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Clozapine (CLZ) is extensively used for treatment-resistant schizophrenia (TRS) with caution to avoid serious adverse events such as agranulocytosis and drug-drug interactions (DDIs). In the current report, we present a case of a 35-year-old male non-smoking TRS patient whose steady-state plasma trough concentrations (C trough ) of CLZ and its active metabolite, N-desmethylclozapine (NDMC), were significantly increased after initiating oral administration of lemborexant (LEM), a dual orexin receptor antagonist, for the treatment of insomnia. The patient experienced oversedation with sleepiness and fatigue while maintaining high levels of C trough of CLZ. The increased concentrations of CLZ returned to normal ranges after the discontinuation of LEM dosing, implying a pharmacokinetic DDI between CLZ and LEM. To gain insight into possible mechanisms, we performed in vitro assays of CYP1A2- and CYP3A4-mediated CLZ metabolism by measuring the formations of NDMC and clozapine N-oxide (CNO). In accordance with previous studies, the incubation of CLZ with each enzyme resulted in the production of both metabolites. LEM had only a weak inhibitory effect on CYP1A2- and CYP3A4-mediated CLZ metabolism. However, the preincubation of LEM with CYP3A4 in the presence of NADPH showed a significant enhancement of inhibitory effects on CLZ metabolism with IC 50 values for the formations of CNO and NDMC of 2.8 μM and 4.1 μM, respectively, suggesting that LEM exerts as a potent time-dependent inhibitor for CYP3A4. Taken together, the results of the current study indicate that co-medication of CLZ with LEM may lead to increase in exposure to CLZ and risks of CLZ-related adverse events., (© 2023 British Pharmacological Society.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS., Competing Interests: TF has received honoraria from Takeda Pharmaceutical; TT has received honoraria from Bristol Myers Squibb (BMS), Janssen Pharmaceutical, Sanofi, Kyowa Kirin and Chugai Pharmaceutical; YS has received honoraria from Ono Pharmaceutical, BMS, Janssen Pharmaceutical, Sanofi, Kyowa Kirin, Takeda Pharmaceutical and Chugai Pharmaceutical; SM has received honoraria from Sanofi and Ono Pharmaceutical; and NU has received honoraria from BMS and Takeda. JK is a consultant for Janssen Pharmaceutical, Abbvie and BMS; has received research funding from Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Shionogi and BMS; and has received honoraria from Janssen Pharmaceutical, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi and BMS. None of the pharmaceutical companies aforementioned benefited from the present research or played any role in our study. All other authors declare that they have no competing interests., (Copyright: © Inoue et al.)

B-cell lymphomas (BCLs) are the most common disease entity among hematological malignancies and have various genetically and molecularly distinct subtypes. In this study, we revealed that the blockade of phosphoinositide-dependent kinase-1 (PDPK1), the master kinase of AGC kinases, induces a growth inhibition via cell cycle arrest and the induction of apoptosis in all eight BCL-derived cell lines examined, including those from activated B-cell-like diffuse large B-cell lymphoma (DLBCL), double expressor DLBCL, Burkitt lymphoma, and follicular lymphoma. We also demonstrated that, in these cell lines, RSK2, AKT, and S6K, but not PLK1, SGK, or PKC, are the major downstream therapeutic target molecules of PDPK1 and that RSK2 plays a central role and AKT and S6K play subsidiary functional roles as the downstream effectors of PDPK1 in cell survival and proliferation. Following these results, we confirmed the antilymphoma efficacy of TAS0612, a triple inhibitor for total RSK, including RSK2, AKT, and S6K, not only in these cell lines, regardless of disease subtypes, but also in all 25 patient-derived B lymphoma cells of various disease subtypes. At the molecular level, TAS0612 caused significant downregulation of MYC and mTOR target genes while inducing the tumor suppressor TP53INP1 protein in these cell lines. These results prove that the simultaneous blockade of RSK2, AKT, and S6K, which are the pivotal downstream substrates of PDPK1, is a novel therapeutic target for the various disease subtypes of BCLs and line up TAS0612 as an attractive candidate agent for BCLs for future clinical development., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

