomplete in 23 patients (42%) after the last treatment cycle. The percentage change in all PET/CT parameters except for the area under the curve of the cumulative standardized uptake value-volume histogram was significantly greater in complete response patients than in non-complete response patients after two cycles and the last cycle. The Cox proportional hazard model and best subset selection method revealed that the percentage change of the sum of total lesion glycolysis after the last cycle (relative risk, 5.24; P = 0.003) was an independent predictor of progression-free survival. The percent change of sum of total lesion glycolysis, calculated from PET/CT, can be used to quantify the response to treatment and can predict progression-free survival after the last treatment cycle in patients with relapsed or refractory DLBCL treated with bendamustine-rituximab.

Concurrent chemoradiotherapy has become one of the standard management approaches for newly diagnosed localized nasal natural killer (NK)/T-cell lymphoma (NKTCL). Few data are available on the prognostic biomarkers of NKTCL among patients treated with concurrent chemoradiotherapy. To evaluate the prognostic significance of immunophenotypic biomarkers for patients treated with concurrent chemoradiotherapy, latent membrane protein 1 (LMP1), cutaneous lymphocyte antigen (CLA) and cell origin were examined in samples from 32 patients who were enrolled in the Japan Clinical Oncology Group 0211 trial and treated with concurrent chemoradiotherapy. LMP1 and CLA were positive in 66% (19/29) and 29% (9/31) of the cases examined, respectively. The median follow-up duration was 68 months (range, 61–94). The patients with LMP1-positive tumors showed a better overall survival (OS) than the patients with LMP1-negative tumors (hazard ratio, 0.240; 95% confidence interval [CI], 0.057–1.013; 80% CI, 0.093–0.615; P = 0.035). All five patients with LMP1-negative tumors who experienced disease progression died of lymphoma, and both patients with local failure had LMP1-negative tumors. There was no significant difference in OS according to CLA expression. A total of 27 (84%) cases were of NK-cell origin, two were of αβ T-cell origin and three were of γδ T-cell origin. In contrast to those with tumors of NK-cell origin, all five patients with NKTCL of T-cell origin were alive without relapse at the last follow up. Our results indicate that LMP1 expression is a favorable prognostic marker and suggest that a T-cell origin of the tumor may be a favorable prognostic marker for patients with localized NKTCL treated with concurrent chemoradiotherapy.

To investigate the clinicopathological and prognostic significance of a nodular pattern and immunophenotypes in primary mediastinal large B-cell lymphoma (PMBL), histopathological features, including a nodular pattern and immunophenotypes, were analyzed in 58 Japanese PMBL patients. The patients were 23 men and 35 women with a median age of 31 years. The 4-year progression free survival (PFS) rate was 78%, and the 4-year overall survival (OS) rate was 89%. Among the histopathological and immunohistochemical features, Bcl6(+) (P = 0.013), MUM1(+) (P = 0.091), and pale cytoplasm (P = 0.064) were favorable prognostic indicators of PFS, and Bcl6(+) (P = 0.051) and MUM1(+) (P = 0.07) were favorable prognostic indicators of OS. Patients with Bcl2 negativity (n = 11) had 4-year PFS and OS rates of 100%. Histologically, a nodular pattern, resembling nodular sclerosis classical Hodgkin lymphoma (CHL), was observed in 22 patients (38%). However, this was not a significant prognostic indicator. In conclusion, Bcl6(+) , MUM1(+) , Bcl2(-) , and pale cytoplasm are candidate favorable prognostic indicators for PMBL and should be further examined in larger studies. We suggest that PMBL with a nodular pattern may belong to the same histological spectrum as nodular sclerosis CHL.

