Impact of the Clinical Trials Act on Noncommercial Clinical Research in Japan: An Interrupted Time-series Analysis.

BACKGROUND: The number of new noncommercial clinical studies conducted in Japan declined within the first year of the implementation of the Clinical Trials Act (CTA) on April 1, 2018. This study aimed to examine the impact of the CTA's enforcement on the number of new noncommercial clinical studies registered in the Japanese Clinical Trial Registry. METHODS: An interrupted time-series design was used in the analysis, which was conducted from April 2015 to March 2019. We collected data for studies registered in the Clinical Trial Registry, managed by the University Hospital Medical Information Network. RESULTS: In total, 35,811 studies were registered; of these, 16,455 fulfilled the eligibility criteria. The difference in the trend of monthly number of new studies after CTA enforcement decreased significantly by 15.0 (95% confidence interval [CI], -18.7 to -11.3), and the level decreased by 40.8 (95% CI, -68.2 to -13.3) studies from the pre-enforcement to the post-enforcement period. Multigroup analyses indicated that the act exerted a significant effect on the trend of new clinical studies, particularly those with smaller sample sizes, interventional study designs, and nonprofit funding sponsors. CONCLUSIONS: The number of Japanese noncommercial clinical studies declined significantly following implementation of the CTA. It is necessary to establish a system to promote clinical studies in Japan while ensuring transparency and safety.

A phase 2, open-label, multicenter study of ixazomib plus lenalidomide and dexamethasone in adult Japanese patients with relapsed and/or refractory multiple myeloma.

BACKGROUND: TOURMALINE-MM1 was a global study that demonstrated a significant improvement in progression-free survival with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone, in patients with relapsed and/or refractory multiple myeloma. The current study was conducted to evaluate further the efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients. METHODS: This phase 2, open-label, single-arm, multicenter study enrolled patients aged ≥ 20 years with relapsed and/or refractory multiple myeloma at 16 sites in Japan. Patients refractory to lenalidomide or proteasome inhibitor-based therapy at any line were excluded. The primary endpoint was the rate of very good partial response or better in the response-evaluable analysis set. Secondary endpoints were progression-free survival, overall response rate, duration of response, time to progression, overall survival and safety. RESULTS: In total, 34 patients were enrolled. The rate of very good partial response or better was 50.0% (95% confidence interval 31.9-68.1) and the overall response rate was 84.4% (95% confidence interval 67.2-94.7). Median progression-free survival was 22.0 months (95% confidence interval 17.3-not evaluable) and median overall survival was not estimable. The safety profile of ixazomib plus lenalidomide and dexamethasone in this study was similar to that in the TOURMALINE-MM1 study. CONCLUSIONS: The efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma are comparable with reported TOURMALINE-MM1 study results. CLINICALTRIALS. GOV IDENTIFIER: NCT02917941; date of registration September 28, 2016.

[Acquired platelet dysfunction with severe bleeding tendency in triple-negative myelofibrosis].

A 50-year-old man demonstrated markedly increased number of white blood cells, anemia, severe splenomegaly, and bleeding tendency. Bone marrow analysis revealed remarkable hypercellularity; dysplasia in multilineage cells, including megakaryocytes; and fibrosis. He was eventually diagnosed with triple-negative myelofibrosis. A massive hematoma developed at the bone marrow biopsy site. A similar episode recurred after the second bone marrow biopsy. The von Willebrand factor and other coagulation factor activities were within normal ranges. Platelet aggregation analyses demonstrated highly impaired aggregation induced by ADP, collagen, and epinephrine. Treatment with hydroxyurea and ruxolitinib, a JAK inhibitor, was ineffective, and he eventually died on day 144 after hospitalization. Acquired platelet dysfunction uncommonly occurs in patients with myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), without precise elucidation of the frequency and underlying mechanism. The onset of bleeding tendency in the current patient suggested that platelet dysfunction may be caused by somatic genetic events. Here, we discuss the mechanisms of acquired platelet dysfunction in MDS or MPN with a literature review.

