Efficacy, Safety and Quality of Life of Pegcetacoplan in Japanese Patients With Paroxysmal Nocturnal Hemoglobinuria Treated Within the Phase 3 PEGASUS Trial.

INTRODUCTION: Pegcetacoplan, the first approved proximal complement C3 inhibitor, showed superiority to eculizumab in improving hemoglobin levels and clinical outcomes in the phase 3 PEGASUS study in patients with paroxysmal nocturnal hemoglobinuria (PNH) and inadequate response to eculizumab. METHODS: This analysis evaluates the efficacy and safety of pegcetacoplan for Japanese patients in PEGASUS, as they are known for different clinicopathologic features compared to non-Asian patients. Ten Japanese patients were enrolled to receive pegcetacoplan (n=5) or eculizumab (n=5) during the 16-week randomized controlled period. All patients received pegcetacoplan monotherapy during the open-label period until Week 48. RESULTS: Treatment with pegcetacoplan improved hemoglobin with a mean change from baseline of 2.4 g/dL at Week 16, which was sustained through 48 weeks. Pegcetacoplan-treated Japanese patients experienced sustained improvements in key secondary efficacy endpoints, including freedom from transfusion, lactate dehydrogenase level, reticulocyte count, and FACIT-Fatigue score. The safety profile was consistent with previously reported data from pegcetacoplan studies. No events of hemolysis, meningococcal infection, or thrombosis were reported in the Japanese population and all Japanese patients remained on treatment throughout the study. CONCLUSION: These data suggest that Japanese patients with PNH can be effectively and safely managed with pegcetacoplan. CLINICALTRIALS: gov identifier: NCT03500549.

Oral HDAC inhibitor tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: phase IIb results.

Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval : 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652).

[Cyclic thrombocytopenia diagnosed by periodic platelet count measurements].

Cyclic thrombocytopenia (CTP) is characterized by periodic platelet count fluctuations and is commonly misdiagnosed as immune thrombocytopenia (ITP) because of their similar clinical characteristics. Here, we present the case of a 74-year-old man with CTP diagnosed by weekly platelet count measurements. The patient initially developed mild bleeding symptoms with a platelet count of 0.8×104/µl. Bone marrow biopsy exhibited reduced megakaryocyte counts, an atypical characteristic of ITP. Weekly follow-up of platelet counts demonstrated an apparent cyclic pattern, resulting in CTP diagnosis. Regular platelet count measurements can help diagnose CTP in thrombocytopenia.

Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. METHODS: CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. FINDINGS: Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4-28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8-33·0) versus 13·8 months (10·2-17·5; hazard ratio 0·52 [95% CI 0·39-0·69]; p<0·0001). The most common grade 3-4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group. INTERPRETATION: Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma. FUNDING: Bayer.

Phase II study of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma.

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.

Prophylactic antiviral therapy for hepatitis B virus surface antigen-positive patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy.

We conducted a nationwide retrospective analysis of 116 hepatitis B virus (HBV) surface antigen (HBsAg)-positive patients with diffuse large B-cell lymphoma (DLBCL) and 278 HBsAg-negative patients with DLBCL, as a control cohort, who received rituximab-containing regimens as an induction chemotherapy at 30 Japanese medical centers between January 2004 and December 2014. Hepatitis was defined as an absolute serum alanine aminotransferase (ALT) level of ≥100 U/L. HBV reactivation-related hepatitis was defined as hepatitis with an absolute serum HBV DNA level of ≥3.3 log IU/mL or an absolute increase of ≥2 log compared with the baseline value. HBsAg-positive patients were divided into three groups based on anti-HBV prophylactic therapy: no nucleos(t)ide analogue (non-NA, n = 9), lamivudine (LAM, n = 20), and entecavir (ETV, n = 87). The 4-year cumulative incidence (CI) of hepatitis in HBsAg-positive and HBsAg-negative patients was 21.1% and 14.6% (P = .081), respectively. The 4-year CI of HBV reactivation-related hepatitis was higher in HBsAg-positive patients than in HBsAg-negative patients (8.0% vs 0.4%; P < .001). Among HBsAg-positive patients, the 4-year CI of HBV reactivation-related hepatitis was the highest in the non-NA group (33.3%), followed by the LAM (15.0%) and ETV (3.8%) groups (P < .001). Of note, 3 non-NA patients (33%) and 1 LAM patient (5%) (but no ETV patients) died due to HBV hepatitis. Based on Cox multivariate analysis, HBsAg positivity was not associated with poor overall survival. Prophylactic use of ETV would reduce the occurrence of HBV reactivation-related hepatitis and mortality in HBsAg-positive DLBCL patients receiving rituximab-containing chemotherapy.

