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The Japan Children's Cancer Group Relapsed Acute Lymphoblastic Leukemia (ALL) Committee conducted a prospective observational study (ALL-R14) to explore promising reinduction therapy regimens for relapsed ALL to investigate in future trials. In Japan, clofarabine- and bortezomib-based regimens were of interest since they were newly introduced for ALL in the study period (2015-2018). Seventy-five pediatric patients were enrolled in total. The 2-year event-free/overall survival rates in patients with first (n = 59) or second (n = 11) relapse were 40.1% (95% confidence interval [CI]: 25.5-52.3%)/66.3% (95% CI 52.3-77.0%) and 34.1% (95% CI 9.1-61.6%)/62.3% (95% CI 27.7-84.0%), respectively. Clofarabine- or bortezomib-based regimens were used only in patients with high-risk disease. The first reinduction therapy used in the 41 patients with early or multiple relapsed B-cell precursor ALL was clofarabine in 7 patients and bortezomib in 9 patients. The odds ratio for reinduction failure risk with a clofarabine- or bortezomib-based regimen compared with other regimens was 9.0 (95% CI 0.9-86.4, P = 0.057) or 1.9 (95% CI 0.4-8.7, P = 0.42), respectively. Thus, clofarabine- or bortezomib-based regimens had no obvious advantage as reinduction therapy for relapsed ALL in children., (© 2024. Japanese Society of Hematology.)

We report the first large-scale retrospective cohort study on adolescent and young adult (AYA) polycythemia vera (PV) and essential thrombocythemia (ET) in Japan, a subgroup analysis using Japanese multicenter registry data (JSH-MPN-R18). This study included patients with PV (n = 31) or ET (n = 141) aged 20 to 39 years at the initial visit. Hemorrhage-free survival (HFS) was better in AYA ET than in non-AYA ET (5-year HFS: 100% vs. 88.6%, p < 0.01), which might be attributed to differences in antithrombotic treatment rates between AYA and non-AYA patients. Although thrombosis-free survival did not differ statistically, the percentage of venous thrombotic events (TEs) among total TEs was higher in AYA compared to non-AYA PV and ET in Japan (26.0% vs. 6.0%, p < 0.01), but much lower than figures reported in European or US cohorts. Cytoreductive therapy (CRT) was administered to 25.8% of AYA patients with PV and 43.3% of AYA patients with ET, and the reason was usually unrelated to high risk of thrombosis. These results could be used to develop a more appropriate strategy for managing PV and ET in the Japanese AYA population., (© 2024. Japanese Society of Hematology.)

Idiopathic hypereosinophilic syndrome (iHES) is a condition wherein persistent hypereosinophilia associated with end-organ damage occurs without any known causes. Due to the rarity of the disease, insufficient knowledge has been accumulated. We therefore conducted a retrospective, multicentre, nationwide survey on iHES in Japan. A total of 57 patients were identified. For 43 patients who received any treatment, all cases were first treated with corticosteroids. An eosinophil percentage of less than 30% in the bone marrow and the absence of oedema were identified as factors associated with steroid dependency. The 5-year overall survival was 88.2%, and five patients died during follow-up; factors associated with worse overall survival were age >50, haemoglobin <12 g/dL, activated partial thromboplastin time >34 s, the presence of dyspnoea, the presence of thrombotic tendency and the presence of renal failure. Given the rarity of fatalities in our cohort, time-to-next-treatment (TTNT) was further analysed; the presence of renal failure, splenomegaly and lung abnormalities were associated with worse TTNT. Our nationwide study not only demonstrated clinical characteristics and the outcome of patients with iHES but also for the first time revealed clinical factors associated with steroid dependency and duration of first-line corticosteroid efficacy., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Thrombosis in myeloproliferative neoplasms (MPNs) is an important clinical problem, and risk-stratified management is essential. To identify the clinical characteristics of thrombosis in patients with MPNs, a nationwide multi-institutional retrospective analysis (JSH-MPN-R18) was conducted. The aim of the present study was to perform a sub-analysis of JSH-MPN-R18 findings to clarify the predictive parameters for thrombosis among complete blood count (CBC) results. Among the patients enrolled in JSH-MPN-R18, those with essential thrombocythemia (ET; n = 1152) and polycythemia vera (PV; n = 456) were investigated. We analyzed and compared CBC parameters between patients with and those without any thrombotic events using Welch's T-test. Statistical analyses were performed using the R statistical software. Thrombotic events were observed in 74 patients with ET. In multivariate analysis, only the neutrophil ratio was slightly but significantly higher for ET patients with thrombosis than for those without (p < 0.05). Of note, the absolute neutrophil count (aNeu) was considered a useful predictive tool for thrombosis among patients classified as low-risk according to the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia. Among PV patients, those with thrombosis showed significantly higher hematocrit and aNeu than did those without thrombosis. As a thrombosis-associated factor, the neutrophil ratio was slightly but significantly elevated in patients with ET. This myeloid skew might reflect a higher value of JAK2 V617F allelic frequency in patients with ET with thrombosis; this was not clarified in JSH-MPN-R18. Further accumulation of evidence, including genetic information for JAK2 and other passenger mutations, is warranted., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/objectives: The Berlin-Frankfurt-Münster (BFM)-S classification is a crucial prognostic indicator in children experiencing first-relapsed acute lymphoblastic leukemia (ALL). Early molecular response to therapy, evaluated by measurable/minimal residual disease (MRD), has a significant impact on the survival of patients with childhood ALL. Applying risk stratification based on the BFM-S classification and MRD response after induction, the first nationwide prospective multicenter study, ALL-R08, was conducted in children with first-relapsed ALL in Japan., Methods: The ALL-R08 study comprised two parts: ALL-R08-I, an observational study aimed at obtaining an overall picture of outcomes in first-relapsed childhood ALL, and ALL-R08-II, a clinical trial for the non-T-ALL S2 risk group. In ALL-R08-II, patients with an MRD level of ≥10 -3 at the end of induction therapy were assigned to undergo allogeneic hematopoietic stem cell transplantation (allo-HCT), whereas those with an MRD level less than 10 -3 and isolated extramedullary relapse continued to receive chemotherapy., Results: In total, 163 patients were enrolled in the ALL-R08 study, and 82 and 81 patients were enrolled in the ALL-R08-I and the ALL-R08-II, respectively. In ALL-R08-I, the probability of 3-year event-free survival (EFS) for patients with S1, S2, S3, S4, and post-HCT groups was 83% ± 15%, 37% ± 11%, 28% ± 8%, 14% ± 7%, and 0%, respectively. In the ALL-R08-II trial, 3-year EFS in patients with post-induction MRD less than 10 -3 and ≥10 -3 was 70% ± 9% (n = 27) and 68% ± 8% (n = 31) (p = .591), respectively., Conclusions: ALL-REZ BFM-type treatment is equally effective for children with first-relapsed ALL treated according to the Japanese frontline protocols and for children with first-relapsed ALL treated according to the BFM-type frontline protocols., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Objective: large-scale multicentre clinical trials conducted by cooperative groups have generated a lot of evidence to establish better standard treatments. The Clinical Trials Act was enforced on 1 April 2018, in Japan, and it has remarkably increased the operational burden on investigators, but its long-term impact on cancer cooperative groups is unknown., Methods: a survey was conducted across the nine major cooperative groups that constitute the Japan Cancer Trials Network to assess the impact of Clinical Trials Act on the number of newly initiated trials from fiscal year (from 1 April to 31 March) 2017 to 2022 and that of ongoing trials on 1 April in each year from 2018 to 2023., Results: the number of newly initiated trials dropped from 38 trials in fiscal year 2017 to 26 trials in fiscal year 2018, surged to 50 trials in fiscal year 2019, but then gradually decreased to 25 trials by fiscal year 2022. Specified clinical trials decreased from 32 trials in fiscal year 2019 to 12 trials in fiscal year 2022. The number of ongoing trials was 220 trials in 2018, peaked at 245 trials in 2020, but then gradually decreased to 219 trials by 2023. The number of specified clinical trials has been in consistent decline. By April 2023, of the 20 ongoing non-specified clinical trials, nine adhered to Clinical Trials Act and 11 followed the Ethical Guidelines for Medical and Health Research Involving Human Subjects., Conclusion: the number of multicentre clinical trials in oncology gradually decreased after the Clinical Trials Act's enforcement, which underscores the need for comprehensive amendment of the Clinical Trials Act to streamline the operational process., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Although the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved. Based on previous reports that patients with high-risk multisystem LCH show elevated levels of inflammatory molecules, we hypothesised that dexamethasone would more effectively suppress LCH-associated inflammation, especially in the central nervous system (CNS). We further hypothesised that intrathecal chemotherapy would effectively reduce CNS complications. We administer zoledronate to patients with multifocal bone LCH based on an efficacy report from a small case series., Methods and Analysis: This phase II study (labelled the LCH-19-MSMFB study) is designed to evaluate the significance of introducing dexamethasone and intrathecal chemotherapy for multisystem disease and zoledronate for multifocal bone disease in previously untreated, newly diagnosed children, adolescents (under 20 years) and adults under 40 years. The primary endpoint is the 3-year event-free survival rate by risk group of under 20 years and the 3-year event-free survival rate of 20 years and over., Ethics and Dissemination: This study was approved by the Central Review Board of the National Hospital Organisation Nagoya Medical Centre (Nagoya, Japan) on 21 January 2022 and was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp/en-latest-detail/jRCTs041210027). Written informed consent will be obtained from all patients and/or their guardians., Trial Registration Number: jRCTs041210027., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Romidepsin is an important therapeutic option for patients with peripheral T-cell lymphoma (PTCL). However, the timing of romidepsin administration remains controversial. The objective of this study was to characterize the safety and efficacy of romidepsin as consolidation therapy after gemcitabine, dexamethasone, and cisplatin (GDP) therapy (GDPR). This study of patients treated between March 2019 and March 2021 was registered with the Japan Registry of Clinical Trials (registration number: jRCT0000000519). If complete response, partial response, or stable disease was confirmed after 2-4 GDP cycles, romidepsin was administered every 4 weeks for 1 year. Seven patients with relapsed/refractory (R/R) PTCL (T-follicular helper phenotype [n = 1] and angioimmunoblastic T-cell lymphoma [n = 6]) were included in this prospective study (PTCL-GDPR). After a median follow-up of 34 months of patients in PTCL-GDPR, the 2-year overall survival rate was 71%, and the overall response rate after treatment was 57%. Common adverse events in patients with PTCL-GDPR included hematological toxicities such as neutropenia, which improved with supportive treatment. There were no treatment-related mortalities. GDPR might be safe and effective in elderly transplant-ineligible patients with R/R PTCL; however, further investigation is required.