To evaluate the specific prognostic value of CAs, we conducted an analysis of 923 symptomatic multiple myeloma patients. Among this cohort, 480 patients had complete data set of high-risk CAs by interphase fluorescent in situ hybridization at diagnosis. In the high-risk group analysis, the median OS of patients without CAs ( n  = 338, 72 %) was 6.5 years, patients with del(17p) ( n  = 42, 9 %) was 4.4 years, patients with t(4;14) or t(14;16) ( n  = 72, 15 %) was 4.4 years, and patients with double-positive CAs(del(17p) and t(4;14) or t(14;16)) ( n  = 18, 4 %) was 2.1 years ( p  = 0.032). Patients with double-positive CAs had a significantly worse prognosis., Competing Interests: All authors received research funding from ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb Company. JKU is appointed as an officer or advisor at Kansai Medical Net. JKU received lecture honoraria from Bristol-Myers Squibb Company, Janssen Pharmaceutical K. K., Sanofi K.K., ONO PHARMACEUTICAL CO., LTD., AbbVie GK., Takeda Pharmaceutical Company Limited, and Novartis Pharma KK. AT received lecture honoraria from Bristol-Myers Squibb Company, Novartis Pharma KK, Kyowa Kirin Co., Ltd., Astellas Pharma Inc., Nippon Shinyaku Co., Ltd., JANSSEN PHARMACEUTICAL K.K., Otsuka Pharmaceutical Co., Ltd. MH received lecture honoraria from Novartis Pharma K.K., Takeda Pharmaceutical Company, Limited, Bristol-Myers Squibb., Otsuka Pharmaceutical Co., Ltd. IM received lecture honoraria from Novartis Pharma KK, Bristol-Myers Squibb Company, Pfizer Japan Inc., DAIICHI SANKYO COMPANY, LIMITED., Otsuka Pharmaceutical Co., Ltd., Astellas Pharma Inc., Janssen Pharmaceutical K.K, AbbVie GK., Takeda Pharmaceutical Company Limited, ONO PHARMACEUTICAL Co., Ltd., SymBio Pharmaceuticals Limited. HS received lecture honoraria from Takeda Pharmaceutical Company, Limited., ONO PHARMACEUTICAL CO., LTD., Novartis Pharma K.K., Bristol-Myers Squibb K.K., JANSSEN PHARMACEUTICAL K.K., CHUGAI PHARMACEUTICAL CO., LTD., Sanofi K.K., AstraZeneca K.K. TI received lecture honoraria from Bristol-Myers Squibb, Mundipharma K.K., Novartis Pharma K.K., Pfizer Japan Inc., Takeda Pharmaceutical Company, Limited., AbbVie GK., CHUGAI PHARMACEUTICAL CO., LTD., Sanofi K.K., Nippon Shinyaku Co., Ltd., CSL Behring K.K., Otsuka Pharmaceutical Co., Ltd., NIHON PHARMACEUTICAL CO., LTD., JANSSEN PHARMACEUTICAL K.K.. SF received lecture honoraria from Takeda Pharmaceutical Company, Ltd., Sanofi K.K., JANSSEN PHARMACEUTICAL K.K., ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb K.K. TT received lecture honoraria from Sanofi K.K.. JKU received writing fees from JANSSEN PHARMACEUTICAL K.K., Bristol-Myers Squibb K.K. JKU received grants for research from Bristol-Myers Squibb Company, ONO PHARMACEUTICAL CO., LTD., Sysmex Corporation, Takeda Pharmaceutical Company, Limited, Otsuka Pharmaceutical Co., Ltd., Incyte Corporation, JANSSEN PHARMACEUTICAL K.K., Pfizer Japan Inc., CHUGAI PHARMACEUTICAL Co., Ltd., Kyowa Kirin Co., Ltd., IQVIA Services Japan K.K. AT received grants for research from ONO PHARMACEUTICAL Co., Ltd., COGNANO, Inc., DKS Co., Ltd.. IM received grants for research from Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., Astellas Pharma Inc., AbbVie GK., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited., Alexion, Otsuka Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K. NH received grants for research from Otsuka Pharmaceutical Co., Ltd. HS received grants for research from JANSSEN PHARMACEUTICAL K.K., ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb K.K., Novartis Pharma K.K., AstraZeneca K.K., AbbVie GK., Eisai Co., Ltd., HUYABIO International, CHUGAI PHARMACEUTICAL CO., LTD., PharmaEssentia Japan KK. TI received grants for research from Bristol-Myers Squibb. JKU recieved scolarship grant from Kyowa Kirin Co., Ltd., CHUGAI PHARMACEUTICAL CO., LTD., DAIICHI SANKYO COMPANY, LIMITED, ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Eisai Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Takeda Pharmaceutical Company, Limited., Nippon Shinyaku Co., Ltd. AT received scholarship grants from Takeda Pharmaceutical Company, Limited, Nippon Shinyaku Co., Ltd., Kyowa Kirin Co., Ltd., CHUGAI PHARMACEUTICAL CO., LTD., Sanofi K.K., Otsuka Pharmaceutical Co., Ltd., Astellas Pharma Inc., Eisai Co., Ltd., OHARA Pharmaceutical Co., Ltd., Popuri, Kinshikouraininjin, AbbVie, SHIONOGI & CO., LTD., Asahi Kasei Pharma Corporation., the Japanese Society of Hematology. MH recieved scholarship grants from CHUGAI PHARMACEUTICAL CO., LTD., Kyowa Kirin Co., Otsuka Pharmaceutical Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., Takeda Pharmaceutical Company, Limited., ONO PHARMACEUTICAL CO., LTD. IM received scholarship grants from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited., Shionogi & Co., Ltd., ASAHI KASEI PHARMA CORPORATION, Eisai Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., NIPPON SHINYAKU CO.,LTD., Otsuka Pharmaceutical Co., Ltd, AbbVie GK., ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. IM received scholarship grants from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited., Shionogi & Co., Ltd., ASAHI KASEI PHARMA CORPORATION, Eisai Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., NIPPON SHINYAKU CO.,LTD., Otsuka Pharmaceutical Co., Ltd, AbbVie GK., ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. HS received scholarship grants from Astellas Pharma Inc., TEIJIN PHARMA LIMITED, SHIONOGI & CO., LTD., Eisai Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., Nippon Shinyaku Co., Ltd. CS received lecture honoraria from Sanofi K.K., JANSSEN PHARMACEUTICAL K.K., Bristol-Myers Squibb K.K., (© 2023 The Author(s).)

Primary central nervous system lymphoma (PCNSL), a relatively rare brain tumor, bears a dire prognosis. On occasion, the rapid progression of the tumor makes immediate diagnosis and initiation of therapy imperative. To achieve swift diagnosis, we adopt flow cytometry (FCM) in addition to conventional histopathology. This study aimed to reveal the utility of FCM diagnosis for PCNSL and the cause of false-negative results of FCM diagnosis. We investigated 33 patients with suspected PCNSL on neuroradiological findings and received both FCM and histological diagnosis. The patients' electronic medical records were investigated, and histological findings, results of FCM, and other clinical data were evaluated. Overall, 27 patients (14 males and 13 females) were diagnosed with PCNSL by histological confirmation. The median age at diagnosis was 68 years. FCM analysis showed lymphoma pattern in 24 cases; however, FCM results did not show lymphoma pattern (sensitivity: 88.9%, specificity: 100%) in the other three lymphoma cases (FCM discordant: FCM-D) and six nonlymphomatous tumor cases. Analysis of FCM-D cases showed the infiltration of T lymphocytes or astrocytes into the tumor tissue, indicating tumor microenvironmental reaction; it is assumed that these reactions deceived FCM diagnosis. The survival of FCM-D patients was superior to FCM concordant counterpart, although the difference was not significant (p = 0.459). The diagnosis of PCNSL by FCM is rapid and highly reliable. Some FCM-D cases are PCNSLs with strong tumor microenvironmental reactions.

The shift of the tumour immune microenvironment to a suppressive state promotes not only the development and progression of the disease in multiple myeloma (MM) but also the development of resistance to immunotherapy. We previously demonstrated that myeloma cells can induce monocytic myeloid-derived suppressor cells (M-MDSCs) from healthy peripheral blood mononuclear cells (PBMCs) via the concomitant secretion of CC motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF), but an unknown mediator also promotes M-MDSC induction. This study demonstrates that miR-106a-5p and miR-146a-5p delivered by tumour-derived exosomes (TEXs) from myeloma cells play essential roles in M-MDSC induction in MM. MiR-106a-5p and miR-146a-5p upregulate various immunosuppressive/inflammatory molecules in PBMCs, such as IDO1, CD38, programmed death-ligand 1, CCL5 or MYD88, which are involved in interferon (IFN)-α response, IFN-γ response, inflammatory response, tumour necrosis factor-α signalling and Interleukin-6-JAK-STAT3 signalling. These molecular features mirror the increases in myeloid cellular compartments of PBMCs when co-cultured with myeloma cells. MiR-106a-5p and miR-146a-5p have a compensatory relationship, and these two miRNAs collaborate with CCL5 and MIF to promote M-MDSC induction. Collectively, novel therapeutic candidates may be involved in TEX-mediated sequential cellular and molecular events underlying M-MDSC induction, potentially improving the efficacy of immunotherapy., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

To investigate the real-world clinical outcomes and management of novel drug-containing therapies for newly diagnosed multiple myeloma (MM) patients, we retrospectively analyzed data on the first-line treatment for newly diagnosed transplant-ineligible MM patients from Kansai Myeloma Forum, a registry network in Japan. A total of 598 patients treated with novel drugs between March 2007 and February 2018 were analyzed. Regimens used were VD (n = 305), Rd (n = 103), VMP (n = 97), VCD (n = 71), and VRd (n = 22). Younger patients tended to receive VRd or VCD, whereas the regimen with the highest median patient age was Rd. More than three-quarters of patients in the Rd group received a reduced dose of lenalidomide. The Rd and VRd groups had a relatively high incidence of infection and skin complications, and the VMP group had the highest incidence of peripheral neuropathy. Overall response rate did not differ significantly between regimens. Multivariate analysis in all patients revealed several poor prognostic factors, such as poor performance status. Novel drug-containing regimens for newly diagnosed MM showed a durable response with manageable AEs in the real-world setting., (© 2023. Japanese Society of Hematology.)