Phase I studies of darinaparsin in patients with relapsed or refractory peripheral T-cell lymphoma: a pooled analysis of two phase I studies conducted in Japan and Korea.

OBJECTIVE: Two phase I studies of darinaparsin including Japanese and Korean patients with relapsed/refractory peripheral T-cell lymphoma were performed to evaluate its safety (primary purpose), efficacy and pharmacokinetic profile (ClinicalTrials.gov: NCT01435863 and NCT01689220). METHODS: Patients received intravenous darinaparsin for 5 consecutive days at 200 mg/m2/day in 4-week cycles, 300 mg/m2/day in 4-week cycles or 300 mg/m2/day in 3-week cycles. RESULTS: Seventeen Japanese and 6 Korean patients were enrolled and treated. Drug-related adverse events developed in 18 patients (78%). Dose-limiting toxicity, grade 3 hepatic dysfunction, was reported on Day 15 of cycle 1 in 1 Japanese patient who received 300 mg/m2/day. The most common drug-related, grade ≥ 3 adverse events were lymphopenia (9%), neutropenia (9%) and thrombocytopenia (9%). No deaths occurred. In 14 evaluable patients, 1 and 3 patients had complete response and partial response, respectively. The plasma concentration-time profiles of arsenic, a surrogate marker for darinaparsin, were similar between Japanese and Korean patients. No significant difference was found in its pharmacokinetic profile. CONCLUSIONS: These data indicate the good tolerability and potential efficacy of darinaparsin in patients with relapsed/refractory peripheral T-cell lymphoma. Darinaparsin 300 mg/m2/day for 5 consecutive days in 3-week cycles is the recommended regimen for phase II study.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. METHODS: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. FINDINGS: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. INTERPRETATION: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. FUNDING: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.

R-CHOP-14 versus R-CHOP-14/CHASER for upfront autologous transplantation in diffuse large B-cell lymphoma: JCOG0908 study.

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).

Ultra-high sensitivity HBsAg assay can diagnose HBV reactivation following rituximab-based therapy in patients with lymphoma.

BACKGROUND & AIMS: HBV reactivation is a risk in patients receiving anti-CD20 antibodies for the treatment of lymphoma. The purpose of this post hoc analysis was to evaluate the efficacy of an ultra-high sensitivity HBsAg assay to guide preemptive antiviral treatment in patients with lymphoma and resolved HBV infections using prospectively stored samples from an HBV DNA monitoring study. METHODS: HBV reactivation (defined as HBV DNA levels of ≥11 IU/ml) was confirmed in 22 of 252 patients. A conventional HBsAg assay (ARCHITECT, cut-off value: 0.05 IU/ml) and an ultra-high sensitivity HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA, cut-off value: 0.0005 IU/ml) were performed at baseline, at confirmed HBV reactivation and monitored after HBV reactivation. RESULTS: Baseline HBsAg was detected using ICT-CLEIA in 4 patients; in all of whom precore mutants with high replication capacity were reactivated. Of the 6 patients with HBV DNA detected below the level of quantification at baseline, 5 showed HBV reactivation and 3 of the 5 had precore mutations. Sensitivity for detection by ARCHITECT and ICT-CLEIA HBsAg assays at HBV reactivation or the next sampling after HBV reactivation was 18.2% (4 of 22) and 77.3% (17 of 22), respectively. Of the 5 patients undetectable by ICT-CLEIA, HBV reactivation resolved spontaneously in 2 patients. All 6 patients reactivated with precore mutations including preS deletion could be diagnosed by ICT-CLEIA HBsAg assay at an early stage of HBV reactivation. Multivariate analysis showed that an anti-HBs titer of less than 10 mIU/ml, HBV DNA detected but below the level of quantification, and HBsAg detected by ICT-CLEIA at baseline were independent risk factors for HBV reactivation (adjusted hazard ratios, 15.4, 31.2 and 8.7, respectively; p <0.05). CONCLUSIONS: A novel ICT-CLEIA HBsAg assay is an alternative method to diagnose HBV reactivation. CLINICAL TRIAL NUMBER: UMIN000001299. LAY SUMMARY: Hepatitis B virus can be reactivated in lymphoma patients receiving anti-CD20 antibodies such as rituximab. Currently, reactivation requires the monitoring of HBV DNA, but monitoring of the surface antigen (HBsAg) could provide a relatively inexpensive, quick and easy alternative. We assessed the performance of an ultra-high sensitivity HBsAg assay and showed that it could be effective for the diagnosis and monitoring of HBV reactivation.

