研究等業績 - その他 - 髙橋 直人
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Takahashi N.
International Journal of Hematology ( International Journal of Hematology ) 2026年
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慢性骨髄性白血病におけるtreatment-free remissionへの挑戦
髙橋 直人
臨床血液 ( 一般社団法人 日本血液学会 ) 67 ( 2 ) 158 - 164 2026年
<p>チロシンキナーゼ阻害薬（TKI）は慢性骨髄性白血病（CML）の予後を著しく改善したが，生涯にわたる内服は晩期の血管事象や経済的毒性といった課題を伴う。このため，TKIを安全に中止し寛解を維持する無治療寛解（treatment-free remission, TFR）は，患者のQoLを改善する重要な治療ゴールとして位置づけられている。国内外の多くの臨床試験によりTFRの安全性と有効性が確立されており，大規模観察研究J-SKIの中間解析では5年TFR率65.2％と良好で，TKI中止前の深い分子遺伝学的寛解（DMR）の期間が成功の鍵であることが示された。課題としては，TKI離脱症候群や，2回目のTFRの挑戦，ごく稀な急性転化リスクが挙げられる。今後，新規薬剤を用いてより多くの患者がDMRを達成し，TFRに挑戦できる機会を増やすことが期待される。</p>
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Kusuda S.
Scientific Reports ( Scientific Reports ) 15 ( 1 ) 2025年12月
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Kumagai T.
BMC Nephrology ( BMC Nephrology ) 26 ( 1 ) 2025年12月
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Miura M.
Journal of Chromatographic Science ( Journal of Chromatographic Science ) 63 ( 10 ) 2025年11月
A rapid, simple and highly sensitive stability-indicating high-performance liquid chromatography (HPLC) method was developed and validated for the estimation of asciminib in human plasma. Plasma samples (100 μL) were processed by solid-phase extraction. Chromatographic separation was performed using a CAPCELL PAK C18 MGII column (4.6 × 250 mm, 5 μm); the mobile phase consisted of 0.5% potassium dihydrogen phosphate (KH2PO4, pH 3.5): acetonitrile: methanol (50:45:5, v/v/v) at a flow rate of 0.5 mL/min. Detection was carried out at a wavelength of 250 nm. The developed method showed good linearity over the concentration range of 10-5000 ng/mL (correlation coefficient: 0.9999). The method was then validated according to guidelines published by the US Food and Drug Administration. The coefficients of variation for intra- and interday assays for asciminib were less than 13.9%, whereas accuracies for intra- and interday assays were within 8.9%. The limit of quantification was 10 ng/mL. The mean (minimum - maximum) plasma trough concentration of asciminib in 29 Japanese patients with chronic myeloid leukemia who received repeated administration of 40 mg twice daily was 367 (101-807) ng/mL. The validated method can be used as a routine method to support pharmacokinetic studies of asciminib.
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Tanabe R.
Sensors ( Sensors ) 25 ( 21 ) 2025年11月
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The impact of NR1I2 gene polymorphism and body weight on asciminib pharmacokinetics in patients with chronic myeloid leukemia
Naoto Takahashi, Yumiko Akamine, Masatomo Miura
BLOOD 146 2025年11月
研究発表要旨（国際会議）
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Kikuchi R.
International Journal of Innovative Computing Information and Control ( International Journal of Innovative Computing Information and Control ) 21 ( 5 ) 1167 - 1185 2025年10月
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Kikuchi R.
Sensors ( Sensors ) 25 ( 18 ) 2025年09月
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Lang F.
Haematologica ( Haematologica ) 111 ( 2 ) 597 - 608 2025年07月
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Bosutinib for Successful Treatment-Free Remission in Chronic Myeloid Leukemia
Fujioka Y.
Cancer Medicine ( Cancer Medicine ) 14 ( 9 ) 2025年05月
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藤岡 優樹, 永沼 綾子, 齊藤 由紀子, 植木 重治, 高橋 直人
検査と技術 ( (株)医学書院 ) 53 ( 4 ) 446 - 452 2025年04月
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c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment
Osada N.
