Ken Ohmachi

Multicenter Phase II Study of Bendamustine Plus Rituximab in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

PURPOSE Effective and less aggressive therapies are required for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for or have undergone autologous stem-cell transplantation (ASCT). The present phase II study assessed the efficacy and safety of bendamustine plus rituximab (BR) in this population. PATIENTS AND METHODS Patients with relapsed or refractory DLBCL treated with one to three prior chemotherapy regimens received rituximab 375 mg/m(2) intravenous (IV) infusion on day 1 and bendamustine 120 mg/m(2) by IV infusion on days 2 and 3 of each 21-day cycle for up to six cycles. The primary end point was overall response rate (ORR), and the secondary end points were complete response (CR) rate, progression-free survival (PFS), and safety. RESULTS Sixty-three patients were enrolled, and 59 received BR. The median age was 67 years (range, 36 to 75 years), and 62.7% of patients were 65 years of age or older. Fifty-seven patients (96.6%) were previously treated with rituximab-containing chemotherapy. The ORR was 62.7% (95% CI, 49.1% to 75.0%), with a CR rate of 37.3% (95% CI, 25.0% to 50.9%). The ORRs were comparable between patients ≥ 65 years of age and less than 65 years (62.2% and 63.6%, respectively). The median PFS was 6.7 months (95% CI, 3.6 to 13.7 months). The most frequently observed grade 3 or 4 adverse events were hematologic: lymphopenia (78.0%), neutropenia (76.3%), leukopenia (72.9%), CD4 lymphopenia (66.1%), and thrombocytopenia (22.0%). CONCLUSION BR is a promising salvage regimen for patients with relapsed or refractory DLBCL after rituximab-containing chemotherapy, warranting further investigation.

Multicenter phase II study of bendamustine for relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Bendamustine is a unique cytotoxic agent that has demonstrated efficacy in the treatment of indolent B‐cell non‐Hodgkin lymphomas (B‐NHLs). In this multicenter phase II trial, the efficacy and safety of bendamustine were evaluated in Japanese patients with relapsed or refractory indolent B‐NHL or mantle‐cell lymphoma (MCL). Patients received bendamustine (120 mg/m2) on days 1–2 of a 21‐day cycle, for up to six cycles. The primary endpoint was the overall response rate (ORR) as assessed by an extramural committee according to International Workshop Response Criteria (IWRC). Secondary endpoints included complete response (CR) rate, ORR according to Revised Response Criteria (revised RC), progression‐free survival (PFS), and safety. Fifty‐eight patients with indolent B‐NHL and 11 with MCL were enrolled. By IWRC, bendamustine produced an ORR of 91% (95% confidence interval [CI], 82–97%; 90% and 100% in patients with indolent B‐NHL and MCL, respectively), with a CR rate of 67% (95% CI, 54–78%). ORR and CR rates according to revised RC were 93% (95% CI, 84–98%) and 57% (95% CI, 44–68%), respectively. After a median follow‐up of 12.6 months, median PFS had not been reached. Estimated PFS rates at 1 year were 70% and 90% among indolent B‐NHL and MCL patients, respectively. Bendamustine was generally well tolerated. Reversible myelosuppression, including grade 3/4 leukopenia (65%) and neutropenia (72%), was the most clinically significant toxicity observed. Common non‐hematologic toxicities included mild gastrointestinal events and fatigue. These results demonstrate the high efficacy and tolerability of single‐agent bendamustine in relapsed patients with indolent B‐NHL or MCL histologies. (ClinicalTrials.gov ID: NCT00612183). (Cancer Sci 2010;)

Phase I and pharmacokinetic study of bendamustine hydrochloride in relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma

Bendamustine is a cytotoxic agent with a novel mechanism of action. This phase I, dose‐escalation study evaluated the safety, tolerability, efficacy, and pharmacokinetics of bendamustine in Japanese patients with relapsed/refractory indolent B‐cell non‐Hodgkin lymphoma (B‐NHL) or mantle cell lymphoma (MCL) without major organ dysfunction. Bendamustine 90 or 120 mg/m2 (dose escalation) was administered intravenously over 60 min on days 1 and 2 every 3 weeks for up to three cycles. Nine patients (eight indolent B‐NHL and one MCL) received per‐protocol treatment, three at 90 mg/m2 and six at 120 mg/m2. No dose‐limiting toxicities were observed; thus, the maximum‐tolerated dose was not reached. Grade 3/4 hematologic toxicities were neutropenia (33%) and leukopenia (33%). Non‐hematologic toxicities were grade 1/2 and included gastrointestinal events and fatigue. Peak plasma concentrations of bendamustine occurred near the end of infusion in both dose groups and were equivalent to therapeutic concentrations observed in vitro. Bendamustine was rapidly eliminated, with a mean elimination half‐life (t1/2) of 29 min. Plasma concentrations of active metabolites M3 and M4 were approximately 4 and <1% of the plasma concentration of the parent molecule, with t1/2 of 42 and 33 min, respectively. Two unconfirmed complete responses and six partial responses were observed for an overall response rate (ORR) of 89%. The recommended dose for this schedule in phase II trials is 120 mg/m2. The acceptable safety profile and high ORR warrant further investigation of bendamustine in relapsed or refractory indolent B‐NHL and MCL. (ClinicalTrials.gov ID: NCT00389051). (Cancer Sci 2010)