Brentuximab vedotin is an antibody–drug conjugate that selectively delivers the antimicrotubule agent monomethyl auristatin E into CD30-expressing cells. To assess its safety, pharmacokinetics, and efficacy in Japanese patients with refractory or relapsed CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, we carried out a phase I/II study. Brentuximab vedotin was given i.v. on day 1 of each 21-day cycle up to 16 cycles. In the phase I part of a dose-escalation design, three patients per cohort were treated at doses of 1.2 and 1.8 mg/kg. In the phase II part, a dose of 1.8 mg/kg was given to 14 patients (nine with Hodgkin's lymphoma and five with systemic anaplastic large-cell lymphoma). The median number of treatment cycles was 16 (range, 4–16). In the phase I part, no dose-limiting toxicity event was observed. In the total population, common adverse events included lymphopenia (80%), neutropenia (65%), leukopenia (65%), and peripheral sensory neuropathy (60%). Grade 3/4 adverse events in more than two patients were lymphopenia (50%) and neutropenia (15%). The pharmacokinetic profile was similar to that observed in the previous studies in the USA. In the phase II part, six patients (67%) with Hodgkin's lymphoma achieved an objective response with 56% of complete response rate, and five patients (100%) with systemic anaplastic large-cell lymphoma achieved an objective response with 80% of complete response rate. These results show that brentuximab vedotin has an acceptable safety profile and promising antitumor activity in the Japanese population. This trial was registered in JAPIC Clinical Trials Information (JapicCTI-111650). This phase I/II study was to investigate the tolerability, safety and efficacy of brentuximab vedotin. This study indicates that 1.8 mg/kg brentuximab vedotin given every 3 weeks has a manageable safety profile and has high overall tumor response rate in Japanese patients with relapsed or refractory Hodgkin lymphoma or systemic anaplastic large-cell lymphoma.

This study aimed to clarify the clinicopathological prognostic parameters of de novo diffuse large B‐cell lymphoma (DLBCL) in the rituximab era. We examined the correlation of 22 clinicopathological parameters with progression‐free survival (PFS), overall survival (OS), and primary refractory disease in 285 DLBCL patients treated with rituximab‐containing chemotherapy. Complete response rate was 87%, overall response rate was 91%, 5‐year PFS rate was 72%, and 5‐year OS rate was 91%. By log–rank test, higher International Prognostic Index (IPI) (P

The outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT) for diffuse large B-cell lymphoma (DLBCL) associated with follicular lymphoma (FL), which includes DLBCL with pre- or co-existing FL, remains controversial, and few previous reports have compared the outcomes after allo-HCT for FL, DLBCL associated with FL, and de novo DLBCL. We retrospectively analyzed 97 consecutive patients with FL (n = 46), DLBCL associated with FL (n = 22), or de novo DLBCL (n = 29) who received allo-HCT at our institute between 2000 and 2010. With a median follow-up of 53 months, the 5-year overall survival (OS) and progression-free survival (PFS) were, respectively, 77% and 70% for FL, 62% and 57% for DLBCL associated with FL, and 26% and 23% for de novo DLBCL. The 5-year cumulative incidences of non-relapse mortality and disease progression/relapse were, respectively, 16% and 15% for FL, 19% and 24% for DLBCL associated with FL, and 36% and 41% for de novo DLBCL. By a multivariate analysis, the OS and PFS for DLBCL associated with FL were significantly better than those for de novo DLBCL, whereas they were not significantly different from those for FL. These results suggest that allo-HCT may be a promising option for patients with not only advanced FL but also DLBCL associated with FL.

BCX1777 (forodesine), a novel purine nucleoside phosphorylase inhibitor, induces apoptosis, mainly in T cells. To evaluate the safety, tolerability, and pharmacokinetics of BCX1777, we conducted a phase I study in patients with relapsed or refractory peripheral T/natural killer‐cell malignancies. Eligible patients had relapsed or refractory peripheral T/natural killer‐cell malignancies without any major organ dysfunction. BCX1777 was administered orally once daily (dose escalation: 100, 200, and 300 mg) until disease progression requiring new therapy or unacceptable adverse events occurred. A total of 13 patients were enrolled and treated in three dose cohorts (100 mg/day, five patients; 200 mg/day, three patients; 300 mg/day, five patients). Although none of the patients developed dose‐limiting toxicities, further dose escalation was not performed based on data from overseas. Therefore, the maximum tolerated dose was not determined. Adverse events of grade 3 or greater (≥2 patients) included lymphopenia (62%), anemia (15%), leukopenia (8%), and pyrexia (8%). Plasma pharmacokinetics parameter of BCX1777 (area under the plasma concentration‐time curve) at day 1 in each cohort was 1948 ± 884, 4608 ± 1030, and 4596 ± 939 ng•h/mL, respectively. Disease control was achieved in approximately half of patients. One patient with anaplastic large cell lymphoma, which was negative for anaplastic lymphoma kinase, achieved a complete response, and two patients with cutaneous T‐cell lymphoma achieved partial responses. BCX1777 was well tolerated at doses up to 300 mg once daily and showed preliminary evidence of activity in relapsed or refractory peripheral T/natural killer‐cell malignancies, warranting further investigation. (Cancer Sci 2012; 103: 1290–1295)