Background: In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care., Procedure: We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025)., Results: Twenty patients with post-induction MRD ≥ 10 -3 and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively., Conclusion: Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL., (© 2024. Japanese Society of Hematology.)

Background: The benefit of adding rituximab to standard lymphomes malins B (LMB) chemotherapy for children with high-risk mature B-cell non-Hodgkin lymphoma (B-NHL) has previously been demonstrated in an international randomized phase III trial, to which the Japanese Pediatric Leukemia/Lymphoma Study Group could not participate., Methods: To evaluate the efficacy and safety of rituximab in combination with LMB chemotherapy in Japanese patients, we conducted a single-arm multicenter trial., Results: In this study, 45 patients were enrolled between April 2016 and September 2018. A total of 33 (73.3%), 5 (11.1%), and 6 (13.3%) patients had Burkitt lymphoma/leukemia, diffuse large B-cell lymphoma, and aggressive mature B-NHL, not otherwise specified, respectively. Ten (22.2%) and 21 (46.7%) patients had central nervous system disease and leukemic disease, respectively. The median follow-up period was 47.5 months. Three-year event-free survival and overall survival were 97.7% (95% confidence interval, 84.9-99.7) and 100%, respectively. The only event was relapse, which occurred in a patient with diffuse large B-cell lymphoma. Seven patients (15.6%) developed Grade 4 or higher non-hematologic adverse events. Febrile neutropenia was the most frequent Grade 3 or higher adverse event after the pre-phase treatment, with a frequency of 54.5%., Conclusion: The efficacy and safety of rituximab in combination with LMB chemotherapy in children with high-risk mature B-NHL was observed in Japan., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Secondary pneumothorax, which occurs most commonly in the elderly, is caused by underlying diseases. Cardiac dysfunction and other organ inefficiencies may render surgical repair impossible. Such non-operative and poor-risk cases are targets for pleurodesis, which involves the instillation of chemicals or irritants to the thoracic cavity through injection, bronchoscopic bronchial occlusion, or other procedures. Sterile graded talc has been used for pleurodesis mainly in Europe and the United States; however, only a few studies and case series investigating this topic have been published. This study evaluates the efficacy and safety of talc slurry pleurodesis., Methods: Patients with inoperable secondary intractable pneumothorax, who were not candidates for surgical repair, were recruited. Four grams of sterilized talc was suspended in 50 mL of physiological saline and injected through a tube into the pleural cavity. Additional 50 mL of saline was subsequently injected through the same channel to clean the residual saline in the injection tube. Another additional talc instillation was allowed to control persistent air leakage. The primary endpoint was the proportion of drainage tube removal within 30 days after talc pleurodesis., Results: Thirty-one patients were included in this study. In 23 out of 28 patients, the drainage tube could be removed within 30 days of talc instillation (82.1 %, 95 % CI = 63.1-93.9), exceeding the threshold of 36.0 % (p < 0.0001). The most common event was pain (11/28 patients, 39.3 %)., Conclusions: Talc slurry pleurodesis is effective for intractable secondary pneumothorax, with minor side effects., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Intractable lymphatic anomalies (LAs) include cystic lymphatic malformation (LM; macrocystic, microcystic, or mixed), generalized lymphatic anomaly, and Gorham-Stout disease. LAs can present with severe symptoms and poor prognosis. Thus, prospective studies for treatments are warranted. We conducted a prospective clinical trial of sirolimus for intractable LAs., Methods: This was an open-label, single-arm, multicenter, prospective trial involving five institutions in Japan. All patients with LAs received oral sirolimus once daily, and the dose was adjusted to ensure that the trough concentration remained within 5-15 ng/mL. We prospectively assessed the drug response (response rate for radiological volumetric change in target lesion), performance state, change in respiratory function, visceral impairment (pleural effusion, ascites, bleeding, pain), laboratory examination data, quality of life (QOL), and safety at 12, 24, and 52 weeks of administration., Results: Eleven patients with LAs (9 generalized lymphatic anomaly, 1 cystic LM, 1 Gorham-Stout disease) were treated with sirolimus, of whom 6 (54.5%; 95% confidence interval: 23.4-83.3%) demonstrated a partial response on radiological examination at 52 weeks of administration. No patients achieved a complete response. At 12 and 24 weeks of administration, 8 patients (72.7%) already showed a partial response. However, patients with stable disease showed minor or no reduction after 12 weeks. Adverse events, such as stomatitis, acneiform dermatitis, diarrhea, and fever, were common with sirolimus. Sirolimus was safe and tolerable., Conclusion: Sirolimus can reduce the lymphatic tissue volume in LAs and may lead to improvements in clinical symptoms and QOL., Competing Interests: MO received research funding from Nobelpharma Co. Ltd. in Tokyo. Sirolimus tablets were supplied by Nobelpharma Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ozeki, Endo, Yasue, Nozawa, Asada, Saito, Hashimoto, Fujimura, Yamada, Kuroda, Ueno, Watanabe, Nosaka, Miyasaka, Umezawa, Matsuoka, Maekawa, Hirakawa, Furukawa, Fumino, Tajiri, Takemoto, Souzaki, Kinoshita and Fujino.)