The prognostic impact of patient-related factors, including age, nutritional parameters, and inflammation status, in higher-risk myelodysplastic syndromes (HR-MDS) has been largely unexplored. This multicenter retrospective study aimed to establish a real-world practice-based prognostic model for HR-MDS by considering both disease- and patient-related parameters in 233 patients treated with AZA monotherapy at seven institutions. We found that anemia, presence of circulating blasts in peripheral blood, low absolute lymphocyte count, low total cholesterol (T-cho) and albumin serum levels, complex karyotype, and del(7q) or  - 7 were poor prognostic factors. Therefore, we developed a new prognostic model called the Kyoto Prognostic Scoring System (KPSS) by incorporating the two variables with the highest C-indexes (complex karyotype and serum T-cho level). The KPSS classified patients into the following three groups: good (0 risk factors), intermediate (1), and poor (2). Median overall survival for these groups was 24.4, 11.3, and 6.9, respectively (p < 0.001). The discriminatory power of the KPSS was higher than that of the traditional International Prognostic Scoring System. In conclusion, we identified several nutritional parameters with prognostic relevance in patients with HR-MDS and generated a prognostic model consisting of complex karyotype and serum T-cho level that enabled excellent risk stratification., (© 2023. Japanese Society of Hematology.)

Three types of chromosomal translocations, t(4;14)(p16;q32), t(14;16)(q32;q23), and t(11;14)(q13;q32), are associated with prognosis and the decision making of therapeutic strategy for multiple myeloma (MM). In this study, we developed a new diagnostic modality of the multiplex FISH in immunophenotyped cells in suspension (Immunophenotyped-Suspension-Multiplex (ISM)-FISH). For the ISM-FISH, we first subject cells in suspension to the immunostaining by anti-CD138 antibody and, then, to the hybridization with four different FISH probes for genes of IGH, FGFR3, MAF, and CCND1 tagged by different fluorescence in suspension. Then, cells are analyzed by the imaging flow cytometry MI-1000 combined with the FISH spot counting tool. By this system of the ISM-FISH, we can simultaneously examine the three chromosomal translocations, i.e, t(4;14), t(14;16), and t(11;14), in CD138-positive tumor cells in more than 2.5 × 10 4 nucleated cells with the sensitivity at least up to 1%, possibly up to 0.1%. The experiments on bone marrow nucleated cells (BMNCs) from 70 patients with MM or monoclonal gammopathy of undetermined significance demonstrated the promising qualitative diagnostic ability in detecting t(11;14), t(4;14), and t(14;16) of our ISM-FISH, which was more sensitive compared with standard double-color (DC) FISH examining 200 interphase cells with its best sensitivity up to 1.0%. Moreover, the ISM-FISH showed a positive concordance of 96.6% and negative concordance of 98.8% with standard DC-FISH examining 1000 interphase cells. In conclusion, the ISM-FISH is a rapid and reliable diagnostic tool for the simultaneous examination of three critically important IGH translocations, which may promote risk-adapted individualized therapy in MM., (© 2023. The Author(s).)

Despite recent advances in the range of therapies available for the treatment of multiple myeloma (MM), there are limited data surrounding survival outcomes and baseline characteristics influencing survival in general clinical practice in Japan. The aim of this study was to use electronic medical records (EMRs) to examine overall survival (OS) and prognostic factors in Japanese patients with MM. We extracted EMRs in the Real World Data (RWD) database of patients with a confirmed diagnosis of MM and treatment history with bortezomib, thalidomide, and/or lenalidomide. OS and prognostic factors for OS were analyzed using a univariate analysis and decision tree model. Of the 6509 patients in the database with a diagnosis of MM, 1565 were eligible. Patients had a median (range) age of 72 (23-92) years, a median OS of 53.5 months, and a 5-year OS rate of 45.6%. In alignment with previous studies, International Staging System stage and age were prognostic of OS. In addition, platelet and erythrocyte counts, chloride, total protein, C-reactive protein, and lactate dehydrogenase levels were identified as important prognostic factors for OS and were used to pilot a simple prognostic tool. In conclusion, we found that the survival outcomes extracted from EMRs in the RWD of Japanese patients with MM aligned with a previous retrospective study from Japan. Baseline laboratory parameters prognostic for OS were explored with additional factors to International Staging System and age identified. These might be used to optimize treatment selection, although further investigation using additional data sources is required., Competing Interests: S.U. and S.M. are employees of Bristol Myers Squibb K.K. and stockholders of Bristol Myers Squibb. K.I. and D.I. are employees of SUSMED Inc. These do not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. T.I. reports study funding from Bristol Myers Squibb K.K. and honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Chugai, CSL Behring, Novartis, Sanofi, and Takeda. J.K. reports grants or contracts from Asahi Kasei, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eizai, Fujimoto Pharmaceutical, Kyowa Kirin, Nippon Shinyaku, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Shionogi, Sumitomo Pharmaceutical, Takeda Pharmaceutical, and Taiho Pharmaceutical; consulting fees from Bristol Myers Squibb and Janssen Pharmaceutical; and payments or honoraria from Bristol Myers Squibb, Janssen Pharmaceutical, Ono Pharmaceutical, and Sanofi. K.S. reports honoraria from Abbvie, Amgen, Bristol Myers Squibb, Janssen, Novartis, ONO, Sanofi, and Takeda; consulting fees from Amgen, Bristol Myers Squibb and Takeda; and research funding from Bristol Myers Squibb., (Copyright: © 2023 Uno et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Next-generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)-SCREEN-Japan 01 is a multicenter study to detect actionable mutations using paraffin-embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R-AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High-quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1-RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R-AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP53 mutations had a poor prognosis. As for the detection of actionable mutations, 38% (n = 69) of patients had useful genetic mutation (FLT3-ITD/TKD, IDH1/2, and DNMT3A R822 ) for treatment selection. Comprehensive genomic profiling using paraffin-embedded BM clot specimens successfully identified leukemic-associated genes that can be used as therapeutic targets., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Teleost fish fins are supported by spear-shaped collagen crystals called actinotrichia. Actinotrichia are distributed radially at the distal end of the fins and thought to be necessary for proper formation of the fin and fin-bones. We previously reported that collagen9a1c ( col9a1c ) gene product is essential for the regular arrangement of actinotrichia using col9a1c -knockout zebrafish. Here, we examined the localization pattern of the EGFP-tagged Col9a1c protein in the fins to understand its role in the arrangement of actinotrichia. We found that EGFP-Col9a1c specifically localizes to actinotrichia., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2023 by the authors.)