Cells ( Cells ) 14 ( 7 ) 474 - 474 2025年04月
Multiple myeloma (MM) is the second most common hematologic malignancy and has a poor prognosis. Although the outcomes of MM have markedly improved with the approval of novel agents, the high incidence of relapse means that MM remains incurable. The bone marrow microenvironment (BMME) contributes to drug resistance and minimal residual disease (MRD), which is a major source of relapse in patients with MM. However, the underlying molecular mechanisms are not fully understood. We have previously shown that the upregulation of the AP-1 transcription factor c-FOS confers lenalidomide resistance by maintaining IRF4 expression in MM cells. In this study, we show that upregulated expression of c-FOS confers a poor prognosis and cancer stem cell-like features, including drug resistance, within BMME, both in vitro and in vivo, via IRF4 upregulation; and that inhibition of c-FOS by the AP-1 inhibitor, T-5224, prevents regeneration of MM cells via IRF4 downregulation in a murine serial transplantation assay. These results suggest a functional role for c-FOS in conferring cancer stem cell-like features to MM cells in the BMME for the first time. Therefore, c-FOS inhibition may be an effective treatment strategy for improving the outcomes of patients with MM by eliminating drug-resistant cancer stem cell-like MM cells in MRD.
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藤岡 優樹, 永沼 綾子, 齊藤 由紀子, 植木 重治, 髙橋 直人
検査と技術 ( 株式会社医学書院 ) 53 ( 4 ) 446 - 452 2025年04月
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Kondo H.
Therapeutic Innovation and Regulatory Science ( Therapeutic Innovation and Regulatory Science ) 59 ( 1 ) 71 - 79 2025年01月
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Kondo T.
Cancer ( Cancer ) 131 ( 1 ) e35611 2025年01月
BACKGROUND: Young female patients with chronic myeloid leukemia (CML) often face challenges becoming pregnant due to the teratogenicity of tyrosine kinase inhibitors (TKIs). METHODS: The authors conducted a nationwide survey of female patients with CML who experienced pregnancy between 2002 and 2020. RESULTS: Information for 70 pregnancies in 49 patients was obtained. There were three types of pregnancies: CML onset during pregnancy (n = 9), unplanned pregnancy mostly during treatment with a TKI (n = 25), and planned pregnancy during treatment-free remission (TFR) or treatment with interferon-alpha (IFN-α) (n = 36). The median duration from CML diagnosis to pregnancy in patients with planned pregnancy was significantly longer than that in patients with unplanned pregnancy (10.6 years vs. 4.1 years, p < .001). In 48 pregnancies that resulted in childbirth, TFR and treatment with IFN-α were chosen in 26 and 17 pregnancies, respectively. Sustained major or deeper molecular response was observed in 18 of 26 pregnancies with TFR. The patients who fulfilled the requirements for TKI therapy discontinuation by European LeukemiaNet recommendations achieved a TFR rate of 77% in pregnancy. Treatment with IFN-α might be effective for patients who are in complete cytogenetic response or deeper response (response rate, 76%). CONCLUSION: Pregnancy by TFR or treatment with IFN-α could be a safe and feasible way for patients with CML. However, a substantial duration of treatment with a TKI before conception may be needed for planned pregnancy. Planning and evaluation for pregnancy should be considered at the time of CML onset for female patients with childbearing potential.
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Kumagai Takuya, Saito Masaya, Sato Takahiko, Inoue Junichi, Ishikawa Norihisa, Ono Tsuyoshi, Kono Michihiro, Takahashi Naoto
Internal Medicine ( 一般社団法人 日本内科学会 ) advpub ( 0 ) 1933 - 1940 2025年
<p>We herein report a case of cutaneous squamous cell carcinoma (SCC) characterized by paraneoplastic hypercalcemia-leukocytosis syndrome. The patient presented with systemic symptoms, including anorexia, a fever, and a tumoral lesion on the upper arm. Laboratory test results revealed hypercalcemia and leukocytosis. A tissue biopsy confirmed SCC, and further investigation revealed elevated parathyroid hormone-related protein (PTHrP) and granulocyte-colony stimulating factor (G-CSF) levels. Immunostaining demonstrated G-CSF production by the tumor cells. Radiation therapy was administered, which improved leukocytosis and decreased G-CSF and PTHrP levels. Through a case report and literature review, we explored the clinical characteristics of tumors that produce G-CSF and PTHrP. </p>
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Takahashi N.