A phase I study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of the oral histone deacetylase (HDAC) inhibitor vorinostat in Japanese patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL). Six patients received vorinostat (400 mg p.o., once daily). Dose-limiting toxicities (DLT) were evaluated in all six patients during the 28 days of the first cycle. One of the six patients who received vorinostat developed a DLT (grade 4 thrombocytopenia). The most common drug-related adverse events included nausea (4/6, 67%), thrombocytopenia (4/6, 67%), hyperbilirubinemia (3/6, 50%) and vomiting (3/6, 50%). Most of these events were reversible and were resolved by supportive care and/or the interruption of vorinostat treatment. The safety and PK profiles of vorinostat in Japanese patients with CTCL did not appear to differ from those previously observed in non-Japanese and Japanese patients with advanced solid tumors. None of the patients achieved an objective response in this study. However, one unconfirmed partial response and two cases of sustained stable disease for 12 weeks or longer were observed among the six patients in the study. One of the three evaluable patients experienced pruritus relief. Vorinostat was well tolerated at a dose of 400 mg p.o. once daily and showed potential efficacy in Japanese patients with CTCL, warranting further investigation.

Inotuzumab ozogamicin (CMC‐544), a humanized anti‐CD22 antibody conjugated to the potent cytotoxic antibiotic calicheamicin, targets the CD22 antigen expressed on the majority of B‐cell non‐Hodgkin lymphomas. This phase I study assessed the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered intravenously in combination with rituximab in Japanese patients with relapsed or refractory B‐cell non‐Hodgkin lymphoma. Ten patients were administered rituximab 375 mg/m(2) followed by inotuzumab ozogamicin at the maximum tolerated dose (1.8 mg/m(2)). Treatment was repeated every 28 days up to eight cycles, or until occurrence of disease progression or intolerable toxicity. The safety profile was similar to that of inotuzumab ozogamicin monotherapy, with hematologic adverse events occurring most frequently. The most common grade three or higher adverse events were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). The overall response rate was 80% (8/10; 95% CI, 44–98%). Drug exposure increased with successive doses, similar to the pharmacokinetic profiles observed in previous phase I monotherapy studies. Efficacy results suggested promising antitumor activity, and the overall findings support the continued clinical development of this therapeutic regimen in patients with relapsed or refractory B‐cell non‐Hodgkin lymphoma. This trial was registered at www.ClinicalTrials.gov as NCT00724971. (Cancer Sci 2012; 103: 933–938)

Objectives Primary breast lymphoma (PBL) is rare, and its clinical behavior and standard initial treatment are not yet established. Methods We retrospectively analyzed the clinicopathological features and treatment outcomes of 14 patients with primary breast diffuse large B-cell lymphoma. Results There were nine patients with stage IE and five with stage IIE disease. The median largest tumor diameter was 4.5 cm, and five patients had bulky disease >5 cm. The complete response rate was 94%. However, the 5-year progression-free survival rate was 52% with a median follow-up of 5.2 years. Patients with bulky disease had an unfavorable prognosis. All five patients with bulky disease progressed or relapsed. Of the four patients that recurred in the central nervous system (CNS), three had bulky disease although some received rituximab. There were no CNS recurrences in the three patients who received CNS prophylaxis. All eight patients who responded to radiotherapy (RT) did not have recurrences in the ipsilateral breast, although one patient with bulky disease relapsed in the adjacent regional lymph nodes within the RT field despite immunochemotherapy. Conclusions Patients with bulky disease had a poorer prognosis and recurred frequently in the CNS. CNS prophylaxis might yield better outcomes, but a larger, prospective trial is needed to elucidate the optimal initial treatment of PBL in the rituximab era.