Clinical outcome of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly in the rituximab era.

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. The incidence of Epstein–Barr virus (EBV)‐positive DLBCL in Asian and Latin American countries ranges from 8 to 10%. The prognosis of patients with EBV‐positive DLBCL is controversial. To compare the clinical outcome of EBV‐positive and EBV‐negative patients with DLBCL in the rituximab era, we analyzed 239 patients with de novo DLBCL diagnosed between January 2007 and December 2011. The presence of EBV in lymphoma cells was detected using EBV‐encoded RNA in situ hybridization, and it was found that 18 (6.9%) of 260 patients with diagnosed DLBCL tested positive. Among the 260 cases, 216 cases were treated with rituximab plus chemotherapy, as were 8 EBV‐positive DLBCL patients. The median overall survival and progression‐free survival times in patients with EBV‐positive DLBCL were 8.7 months and 6.8 months, respectively. The median overall survival and progression‐free survival could not be determined in EBV‐negative DLBCL patients (P = 0.0002, P < 0.0001, respectively). The outcome of patients with EBV‐positive DLBCL remains poor, even in the rituximab era.

Feasibility and pharmacokinetic study of bendamustine hydrochloride in combination with rituximab in relapsed or refractory aggressive B cell non-Hodgkin's lymphoma.

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/m2, i.v., on Day 1 and bendamustine at either 90 (Cohort 1) or 120 mg/m2 (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/m2 plus rituximab 375 mg/m2 was feasible and generally well tolerated, with promising efficacy in relapsed or refractory aggressive B‐NHL. (Cancer Sci 2011; 102: 1687–1692)

Phase III trial of CHOP-21 versus CHOP-14 for aggressive non-Hodgkin’s lymphoma: final results of the Japan Clinical Oncology Group Study, JCOG 9809

BACKGROUND CHOP-21 has remained the standard chemotherapy for aggressive non-Hodgkins lymphoma (NHL), and dose intensification is a potential strategy for improving therapeutic results. We conducted a phase III trial to determine whether dose-dense strategy involving interval shortening of CHOP (CHOP-14) is superior to CHOP-21. PATIENTS AND METHODS A total of 323 previously untreated patients (aged 15-69 years) with stages II-IV aggressive NHL were randomized. The primary end point was progression-free survival (PFS). RESULTS Treatment compliance was comparable in both study arms. At 7-year follow-up, no substantial differences were observed in PFS and overall survival (OS) between CHOP-21 (n = 161) and CHOP-14 (n = 162) arms. Median PFS was 2.8 and 2.6 years with CHOP-21 and CHOP-14, respectively (one-sided log-rank P = 0.79). Eight-year OS and PFS rates were 56% and 42% [95% confidence interval (CI) 47% to 64% and 34% to 49%], respectively, with CHOP-21 and 55% and 38% (95% CI 47% to 63% and 31% to 46%), respectively, with CHOP-14. Subgroup analyses showed no remarkable differences in PFS or OS for patients stratified as per the International Prognostic Index or by age. CONCLUSION Dose-intensification strategy involving interval shortening of CHOP did not prolong PFS in advanced, aggressive NHL.

Prognostic significance of pleural or pericardial effusion and the implication of optimal treatment in primary mediastinal large B-cell lymphoma: a multicenter retrospective study in Japan.