The Japanese Society of Hematology performed an observational cross-sectional study to clarify the morbidity, prognosis, and prognostic factors in patients with COVID-19 with hematological diseases (HDs) in Japan. The study included patients with HDs who enrolled in our epidemiological survey and had a COVID-19 diagnosis and a verified outcome of up to 2 months. The primary endpoints were characteristics and short-term prognosis of COVID-19 in patients with HDs. A total of 367 patients from 68 institutes were enrolled over 1 year, and the collected data were analyzed. The median follow-up among survivors was 73 days (range, 1-639 days). The 60-day overall survival (OS) rate was 86.6%. In the multivariate analysis, albumin ≤ 3.3 g/dL and a need for oxygen were independently associated with inferior 60-day OS rates (hazard ratio [HR] 4.026, 95% confidence interval (CI) 1.954-8.294 and HR 14.55, 95% CI 3.378-62.64, respectively), whereas 60-day survival was significantly greater in patients with benign rather than malignant disease (HR 0.095, 95% CI 0.012-0.750). Together, these data suggest that intensive treatment may be necessary for patients with COVID-19 with malignant HDs who have low albumin levels and require oxygen at the time of diagnosis., (© 2024. The Author(s).)

Many effective new agents for relapsed childhood acute lymphoblastic leukemia (ALL) are now becoming available, and international standard chemotherapy should be developed to optimize use of these agents. Randomized controlled trials (RCTs) are needed to establish a standard treatment, but few have been conducted for relapsed childhood ALL in Japan due to the small patient population. Participation in international RCTs is necessary to access sufficient patients for informative study results, but differences in approved drugs and healthcare systems between countries make this challenging. In 2014, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) participated in an international study on standard-risk relapsed childhood ALL (IntReALL SR 2010) involving two RCTs and multiple drugs not approved in Japan, which was addressed by replacing the unapproved drugs with alternative approved drugs with the same or similar efficacy. This article discusses the historical background of treatment development for relapsed childhood ALL, our experience in participating in the IntReALL SR 2010 trial, and prospects for treating relapsed childhood ALL.

Objectives: Balloon pulmonary angioplasty (BPA) and medical therapy, such as soluble guanylate cyclase stimulators, are recommended treatments for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are ineligible for pulmonary endarterectomy (PEA). However, monotherapy with BPA or medical therapy cannot always eliminate symptoms such as exertional dyspnoea. Thus, this study aims to clarify the efficacy of continuous treatment with riociguat in inoperable CTEPH patients with normalised haemodynamics after BPA., Methods and Analysis: This is a double-blind, multicentre, randomised, placebo-controlled trial. Participants with CTEPH who are ineligible for PEA will receive riociguat followed by BPA. Subsequently, participants will be randomised (1:1) into either riociguat continuing or discontinuing groups and will be observed for 16 weeks after randomisation. The primary endpoint will be the change in peak cardiac index (CI) during the cardiopulmonary exercise test. In the primary analysis, the least square mean differences and 95% CIs for the change in peak CI at 16 weeks between the groups will be estimated by a linear mixed-effects model with baseline value as a covariate, treatment group as a fixed effect and study institution as a random effect., Ethics and Dissemination: National Hospital Organisation Review Board for Clinical Trials (Nagoya) and each participating institution approved this study and its protocols. Written informed consent will be obtained from all participants. The results will be disseminated at medical conferences and in journal publications., Registration Details: Japan Registry of Clinical Trials: jRCT no. 041200052., Clinicaltrials: gov by National Library of Medicine Registry ID: NCT04600492., Trial Registration Number: NCT04600492., Competing Interests: Competing interests: HS and HM received honoraria for scientific lectures from Bayer Yakuhin., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chemotherapy with cytarabine, vincristine (VCR), and prednisolone has achieved low mortality rates in pediatric patients with Langerhans cell histiocytosis (LCH). However, relapse rates remain high, making event-free survival (EFS) rates unsatisfactory. A nationwide clinical trial, LCH-12, tested a modified protocol in which the early maintenance phase was intensified with increasing dosages of VCR. Patients newly diagnosed with multifocal bone (MFB) or multisystem (MS) LCH and aged < 20 years at diagnosis were enrolled between June 2012 and November 2017. Of the 150 eligible patients, 43 with MFB were treated for 30 weeks and 107 with MS LCH were treated for 54 weeks. One patient with MS LCH died of sepsis during the induction phase. The 3-year EFS rates among patients with MFB LCH, risk organ (RO)-negative MS LCH, and RO-positive MS LCH were 66.7% (95% confidential interval [CI], 56.5-77.0%), 66.1% (95% CI 52.9-76.4%), and 51.1% (95% CI 35.8-64.5%), respectively, similar to previously observed rates. EFS rates were significantly lower in patients with disease activity scores > 6 than in those with scores ≤ 6. The strategy that included more intense treatment with VCR was not effective. Other strategies are required to improve outcomes in patients with pediatric LCH., (© 2023. Japanese Society of Hematology.)

