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Allogeneic hematopoietic stem cell transplantation using reduced intensity conditioning regimen for patients with acute myeloid leukemia not in complete remission. 国際誌

Yoshimitsu Shimomura, Tetsuhisa Kitamura, Masamitsu Yanada, Shohei Mizuno, Tadakazu Kondo, Satoshi Yoshihara, Masatsugu Tanaka, Kazuki Inai, Yuta Katayama, Makoto Onizuka, Takahiro Fukuda, Hirohisa Nakamae, Mineo Kurokawa, Shingo Yano, Miho Nara, Masayoshi Masuko, Shigesaburo Miyakoshi, Tetsuya Eto, Makoto Yoshimitsu, Fumihiko Ishimaru, Junya Kanda, Yoshiko Atsuta, Takaaki Konuma

Cytotherapy 27 ( 3 ) 316 - 323 2024年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI LTD

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment option for patients with refractory and relapsed acute myeloid leukemia (R/R AML) not in complete remission. Many studies investigating the prognosis of patients with R/R AML not in remission focused on patients who received myeloablative conditioning regimen (MAC). Conversely, reduced intensity conditioning regimen (RIC) could be a considerable conditioning regimen for some patients because of the high frequency of R/R AML in older patients who are not candidates for MAC. OBJECTIVE: This study aimed to evaluate the prognosis and identify factors associated with outcomes in patients with R/R AML who underwent allogeneic HSCT with RIC. STUDY DESIGN: This study included 707 adult patients with AML not in complete remission who had received RIC. The primary endpoint was progression-free survival (PFS), which was estimated using the Kaplan-Meier method. Prognostic factors were identified using a Cox proportional hazards model with multiple imputations using a chained equation approach. RESULTS: The 5-year PFS, overall survival, relapse, and nonrelapse mortality were 18.8% (95% confidence interval [CI]: 15.6-22.2), 22.0% (95% CI: 8.5-25.7), 53.6% (95% CI 49.7-57.4%) and 27.5% (95% CI: 24.0-31.2), respectively. Multivariable analysis revealed that male sex, poor performance status, karyotype risk, and blasts in the peripheral blood were significantly associated with PFS. CONCLUSIONS: This study identified prognostic factors in patients with R/R AML not in complete remission. These results can help to develop a transplant strategy for the treatment of R/R AML.

DOI： 10.1016/j.jcyt.2024.11.012

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皮膚硬化型慢性GVHDに対してイブルチニブが有効であった1例

佐藤美紀, 濱菜摘, 木村春奈, 長谷川瑛人, 阿部理一郎, 諏訪部達也, 柴崎康彦, 増子正義, 阿部由紀子

日本皮膚科学会雑誌 134 ( 7 ) 1923 - 1923 2024年6月

Reduced chondroitin sulfate content prevents diabetic neuropathy through transforming growth factor-β signaling suppression. 国際誌

Hajime Ishiguro, Takashi Ushiki, Atsuko Honda, Yasuhiro Yoshimatsu, Riuko Ohashi, Shujiro Okuda, Asami Kawasaki, Kaori Cho, Suguru Tamura, Tatsuya Suwabe, Takayuki Katagiri, Yiwei Ling, Atsuhiko Iijima, Tadahisa Mikami, Hiroshi Kitagawa, Akiyoshi Uemura, Kazunori Sango, Masayoshi Masuko, Michihiro Igarashi, Hirohito Sone

iScience 27 ( 4 ) 109528 - 109528 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Diabetic neuropathy (DN) is a major complication of diabetes mellitus. Chondroitin sulfate (CS) is one of the most important extracellular matrix components and is known to interact with various diffusible factors; however, its role in DN pathology has not been examined. Therefore, we generated CSGalNAc-T1 knockout (T1KO) mice, in which CS levels were reduced. We demonstrated that diabetic T1KO mice were much more resistant to DN than diabetic wild-type (WT) mice. We also found that interactions between pericytes and vascular endothelial cells were more stable in T1KO mice. Among the RNA-seq results, we focused on the transforming growth factor β signaling pathway and found that the phosphorylation of Smad2/3 was less upregulated in T1KO mice than in WT mice under hyperglycemic conditions. Taken together, a reduction in CS level attenuates DN progression, indicating that CS is an important factor in DN pathogenesis.

DOI： 10.1016/j.isci.2024.109528

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Decade-long WT1-specific CTLs induced by WT1 peptide vaccination.