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1-mutated AML. Although patients with NPM1-mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3A R882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1-mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3A R882 mutations and the co-occurrence of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3A R882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3A R882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3A R882 mutations and triple mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3A R882 /FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3A R882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3A R882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Novel therapeutic drugs have dramatically improved the overall survival of patients with multiple myeloma. We sought to identify the characteristics of patients likely to exhibit a durable response to one such drug, elotuzumab, by analyzing a real-world database in Japan. We analyzed 179 patients who underwent 201 elotuzumab treatments. The median time to next treatment (TTNT) with the 95% confidence interval was 6.29 months (5.18-9.20) in this cohort. Univariate analysis showed that patients with any of the following had longer TTNT: no high risk cytogenic abnormalities, more white blood cells, more lymphocytes, non-deviated κ/λ ratio, lower β 2 microglobulin levels (B2MG), fewer prior drug regimens, no prior daratumumab use and better response after elotuzumab treatment. A multivariate analysis showed that TTNT was longer in patients with more lymphocytes (≥ 1400/μL), non-deviated κ/λ ratio (0.1-10), lower B2MG (< 5.5 mg/L) and no prior daratumumab use. We proposed a simple scoring system to predict the durability of the elotuzumab treatment effect by classifying the patients into three categories based on their lymphocyte counts (0 points for ≥ 1400/μL and 1 point for < 1400/μL) and κ/λ ratio (0 points for 0.1-10 and 1 point for < 0.1 or ≥ 10) or B2MG (0 points for < 5.5 mg/L and 1 point for ≥ 5.5 mg/L). The patients with a score of 0 showed significantly longer TTNT (p < 0.001) and better survival (p < 0.001) compared to those with a score of 1 or 2. Prospective cohort studies of elotuzumab treatment may be needed to validate the usefulness of our new scoring system., (© 2023. The Author(s).)

Many organs of Drosophila show stereotypical left-right (LR) asymmetry; however, the underlying mechanisms remain elusive. Here, we have identified an evolutionarily conserved ubiquitin-binding protein, AWP1/Doctor No (Drn), as a factor required for LR asymmetry in the embryonic anterior gut. We found that drn is essential in the circular visceral muscle cells of the midgut for JAK/STAT signaling, which contributes to the first known cue for anterior gut lateralization via LR asymmetric nuclear rearrangement. Embryos homozygous for drn and lacking its maternal contribution showed phenotypes similar to those with depleted JAK/STAT signaling, suggesting that Drn is a general component of JAK/STAT signaling. Absence of Drn resulted in specific accumulation of Domeless (Dome), the receptor for ligands in the JAK/STAT signaling pathway, in intracellular compartments, including ubiquitylated cargos. Dome colocalized with Drn in wild-type Drosophila. These results suggest that Drn is required for the endocytic trafficking of Dome, which is a crucial step for activation of JAK/STAT signaling and the subsequent degradation of Dome. The roles of AWP1/Drn in activating JAK/STAT signaling and in LR asymmetric development may be conserved in various organisms., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

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).

Background: Primary ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma (POAML) is the most common subtype of indolent ocular adnexal lymphomas. Although radiotherapy (RT) is the standard of care for localized POAML, it can occasionally lead to permanent side effects. Other treatment strategies, such as rituximab (R) monotherapy and immunochemotherapy, have been used for POAML treatment, but their long-term benefits and relative merits remain unclear. While watchful waiting (WW) is a potential option for some indolent lymphomas, the benefits of WW for POAML patients are also unclear., Methods: We here retrospectively analyzed 75 patients who were diagnosed with POAML between 2008 and 2019 in the institutions of the Kyoto Clinical Hematology Study Group., Results: Commonly involved sites were conjunctiva (42.7%), orbit (36.0%), and lacrimal gland (12.0%), and most patients (92.0%) presented with Ann Arbor stage IE disease. The treatment strategy was selected at the physicians' discretion. More patients without subjective symptoms by tumor mass were subjected to WW (29 patients), while more patients with tumor-derived subjective symptoms were treated by tumor-directed therapy (24 received focal RT, and 19 received R monotherapy). Complete response rates were 79.2% and 42.1% in the RT and R groups, respectively. At 60 months of follow-up, the estimated proportions of POAML patients not requiring new treatment were 69.4%, 85.2%, and 53.8% in the WW, RT, and R groups, respectively. There were no significant differences in the time to start a new treatment between WW and RT groups (median: both not reached [NR], p = 0.187) and between WW and R groups (median: NR vs. 69.0 months, p = 0.554). No specific predictive factor for the future need of treatment was identified in the WW group., Conclusion: Our results demonstrate WW may be an acceptable treatment option for POAML, especially for asymptomatic patients., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Immune checkpoint inhibitors(ICIs)could cause immune-related adverse events(irAEs), of which endocrine disorders are relatively common. Symptoms include fatigue, anorexia, and shock, making diagnosis and treatment difficult. This study aimed to analyze the characteristics of patients with non-small cell lung cancer concomitant with endocrine disorders as irAEs. In total, 83 patients who were administered ICIs for advanced or postoperative recurrent non-small cell lung cancer between February 2016 and February 2021 were identified. We retrospectively studied the clinical course and findings of 7 patients who developed endocrine disorders after treatment. Four patients had hypopituitarism, and 3 patients had thyroid dysfunctions. There were 6 male patients and 1 female patient. Regarding anticancer agents, 5 patients received ICI alone, and 2 patients received ICI plus cytotoxic chemotherapies. The patients received treatment from the irAE treatment team in our hospital, and 5 of 7 patients could were able to be readministered ICIs. Endocrine disorders as irAEs require collaboration with specialized departments for early diagnosis and treatment.