Multicenter phase 1/2 study of forodesine in patients with relapsed peripheral T cell lymphoma.

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.

E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma: A phase I study.

E7777, a recombinant cytotoxic fusion protein comprising diphtheria toxin fragments A and B and human interleukin-2, shares an amino acid sequence with denileukin diftitox but has improved purity and an increased percentage of active protein monomer species. A phase I study was carried out to evaluate the tolerability, safety, pharmacokinetics, and antitumor activity of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma. E7777 (6, 12, and expanded 9 µg/kg/day) was given to 13 patients by i.v. infusion on five consecutive days per 21-day cycle. Dose-limiting toxicities, including increased alanine aminotransferase, hyponatremia (n = 2), hypokalemia, lymphopenia, fatigue, hypoalbuminemia, rash, and increased lipase (n = 1), were observed in all three patients in the 12 µg/kg/day cohort, whereas two of six patients in the 9 µg/kg/day cohort showed decreased appetite or fatigue. The maximum tolerated and recommended dose of E7777 was 9 µg/kg/day for five consecutive days per 21-day cycle. The objective response rate was 38% (5/13) and did not appear to depend on tumor expression of CD25. E7777 was well tolerated, assuming careful management of adverse events during treatment, and preliminary but clinically meaningful antitumor activity was observed. Subsequent studies of E7777 for T-cell lymphomas are warranted. This study was registered with www.ClinicalTrials.gov (NCT1401530).

Correction to: Multicenter phase 1/2 study of forodesine in patients with relapsed peripheral T cell lymphoma.

The original version of this article contained a mistake in Fig. 4. The horizontal axis should be 36 instead of 60.

[Lenalidomide and low-dose dexamethasone therapy for Japanese patients with newly diagnosed multiple myeloma: updated results of the MM-025 study].

In a Japanese phase II study (MM-025), the efficacy and safety of lenalidomide plus low-dose dexamethasone (Rd) were confirmed at a median follow-up of 14.2 months in patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic stem cell transplantation. In the present report, we analyzed the follow-up data from the abovementioned study. Treatment was stopped for all 26 patients after a median follow-up of 31.3 months, and the median treatment duration was approximately 25 months. The overall response rate was 87.5%, and the complete response rate was 20.8%. The median duration of response and progression-free survival were 30.7 and 31.6 months, respectively. The median overall survival has not yet been reached. At least one grade 3/4 adverse event was experienced by 23 patients (88.5%), and 18 patients (69.2%) experienced serious adverse events. There were no treatment-related deaths. Therefore, the efficacy and safety of Rd were confirmed in transplant-ineligible Japanese patients with newly diagnosed multiple myeloma at the present follow-up period.

Efficacy and safety of ibrutinib in Japanese patients with relapsed or refractory mantle cell lymphoma.

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).

Lenalidomide and low-dose dexamethasone in Japanese patients with newly diagnosed multiple myeloma: A phase II study.