International Journal of Hematology ( International Journal of Hematology ) 122 ( 5 ) 647 - 659 2025年
INTRODUCTION: The phase III ASC4FIRST study (NCT04971226) demonstrated superior efficacy and favorable safety and tolerability for asciminib against investigator-selected tyrosine kinase inhibitors (IS-TKI) in newly diagnosed chronic myeloid leukemia (CML). Results of a subgroup analysis in Japanese patients are presented here. METHODS: Adult patients were randomized 1:1 to asciminib or IS-TKI following stratification by European Treatment and Outcome Study long-term survival risk score and prerandomization-selected TKI (imatinib and second-generation [2G] TKI strata). At week 48, major molecular response (MMR) rate in all patients and imatinib stratum (primary endpoints) were assessed along with MR4.0, MR4.5, and safety (cutoff: November 28, 2023). RESULTS: In Japanese patients (asciminib, n = 21; IS-TKI, n = 17 [imatinib/2G TKI, n = 8/9]), the MMR rate was higher with asciminib (81.0%) than IS-TKI (47.1%), and versus imatinib (asciminib: 100%; imatinib: 25.0% [imatinib stratum]). More patients on asciminib than IS-TKI achieved MR4.0 (57.1% vs. 11.8%) and MR4.5 (28.6% vs. 5.9%). Fewer grade ≥ 3 adverse events (AEs; 42.9%, 50.0%, and 55.6%) and AEs leading to treatment discontinuation (0%, 37.5%, and 11.1%) occurred with asciminib than imatinib or 2G TKI. CONCLUSION: Outcomes in Japanese patients were consistent with the ASC4FIRST overall population. Asciminib may be a therapy of choice for Japanese patients with CML.
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Kuroki W.
British Journal of Haematology ( British Journal of Haematology ) 206 ( 6 ) 1615 - 1626 2025年
Multiple myeloma (MM) with chromosome 1q21 gain/amplification (1q+) has been reported to respond poorly to daratumumab. We aimed to explore the mechanism of daratumumab resistance in 1q+ MM. Our findings revealed significantly lower CD38 expression in patients with 1q+ MM than in those with 1q wild type (WT) MM. Next, we focused on the interleukin-6 receptor (IL6R) located in the 1q21 region because a previous report shows that interleukin-6 (IL-6) reduces CD38 expression via the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway activation in MM. Indeed, IL6R expression was significantly higher in 1q+ MM than in 1q WT MM. We verified that the 1q+ human myeloma cell lines (HMCLs) expressed higher IL6R levels than the 1q WT HMCLs. IL-6 treatment induced CD38 downregulation in both the 1q+ HMCLs and primary bone marrow (BM) samples but not in their 1q WT HMCLs and BM samples. IL-6 also resulted in the upregulation of phosphorylated STAT3 in 1q+ HMCLs but not in the 1q WT HMCLs. Furthermore, inhibition of the IL-6/JAK/STAT pathway by treatment with ruxolitinib or tocilizumab restored CD38 expression in the 1q+ HMCLs and BM samples. These findings elucidate the mechanisms underlying daratumumab resistance in 1q+ MM and provide insights for future therapeutic strategies.
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Fujishima Takashi, Kobayashi Takahiro, Kobayashi Isuzu, Kitadate Akihiro, Kameoka Yoshihiro, Takahashi Naoto
Internal Medicine ( 一般社団法人 日本内科学会 ) advpub ( 0 ) 3020 - 3026 2025年
<p>We herein present the case of a 73-year-old man with IgM multiple myeloma (IgM-MM) and t(11;14). The tumor cells showed a small lymphoplasmacytic morphology and dim expression of CD38 and CD138. The MYD 88<sup>L265P</sup> mutation was found to be negative. After plasma exchange, bortezomib and dexamethasone treatments were refractory. Subsequent daratumumab, lenalidomide, and dexamethasone therapy failed to respond despite the standard therapy for non-IgM MM. Subsequently, pomalidomide, cyclophosphamide, and dexamethasone therapies demonstrated a good response, and a stringent complete response was therefore achieved. This case highlights the need for different treatment strategies for IgM-MM compared with non-IgM-MM because the biological features of IgM-MM and non-IgM-MM are different. </p>