Background and Purpose: Anti-CD20 monoclonal antibodies (MoAbs), rituximab (RIT), and obinutuzumab (OBZ) are the central components of immunochemotherapy for B-cell lymphoma (BCL). However, these agents potentially cause B-cell depletion, resulting in the impairment of antibody (Ab) production. During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the optimal prediction of Ab response against anti-SARS-CoV-2 vaccination is critically important in patients with BCL treated by B-cell depletion therapeutics to prevent coronavirus disease 2019 (COVID-19)., Patients and Methods:  We investigated the effect of using RIT and/or OBZ on the Ab response in 131 patients with various types of BCL who received the second SARS-CoV-2 mRNA vaccine either after, during, or before immunochemotherapy containing B-cell-depleting moiety between June and November 2021 at seven institutes belonging to the Kyoto Clinical Hematology Study Group. The SARS-Cov-2 neutralizing Ab (nAb) was measured from 14 to 207 days after the second vaccination dose using the iFlash3000 automatic analyzer and the iFlash-2019-nCoV Nab kit., Results: Among 86 patients who received the vaccine within 12 months after B-cell depletion therapy, 8 (9.3%) were seropositive. In 30 patients who received the vaccine after 12 months from B-cell depletion therapy, 22 (73%) were seropositive. In 15 patients who were subjected to B-cell depletion therapy after vaccination, 2 (13%) were seropositive. The multivariate analysis indicated that an interval of 12 months between B-cell depletion therapy and the subsequent vaccination was significantly associated with effective Ab production. Receiver operating characteristic curve analysis identified the optimal threshold period after anti-CD20 MoAb treatment, which determines the seropositivity against SARS-CoV-2, to be 342 days., Conclusion: The use of anti-CD20 MoAb within 12 months before vaccination is a critical risk for poor Ab response against anti-SARS-CoV-2 vaccination in patients with BCL., Competing Interests: Y. M-K. has received honoraria from Bristol-Myers Squibb (BMS) and Janssen Pharmaceutical. S.M. has received honoraria from Sanofi and Ono Pharmaceutical. T.T. has received honoraria from BMS, Janssen Pharmaceutical, Sanofi, Kyowa Kirin, and Chugai Pharmaceutical. D.N. has received honoraria from Janssen Pharmaceutical and Chugai Pharmaceutical. K.S. has received honoraria from Chugai Pharmaceutical and Sanofi. T.K. has received honoraria from BMS, Ono Pharmaceutical, Chugai Pharmaceutical, Sanofi, and Janssen Pharmaceutical. N.U. has received honoraria from BMS, Janssen Pharmaceutical and Takeda. Y.S. has received honoraria from Ono Pharmaceutical, BMS, Janssen Pharmaceutical, Sanofi, Kyowa Kirin, Takeda Pharmaceutical, and Chugai Pharmaceutical. J.K. is a consultant for Janssen Pharmaceutical and BMS and has received research funding from Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi, Takeda Pharmaceutical, and Mochida Pharmaceutical and has received honoraria from Janssen Pharmaceutical, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi, BMS, and Takeda Pharmaceutical. All other authors have no conflicts of interest in this work., (© 2023 Onishi et al.)

Objective: An autologous formalin-fixed tumor vaccine (AFTV) derived from resected glioblastoma (GBM) tissue can be used against unidentified tumor antigens. Thus, the authors conducted a multicenter double-blind phase IIb trial to investigate the efficacy of an AFTV., Methods: Eligible patients were adults with supratentorial GBMs, 16-75 years of age, with Karnofsky Performance Scale (KPS) scores ≥ 60%, and no long-term steroid administration. An AFTV comprising fixed paraffin-embedded tumor tissue with immune adjuvants or an identical placebo without fixed tumor tissue was injected intradermally over three courses before and after chemoradiotherapy. The primary and secondary end points were overall survival (OS), progression-free survival (PFS), and 3-year survival rate., Results: Sixty-three patients were enrolled. The average patient age was 61 years. The median KPS score was 80%, and the median resection rate was 95%. The full analysis set of 57 patients indicated no significant difference in OS (p = 0.64) for the AFTV group (median OS 25.6 months, 3-year OS rate 38%) compared with the placebo group (31.5 months and 41%, respectively) and no difference in PFS (median PFS 13.3 months in both groups, p = 0.98). For patients with imaging-based total tumor removal, the 3-year PFS rate was 81% in the AFTV group versus 46% in the placebo group (p = 0.067), whereas the 3-year OS rate was 80% versus 54% (p = 0.16), respectively. Similar results were obtained in the p53-negative subgroups. Severe adverse effects were not observed., Conclusions: The AFTV may have potential effects in certain patient subgroups. A phase III study for patients with total tumor removal remains warranted to confirm these findings. Clinical trial registration no.: UMIN000010602 (UMIN Clinical Trials Registry).

Coagulation factor X (FX) deficiency causes severe hemorrhagic symptoms. We herein report a 90-year-old man with hemorrhagic symptoms and prolongation of prothrombin time (PT) and activated partial thromboplastin time (APTT). Cross-mixing tests showed a factor deficiency pattern, but administration of plasma products was not effective. Acquired coagulation factor deficiency was suspected, and immunosuppressive therapy was started. After the intervention, his hemorrhagic symptoms improved. A decrease in FX activity was later confirmed, and anti-FX autoantibody was retrospectively detected by an enzyme-linked immunosorbent assay. Immediate intervention is important for patients suspected of having acquired coagulation factor deficiency.

The safety, efficacy, and pharmacokinetics of copanlisib were evaluated in this phase Ib/II study in Japanese patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL). The primary endpoint was safety at the recommended dose; efficacy endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival. In phase Ib, patients received copanlisib 45 mg intravenously on days 1, 8, and 15 of a 28-day cycle, and when tolerated, consecutive patients received copanlisib 60 mg. As no dose-limiting toxicities occurred at the 45 mg (n = 3) or 60 mg (n = 7) dose in phase Ib, the recommended dose for Japanese patients was determined to be 60 mg, and this dose was used in phase II (n = 15). Although all patients experienced at least one treatment-emergent adverse event (TEAE), with hyperglycemia being the most common AE, no AE-related deaths were reported. The ORR was 68.0% (17/25 patients), median PFS was 302 (95% CI 231-484) days, and the duration of response was 330 (range 65-659) days. The pharmacokinetic properties of copanlisib were similar between Japanese and non-Japanese patients. Overall, copanlisib 60 mg had an acceptable safety profile and showed promising antitumor activity in Japanese patients with relapsed/refractory indolent NHL., (© 2022. The Author(s).)