Background: T-cell acute lymphoblastic leukaemia has distinct biological characteristics and a poorer prognosis than B-cell precursor acute lymphoblastic leukaemia. This trial aimed to reduce the rate of radiation and haematopoietic stem-cell transplantation (HSCT) while improving outcomes by adding nelarabine, intensified L-asparaginase, and protracted intrathecal therapy in the Berlin-Frankfurt-Münster (BFM)-type treatment., Methods: In this nationwide, multicenter, phase 2 trial, we enrolled patients with newly diagnosed T-cell acute lymphoblastic leukaemia (age <25 years at diagnosis) conducted by Japan Children's Cancer Group and Japan Adult Leukemia Study Group. Patients were stratified into standard-risk, high-risk, and very-high-risk groups according to prednisolone response, CNS status, and end-of-consolidation minimal residual disease. We used the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP)-BFM-ALL 2000-backbone chemotherapy. Nelarabine (650 mg/m 2 per day for 5 days) was given to high-risk and very high-risk patients. All patients received, until the measurement of end-of-consolidation minimal residual disease, an identical therapy schedule, which included the prednisolone pre-phase remission induction therapy with dexamethasone (10 mg/m 2 per day, for 3 weeks [for patients <10 years] or for 2 weeks including a 7-day off interval [for patients ≥10 years]) instead of prednisolone, and consolidation therapy added with Escherichia coli-derived L-asparaginase. On the basis of the stratification, patients received different intensities of treatment; L-asparaginase-intensified standard BFM-type therapy for standard risk and nelarabine-added high risk BFM-type therapy for high risk. In the very high-risk group, patients were randomly assigned (1:1) to group A (BFM-based block therapy) and group B (another block therapy, including high-dose dexamethasone) stratified by hospital, age (≥18 years or <18 years), and end-of-induction bone marrow blast percentage of M1 (<5%) or M2 (≥5%, <25%)+M3 (≥25%). Cranial radiotherapy was limited to patients with overt CNS disease at diagnosis (CNS3; >5 white blood cells per μL with blasts) and patients with no evidence of CNS disease received protracted triple intrathecal therapy. Only very high-risk patients were scheduled to receive HSCT. The primary endpoint was 3-year event-free survival for the entire cohort and the proportion of patients with disappearance of minimal residual disease between randomly assigned groups A and B in the very high-risk group. Secondary endpoints were overall survival, remission induction rate, and occurrence of adverse events. 3 years after the completion of patient accrual, a primary efficacy analysis was performed in the full analysis set and the per-protocol set. This study is registered with the Japan Registry of Clinical Trials, jRCTs041180145., Findings: Between Dec 1, 2011, and Nov 30, 2017, of 349 eligible patients (median age 9 years [IQR 6-13]), 238 (68%) were male, and 28 (8%) patients had CNS3 status. 168 (48%) patients were stratified as standard risk, 103 (30%) as high risk, 39 (11%) as very high risk, and 39 (11%) as no risk (patients who had off protocol treatment before risk assessment. The composite complete remission (complete remission plus complete remission in suppression) rate after remission induction therapy was 89% (298 of 335 patients). HSCT was performed in 35 (10%) of 333 patients. With a median follow-up of 5·2 years (IQR 3·6-6·7), 3-year event-free survival was 86·4% (95% CI 82·3-89·7%) and 3-year overall survival was 91·3% (87·7-93·8%). The proportion of minimal residual disease disappearance was 0·86 (12 of 14 patients; 95% CI 0·57-0·98) in group A and 0·50 (6 of 12 patients, 0·21-0·79) in group B. Grade 3 peripheral motor neuropathy was seen in 11 (3%) of 349 patients and sensory neuropathy was seen in 6 (2%) patients. The most common grade 3 or worse adverse event was febrile neutropenia (294 [84%] of 349 patients). Treatment-related death occurred in three patients due to sepsis, gastric perforation, or intracranial haemorrhage during remission induction., Interpretation: The ALL-T11 protocol produced encouraging outcomes with acceptable toxicities despite limited cranial radiotherapy and HSCT use., Funding: Ministry of Health, Labor and Welfare of Japan, and Japan Agency for Medical Research and Development., Translation: For the Japanese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AS has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Chugai Pharmaceutical. YH has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Kyowa Kirin, Novartis Pharma, and Nippon Shinyaku. CI has received patent royalty in Juno Therapeutics and CURED, consulting fees from CURED and, as a filing of a new patent is being planned in CURED, has a Stock option in CURED. MK received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Amgen, Chugai Pharmaceutical, and Novartis Pharma, and received grants from from Otsuka Pharmaceutical. SSu has a contract from the Division of General Pediatrics and Emergency Medicine, Oita City, and also has leadership in Japan Children's Cancer Group and The Japanese Society of Pediatric Hematology and Oncology. HK has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Abbvie, Chugai Pharmaceutical, Astellas Pharma, and Novartis Pharma. IM has received grants from Ono Pharmaceutical, Janssen Pharmaceutical, Nippon Shinyaku, Kyowa Kirin, Sumitomo Dainippon Pharma, Shionogi & Co, Teijin Pharma, Boehringer Ingelheim, Sanofi, Chugai Pharmaceutical, Eisai, MSD, Asahi Kasei Pharma Corporation, Astellas Pharma, Takeda Pharmaceutical, Nihon Pharmaceutical, Daiichi Sankyo, AbbVie, Taiho Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku, CSL Behring, Mundipharma, AYUMI Pharmaceutical Corporation, Eli Lilly Japan, Actelion Pharmaceuticals Japan, and Amgen BioPharma. IM has also received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Bristol-Myers Squibb (Celgene), Novartis, Otsuka Pharmaceutical, Pfizer Japan, Janssen, Astellas Pharma, Takeda Pharmaceutical, and Daiichi Sankyo, and has received consulting fees from Otsuka Pharmaceutical. YM has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Novartis Pharma and Kyowa-Kirin. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Asthma is a heterogeneous disease with multiple phenotypes that are useful in precision medicine. As the population ages, the elderly asthma (EA, aged ≥ 65 years) population is growing, and EA is now a major health problem worldwide., Objective: To characterize EA and identify its phenotypes., Methods: In adult patients with asthma (aged ≥ 18 years) who had been diagnosed with having asthma at least 1 year before study enrollment, 1925 were included in the NHOM-Asthma (registered in UMIN-CTR; UMIN000027776), and the data were used for this study, JFGE-Asthma (registered in UMIN-CTR; UMIN000036912). Data from EA and non-EA (NEA) groups were compared, and Ward's minimum-variance hierarchical clustering method and principal component analysis were performed., Results: EA was characterized by older asthma onset, longer asthma duration and smoking history, more comorbidities, lower pulmonary function, less atopic, lower adherence, and more hospital admissions because of asthma. In contrast, the number of eosinophils, total immunoglobulin E level, oral corticosteroid use, and asthma control questionnaire scores were equivalent between EA and NEA. There were 3 distinct phenotypes in EA, which are as follows: EA1: youngest, late onset, short duration, mild; EA2: early onset, long duration, atopic, low lung function, moderate; and EA3: oldest, eosinophilic, overweight, low lung function, most severe. The classification factors of the EA phenotypes included the age of onset and asthma control questionnaire-6. Similarities were observed between EA and NEA phenotypes after principal component analysis., Conclusion: The EA in Japan may be unique because of the population's high longevity. Characterization of EA phenotypes from the present cohort indicated the need for distinct precision medicine for EA., Trial Registration: JFGE-Asthma registered in UMIN-CTR (https://www.umin.ac.jp/ctr/); UMIN000036912., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: In the CAPITAL study, a randomized phase 3 study, wherein carboplatin plus nab-paclitaxel treatment was compared with docetaxel treatment for older patients with squamous-cell lung cancer, the former became the new standard of care for such patients. Our study aimed to evaluate whether the efficacy of second-line immune checkpoint inhibitors (ICIs) affected the primary analysis of overall survival (OS)., Methods: Herein, we performed a post hoc analysis of the impact of second-line ICIs on OS, safety in each group of participants aged more than 75 years, and intracycle nab-paclitaxel skip status., Results: Patients were randomly allocated to the carboplatin plus nab-paclitaxel (nab-PC) arm (n = 95) or the docetaxel (D) arm (n = 95). Of these patients, 74 of 190 (38.9%) were transferred to ICIs for second-line treatment (nab-PC arm: 36, D arm: 38). A survival benefit was numerically observed only for patients for whom first-line therapy was terminated owing to disease progression (median OS [nab-PC arm]: with and without ICIs, 321 and 142 d, respectively; median OS [D arm]: with and without ICIs, 311 and 256 d, respectively). The OS among patients who received ICI after adverse events was similar in the two arms. In the D arm, a significantly higher frequency of grade greater than or equal to 3 adverse events was observed among patients aged more than or equal to 75 years (86.2%) than among those aged less than 75 years (65.6%, p  = 0.041), including a significantly higher frequency of neutropenia (84.6% versus 62.5%, p  = 0.032); no such differences were observed in the nab-PC arm., Conclusions: We found that second-line ICI treatment seemed to have a little impact on OS., (© 2023 The Authors.)

Background: Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes., Methods: Adult asthma patients (n = 1925) from 27 national hospitals in Japan were enrolled and divided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1-3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5 patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis were performed for phenotyping. Analysis of variance, the Kruskal-Wallis, and chi-square tests were used to compare cluster differences., Results: The following five clusters were identified: 1) late-onset, old, less-atopic; 2) late-onset, old, eosinophilic, low FEV 1 ; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young, female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers, FEV 1 , body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes., Conclusions: Five distinct phenotypes were identified for moderate to severe asthma and may be classified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.)., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

The presence of a JAK2 V617F or JAK2 exon 12 mutation is one of the three major criteria listed for the diagnosis of polycythemia vera (PV) in the 2017 World Health Organization Classification. However, a nationwide study has not yet been conducted in Japan since the discovery of JAK2 mutations. Therefore, the Japanese Society of Hematology (JSH) retrospectively analyzed the clinical characteristics of 596 Japanese patients with PV diagnosed between April 2005 and March 2018. Among the 473 patients with complete data on JAK2 mutations available, 446 (94.3%) and 10 (2.1%) were positive for the JAK2 V617F and JAK2 exon 12 mutations, respectively. During a median follow-up of 46 months (range: 0-179 months), 47 (7.9%) deaths occurred. The major causes of death were secondary malignancies (23.4%), acute leukemia (12.8%), non-leukemic progressive disease (10.6%) and thrombotic (6.4%) and hemorrhagic complications (6.4%). Thrombotic and hemorrhagic events occurred during the clinical course in 4.0% (n = 24) and 3.5% (n = 21) of patients, respectively. These results show that the international PV prognostic score (age, venous thrombosis and leukocytosis) is applicable to Japanese patients with PV., (© 2022. Japanese Society of Hematology.)