Correction to: Impact of oral voriconazole during chemotherapy for acute myeloid leukemia and myelodysplastic syndrome: a Japanese nationwide retrospective cohort study.

In the original publication, in Figure 1 the month range of DPC Database has been given incorrectly.

Intravenous itraconazole compared with liposomal amphotericin B as empirical antifungal therapy in patients with neutropaenia and persistent fever.

BACKGROUND: Fungal infections are a major complication of neutropaenia following chemotherapy. Their early diagnosis is difficult, and empirical antifungal treatment is widely used, and uses of less toxic drugs that reduce breakthrough infection are required. OBJECTIVE: We conducted a multicentre, open-label, randomised, non-inferiority trial to compare the safety and efficacy of intravenous itraconazole (ivITCZ) and liposomal amphotericin B (LAmB) as empirical antifungal therapy in patients with haematological malignancies with neutropaenia and persistent fever. METHODS: Patients with haematological malignancies who developed fever refractory to broad-spectrum antibacterial agents under neutropaenia conditions were enrolled. Patients were randomised for treatment with LAmB (3.0 mg/kg/d) or ivITCZ (induction: 400 mg/d, maintenance: 200 mg/d). RESULTS: Observed overall favourable response rates of 17/52 (32.7%) and 18/50 (36.0%) in the LAmB and ivITCZ groups, with a model-based estimate of a 4% difference (90% CI, -12% to 20%), did not fulfil the statistical non-inferiority criterion. In the LAmB group, there were two cases of breakthrough infection and five cases of probable invasive fungal disease, whereas in the itraconazole group, neither breakthrough infection nor probable invasive fungal disease occurred. Patients in the ivITCZ group had significantly fewer grade 3-4 hypokalaemia-related events than LAmB group patients (P < .01). The overall incidence of adverse events tended to be lower in the ivITCZ group (P = .07). CONCLUSION: ivITCZ showed similar efficacy and safety as LAmB as empirical antifungal therapy in haematological malignancy patients with febrile neutropaenia, although the small sample size and various limitations prevented demonstration of its non-inferiority.

Efficacy and Safety of a Weekly Cyclophosphamide-Bortezomib-Dexamethasone Regimen as Induction Therapy Prior to Autologous Stem Cell Transplantation in Japanese Patients with Newly Diagnosed Multiple Myeloma: A Phase 2 Multicenter Trial.

We assessed the efficacy and safety of weekly cyclophosphamide-bortezomib-dexamethasone (CBD) induction prior to autologous stem cell transplantation (ASCT) in newly diagnosed Japanese patients with multiple myeloma (MM). This regimen consisted of four 28-day cycles of once-weekly oral cyclophosphamide (300 mg/m2), subcutaneous bortezomib (1.3 mg/m2), and oral dexamethasone (40 mg). Responding patients underwent stem cell collection followed by ASCT. The primary endpoint was the postinduction rate of achieving a near complete response (nCR) or better. Among the 38 enrolled patients, a complete response (CR), an nCR, a very good partial response (VGPR), and a partial response (PR) were achieved in 10.5, 2.6, 23.7, and 36.8% of cases, respectively. A grade 4 hematological adverse event (AE) was observed in 1 patient. Grade 3-4 infection, including febrile neutropenia, was observed in 4 patients (10.5%). Although 2 patients dropped out due to AE, 94.7% of the patients completed the induction phase. However, because of a poor response to induction chemotherapy (

Impact of oral voriconazole during chemotherapy for acute myeloid leukemia and myelodysplastic syndrome: a Japanese nationwide retrospective cohort study.