Although bendamustine plus rituximab has demonstrated efficacy in indolent B cell non-Hodgkin's lymphoma (B-NHL), data for this combination in aggressive B-NHL are extremely limited. The present dose-escalation study evaluated the safety, efficacy, and pharmacokinetics of bendamustine hydrochloride in combination with rituximab in patients with relapsed/refractory, CD20-positive, aggressive B-NHL. Patients received rituximab 375 mg/m(2) , i.v., on Day 1 and bendamustine at either 90 (Cohort 1) or 120 mg/m(2) (Cohort 2), i.v., on Days 2 and 3 of a 21-day cycle. The primary endpoint was the proportion of patients experiencing dose-limiting toxicity (DLT). Secondary endpoints were adverse events (AE), the overall response rate (ORR), and pharmacokinetic parameters. Nine patients received rituximab plus bendamustine: three in Cohort 1 and six in Cohort 2. Histologies included diffuse large B cell lymphoma (n = 5), mantle cell lymphoma (n = 2), and transformed lymphoma (n = 2). No DLT was observed at either dose level. Grade 3/4 hematologic AE included lymphocytopenia, leukocytopenia, and neutropenia (n = 9 each; 100%), and thrombocytopenia (n = 2; 22%). No Grade 3/4 gastrointestinal AE were reported. The ORR was 33% (one partial response) in Cohort 1 and 100% (five complete and one partial response) in Cohort 2. The maximum drug concentration and area under the blood concentration-time curve for bendamustine increased dose dependently, with time to maximum blood concentration = 1.0 h in both cohorts; these pharmacokinetic data were similar to those reported previously for single-agent bendamustine in patients with indolent B-NHL. In conclusion, bendamustine 120 mg/m(2) plus rituximab 375 mg/m(2) was feasible and generally well tolerated, with promising efficacy in relapsed or refractory aggressive B-NHL.

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

CHOP combined with rituximab (R-CHOP) is regarded as one of the most effective treatments for indolent B-cell non-Hodgkin lymphoma (B-NHL), however, its optimal combination schedule remains unknown. We performed a randomized phase II study to explore a more promising schedule in untreated, advanced indolent B-NHL. Patients were randomized to receive either six courses of CHOP concurrently with rituximab (Arm C), or six courses of CHOP followed by six courses of weekly rituximab (Arm S). A total of 69 patients received the concurrent (n=34) or sequential (n=35) regimen. Overall response rate (ORR) in Arm C was 94% (95% confidence interval [CI], 79 to 99), including a 66% complete response (CR) compared with 97% (95% CI, 85-100), including a 68% CR in Arm S. Patients in Arm C experienced more grade 4 neutropenia (85%versus 70%) and experienced more grade 3 or greater non-hematological toxicities (21%versus 12%). Both arms were tolerated well. With a median follow-up of 28.2 months, the median progression-free survival (PFS) time was 34.2 months in Arm C, and was not reached in Arm S. R-CHOP is highly effective in untreated indolent B-NHL, either concurrent or in a sequential combination. Both combination schedules deserve further investigation.

Primary gastric diffuse large B-cell lymphomas are generally well controlled by non-surgical treatment with combination chemotherapy followed by radiotherapy. We have previously reported that over 90% of patients achieved complete response (CR) with this therapeutic strategy: three cycles of cyclophosphamide, adriamycin, vincristine and prednisone followed by radiotherapy (40.5 Gy). Although the CR rate was very high, some patients still showed resistance to this combination therapy. In order to clarify the factors related to therapy resistance, we examined the relationship between Epstein-Barr virus (EBV), which was examined using an in situ hybridization technique, and the patients' clinical courses. Out of the 50 patients, four were EBV positive; over half of lymphoma cells were positive for EBV by in situ hybridization. Of the three EBV-positive patients, two showed progressive disease and one achieved partial response (PR). Two of the patients died of disease progression. The other patient achieved CR, but the lymphoma recurred with distant metastasis in the cerebellum 3 months after remission. In the present study, eight patients did not achieve CR or they relapsed, four patients showed progressive disease, one patient achieved PR, and three patients achieved CR with recurrence. Therefore, half of these unfavorable patients were EBV positive. This finding strongly indicated that EBV-associated gastric diffuse large B-cell lymphomas frequently show resistance to standard chemoradiotherapy, although some other adverse factors remain unclear.