In the FIRST trial (MM-020), lenalidomide plus low-dose dexamethasone (Rd) reduced the risk of disease progression or death compared with combination melphalan-prednisone-thalidomide. As the FIRST trial did not include any Japanese patients, the efficacy and safety of continuous treatment with Rd was evaluated in 26 Japanese patients with newly diagnosed multiple myeloma (NDMM) in a single-arm, multicenter, open-label phase II trial (MM-025). Patients received lenalidomide on days 1-21 of each 28-day cycle, with a starting dose of 25 mg/day (dose adjusted for renal impairment), and 40 mg/day dexamethasone (dose adjusted for age) on days 1, 8, 15 and 22 of each 28-day cycle until disease progression or discontinuation for any reason. In the efficacy evaluable population, overall response rate was 87.5%, including 29.2% of patients who achieved a complete response/very good partial response. Median durations of response, progression-free survival and overall survival have not been reached. The most common grade 3-4 adverse events were neutropenia (23%) and anemia (19%). The efficacy and safety of Rd were consistent with data from larger studies, including the FIRST trial, thereby supporting the use of Rd continuous in Japanese patients with NDMM who are ineligible for stem cell transplantation.

Long-term follow-up results of a phase I/II study of melphalan, prednisolone and bortezomib in Japanese transplant-ineligible multiple myeloma patients (JPN-102).

The phase I/II study of melphalan-prednisolone-bortezomib (MPB) therapy in Japanese patients with previously untreated multiple myeloma (MM) who are ineligible for hematopoietic stem cell transplantation (JPN-102 trial) (registered between July 2008 and March 2011) showed an overall response rate in the MPB arm equivalent to that of the VISTA trial. In this study, we followed up the clinical data of 92 of the 101 patients registered in the JPN-102 trial to clarify the long-term outcomes of MPB therapy. The median follow-up period was 50.8 (0.9-66.1) months. The median age of this cohort was 72 (48-84) years. The median progression-free survival was 25.7 (95%CI: 21.3-33.9) months and the overall survival rates at 1, 3 and 5 years were 98, 86 and 76%, respectively. There was no significant difference in either progression-free survival or overall survival when comparing a total bortezomib amount of 39 mg/m2 or more being administered versus less than 39 mg/m2. The outcomes of the JPN-102 cohort appeared, at a minimum, to not be inferior to those of the MPB cohort in the VISTA trial. A prospective trial is needed to establish the MPB regimen as being suitable for Japanese patients with multiple myeloma.

[Safety Assessment of a Short Hydration Regimen for Outpatient Cisplatin-Based Chemotherapy].

BACKGROUND: During administration of thecisplatin (CDDP)containing regimen, hospitalization is necessary to ensure adequate hydration. However, short hydration is widely used when administering CDDP in outpatient chemotherapy centers. METHOD: To assess the safety of the administration of CDDP during short hydration, we retrospectively evaluated adverse events and complications in the outpatients who received CDDP during short hydration between April 2012 and December 2014 in our hospital. RESULT: Sixty patients received CDDP during short hydration. Eighteen patients with non-small cell lung cancer, 17 with gastric cancer, 10 with small cell lung cancer, 9 with cervical cancer, 4 with biliary tract cancer, 1 with endometrial cancer, and 1 with duodenal papilla cancer were retrospectively evaluated. Fifty-five patients completed CDDP treatment(including treatment until PD). The reasons for discontinuation of CDDP treatment were deterioration of general condition, ileus, pneumothorax, cholangitis, and rejection of oral rehydration. Hydronephrosis after CDDP treatment during short hydration(weekly CDDP regimen)was observed in 1 patient. No patient discontinued CDDP due to grade 3 or 4 adverse events. CONCLUSION: No discontinuation of CDDP associated with a short hydration regimen suggests that it has enabled thesafeadministration of CDDP to outpatients.

Monitoring of Hepatitis B Virus (HBV) DNA and Risk of HBV Reactivation in B-Cell Lymphoma: A Prospective Observational Study.

BACKGROUND: There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs). METHODS: We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of ≥ 11 IU/mL. RESULTS: With a median HBV DNA follow-up of 562 days, HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5-12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of <10 mIU/mL and detectable HBV DNA remaining below the level of quantification at baseline were independent risk factors for HBV reactivation (hazard ratio, 20.6 and 56.2, respectively; P < .001). Even in 6 patients with a rapid increase of HBV due to mutations, the monthly HBV DNA monitoring was effective at preventing HBV-related hepatitis. CONCLUSIONS: Monthly monitoring of HBV DNA is useful for preventing HBV reactivation-related hepatitis among B-NHL patients with resolved HBV infection following R-steroid-chemo (UMIN000001299).