The purpose of this study is to establish a treatment with appropriate intensity for children (<16 years old at diagnosis) with de novo acute myeloid leukemia (excluding acute promyelocytic leukemia and myeloid leukemia associated with Down syndrome) according to a risk stratification based on recurrent leukemic cytogenetic abnormalities and flow-cytometric minimal residual disease at end of initial induction chemotherapy and to validate the safety and efficacy of gemtuzumab ozogamicin (GO)-combined post-induction chemotherapy for the non-low-risk (non-LR) patients. The primary endpoint of this phase III study is three-year disease-free survival rate, which will be compared between the GO and non-GO arms of the non-LR (intermediate-risk and high-risk [HR]) patients. All HR patients will be allocated to allogeneic hematopoietic stem cell transplantation in first remission. This trial has been registered at the Japan Registry of Clinical Trials (jRCTs041210015)., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Inotuzumab ozogamicin (InO) is a CD22-directed antibody conjugated with calicheamicin approved for adult relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL). This phase 1 study primarily aimed to determine the pediatric recommended doses of InO through the standard 3 + 3 design, and to evaluate the safety, tolerability, pharmacokinetic (PK) profile, immunogenicity and efficacy of InO. Dose level 1 (DL1) was 1.8 mg/m 2 (days 1, 8, and 15: 0.8, 0.5, and 0.5 mg/m 2 , respectively). Six of the seven registered patients were eligible [median age, 7.5 (2-17) years]. Although all six patients started DL1, only five completed the dose. No dose-limiting toxicity was observed. All patients experienced adverse events (AEs), including increased alanine aminotransferase and aspartate aminotransferase in four patients. Three patients experienced serious AEs, which were hepatic veno-occlusive disease (VOD), ALL, and fever. Five patients achieved complete remission (CR) or CR with incomplete blood cell recovery (CRi), among whom 3 (60%) were negative for minimal residual disease. PK findings were similar to those in adults. No patient had anti-drug antibodies to InO. In conclusion, InO was well tolerated in children and promoted similar antileukemic efficacy as in adults. Nonetheless, the risk for VOD requires attention., (© 2022. Japanese Society of Hematology.)

Background: The feasibility of tyrosine kinase inhibitor (TKI) discontinuation in pediatric chronic myeloid leukemia (CML) remains to be fully elucidated., Procedures: TKI was prospectively discontinued in patients who were diagnosed with CML at <20 years of age, treated with TKI for ≥3 years, and sustained molecular response 4.0 (MR4.0) for ≥2 years. Molecular relapse was defined as a single loss of major molecular response (MMR) (BCR-ABL1 IS >0.1%). Relapsed patients resumed the same TKI therapy administered before discontinuation., Results: Twenty-two patients with chronic-phase CML were enrolled, and the median ages at diagnosis and at TKI discontinuation were 9 (range: 1-14) years and 16 (5-26) years, respectively. The median follow-up time after TKI discontinuation was 37 months (range: 24-41 months). The median duration of TKI treatment before discontinuation was 100 (42-178) months, and that of MR4.0 was 53.5 (25-148) months. The treatment-free remission (TFR) rate at 12 months was 50.0% (90% confidence interval: 31.7%-65.8%). Eleven patients experienced loss of MMR within 4 months after TKI discontinuation and resumed TKI as originally prescribed. No progression was observed, and all 11 patients regained MR4.0 after TKI resumption. No patient had a withdrawal syndrome. The quality-of-life analysis suggested that successful TFR may improve academic performance in some patients. In patients who discontinued TKI therapy before puberty, the possibility of improvement in growth velocity upon TKI discontinuation was observed., Conclusions: TKI could be discontinued safely in patients with pediatric CML showing a sustained deep MR., (© 2022 Wiley Periodicals LLC.)

Background: The transient receptor potential cation channel subfamily V member 2 (TRPV2) is a stretch-sensitive calcium channel. TRPV2 overexpression in the sarcolemma of skeletal and cardiac myocytes causes calcium influx into the cytoplasm, which triggers myocyte degeneration. In animal models of cardiomyopathy and muscular dystrophy (MD), TRPV2 inhibition was effective against heart failure and motor function. Our previous pilot study showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide (BNP) levels in two MD patients with advanced heart failure. Thus, this single-arm, open-label, multicenter study aimed to evaluate the safety and efficacy of tranilast for heart failure., Methods: The study enrolled MD patients with advanced heart failure whose serum BNP levels were > 100 pg/mL despite receiving standard cardioprotective therapy. Tranilast was administered orally at 100 mg, thrice daily. The primary endpoint was the change in log (BNP) (Δlog [BNP]) at 6 months from baseline. The null hypothesis was determined based on a previous multicenter study of carvedilol results in a mean population Δlog (BNP) of 0.18. TRPV2 expression on peripheral blood mononuclear cell surface, cardiac events, total mortality, left ventricular fractional shortening, human atrial natriuretic peptide, cardiac troponin T, and creatine kinase, and pinch strength were also assessed., Results: Because of the poor general condition of many patients, only 18 of 34 patients were included and 13 patients could be treated according to the protocol throughout the 6-month period. However, there were no serious adverse events related to tranilast except diarrhea, a known adverse effect, and the drug was administered safely. TRPV2 expression on the mononuclear cell surface was elevated at baseline and reduced after treatment. Cardiac biomarkers such as BNP, human atrial natriuretic peptide, and fractional shortening remained stable, suggesting a protective effect against the progression of heart failure. In the per protocol set group, Δlog [BNP] was - 0.2 and significantly lower than that in the null hypothesis., Conclusions: Tranilast is safe and effective in inhibiting TRPV2 expression, even in MD patients with advanced heart failure. Further trials are needed to evaluate the efficacy of tranilast in preventing myocardial damage, heart failure, motor impairment, and respiratory failure. Clinical trial registration The study was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000031965, URL: http://www.umin.ac.jp/ctr/ ) [March 30, 2018] and the Japan Registry of Clinical Trials (jRCT, registration number: jRCTs031180038, URL: https://jrct.niph.go.jp/ ) [November 12, 2021]. Patient registration was started in December 19, 2018., (© 2022. The Author(s).)

To improve component-placement accuracy in total knee arthroplasty, we developed two devices: an original extramedullary patient-specific guide for the femur and an original extramedullary universal guide for the tibia (EM-TIBIA). We also developed a new function in ZedView, a three-dimensional surgical assistive software, that provides the parameters necessary to install the EM-TIBIA. Compared with conventional manual methods based on X-ray two-dimensional images or ZedView, these newly developed devices function as an extramedullary intraoperative support guide in conjunction with ZedView, simplifying surgical procedures. We conducted a study to evaluate the efficacy and safety of the surgery using the new guides and software function. Nineteen patients underwent surgery. On the femoral side, the mean absolute difference of the installation alignment was within 3° for all parameters. On the other hand, on the tibial side, the mean absolute difference from the preoperative plan for the rotation was 5.26±5.30°. The proportion of patients whose difference fell within ±3° was 52.6% (95% confi dence interval: 28.9 to 75.6%), and did not meet the pre-specified criteria for efficacy (P=0.261). No serious adverse events were reported, and no excessive bleeding, thrombosis, infections, or intraoperative or postoperative fractures were noted. The two new guides can easily reproduce the preoperative plan as 3D intraoperative support jigs, but errors can occur on the tibia side due to soft tissue that is not recognized by CT, creating problems in installation accuracy.