BACKGROUND: The prevention of invasive fungal infections is important in patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) receiving cytoreductive chemotherapy. However, the role of oral voriconazole (VRCZ) in such patients has not been established. This study aimed to investigate the effectiveness of oral VRCZ compared to that of first-generation azoles prescribed within 7 days after the onset of chemotherapy in adult patients with AML/MDS using the Japanese administrative database. METHODS: This nationwide retrospective cohort study was conducted using the Diagnosis Procedure Combination/Per-Diem Payment System. The primary outcome was the proportion of patients who switched to intravenous antifungal agents. Analyses using the instrumental variable method were performed to address unmeasured confounding. RESULTS: In total, data on 5517 inpatients from 142 hospitals were analyzed. An oral VRCZ prescription was significantly associated with a reduction in the proportion of patients switching to intravenous antifungal agents compared to first-generation azole prescription (21.0% (95% confidence interval [CI] - 33.4 to - 8.6)). The impact of oral VRCZ in reducing the proportion of patients switching to intravenous antifungal agents was stronger in patients aged < 65 years than in those aged ≥ 65 years (- 40.6%, 95% CI - 63.2 to - 17.9; - 21.9%, 95% CI - 35.8 to - 8.1, respectively) and in patients prescribed oral azole within 3 days from the onset of chemotherapy than in those prescribed the same later (- 32.9%, 95% CI - 46.7 to - 19.2; - 9.0%, 95% CI - 33.7 to 15.7, respectively). CONCLUSION: Oral VRCZ administration may benefit adult patients with AML/MDS undergoing chemotherapy.

Phase II Study of Treatment for Newly Diagnosed Multiple Myeloma Patients Over 75 Years Old with Alternating Bortezomib/dexamethasone and Lenalidomide/dexamethasone: the MARBLE Trial.

Elderly multiple myeloma (MM) patients, who are generally ineligible for transplantation, have high risks of death and treatment discontinuation, and require a regimen incorporating novel agents that balance safety, tolerability, and efficacy. We evaluated alternating bortezomib-dexamethasone and lenalidomide-dexamethasone treatments administered over a 63-day cycle in transplant-ineligible elderly patients with newly diagnosed MM. Subcutaneous bortezomib 1.3 mg/m2 was administered weekly on Days 1, 8, 15, and 22; oral lenalidomide 15 mg daily on Days 36-56; and oral dexamethasone 20 mg on Days 1, 8, 15, 22, 36, 43, 50, and 57 for 6 cycles. The primary endpoint was the overall response rate.

[Successful Treatment of T-Cell Prolymphocytic Leukemia with Alemtuzumab].

T-cell prolymphocytic leukemia(T-PLL)is a highly aggressive hematopoietic malignancy with poor prognosis and is extremely rare in Japan. Since T-PLL cells usually express high levels of CD52, the anti-CD52 monoclonal antibody alemtuzumab is expected to exhibit an antitumor effect via its antibody-dependent cell cytotoxicity(ADCC)and complement-dependent cytotoxicity(CDC). However, the therapeutic efficiency of alemtuzumab for T-PLL has not been established in Japan. Furthermore, only a few patients have completed the treatment schedule because of adverse events. Here, we report a 64-yearold woman with multiple comorbidities who was successfully treated with alemtuzumab.

[Safety and management of adverse events of ixazomib/lenalidomide/dexamethasone therapy in Japanese patients with relapsed/refractory multiple myeloma].

Based on the outcomes of the TOURMALINE-MM1 trial-a global, randomized, double-blind, placebo-controlled phase III clinical study-the use of an oral proteasome inhibitor has been approved in combination with lenalidomide and dexamethasone (Rd) for the treatment of relapsed/refractory multiple myeloma (MM). In this study, we enrolled 41 Japanese patients, who constituted the safety population. The overall incidence of adverse events (AEs) was similar in IRd and placebo-Rd groups. AEs including thrombocytopenia, skin disorders (rash), vomiting, nausea, and diarrhea occurred more frequently in the IRd group than in the placebo-Rd group. There were no cumulative toxicities, and most toxicities were usually manageable with close monitoring, supportive care, and dose modifications. Compared with the overall safety population, the safety profile of Japanese patients was consistent. Moreover, in Japanese patients, there were no on-study deaths and the incidence of serious AEs was less frequent.

Measurement of Proteasome Activity in Peripheral Blood Mononuclear Cells as an Indicator of Susceptibility to Bortezomib-Induced Severe Neurological Adverse Events in Patients with Multiple Myeloma.