Background: Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab., Objectives: We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status., Design: We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database., Methods: We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database., Results: In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower β 2 microglobulin (B2MG < 5.5 mg/L) or fewer prior regimens (<4). No parameters were correlated with TTNT under the DBd regimen., Conclusion: We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/μl; 1 point for <200/μl) or WBC counts (0 points for ⩾3500/μl; 1 point for <3500/μl) plus B2MG (0 points for <5.5 mg/L; 1 point for ⩾5.5 mg/L). Patients with a score of 0 showed significantly longer TTNT and significantly better survival compared to those with a score of 1 or 2 (both p  < 0.001). To confirm this concept, our results will need to be validated in other cohorts., Competing Interests: The authors declare no conflicts of interest except JK received honorarium from Bristol-Myers Squibb Co, Janssen Pharmaceutical K.K., Takeda Pharmaceutical Co., Ltd., Sanofi K.K. and Ono Pharma Inc., and is an advisory role in Janssen Pharmaceutical K.K, and Novartis Pharma K.K. TI received honorarium from Bristol-Myers Squibb Co, Takeda Pharmaceutical Co., Ltd. and Sanofi K.K.; and research funding from Bristol-Myers Squibb Co. KI received honorarium from Bristol-Myers Squibb Co, Janssen Pharmaceutical K.K., Takeda Pharmaceutical Co., Ltd., Ono Pharma Inc., Novartis Pharma K.K., Kyowa Kirin Co., Ltd., Celgene K.K., Nippon Shinyaku Co., Ltd., Chugai Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co. Ltd., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., Ltd. and Meiji Seika Pharma Co. Ltd. SF received honoraria from Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Sanofi K.K., Bristol-Myers Squibb Co., Ltd., and Celgene K.K. HT received personal fees from Bristol-Myers Squibb Co (Celgene K.K.), personal fees from Novartis Pharma K.K., grants from Kyowa Kirin Co., Ltd. HS reports honoraria from Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Celgene K.K., Janssen Pharmaceutical K.K., Chugai Pharmaceutical Co., Ltd., Sanofi K.K., AstraZeneca K.K., AbbVie G.K., SymBio Pharmaceuticals Ltd., Eisai Co., Ltd., and Kyowa Kirin Co., Ltd.; and research funding from Pharma Essentia Japan K.K., Janssen Pharmaceutical K.K., Ono Pharmaceutical Co., Ltd., Celgene K.K., Novartis Pharma K.K., Sanofi K.K., AstraZeneca K.K., AbbVie G.K., Eisai Co., Ltd., HUYA Bioscience International, LLC., and Chugai Pharmaceutical Co., Ltd.; and scholarship endowment from Astellas Pharma Inc., Teijin Pharma Ltd., Shionogi & Co., Ltd., Eisai Co., Ltd., Sanofi K.K., Taiho Pharmaceutical Co., Ltd., and Nippon Shinyaku Co., Ltd. CS received honoraria from Bristol-Myers Squibb Co., Celgene K.K., Janssen Pharmaceutical K.K., and Sanofi K.K. IM received personal fees from Bristol-Myers Squibb Co. (Celgene K.K.), personal fees from Novartis Pharma K.K., grants and personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Pfizer Japan Inc., during the conduct of the study; grants from Ono Pharmaceutical Co., Ltd., personal fees from Janssen Pharmaceutical K.K, grants from Nippon Shinyaku Co., Ltd., grants from Kyowa Kirin Co., Ltd., grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Shionogi & Co., Ltd., grants from Teijin Pharma Ltd., grants from Boehringer Ingelheim Co., Ltd., grants from Sanofi K.K., grants from Chugai Pharmaceutical Co., Ltd., grants from Eisai Co., Ltd., grants from MSD K.K, grants from Asahi Kasei Pharma Corporation, grants and personal fees from Astellas Pharma Inc., grants and personal fees from Takeda Pharmaceutical Co., Ltd., grants from Japan Blood Products Organization, grants from Nihon Pharmaceutical Co., Ltd., grants and personal fees from AbbVie GK, grants from Taiho Pharmaceutical Co., Ltd., grants from Mitsubishi Tanabe Pharma Corporation, grants from Nippon Kayaku Co., Ltd., grants from CSL Behring LLC, grants from Mundipharma K.K, grants from Ayumi Pharmaceutical Corporation, grants from Eli Lilly Japan K.K., grants from Actelion Pharmaceuticals Japan Ltd., personal fees from Amgen BioPharma K.K., outside the submitted work. AT-K serves as an advisor for Megakaryon and receives research fundings from Ono Pharmaceutical Co., Ltd., DSK, and Cognano. JK received research funding from Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Eisai Co., Ltd., Bristol-Myers Squibb Co., Sysmex, Dainippon Sumitomo Pharma Co., Ltd., Nippon Shinyaku Co., Ltd., AbbVie GK, Teijin Pharma Ltd. and Otsuka Pharmaceutical Co. Ltd., has received honoraria from Janssen Pharmaceutical K.K, Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Eisai Co., Ltd., SymBio Pharmaceutical Limited, Bristol-Myers Squibb Co., Astellas Pharma Inc., Pfizer Japan Inc., Nippon Shinyaku Co., Ltd., Daiichi Sankyo Co. Ltd., Dainippon Sumitomo Pharma Co., Ltd., AbbVie G.K. and Otsuka Pharmaceutical Co. Ltd., and is a consultant for Janssen Pharmaceutical K.K, and Bristol-Myers Squibb Co., (© The Author(s), 2022.)

Chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen have shown positive responses in patients with multiple myeloma (MM). The phase 2 portion of the CARTITUDE-1 study of ciltacabtagene autoleucel (cilta-cel) included a cohort of Japanese patients with relapsed/refractory MM. Following a conditioning regimen of cyclophosphamide (300 mg/m 2 ) and fludarabine (30 mg/m 2 ), patients received a single cilta-cel infusion at a target dose of 0.75 × 10 6 (range, 0.5-1.0 × 10 6 CAR-positive viable T cells/kg). The primary endpoint was overall response rate (ORR; defined as partial response or better) by International Myeloma Working Group criteria. A key secondary endpoint was the rate of very good partial response (VGPR) or better (defined as VGPR, complete response, stringent complete response). This first analysis was performed at 6 months after the last patient received cilta-cel. Thirteen patients underwent apheresis, nine of whom received cilta-cel infusion. Eight patients who received cilta-cel at the target dose responded, yielding an ORR of 100%. Seven of eight (87.5%) patients achieved a VGPR or better. One additional patient who received a below-target dose of cilta-cel also achieved a best response of VGPR. MRD negativity (10 -5 threshold) was achieved in all six evaluable patients. Eight of nine (88.9%) patients who received cilta-cel infusion experienced a grade 3 or 4 adverse event, and eight (88.9%) patients experienced cytokine release syndrome (all grade 1 or 2). No CAR-T cell neurotoxicity was reported. A positive benefit/risk profile for cilta-cel was established for heavily pretreated Japanese patients with relapsed or refractory MM., (© 2022 Janssen Research and Development, LLC. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Accurate detection of myeloproliferative neoplasms (MPN)-associated gene mutations is necessary to correctly diagnose MPN. However, conventional gene testing has various limitations, including the requirement of skilled technicians, cumbersome experimental procedures, and turnaround time of several days. The gene analyzer i-densy IS-5320 allows gene testing using the quenching probe-Tm method. Specifically, pretreatment of samples including DNA extraction, amplification and detection of genes, and analysis of results are performed in a fully automatic manner after samples and test reagents are added into this system, which is compact and can be easily installed in a laboratory. The aim of this study is to investigate the sensitivity and specificity associated with the simultaneous detection of MPN-associated gene mutations., Methods: We conducted an analysis of MPN-associated genes using i-densy IS-5320. We analyzed 384 samples (171 JAK2 V617F mutations, 10 JAK2 exon12 mutations, 104 CALR mutations, and 26 MPL mutations) that had been examined using conventional approaches such as allele-specific polymerase chain reaction (PCR), droplet digital PCR, and the direct sequencing method., Results: The detection accuracy of JAK2 V617F, JAK2 exon 12, CALR, and MPL was 100.0% (383/383), 99.7% (383/384), 100.0% (370/370), and 99.7% (377/378), respectively. There was a strong positive correlation between the JAK2 V617F allele burden measured using conventional methods and i-densy IS-5320 (r = .989)., Conclusion: Overall, i-densy IS-5320 exhibited good accuracy in terms of analyzing MPN-associated genes; thus, it can serve as a replacement for conventional methods of MPN-associated gene testing., (© 2022 John Wiley & Sons Ltd.)