Background: Patients who exhibit gastrointestinal (GI) involvement due to graft-versushost disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) are often recommended to withhold oral intake (NPO) to avoid further damage to the GI mucosa. However, it is possible that continuing oral intake could be beneficial in many patients compared to total parenteral nutrition (TPN). Objective: The primary objective of this prospective study was to evaluate whether programmed step-ladder oral dieting (enteral nutrition; EN) is feasible and beneficial for these patients. Methods: A total of 18 patients who exhibited GI-acute GVHD (stage I to III gut GVHD) after SCT received an EN dieting program, and changes in clinical and laboratory parameters were compared to those in a control cohort of 17 patients who were placed on NPO with TPN. Patients with GVHD were included prospectively and those with intestinal bleeding/obstruction, severe pancreatitis, and cytomegalovirus enterocolitis were excluded. Results: None of the patients in the EN group experienced significant adverse events, including exacerbation of GI symptoms. Although there was no statistically significant difference in the volume or frequency of diarrhea or the time to complete dietary recovery, parameters including body weight and serum levels of total protein and albumin tended to improve faster in the EN group. Conclusion: The EN diet is safely applicable to patients suffering from GI involvement by GVHD. Am. J. Hematol. 81:747–752, 2006. V C 2006 Wiley-Liss, Inc.

We conducted a phase I study to evaluate the safety and efficacy of radioimmunotherapy with yttrium-90-ibritumomab tiuxetan (Y2B8) in Japanese patients with relapsed or refractory indolent B-cell lymphoma. Indium-111-labeled ibritumomab tiuxetan (In2B8; 3.5 or 5 mCi [129.5 or 185 MBq]) was administered on day 1, followed by serial gamma-camera imaging to investigate the distribution of In2B8 in the whole body of patients and to judge the feasibility of Y2B8 administration. Y2B8 with a dose of 0.3 mCi/kg (11.1 MBq/kg) or 0.4 mCi/kg (14.8 MBq/kg) was administered on day 8. Grade 4 neutropenia and grade 3 thrombocytopenia were observed in three of nine of the patients evaluated for safety. Critical toxicities (prolonged thrombocytopenia or severe non-hematological toxicities) were observed in two of six patients in the 0.4 mCi/kg (14.8 MBq/kg) dose group but were not seen in any of the three patients in the 0.3 mCi/kg (11.1 MBq/kg) dose group. The non-hematological toxicities of the nine patients were of grade 2 or less, except in two patients who had been heavily treated previously. They experienced critical toxicities such as infection, diarrhea, hyponatremia and prolonged thrombocytopenia, as well as other frequent grade 2 non-hematological toxicities. Although the pharmacokinetic profiles were similar to those in the US study, one of the two patients was clarified retrospectively as showing abnormal biodistribution of In2B8 in the bone marrow, as judged by an independent third party panel of radiologists. Five of the 10 participants achieved complete responses or unconfirmed complete responses and two partial responses. In conclusion, the recommended dose of Y2B8 for the subsequent phase II study for Japanese patients is 0.4 mCi/kg (14.8 MBq/kg). This dose of radioimmunotherapy was feasible when patients with altered biodistribution of In2B8 were excluded, and it was highly effective. (Cancer Sci 2005; 96: 903-910).

CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) followed by radiotherapy is regarded as standard care for localized aggressive lymphoma; however, prospective confirmation of its applicability to localized primary gastric lymphoma is inadequate, and most patients in Japan have been initially treated with gastrectomy. We conducted a multicenter phase II study to evaluate the feasibility and efficacy of the non-surgical treatment. Eligibility criteria required primary gastric diffuse large B-cell lymphoma, stage I-II(1), age 20-75, performance status 0-1 and adequate organ function. Treatment consisted of three cycles of CHOP followed by radiotherapy 40.5 Gy. Fifty-five patients were enrolled between December 1999 and February 2003, and 52 eligible patients were analyzed. Patient characteristics were as follows: median age, 61 years; 28 men, 24 women; 36 with stage I, 16 with stage II(1); 47 with a low International Prognostic Index (IPI) and five with a low-intermediate IPI. All but one patient completed planned treatment. No serious complications including massive hemorrhage or perforation were observed. A complete response was achieved in 48 of the 52 patients (92%, 95% confidence interval: 82-98%) and progressive disease in three. Two patients underwent salvage gastrectomy due to disease persistence or recurrence. With a median follow-up period of 28 months, 2-year progression-free and overall survivals were 88 and 94%, respectively. CHOP followed by radiotherapy is safe and highly effective in localized gastric diffuse large B-cell lymphoma. This organ-preserving treatment should be considered as a very reasonable therapeutic option.