AIMS: To explore the biomarker for predicting the occurrence of adverse events in myeloma patients treated by intravenous bortezomib, we measured proteasome activity in peripheral blood mononuclear cells. METHODS: Samples were obtained from 34 bortezomib-naïve patients. Proteasome activity was measured at pre- and postchemotherapy phase by using a synthetic substrate. RESULTS: Bortezomib injection resulted in a dramatic decrease in proteasome activity, reaching 32.4 ± 18.79% (mean ± SD) of the pretreatment level at 1 h, but it generally recovered at the end of the first course. In total, 6 patients manifested with severe bortezomib-induced peripheral neuropathy (sBIPN) in the second-third course. There was a nonsignificant trend for these patients to have lower levels of the relative proteasome activity at the end of the first course than those without sBIPN (median: 74.03 vs. 103.2%, p = 0.052). Moreover, in all of them, proteasome activity did not recover to the pretreatment level, whereas no patients with complete recovery manifested with sBIPN. Analysis with Fisher's exact test demonstrated that incomplete recovery of proteasome activity is a significant risk factor for sBIPN (p = 0.014). CONCLUSION: Patients with incomplete recovery of proteasome activity are at high risk for developing sBIPN, and the susceptible patients can be indicated by monitoring proteasome activity.

Alternating bortezomib-dexamethasone and lenalidomide-dexamethasone in patients with newly diagnosed multiple myeloma aged over 75 years.

More than 40% of Japanese patients with multiple myeloma (MM) are over 75 years of age at diagnosis. Regardless of the treatment benefits, complications and relapses obstruct long-term survival. We conducted a phase II, open-label, single-arm, multicenter clinical trial to assess the efficacy and safety of alternating bortezomib-dexamethasone (Bd) and lenalidomide-dexamethasone (Ld) (Bd/Ld) treatment in MM patients aged over 75 years (MARBLE trial). Patients received Bd therapy from days 1 to 35 and Ld therapy from days 36 to 63. For Bd therapy, patients were administered bortezomib 1.3 mg/m2 and oral dexamethasone 20 mg on days 1, 8, 15, and 22. For Ld therapy, they were administered lenalidomide 15 mg from days 36 to 56 and dexamethasone 10 mg on days 36, 43, 50, and 57. They underwent six treatment cycles in total, each consisting of a 63-day regimen. In total, 10 patients were enrolled, with a median age of 81 years. Efficacy was not evaluated because the patients were fewer than planned. The overall response rate was 80.0% and complete response rate 40.0%. Seventy percent of patients completed the study treatment. Progression-free survival and overall survival at 2 years were 40.0% and 80.0%, respectively. Adverse events of grade 3 or higher, including anemia, decreased lymphocyte count, neutropenia, and hypokalemia, were observed in eight patients. Alternating chemotherapy with Bd/Ld might be feasible, but its efficacy should be verified further.

Real-world treatment patterns and clinical outcomes in patients with AML in Japan who were ineligible for first-line intensive chemotherapy.

Acute myeloid leukemia (AML) predominantly affects elderly adults, and its prognosis worsens with age. Treatment options for patients in Japan ineligible for intensive chemotherapy include cytarabine/aclarubicin ± granulocyte colony-stimulating factor (CA ± G), azacitidine (AZA), low-dose cytarabine (LDAC), targeted therapy, and best supportive care (BSC). The country's aging population and the evolving treatment landscape are contributing to a need to understand treatment pathways and associated outcomes. This retrospective chart review evaluated outcomes in patients across Japan with primary/secondary AML who were ineligible for intensive chemotherapy and began first-line treatment or BSC between 01/01/2015 and 12/31/2018. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and healthcare resource utilization (HRU). Of 199 patients (58% > 75 years), 121 received systemic therapy (38 CA ± G, 37 AZA, 7 LDAC, 39 other) and 78 received BSC. Median OS was 5.4, 9.2, 2.2, 3.8, and 2.2 months for CA ± G, AZA, LDAC, other systemic therapy, and BSC, respectively; median PFS was 3.4, 7.7, 1.6, 2.3, and 2.1 months, respectively. HRU rates were uniformly high, with > 80% patients hospitalized in each cohort. The poor clinical outcomes and high HRU among Japanese AML patients who are ineligible for intensive chemotherapy highlight an unmet need for novel therapies.