Competing Interests: None.

The BLd regimen, which is a triplet regimen of bortezomib (Bor), lenalidomide (Len), and dexamethasone (Dex), is effective against newly diagnosed multiple myeloma (NDMM). However, non-hematological toxicities, such as peripheral neuropathy (PN), often hamper long-term continuation of the regimen, particularly in older adult patients. In this study, we examined the efficacy and safety of the modified BLd regimen with reduced-intensity Bor and standard-dose Len. The chemotherapy regimen consisted of 1.3 mg/m 2 Bor administered subcutaneously on days 1 and 8, 25 mg Len administered on days 1-14, and 20 mg Dex on days 1-2 and 8-9 of a 3 week cycle for 8 cycles, followed by a 4 week cycle of Dex (40 mg weekly). Among the 30 patients enrolled, 60.0% (95% CI 40.6-77.3) had a very good partial response or better, and the best overall response rate was 96.7% (95% CI 82.8-99.9). Eight patients (26.7%) achieved a complete response. Grade 3 or higher PN was not observed and hematological toxicity was the most common adverse event. The modified BLd regimen showed favorable efficacy with a manageable safety profile, which suggests it could be a treatment option for transplant-ineligible NDMM., (© 2022. Japanese Society of Hematology.)

Recent studies have reported that measurable residual disease (MRD) analysis using NPM1 mutations helps determine whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in acute myeloid leukemia (AML) patients. However, the optimal timing and cutoff value for measuring MRD using genomic DNA remain undetermined. This study aimed to investigate the optimal timing and cutoff value to ascertain the value of NPM1 mutation in MRD assessment. NPM1-mutated MRD was quantified by real-time polymerase chain reaction of bone marrow samples from 56 patients with NPM1-positive AML who achieved hematological remission. The area under the receiver-operating characteristic curve was greatest when MRD was assessed after two courses of post-remission therapy with a cutoff value of 0.010% (specificity, 68.4%; sensitivity, 87.0%). Patients whose MRD was below the cutoff value throughout the course of treatment had significantly better overall survival and relapse-free survival rates. Of the 33 patients who did not undergo transplantation during the first remission, all of the 11 who were never MRD-negative at any point experienced a relapse. Evaluating MRD with a cutoff value of 0.010% after two courses of post-remission therapy helps predict prognosis and determine the indication for allo-HSCT., (© 2022. Japanese Society of Hematology.)

Carfilzomib (CFZ) constitutes powerful combinatory therapy for relapsed/refractory multiple myeloma (RRMM); however, cardiovascular adverse events (CVAEs) have been shown as major treatment obstacles with the use of CFZ. Along with our multi-institutional prospective observational study by the Kyoto Clinical Hematology Study Group on the efficacy and safety of CFZ-based treatments (UMIN000025108), we here performed an ad hoc analysis of CFZ-related CVAEs in 50 patients with RRMM. We analyzed the association between CFZ-related CVAEs and pre-planned examinations, including patients' background, electrocardiographic findings, echocardiographic findings, and serum/plasma levels of 18 potential candidate biomarkers. The common CVAEs were hypertension (42%), arrhythmia (14%), and prolongation of QT corrected interval (10%), whereas no serious CVAEs occurred. The pretreatment serum level of interleukin-6 was identified as a significant risk factor for CFZ-related hypertension. This study revealed hypertension as the most frequent CFZ-related CVAE and suggested that baseline serum interleukin-6 is a useful predictor for CFZ-induced hypertension.

In cohort C of the phase 2 MM-014 trial, the efficacy and safety of pomalidomide, dexamethasone, and daratumumab therapy were investigated in 18 Japanese patients with relapsed/refractory multiple myeloma (RRMM) after their most recent regimen of lenalidomide-based therapy (NCT01946477). Patients received oral pomalidomide (4 mg daily), oral dexamethasone (20-40 mg weekly), and intravenously infused daratumumab (16 mg/kg). Median age was 67.5 years. All patients received prior lenalidomide per protocol; 89% received prior bortezomib. Twelve patients (67%) had lenalidomide-refractory disease, and 6 (33%) had lenalidomide-relapsed disease. Ten patients (56%) had only 1 prior treatment line. As of August 3, 2020, 15 patients (83%) were still on treatment; median follow-up was 8.1 months. Three patients (17%) discontinued treatment (2 for adverse events; 1 for major protocol deviation). Overall response rate (primary endpoint) was 83% (very good partial response or better, 61%). All patients had ≥ 1 grade 3/4 treatment-emergent adverse events, most commonly neutropenia (78%; febrile, 6%), leukopenia (28%), and lymphopenia (22%). Grade 3/4 infections occurred in 17%; 11% had pneumonia. In Japanese patients with RRMM, a triplet regimen of pomalidomide, dexamethasone, and daratumumab after early-line lenalidomide treatment failure showed high efficacy and safety consistent with the known safety profile., (© 2022. Japanese Society of Hematology.)