The prognosis of patients with primary mediastinal large B-cell lymphoma has improved over recent years. However, the optimal treatment strategy including the role of radiotherapy remains unknown. We retrospectively analyzed the clinical outcomes of 345 patients with newly diagnosed primary mediastinal large B-cell lymphoma in Japan. With a median follow up of 48 months, the overall survival at four years for patients treated with R-CHOP (n=187), CHOP (n=44), DA-EPOCH-R (n=9), 2nd- or 3rd-generation regimens, and chemotherapy followed by autologous stem cell transplantation were 90%, 67%, 100%, 91% and 92%, respectively. Focusing on patients treated with R-CHOP, a higher International Prognostic Index score and the presence of pleural or pericardial effusion were identified as adverse prognostic factors for overall survival in patients treated with R-CHOP without consolidative radiotherapy (IPI: hazard ratio 4.23, 95% confidence interval 1.48–12.13, P=0.007; effusion: hazard ratio 4.93, 95% confidence interval 1.37–17.69, P=0.015). Combined with the International Prognostic Index score and the presence of pleural or pericardial effusion for the stratification of patients treated with R-CHOP without radiotherapy, patients with lower International Prognostic Index score and the absence of effusion comprised approximately one-half of these patients and could be identified as curable patients (95% overall survival at 4 years). The DA-EPOCH-R regimen might overcome the effect of these adverse prognostic factors. Our simple indicators of International Prognostic Index score and the presence of pleural or pericardial effusion could stratify patients with primary mediastinal large B-cell lymphoma and help guide selection of treatment.

Ki-67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL)

BACKGROUND Central nervous system (CNS) relapse is an uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor. Identification of high-risk populations is therefore critical in determining patients who might be candidates for a prophylactic approach. PATIENTS AND METHODS A total of 608 patients (median age, 67 years; range 22-92) with MCL newly diagnosed between 1994 and 2012 were evaluated. Pretreatment characteristics and treatment regimens were evaluated for their association with CNS relapse by competing risk regression analysis. RESULTS None of the patients received intrathecal prophylaxis. Overall, 33 patients (5.4%) experienced CNS relapse during a median follow-up of 42.7 months. Median time from diagnosis to CNS relapse was 20.3 months (range: 2.2-141.3 months). Three-year cumulative incidence of CNS relapse was 5.6% [95% confidence interval (95% CI) 3.7% to 8.0%]. Univariate analysis revealed several risk factors including blastoid variant, leukemic presentation, high-risk MCL International Prognostic Index and high Ki-67 (proliferation marker). Multivariate analyses revealed that Ki-67 ≥ 30 was the only significant risk factor for CNS relapse (hazard ratio: 6.0, 95% CI 1.9-19.4, P = 0.003). Two-year cumulative incidence of CNS relapse in patients with Ki-67 ≥ 30 was 25.4% (95% CI 13.5-39.1), while that in the patients with Ki-67 < 30 was 1.6% (95% CI 0.4-4.2). None of the treatment modalities, including rituximab, high-dose cytarabine, high-dose methotrexate or consolidative autologous stem-cell transplant, were associated with a lower incidence of CNS relapse. Survival after CNS relapse was poor, with median survival time of 8.3 months. There was no significant difference in the survival by the site of CNS involvement.

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy

Cytarabine arabinoside (Ara-C) is the most important agent for treating acute myeloid leukemia (AML). Here, we genotyped 11 single nucleotide polymorphisms (SNPs) of seven Ara-C metabolism-related genes in 39 AML patients who had received high-dose Ara-C as a single-agent treatment. Univariate analysis identified three SNPs that were significantly associated with shorter time-to-relapse (TTR): CTPS rs12144160 GG compared to AA/AG, DCTD rs9990999 AG/GG compared to AA, and SLC29A1 rs693955 CC compared to AA/AC. Multivariate analysis of TTR revealed the SLC29A1 rs693955 CC genotype and first induction failure to be significantly associated with a shorter TTR. The DCTD rs9990999 AG/GG and SLC29A1 rs693955 CC genotypes were also significantly associated with shorter duration of neutropenia. The results of our study suggest that SNP analysis can be an important tool in improving drug responsiveness and enabling a better understanding of this condition and the development of tailor-made treatments for AML patients who benefit from consolidated high-dose Ara-C therapy.

High-dose chemotherapy followed by autologous stem cell transplantation for relapsed/refractory primary mediastinal large B-cell lymphoma

As a different entity of diffuse large B-cell lymphoma (DLBCL) according to the current World Health Organization classification,1 primary mediastinal large B-cell lymphoma (PMBL) is different from DLBCL in terms of clinical, immunohistochemical and genetic features.2 Despite a remarkable advance with first-line treatment of PMBL patients in the rituximab era,3, 4, 5, 6, 7 10–30% of patients still experience progression or relapse. Although patients with relapsed or refractory PMBL are often treated with high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT) after salvage treatment, the progression-free survival (PFS) at 5 years of 27% is unsatisfactory compared with DLBCL in the pre-rituximab era.8, 9, 10 Moreover, information regarding outcomes after HDT/ASCT for relapsed or refractory PMBL is limited in the rituximab era. Therefore, clarifying the current role of HDT/ASCT is vital to establish the optimal treatment strategy.