Primary Intramuscular Classic Hodgkin Lymphoma: A Rare Case Report.

Hodgkin lymphoma (HL) is a hematologic malignancy that typically presents with lymphadenopathy. We herein report a patient with HL who presented with an intramuscular mass that required differentiation from an inflammatory lesion. A 65-year-old Japanese woman was referred to our hospital with a chief complaint of chronic and expanding tumor in her left thigh. By surgical resection, she was diagnosed with primary intramuscular, Epstein-Barr virus-positive, mixed-cellularity classic HL. She received combined modality therapy, resulting in a complete response. Primary intramuscular classic HL is extremely rare. It should be listed as a differential diagnosis of intramuscular tumors.

The Conspicuousness of High Endothelial Venules in Angioimmunoblastic T-cell Lymphoma Is Due to Increased Cross-sectional Area, Not Increased Distribution Density.

Angioimmunoblastic T-cell lymphoma (AITL) is a T-cell lymphoma of follicular helper T-cell origin. Histologically, neoplastic T-cells proliferate to form clusters adjacent to or between arborizing high endothelial venules (HEVs). HEVs in normal lymph nodes express sulfated glycans called peripheral lymph node addressin (PNAd); however, it remains unclear whether PNAd is also expressed on HEVs in AITL. Furthermore, although it is widely accepted that HEVs are conspicuous in AITL due to their proliferation, quantitative histological support for this concept is lacking. To investigate these issues, we employed monoclonal antibodies recognizing PNAd, namely, MECA-79, HECA-452, and 297-11A, and performed quantitative immunohistochemical analysis of HEVs in 36 AITL-affected and 67 normal lymph nodes. Staining with all three antibodies confirmed that AITL HEVs express PNAd. Moreover, AITL HEVs were bound calcium-dependently by L-selectin-IgM fusion proteins, indicating that they function in the recruitment of L-selectin-expressing lymphocytes. Unexpectedly, HEV distribution density was not increased but rather decreased in AITL compared with normal lymph nodes, but HEV cross-sectional area in AITL was significantly greater than that seen in normal lymph nodes. Overall, these results indicate that the prominence of AITL HEVs is likely due to increased cross-sectional area rather than increased distribution density.

Comparison of prognostic scores in transplant-ineligible patients with peripheral T-cell lymphoma not otherwise specified and angioimmunoblastic T-cell lymphoma: a retrospective study from the national hospital organization in Japan.

We retrospectively analyzed the risk factors for outcomes among patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, n = 100) and angioimmunoblastic T-cell lymphoma (AITL, n = 128) who did not receive hematopoietic stem cell transplantation between 2008 and 2018. We designed a comparison of prognostic scores specifically for PTCL-NOS and AITL. The international prognostic index (IPI) was useful for investigating the risk factors associated with outcomes among transplant-ineligible patients with PTCL-NOS (Harrell's c-statistic 0.715) and AITL (c-statistic 0.615). The prognostic index for T-cell lymphoma (PIT), modified PIT, and the International Peripheral T Cell Lymphoma Project for overall survival (OS) seemed to identify separate prognostic groups, based on visual assessment of Kaplan-Meier curves. However, better c-statistics (>0.7) were only found for the IPI score for OS in PTCL-NOS. Strategies that carefully select PTCL patients with higher IPI scores may help to identify individuals suitable for novel therapies.

[Progressive multifocal leukoencephalopathy after rituximab therapy in a patient with mantle cell lymphoma].