Objectives: This study aimed to evaluate the efficacy and safety of apixaban replacement (AR) as an alternative to heparin bridging (HB) in patients taking warfarin and scheduled for endoscopic mucosal resection (EMR) in the colorectum., Methods: This trial was conducted at seven institutes in Japan between May 2016 and May 2018. Enrolled patients had been taking oral warfarin and were diagnosed within 3 months with colorectal polyps for which EMR was indicated. Patients were randomly assigned to receive HB or AR. The primary endpoint was the incidence of postoperative bleeding. Secondary endpoints were the length of hospital stay, therapeutic endoscopy outcomes, and adverse events., Results: The planned sample size was 160 patients, but due to a decrease in the number of patients taking warfarin, the target number of cases could not be achieved within the case enrollment period, 44 cases were enrolled. They were divided into HB and AR groups. The incidence of postoperative bleeding was 15% (3/20) in HB and 0% in AR (P = 0.199). The total number of postoperative bleeding events was five in HB and none in AR. The length of hospital stay was significantly shorter in AR than in HB (median: 3.0 vs. 13.5 days, p < 0.001). There were no serious adverse events and no cerebral infarction/systemic embolism events., Conclusion: AR for colorectal EMR may prove safe and has the potential to shorten hospital stay and reduce medical costs, though we were unable to evaluate the primary endpoint due to insufficient sample size., Competing Interests: Author Toshio Uraoka is a Deputy EIC of DEN Open. The rest of the authors do not have any conflict of interest., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

We conducted a large-scale, nationwide retrospective study of Japanese patients who were diagnosed with essential thrombocythemia based on the diagnostic criteria in the World Health Organization classification. We investigated clinical characteristics, survival rates, and the incidence of thrombohemorrhagic events as well as risk factors for these events. A total of 1152 patients were analyzed in the present study. Median age at diagnosis was 65 years, the median platelet count was 832 × 10 9 /L, and the positive mutation rates of JAK2V617F, CALR, and MPL were 62.8, 25.1, and 4.1%, respectively. Compared with European and American patients, Japanese patients were more likely to have cardiovascular risk factors and less likely to have systemic symptoms including palpable splenomegaly. Thrombocytosis was identified as a risk factor for hemorrhagic events and prognosis, but not for thrombotic events. The prognostic factors and risk classifications reported in Europe and the United States were generally applicable to Japanese patients. Regarding transformations, secondary myelofibrosis progressed in a time-dependent manner, but progression to acute leukemia was low in "true" ET patients. Skin cancers were less common and gastrointestinal cancers more common as secondary malignancies in Japanese patients, suggesting ethnic differences., (© 2021. Japanese Society of Hematology.)

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/m 2 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., Competing Interests: AK reports personal fees from Bayer Yakuhin, Ltd., as a member of the independent data monitoring committee of clinical trials outside the submitted work. KS received research funding from Ono Pharmaceutical, MSD, Celgene, AbbVie, Takeda Pharmaceutical, Sanofi, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Novartis, Alexion Pharma, and GlaxoSmithKline and received honoraria from Ono Pharmaceutical, Celgene, Takeda Pharmaceutical, and Bristol-Myers Squibb. The other authors have no conflicts of interest to declare.

Objective: To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II., Methods: Sixteen patients (aged 6-57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS-01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5-15 ng/mL, followed by a 12-week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES-FCD) in which 60 patients with FCD type II were included as an external control group., Results: The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1-4-, 5-8-, and 9-12-week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus-treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL-6 level was elevated over time., Interpretation: The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Febrile neutropenia, a serious complication that can occur during the treatment of hematological malignancies, can sometimes be fatal owing to fungal infection. Prospective randomized trials indicated the utility of liposomal amphotericin B or caspofungin as an empirical antifungal therapy. Itraconazole, a broad-spectrum tri azole antifungal agent, is poorly absorbed in the intestines after oral absorption and makes it difficult to achieve a stable serum drug concentration. Therefore, an intravenous formulation might offer a potentially safer and more effective alternative. To compare the efficacy and safety of empirical antifungal therapy, patients will be randomly assigned to either the liposomal amphotericin B 3.0 mg/kg once daily group or the intravenous itraconazole 200 mg dose group with five stratification factors (disease risk, previous antifungal prophylaxis, age, sex, and institute). The primary endpoint will be overall favorable response, comprising five secondary endpoints: successful treatment of baseline infection by the end of the treatment; absence of breakthrough infection; no discontinuation of the antifungal treatment due to drug-related toxicity; fever resolution during neutropenia; and 7-day survival after termination of the antifungal treatment. The target sample size of 850 subjects is sufficient to prove the non inferiority of itraconazole compared with liposomal amphotericin B, with a non-inferiority margin of 10%, one sided significance level of 5%, and power of 90%.