Background: Little is known about the real-world survival benefits and safety profiles of carfilzomib-lenalidomide-dexamethasone (KRd) and carfilzomib-dexamethasone (Kd)., Methods: We performed a retrospective analysis to evaluate their efficacy and safety in 157 patients registered in the Kansai Myeloma Forum database., Results: A total of 107 patients received KRd. Before KRd, 99% of patients had received bortezomib (54% were refractory disease), and 82% had received lenalidomide (57% were refractory disease). The overall response rate (ORR) was 68.2%. The median progression-free survival (PFS) and overall survival (OS) were 8.8 and 29.3 months, respectively. Multivariate analysis showed that reduction of the carfilzomib dose and non-IgG M protein were significantly associated with lower PFS and reduction of the carfilzomib dose and refractoriness to prior bortezomib-based regimens were significantly associated with lower OS. A total of 50 patients received Kd. Before Kd, 96% of patients had received bortezomib (54% were refractory disease). The ORR was 62.0%. The median PFS and OS were 7.1 and 20.9 months, respectively. Based on the multivariate analysis, reduction of the carfilzomib dose and International Staging System Stage III (ISS III) were significantly associated with lower PFS. Grade III or higher adverse events were observed in 48% of KRd cases and 54% of Kd cases. Cardiovascular events, cytopenia, and infections were frequent, and 4 KRd patients died due to heart failure, arrhythmia, cerebral hemorrhage, and pneumonia., Conclusion: Our analysis showed that an adequate dose of carfilzomib is important for achieving the best survival benefits in a real-world setting. Adverse effects after KRd and Kd therapy should also be considered., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All authors received research funding from Ono Pharma. and Celgene (Current Bristol Myers Squibb). JKa, SF, TI, HT, HS, SY, KS, KO, MH, CS, and JKu received speaker’s bureau from Ono Pharma. JKa, SF, TI, HT, HS, SY, SK, KO, IM, MH, CS, AT-K, and JKu received speaker’s bureau from Celgene (Current Bristol Myers Squibb). SF, TI, TH, HS, SY, SK, KO, IM, MH, CS, and JKu received speaker’s bureau from Janssen. JKa, SF, TI, HT, HS, SY, SK, KO, IM, MH, CS, and JKu received speaker’s bureau from Takeda Pharma. JKa, SF, TI, HT, HS, SY, SK, MH, CS, and JKu received speaker’s bureau from Sanofi. JKa, TI, HT, HS, SY, SK, KO, IM, MH, AT-K, and JKu received speaker’s bureau from Novartis. SK and JKu received speaker’s bureau from Fujimoto Pharma. TI, HS, MH, and JKu received research funding from Celgene (Current Bristol Myers Squibb). HS received research funding from Janssen. IM and JKu received research funding from Takeda Pharma. HS, IM, and JKu received research funding from Sanofi. HS and MH received research funding from Novartis. JKu received research funding from Fujimoto Pharma. JKa received consulting fees from Janssen and Takeda Pharma. MH received scholarship donations from Takeda Pharma. and Ono Pharma. AT-K received scholarship donations from Takeda Pharma. and Sanofi., (© The Author(s), 2022.)

Stress has been shown to affect brain activity and exert potent and complex modulatory effects on pain. Several behavioral tests have shown that acute stress produces hyperalgesia, depending on the stress conditions. In the present study, we investigated the effects of single restraint stress on the tactile threshold and anxiety sensitivity in mice. Mice were evaluated for the tactile threshold using von Frey filaments and for anxiety sensitivity using the elevated plus maze (EPM) test. Tactile thresholds were lowered by both 2 and 4 hour of restraint stress, but anxiety-like behaviors were observed only after 4 hour of restraint stress in the EPM test. In addition, we found that alfaxalone, which is a positive allosteric modulator of the γ-aminobutyric acid (GABA) A receptor, prevented restraint stress-induced hyperalgesia-like and anxiety-like behaviors. These results indicate that GABAergic function appears to be critical in the regulation of physical stress-induced hyperalgesia and anxiety., (© 2022 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: There is currently no standard prognostic model optimized for the patients with diffuse large B-cell lymphoma (DLBCL) treated with upfront intensive immunochemotherapy including autologous stem cell transplantation (ASCT). The Kyoto Prognostic Index (KPI) has been proposed as a novel prognostic model for DLBCL, which can accurately identify especially high-risk patients. In this study, we investigated the prognostic value of the KPI in JCOG0908 trial in which higher-risk DLBCL patients defined by the conventional International Prognostic Index (IPI) were treated with upfront high dose therapy followed by ASCT., Methods: Fifty-eight patients with DLBCL, not otherwise specified, enrolled in JCOG0908 and confirmed by the central pathological review were analyzed. The Kaplan-Meier method was used to estimate the probabilities of overall survival (OS) and progression-free survival (PFS). We compared the discrimination ability of the KPI with that of the IPI., Results: According to KPI, 3-year OS and PFS rates were 86.7% and 76.7% in low-intermediate, 73.3% and 60.0% in high-intermediate, and 61.5% and 46.2% in high-risk group. According to IPI, 3-year OS and PFS rates were 75.0% and 50.0% in low-intermediate, 82.9% and 74.3% in high-intermediate, and 63.6% and 54.5% in high-risk group. The concordance-indices of KPI and IPI were 0.642 and 0.580 for OS and 0.606 and 0.606 for PFS., Conclusions: The KPI may be a suitable predictor of outcome than the IPI for patients with higher-risk DLBCL treated with upfront intensive immunochemotherapy including ASCT., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Watchful waiting (WW) is one of the standard approaches for newly diagnosed follicular lymphoma (FL) patients with low-tumor burden. However, the impact of WW in FL patients at the first progression, remains unclear. We reviewed 206 FL patients who experienced the first progression after responding to the initial treatment at our institution between 1998 and 2017. Patients were classified into either the WW cohort (132 patients) or the immediate treatment cohort (74 patients). Overall, the median follow-up from the first progression was 79.8 months (range, 2.1-227.0 months). In the WW cohort, the estimated median time to next treatment (TNT) was 19.7 months (95% confidence interval [CI], 13.4-30.2), and 76.5% (95% CI, 68.0-84.1) of the patients subsequently underwent the second-line treatment at 5 years. There was a significant difference in the median time to treatment failure in the WW cohort (72.8 months; 95% CI, 64.6-94.0) compared to the immediate treatment cohort (23.3 months; 95% CI, 13.4-38.8) (HR, 2.13; 95% CI, 1.48-3.06), whereas overall survival and the cumulative incidence of histological transformation were not significantly different between two cohorts. In a multivariate analysis, rituximab refractory status, progression of disease within 24 months from the induction of first-line therapy, and a high Follicular Lymphoma International Prognostic Index score at diagnosis were significantly associated with shorter TNT. Interestingly, 15 patients (11%) of the WW cohort experienced spontaneous tumor regression during WW, and their TNT (median, 82.1 months, 95% CI, 11.7-NA) was longer than that of the remaining patients in the WW cohort (median, 16.5 months, 95% CI, 13.0-25.4), with a significant difference (p = 0.01). The results of the present study suggested that WW could be a safe and reasonable option even at the first progression for the selected FL patients, without a negative impact on clinical outcomes., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)