Tatsuya Suwabe, Yasuhiko Shibasaki, Suguru Tamura, Takayuki Katagiri, Kyoko Fuse, Tori Ida-Kurasaki, Takashi Ushiki, Hirohito Sone, Miwako Narita, Masayoshi Masuko

International journal of hematology 119 ( 4 ) 399 - 406 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: The peptide-based cancer vaccine targeting Wilms' tumor 1 (WT1) is a promising immunotherapeutic strategy for hematological malignancies. It remains unclear how long and to what extent the WT1-specific CD8 + cytotoxic T cell (CTL) persist after WT1 peptide vaccination. METHODS: The WT1 peptide vaccine was administered with written consent to a patient with CML in the chronic phase who did not respond well to imatinib, and the patient was followed for 12 years after vaccination. Immune monitoring was performed by specific amplification of WT1-specific CTLs using a mixed lymphocyte peptide culture. T-cell receptors (TCRs) of amplified WT1-specific CTLs were analyzed using next-generation sequencing. This study was approved by the Institutional Review Board of our institution. RESULT: WT1-specific CTLs, which were initially detected during WT1 peptide vaccination, persisted at a frequency of less than 5 cells per 1,000,000 CD8 + T cells for more than 10 years. TCR repertoire analysis confirmed the diversity of WT1-specific CTLs 11 years after vaccination. CTLs exhibited WT1 peptide-specific cytotoxicity in vitro. CONCLUSION: The WT1 peptide vaccine induced an immune response that persists for more than 10 years, even after cessation of vaccination in the CML patient.

DOI： 10.1007/s12185-024-03723-1

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Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with BCR::ABL1 fusion. 国際誌

Shohei Mizuno, Akiyoshi Takami, Koji Kawamura, Kaito Harada, Masuko Masayoshi, Shingo Yano, Ayumu Ito, Yukiyasu Ozawa, Fumihiko Ouchi, Takashi Ashida, Yuichiro Nawa, Tatsuo Ichinohe, Takahiro Fukuda, Yoshiko Atsuta, Masamitsu Yanada

EJHaem 5 ( 2 ) 369 - 378 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BCR::ABL1 fusion is found in < 1% of de novo acute myeloid leukemia (AML) cases and confers a poor prognosis. This Japanese nationwide survey analyzed patients with AML (n = 22) and mixed phenotype acute leukemia (MPAL) (n = 10) with t(9;22) or BCR::ABL1 who underwent allogeneic hematopoietic cell transplantation (allo-HCT) between 2002 and 2018. The 3-year overall survival (OS) rates were 81.3% and 56.0%, respectively (p = 0.15), and leukemia-free survival (LFS) rates were 76.2% and 42.0%, respectively (p = 0.10) in patients with AML and MPAL. The relapse rates were 9.5% and 14.0% (p = 0.93), and the non-relapse mortality (NRM) rates were 14.3% and 44.0%, respectively (p = 0.10) in patients with AML and MPAL. One in 17 patients with AML, with pre-transplant tyrosine kinase inhibitors (TKI), and three in five patients with AML, without pre-transplant TKI, did not achieve complete remission (CR) before allo-HCT (p = 0.024). Among the 20 patients with known disease status after allo-HCT, 95.0% were in hematological or molecular CR. None of the four patients who received post-transplant TKI for prophylaxis or measurable residual disease relapse experienced hematological relapse. In conclusion, our results suggest that pre-transplant TKI could improve disease status before allo-HCT. Moreover, allo-HCT resulted in high OS, high LFS, low relapse, and low NRM rates in patients with AML with BCR::ABL1.

DOI： 10.1002/jha2.877

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同種移植後day30の末梢血CD8TN、CD4TEM割合は急性GVHD発症のバイオマーカーとなる

片桐隆幸, 古山悠里, 米沢穂高, 諏訪部達也, 布施香子, 柴崎康彦, 瀧澤淳, 曽根博仁, 増子正義

日本血液学会学術集会 85回 880 - 880 2023年10月

WT1ペプチドワクチン投与後10年間以上にわたり持続するWT1特異的な細胞傷害性T細胞

諏訪部達也, 柴崎康彦, 田村秀, 片桐隆幸, 井田桃里, 布施香子, 牛木隆志, 曽根博仁, 成田美和子, 増子正義

日本血液学会学術集会 85回 117 - 117 2023年10月

単一施設における節外性NK/T細胞リンパ腫、鼻腔(ENKL)における26例の後方視的解析 EBV-DNA定量の有用性

山田隆, 古山悠里, 水戸部正樹, 米沢穂高, 鈴木隆晴, 諏訪部達也, 片桐隆幸, 河本啓介, 布施香子, 柴崎康彦, 増子正義, 大島孝一, 曽根博仁, 瀧澤淳

日本血液学会学術集会 85回 294 - 294 2023年10月

BCR::ABL1融合遺伝子を有する急性骨髄性白血病に対する同種造血細胞移植成績

水野昌平, 高見昭良, 河村浩二, 原田介斗, 増子正義, 矢野真吾, 伊藤歩, 小澤幸康, 大内史彦, 芦田隆司, 名和由一郎, 一戸辰夫, 福田隆浩, 熱田由子, 柳田正光

日本血液学会学術集会 85回 31 - 31 2023年10月

Genetic manipulation resulting in decreased donor chondroitin sulfate synthesis mitigates hepatic GVHD via suppression of T cell activity. 国際誌

Suguru Tamura, Hajime Ishiguro, Tatsuya Suwabe, Takayuki Katagiri, Kaori Cho, Kyoko Fuse, Yasuhiko Shibasaki, Tadahisa Mikami, Takero Shindo, Hiroshi Kitagawa, Michihiro Igarashi, Hirohito Sone, Masayoshi Masuko, Takashi Ushiki