Background: In Japan, docetaxel, a cytotoxic monotherapy, is the standard drug administered to older patients with advanced non-small-cell lung cancer (NSCLC). Carboplatin plus nab-paclitaxel has shown a high objective response rate in patients with squamous histology and was suggested to improve overall survival in patients aged 70 years and older. The CAPITAL trial aimed to assess the safety and efficacy of carboplatin plus nab-paclitaxel versus docetaxel as first-line therapy for patients aged 70 years and older with advanced squamous NSCLC., Methods: This multicentre, open-label, randomised, phase 3 trial was carried out at 92 medical institutions in Japan. Eligible patients were aged 70 years and older, had advanced squamous NSCLC with no previous systemic chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Using an electronic data capture system, patients were randomly assigned (1:1) to intravenous carboplatin (area under the concentration-time curve of 6 mg/mL per min for 30 min) on day 1 of a 21-day cycle and intravenous nab-paclitaxel (100 mg/m 2 for 60 min) on days 1, 8, and 15 every 3 weeks or intravenous docetaxel (60 mg/m 2 for 60 min) on day 1 every 3 weeks. Randomisation was computer-generated per participant and stratified by ECOG performance status, clinical stage, sex, age, and institution. The primary endpoint was overall survival, measured in the full analysis set and defined as the time from registration to the date of death due to any cause. Safety was assessed in all patients who received at least one dose of the trial treatment. This trial is registered with the UMIN Clinical Trials Registry, UMIN000019843, and the Japan Registry of Clinical Trials, jRCTs041180110. After the planned interim analysis in Aug 3, 2020, the independent data monitoring committee recommended that the trial be stopped early. This report represents the final analysis., Findings: Between Feb 24, 2016, and Aug 11, 2020, 196 patients were enrolled and were randomly assigned to the carboplatin plus nab-paclitaxel group (n=98) or the docetaxel group (n=98). Of these patients, four (carboplatin plus nab-paclitaxel group, n=3; docetaxel group, n=1) did not receive any treatment and two patients in the docetaxel group were excluded from the full analysis set. Median overall survival in the full analysis set was 16·9 months (95% CI 12·6-25·4) in the carboplatin plus nab-paclitaxel group and 10·9 months (8·5-12·4) in the docetaxel group (hazard ratio 0·52 [90% CI 0·38-0·70]; p=0·0003). Grade 3-4 adverse events occurred in 79 (83%) patients in the carboplatin plus nab-paclitaxel group and 77 (79%) patients in the docetaxel group (p=0·63). The most common grade 3-4 adverse events in the carboplatin plus nab-paclitaxel group and the docetaxel group were leukopenia (44 [46%] vs 55 [57%]; p=0·20), neutropenia (60 [63%] vs 75 [77%]; p=0·046), febrile neutropenia (nine [10%] vs 19 [20%]; p=0·073), and anaemia (37 [39%] vs two [2%]; p<0·0001). Serious treatment-related adverse events of all grades occurred in 13 (14%) patients in the carboplatin plus nab-paclitaxel group and 11 (11%) patients in the docetaxel group. Treatment-related deaths occurred in two (2%; respiratory failure n=1, visceral arterial ischaemia n=1) patients in the carboplatin plus nab-paclitaxel group and one (1%; sepsis) patient in the docetaxel group., Interpretation: Our study showed that overall survival was longer with carboplatin plus nab-paclitaxel than with docetaxel, suggesting that carboplatin plus nab-paclitaxel can be used as standard first-line treatment for patients aged 70 years and older with advanced squamous NSCLC., Funding: Taiho Pharmaceutical., Competing Interests: Declaration of interests YK reports grants from Taiho Pharmaceutical, during the conduct of the study; and grants and personal fees from MSD, personal fees from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Boehringer Ingelheim, and Ono Pharmaceutical, outside the submitted work. SI reports grants and personal fees from Ono Pharmaceutical; and personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb, Taiho Pharmaceutical, and Daiichi Sankyo, outside the submitted work. HS reports grants from Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from AstraZeneca, MSD, Ono Pharmaceutical; and personal fees from Boehringer Ingelheim, Chugai Pharma, and Kyorin, outside the submitted work. AK reports grants from Taiho Pharmaceutical, during the conduct of the study; and personal fees from Bayer Yakuhin, outside the submitted work. SA reports grants from the National Cancer Center Research and Development Fund (26-A-22, 29-A-15, 2020-A-13) and Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from AstraZeneca, Ono Pharmaceutical, Taiho, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, MSD, Eli Lilly, Chugai, and Merck; grants and non-financial support from F Hoffmann-La Roche; and personal fees from Hisamitsu, Kyowa Hakko Kirin, Novartis Pharma, and Thermo Fisher Scientific, outside the submitted work. YT reports grants and personal fees from Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from Eli Lilly, Ono Pharmaceutical, Chugai Pharmaceutical, MSD, and Takeda; grants from Daiichi Sankyo and Kyowa-Hakko Kirin; and personal fees from Novartis, Boehringer Ingelheim, and AstraZeneca, outside the submitted work. AI reports personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Pfizer, Chugai Pharmaceutical, MSD, and Daiichi Sankyo, outside the submitted work. TK reports personal fees from AstraZeneca, MSD, Eli Lilly, Chugai, Ono Pharmaceutical, Bristol Myers Squibb, and Boehringer Ingelheim; grants from AstraZeneca, MSD, Ono Pharmaceuticals, Eli Lilly, and Takeda, outside the submitted work. IO reports grants from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD Oncology, Eli Lilly, Bristol Myers Squibb, and Chugai Pharma; grants from Astellas Pharma, Novartis, and AbbVie; and personal fees from Pfizer, outside the submitted work. MY reports grants and personal fees from Chugai Pharmaceutical; and grants from Daiichi Sankyo, MSD, and Pfizer Japan, outside the submitted work. MS reports grants and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, and Eli Lilly Japan; and personal fees from AstraZeneca, outside the submitted work. MA reports grants from Kyowa Kirin, outside the submitted work. KK reports grants and personal fees from Ono Pharmaceutical and Boehringer Ingelheim; and personal fees from Chugai, MSD, AstraZeneca, Eli Lilly, Daiichi Sankyo, Bristol Myers Squibb, Kyowa Hakko Kirin, and Taiho, outside the submitted work. MT reports grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Covidien Japan, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, and Taiho Pharmaceutical; personal fees from Bristol Myers Squibb, Johnson & Johnson, and Nippon Kayaku; and grants from KM Biologics, outside the submitted work. TS reports grants and personal fees from Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, MSD, Novartis Pharma, Pfizer Japan, and Takeda Pharmaceutical; grants from AbbVie, Kissei Pharmaceutical, LOXO Oncology, and Merck Biopharma; and personal fees from AstraZeneca, Bristol Myers Squibb, Covidien Japan, Kyowa Hakko Kirin, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, Thermo Fisher Scientific, and Precision Medicine Asia, outside the submitted work. NY reports grants and personal fees from MSD, Chugai Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Takeda Pharmaceutical, Eli Lilly Japan, Boehringer Ingelheim, Novartis, Pfizer, and AstraZeneca; and personal fees from Thermo Fisher Scientific, Bristol Myers Squibb, Life Technologies, Nippon Kayaku, and Merk Biopharma; grants from Astellas Pharma, Tsumura & Co, Shionogi, AbbVie, Amgen, Kyorin Pharmaceutical, Eisai, Terumo, Toppan Printing, and TOSOH, outside the submitted work. AG reports personal fees from Taiho, Nihon Kayaku, AstraZeneca, Chugai, Ono Pharmaceutical, and Boehringer Ingelheim, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The administration of systemic corticosteroids is a key strategy for improving COVID-19 outcomes. However, evidence is lacking on combination therapies of antiviral agents and systemic corticosteroids. The objective of this study was to investigate the efficacy and safety of the combination therapy of favipiravir and methylprednisolone in preventing respiratory failure progression in patients with COVID-19 and non-critical respiratory failure., Methods: We conducted a multicenter, open-label, single-arm phase II study. The patients received favipiravir 3600 mg on the first day, followed by 1600 mg for a total of 10-14 days. Methylprednisolone was administered intravenously at 1 mg/ideal body weight (IBW)/day from days 1 to 5, followed by 0.5 mg/IBW/day from days 6 to 10 if clinically indicated. The primary endpoint was the proportion of patients requiring mechanical ventilation (MV) (including noninvasive positive pressure ventilation) or those who met the criteria for tracheal intubation within 14 days of the study treatment initiation (MVCTI-14)., Results: Sixty-nine patients were enrolled and underwent the study treatment. Of them, the MVCTI-14 proportion was 29.2% (90% confidence interval 20.1-39.9, p = 0.200). The proportion of patients who required MV or who died within 30 days was 26.2%, and 30-day mortality was 4.9%. The most significant risk factor for MVCTI-14 was a smoking history (odds ratio 4.1, 95% confidence interval 1.2-14.2). The most common grade 3-4 treatment-related adverse event was hyperglycemia, which was observed in 21.7%., Conclusion: The MVCTI-14 proportion did not reach a favorable level in the clinical trial setting with the threshold of 35%. However, the proportion of MV or death within 30 days was 26.6%, which might be close to the findings (28.1%) of the RECOVERY trial, which showed the efficacy of dexamethasone for patients with COVID-19 and non-critical respiratory failure. Further evaluation of this combination therapy is needed., Clinical Trial Registration: Japan Registry of Clinical Trials (jRCT) identifier jRCTs041200025., (© 2021. The Author(s).)

Although approximately 70% of pediatric hematological malignancies are curable, approximately 30% remain fatal. No standard treatment is available in patients showing relapse and those with refractory disease. Although different methods are adopted in different hospitals, its efficacy is extremely limited. In recent years, haploidentical stem cell transplantation, involving high-dose cyclophosphamide administration post-transplanta tion, has been used, mainly in adults; however, its application is limited to removal of alloreactive T cells. Multicenter single-arm clinical trials of T-cell replete haploidentical stem cell transplantation (TCR-haplo-SCT) will be conducted in children with relapsed and refractory acute leukemia. After myeloablative conditioning using total body irradiation or busulfan, intensive graft versus host disease prophylaxis is administered, consisting of low-dose rabbit anti-human thymocyte globulin, tacrolimus, methotrexate, and prednisolone. An external control group is set up for the study. The treatment period is around 3 months, and the follow-up period is 2 years from transplantation completion.The aim of this study is to verify the efficacy and safety of TCR-haplo-SCT and present it as a new immune cell therapy for improving survival rate in children with relapsed and refractory acute leukemia.

Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) blockade is a promising therapy for hematological malignancies. However, the association of PD-L1 expression with the clinicopathological features and prognosis in pediatric ALK-positive anaplastic large cell lymphoma (ALCL) remains unclear. Using PD-L1/ALK immunofluorescence double staining, we evaluated the PD-L1 expression on tumor cells/tumor-infiltrating immune cells (TIICs) and the quantity of TIICs in 54 children with ALK-positive ALCL treated with the ALCL99 protocol. The percentages of PD-L1-positive tumor cells were significantly lower in patients with skin/mediastinum involvement, clinical high-risk group, present minimal disseminated disease (MDD), and a low ALK-antibody titer. The percentages of PD-L1-positive TIICs were significantly higher in patients with absent MDD. The percentages of TIICs were significantly lower in patients with absent MDD and a common morphological pattern. We classified patients according to the PD-L1 expression on tumor cells (Tumor-PD-L1), PD-L1 expression on TIICs (TIIC-PD-L1), and quantity of TIICs (TIIC-quantity). The progression-free survival (PFS) did not differ between Tumor-PD-L1 high and Tumor-PD-L1 low ALCL; TIIC-PD-L1 high and TIIC-PD-L1 low ALCL; and TIIC-quantity high and TIIC-quantity low ALCL. According to the combined parameters of Tumor-PD-L1 and TIIC-quantity, Tumor-PD-L1 high /TIIC-quantity high ALCL had a worse 5-year PFS than other ALCL (50% versus 83%; P = .009). Tumor-PD-L1 high /TIIC-quantity high ALCL remained a significant prognostic factor in multivariate analysis (P = .044). This is the first study to demonstrate that a high tumoral PD-L1 expression with a high quantity of TIICs was associated with a poor prognosis in pediatric ALK-positive ALCL. The tumor microenvironment of ALK-positive ALCL may be relevant to the clinicopathological features and prognosis., (Copyright © 2021. Published by Elsevier Inc.)

Myeloid leukemia of Down syndrome (ML-DS) is associated with good response to chemotherapy, resulting in favorable outcomes. However, no universal prognostic factors have been identified to date. To clarify a subgroup with high risk of relapse, the role of minimal residual disease (MRD) was explored in the AML-D11 trial by the Japanese Pediatric Leukemia/Lymphoma Study Group. MRD was prospectively evaluated at after induction therapy and at the end of all chemotherapy, using flow cytometry (FCM-MRD) and GATA1-targeted deep sequencing (GATA1-MRD). A total of 78 patients were eligible and 76 patients were stratified to the standard risk (SR) group by morphology. In SR patients, FCM-MRD and GATA1-MRD after induction were positive in 5/65 and 7/59 patients, respectively. Three-year event-free survival (EFS) and overall survival (OS) rates were 95.0% and 96.7% in the FCM-MRD-negative population, and 60.0% and 80.0% in the positive population. Three-year EFS and OS rates were both 98.1% in the GATA1-MRD-negative population, and 57.1% and 71.4% in the positive population. Adjusted hazard ratios for associations of FCM-MRD with EFS were 14.67 (p = 0.01). Detection of MRD by either FCM or GATA1 after initial induction therapy represents a significant prognostic factor for predicting ML-DS relapse., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)

Duchenne (DMD) and other forms of muscular dystrophy (MD) are collectively rare and affect approx imately 20 per 100,000 people. The on-going development of exon skipping and other novel therapies for DMD is expected to lead to improvements in motor function prognosis. However, improvements in motor dysfunction with these novel therapies are associated with the risk of increase in cardiac burden. Development of therapies to improve cardiac function, therefore, is an urgent issue. This single-arm, open-label, multicenter study will include 20 patients with MD aged 13 years or older. Tranilast, a transient receptor potential cation channel subfamily V member 2 (TRPV2) inhibitor, will be administered orally for a period of 28 weeks at a dose of 300 mg/day divided into three daily doses. If consent to continue administration is obtained at 28 weeks, the drug will be administered for an additional 116 weeks. The primary outcome will be the change in brain natriuretic peptide (BNP) at 6 months after the start of administration compared to baseline. Tranilast is an anti-allergy agent that was developed in Japan. It has been used in a large number of clinical cases, including pediatric cases, and has been shown to be safe. We expect this study to provide basic data for developing new treatment method in cardiomyopathy/skeletal myopathy using TRPV2 inhibitors. Moreover, such therapies may also be effective in treating general heart failure without MD. Therefore, if the effectiveness of TRPV2 inhibitors could be confirmed in this study, great social and economic benefits could be achieved.

Epileptic seizures are core symptoms in focal cortical dysplasia (FCD), a disease that often develops in infancy. Such seizures are refractory to conventional antiepileptic drugs (AED) and temporarily disappear in response to AED in only 17% of patients. Currently, surgical resection is an important option for the treatment of epileptic seizures in FCD. In 2015, Korean and Japanese groups independently reported that FCD is caused by somatic mosaic mutation of the MTOR gene in the brain tissue. Based on these results we decided to test a novel treatment using sirolimus, an mTOR inhibitor, for epileptic seizures in patients with FCD type II. A single arm open-label clinical trial for FCD type II patients is being conducted in order to evaluate the efficacy and safety of sirolimus. The dose of sirolimus is fixed for the first 4 weeks and dose adjustment is achieved to maintain a blood level of 5 to 15 ng/mL during 8 to 24 weeks after initiation of administration, and it is kept within this level during a maintenance therapy period of 12 weeks. Primary endpoint is a reduction in the rate of incidence of focal seizures (including focal to bilateral tonic-clonic seizures) per 28 days during the maintenance therapy period from the observation period. To evaluate the frequency of epileptic seizures, registry data will be used as an external control group. We hope that the results of this trial will lead to future innovative treatments for FCD type II patients.

The variability in myelosuppression after chemotherapy for acute myeloid leukaemia (AML) can affect its prognosis; however, the underlying mechanism remains controversial. In the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study, we showed that prolonged neutropenia was associated with high overall survival (P = 0·011) and low frequency of relapse (P = 0·042) in patients without granulocyte-colony stimulating factor (G-CSF) who completed the indicated treatment protocol. Our data indicate that predisposition to prolonged neutropenia after chemotherapy is correlated with a better outcome of AML treatment. Our results promote the usage of individualised drug dosing strategies to improve the therapeutic outcome in AML patients., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

This phase 1/2 study aimed to identify the maximum tolerated dose, the recommended phase 2 dose (RP2D), and efficacy of the clofarabine, etoposide, and cyclophosphamide combination regimen in adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients aged ≥ 15 years with relapsed/refractory ALL were enrolled. Escalating doses of clofarabine (20-30 mg/m 2 /day × 5 days), etoposide (50-100 mg/m 2 /day × 5 days), and cyclophosphamide (200-440 mg/m 2 /day × 5 days) were administered. Dose-limiting toxicity was defined as Grade 3 or more non-hematological toxicities and others. A total of 18 patients (B-ALL; n = 13, T-ALL; n = 5) were recruited in phase 1; however, the protocol was amended to close study without proceeding to phase 2. Three patients were enrolled in cohort 1, three in cohort 2, six in cohort 3, and six in cohort 4. The RP2D of clofarabine, etoposide, and cyclophosphamide was 30, 100, and 440 mg/m 2 daily, respectively. Complete remission (CR) was achieved in four patients (22%) and CR without platelet recovery in four patients (22%), with an overall response rate of 44%. The RP2D of the combination therapy was successfully determined in this study.