The frequency of t(14;18) in follicular lymphoma (FL) in Japan has been reported to be low compared to North America and other European countries. Recently, it has also been reported that FL lacks t(14;18), mainly among histological grade 3b, and occasionally has a rearranged Bcl-6 gene. It is not known whether a difference in histology or immunostaining pattern exists between FL with and without t(14;18). We performed interphase fluorescence in situ hybridization (FISH) analysis to detect Bcl-2/IgH, Bcl-6 gene rearrangement, Bcl-2 gene amplification, and the cyclinD1/IgH gene in formalin-fixed paraffin embedded specimens from our FL archives. The correlation between morphological features, histological grades, immunohistochemical findings, and cytogenetical aberrations was studied. In total, we found that 28 of 47 cases (59.6%) had t(14;18). Bcl-6 gene rearrangement and extra Bcl-2 gene signals were found in five and two cases, respectively. Only one had cyclinD1/IgH fusion. Ten of 12 grade 1, nine of 17 grade 2, and 0 of two grade 3 cases had fusion signals, respectively. None of the above abnormalities were detected in 12 of 47 cases (25.5%). Our data confirmed a high frequency of t(14;18) in FL in grade 1, but a lower incidence among grade 2, that could be attributed to the lower incidence of the translocation in FL in Japan. Immunostaining of both Bcl-2 and CD10 was highly predictable for the presence of t(14;18); the positive predictive value was 75%, suggesting the usefulness of the staining.

To clarify the impact of graft-versus-host disease (GVHD) on the outcome of reduced-intensity stem cell transplantation (RIST), 40 patients who received RIST were compared with those who received conventional stem cell transplantation (CST). RIST regimens consisted of either cladribine (0.11 mg/kg/d x 6, n = 13) or fludarabine (30 mg/m(2)/d x 6, n = 27) with busulphan (BU, 4 mg/kg/d orally x 2), with or without antithymocyte globulin (ATG). CST regimens were either cyclophosphamide/total body irradiation (CY/TBI, n = 23), BU/CY (n = 19) or others (n = 6). The RIST group contained more patients who were at high risk of transplant-related mortality, including older patients, while the two groups contained the same percentages of patients at high risk of relapse. There were no differences between these groups in the incidences of acute (grade II-IV, 31.6% RIST vs 33.3% CST, P = 0.6742) and chronic GVHD (56.2%vs 64.1%, P = 0.8512), relapse rate (15.0%vs 18.8%, P = 0.6642), or overall (69.3%vs 65.6%, P = 0.4817) and progression-free survival (64.7%vs 63.8%, P = 0.6920) at d 500. Multivariate analysis of progression-free survival identified only grade III-IV acute GVHD and relapse risk dose as adverse risk factors. Although GVHD is a major threat in RIST, appropriate induction of GVHD may be associated with anti-tumour activity in RIST comparable to that of CST.

Summary. We evaluated erythrocyte recovery in 121 allogeneic haematopoietic stem cell transplantation (HSCT) recipients. There were 35 major and minor ABO-incompatible transplants, respectively, including 10 bi-directionally ABO-incompatible transplants. The use of peripheral blood stem cells facilitated erythrocyte recovery, regardless of the presence or absence of major ABO-incompatibility, and was associated with a frequent detection of anti-host isohaemagglutin early after minor ABO-incompatible transplantation, which was not associated with clinically relevant haemolysis. The use of a reduced-intensity regimen combining a purine analogue and busulphan did not delay erythrocyte recovery after major ABO-incompatible transplantation, suggesting this regimen had a strong activity against host plasma cell.