A 74-year-old man, who had mantle cell lymphoma treated with several anticancer drugs including rituximab, was admitted to our hospital because of gait disturbance and progressive paralysis of the right lower limb. T2-weighted MR image showed multiple high intensity lesions in the left parietal lobe. Suspected of being cerebral invasion of lymphoma, high-dose methotrexate was begun, but the patient died of sepsis without neurological improvement. At autopsy, it was proven that neurological symptoms had been caused by progressive multifocal leukoencephalopathy (PML). PML should be considered as a possible complication of heavily treated lymphoma.

[Prediction of treatment efficacy by the M-protein reduction rate after the first cycle of VAD therapy for multiple myeloma].

In recent years, novel drugs for multiple myeloma such as bortezomib and thalidomide have been shown to be effective. However, in Japan, these drugs are indicated only for patients with relapsed or refractory multiple myeloma. There are no established criteria for the definition of refractory cases, and it is often difficult to determine when treatment methods should be changed for those cases. Therefore, we performed a retrospective study to investigate whether treatment responses can be predicted in the early stage of VAD therapy. After the first and third cycles of VAD, the M-protein reduction rate was evaluated. As a result, it was estimated with a 50% probability that an M-protein reduction rate of 87.6% (lower limit of the 95% CI, 73.9%) after the first cycle of VAD can predict a reduction of 90% after the third cycle. The progression-free survival period was slightly longer in the group achieving 90% M-protein reduction after the third cycle than in the group who did not achieve this rate (3.3 vs 2.2 years, p=0.09). These findings suggest that a change from conventional to novel therapeutic drugs in refractory cases identified by the responses to the first cycle of VAD can be a beneficial treatment strategy.

Phase II study of dose-adjusted gemcitabine, dexamethasone, cisplatin, and rituximab in elderly relapsed diffuse large B-cell lymphoma patients.

High-dose chemotherapy and autologous stem cell transplantation (ASCT) are too toxic for elderly patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Therefore, effective and tolerable regimens for elderly patients are urgently needed. The present phase II study assessed the efficacy and safety of dose-adjusted therapy with gemcitabine, dexamethasone, cisplatin, and rituximab (GDP-R) in this population. ASCT-ineligible elderly patients with relapsed or refractory DLBCL received dose-adjusted GDP-R in each 28-day cycle for up to six cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints were complete response (CR) rate, progression-free survival (PFS), and safety. Thirty-three patients were enrolled and received dose-adjusted GDP-R. The median age was 75 years (range: 68-87 years). The ORR was 82.8% (90% confidence interval [CI], 67.1-93.0%), with a CR rate of 58.6% (90% CI, 41.7-74.1%). At a median follow-up of 20.9 months, the 2-year PFS rate was 46.8% (90% CI, 30.7-61.5%) and the 2-year overall survival rate was 63.2% (90% CI, 45.8-76.3%). The most frequently observed grade 4 adverse events were neutropenia (63.6%), thrombocytopenia (57.6%), and lymphocytopenia (39.4%). Dose-adjusted GDP-R is a promising salvage regimen for ASCT-ineligible elderly patients with relapsed DLBCL after rituximab-containing chemotherapy and warrants further investigation.

Submassive hepatocellular necrosis associated with infiltration by peripheral T-cell lymphoma of cytotoxic phenotype: report of two cases.

Hepatocellular necrosis may be complicated in the clinical course of T-cell lymphoma. Herein are reported two cases of peripheral T-cell lymphoma associated with a rapid increase of serum transaminases in their final course. The final diagnoses were enteropathy-type T-cell lymphoma of the jejunum (patient 1) and hepatosplenic T-cell lymphoma (patient 2). The livers of both patients had non-zonal, well-demarcated coagulation necrosis (approximately 70% in patient 1 and 40% in patient 2) that was infiltrated by lymphoma cells bearing a cytolytic granule content (granzyme B). Hepatocytes in the necrotic areas in patient 2 showed immunoreactivity for human simplex virus type 1. Although the mechanism of the hepatocyte necrosis is unclear, it is suggested that the hepatocyte submassive necrosis may be related to an infection complicated in the final course of lymphoma or by certain direct effects of the tumor cells.