We here report on two rare cases of intrafollicular classical Hodgkin lymphoma (CHL). Case 1 was a 34-year-old man who underwent left supraclavicular lymph node biopsy. Case 2 was a 28-year-old woman who underwent surgical resection of an anterior mediastinal mass. The histology and microenvironment of both specimens resembled those of nodular lymphocyte predominant Hodgkin lymphoma. Nodular architecture was observed, which comprised normal-appearing small lymphocytes and scattered lymphocyte predominant (LP)-like cells. CD23(+) follicular dendritic cell meshworks were present in the nodules, surrounded by a mantle zone containing IgD(+) B cells. The LP-like cells were ringed by CD3(+) and PD-1(+) T cells, and numerous CD20(+) B cells were present in the background. However, the immunophenotypes of the LP-like cells resembled those of Hodgkin/Reed-Sternberg cells of CHL; they were positive for CD15, CD30, and PAX5, and negative for CD20, Bcl6, Oct2, and Bob1. These histopathological findings indicate that CHL can be derived from the germinal center.

Immunostaining for cyclin D1 is essential for reliable diagnosis of mantle cell lymphoma (MCL). However, a small number of cyclin D1-positive lymphomas other than MCL have been encountered. Our goal was to investigate the morphological spectrum of MCL as a disease entity, based on cyclin D1 overexpression. We reviewed 181 biopsy specimens obtained from 168 cases of cyclin D1-positive MCL. Typical findings were the presence of nodular (53.9% of cases) or diffuse (46.1%) histological patterns, containing mantle zone patterns (16.8%), naked germinal centers (33.5%) and perivascular hyaline deposition (83.2%). Unusual findings of residual germinal centers with a mantle cuff (four cases) and follicular colonization (two cases) were seen. High magnification showed a monotonous proliferation of tumor cells with cytological diversity including small (3.0%), intermediate (43.1%), medium (34.1%), medium-large (13.2%) and large (6.6%) cells. Pleomorphic and blastic/blastoid variants were encountered in 9.6 and 7.2% of cases, respectively. Three cases had foci of cells of considerable size, with a moderately abundant pale cytoplasm resembling marginal zone B cells. Two cases showed an admixture of cells which appeared transformed and mimicked the histology of chronic lymphocytic leukemia/small lymphocytic leukemia. In one, neoplastic mantle zones were surrounded by sheets of mature plasma cells, resembling the plasma cell type of Castleman's disease. An admixture of areas characteristic of MCL and of other larger cells, indicating histological progression or a composite lymphoma, were observed in seven cases. In high-grade lesions of five cases, nuclear staining of cyclin D1 was rarely detected. In our experience, cyclin D1 expression was also found in nine lymphomas other than MCL (five plasma cell myelomas, three Hodgkin's disease and one anaplastic large cell lymphoma). The application of cyclin D1 staining prompted us to recognize the broad morphological spectrum of MCL. MCL can be diagnosed with the application of cyclin D1 immunostaining, if careful attention is given to architectural and cytological features.

This phase II trial was performed to evaluate the efficacy of a new granulocyte colony-stimulating factor (G-CSF)-supported multi-agent chemotherapy protocol, LSG15, for aggressive adult T-cell leukaemia-lymphoma (ATL). Ninety-six previously untreated patients with aggressive ATL were enrolled and grouped as: acute type (58), lymphoma type (28) and unfavourable chronic type (10). Therapy consisted of seven cycles of VCAP (vincristine, cyclophosphamide, doxorubicin and prednisone), AMP (doxorubicin, ranimustine and prednisone) and VECP (vindesine, etoposide, carboplatin and prednisone). G-CSF was administered during the intervals between chemotherapy until neutrophil reconstitution was achieved. Eighty-one per cent of the 93 eligible patients responded [95% confidence interval (CI), 71.1-88.1%], with 33 patients obtaining complete response (35.5%) and 42 obtaining partial response (45.2%). The median survival time (MST) after registration was 13 months and the median follow-up duration of the 20 surviving patients was 4.2 years (range 2.8-5.6). Overall survival at 2 years was estimated to be 31.3% (95% CI, 22.0-40.5%). Grade 4 haematological toxicity of neutropenia and thrombocytopenia were observed in 65.3% and 52.6% of the patients respectively, but grade 4 non-haematological toxicity was observed in only one patient. LSG15 is feasible with mild non-haematological toxicity and improved the clinical outcome of ATL patients. MST and overall survival at 2 years were superior to those obtained by our previous trials.