Scientific reports 13 ( 1 ) 13098 - 13098 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Donor T cell activation, proliferation, differentiation, and migration are the major steps involved in graft-versus-host disease (GVHD) development following bone marrow transplantation. Chondroitin sulfate (CS) proteoglycan is a major component of the extracellular matrix and causes immune modulation by interacting with cell growth factors and inducing cell adhesion. However, its precise effects on immune function are unclear than those of other proteoglycan families. Thus, we investigated the significance of CS within donor cells in acute GVHD development utilizing CSGalNAc T1-knockout (T1KO) mice. To determine the effects of T1KO, the mice underwent allogenic bone marrow transplantation from major histocompatibility complex-mismatched donors. While transplantation resulted in hepatic GVHD with inflammatory cell infiltration of both CD4+ and CD8+ effector memory T cells, transplantation in T1KO-donors showed milder cell infiltration and improved survival with fewer splenic effector T cells. In vitro T-cell analyses showed that the ratio of effector memory T cells was significantly lower via phorbol myristate acetate/ionomycin stimulation. Moreover, quantitative PCR analyses showed significantly less production of inflammatory cytokines, such as IFN-γ and CCL-2, in splenocytes of T1KO mice. These results suggest that reduction of CS in donor blood cells may suppress the severity of acute GVHD after hematopoietic stem cell transplantation.

DOI： 10.1038/s41598-023-40367-3

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皮膚硬化型慢性GVHDに対してイブルチニブが有効であった1例

佐藤美紀, 濱菜摘, 木村春奈, 長谷川瑛人, 阿部理一郎, 阿部由紀子, 諏訪部達也, 柴崎康彦, 増子正義

日本皮膚科学会雑誌 133 ( 5 ) 1420 - 1420 2023年5月

ヘパプラスチンテストを取り入れた出血原因鑑別の検査戦略後天性第V因子欠乏症における経験

松田将門, 山田隆, 古山悠里, 柴崎康彦, 関義信, 星山良樹, 寺井崇二, 瀧澤淳, 曽根博仁, 増子正義

日本血栓止血学会誌 34 ( 2 ) 262 - 262 2023年5月

Comparable survival outcomes with haploidentical stem cell transplantation and unrelated bone marrow transplantation. 国際誌

Yoshiko Atsuta, Junichi Sugita, Hirohisa Nakamae, Yumiko Maruyama, Ken Ishiyama, Souichi Shiratori, Takahiro Fukuda, Mio Kurata, Naoki Shingai, Yukiyasu Ozawa, Masayoshi Masuko, Koji Nagafuji, Satoru Takada, Shinichi Kako, Yoshinobu Kanda, Junya Kanda, Tatsuo Ichinohe, Takanori Teshima

Bone marrow transplantation 57 ( 12 ) 1781 - 1787 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

We retrospectively compared outcomes of unrelated donor bone marrow transplant (UBMT) and HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide (PTCy-haploPBSCT) using the Japanese registry data. Recipients of first HCT for acute leukemia and myelodysplastic syndromes between 2012 and 2015 were included. The analyzed subjects comprised UBMT recipients with 8/8 matched HLA alleles (n = 1470), 7/8 matched alleles (n = 859), 6/8 matched alleles (n = 186), and recipients of PTCy-haploPBSCT (n = 133). In multivariate analyses with 8/8 matched UBMT as the reference, PTCy-haploPBSCT showed similar overall mortality, decreased risk of non-relapse mortality (NRM), increased risk of relapse, and decreased risk of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD. Adjusted probabilities for 8/8 matched UBMT, PTCy-haploPBSCT, and 7/8 and 6/8 matched UBMT groups at 2 years post-transplant were 61%, 60%, 58%, and 52% for overall survival, 23%, 28%, 21%, and 19% for relapse, and 20%, 7%, 24%, and 33% for NRM. PTCy-haploPBSCT was associated with remarkably low NRM, contributing to survival outcomes that were comparable to 8/8 matched UBMT. The higher relapse rate in the PTCy-haploPBSCT group might be associated with the higher proportion of high-risk patients. PTCy-haploPBSCT may be a viable alternative when HLA-matched related donors are not available.

DOI： 10.1038/s41409-022-01822-3

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Prognostic impact of complex karyotype on post-transplant outcomes of myelofibrosis. 国際誌

Yosuke Okada, Katsuto Takenaka, Makoto Murata, Yutaka Shimazu, Takayoshi Tachibana, Yukiyasu Ozawa, Naoyuki Uchida, Toshio Wakayama, Noriko Doki, Yasuhiro Sugio, Masatsugu Tanaka, Masayoshi Masuko, Hikaru Kobayashi, Kazuko Ino, Jun Ishikawa, Hirohisa Nakamae, Ken-Ichi Matsuoka, Yoshinobu Kanda, Takahiro Fukuda, Yoshiko Atsuta, Tokiko Nagamura-Inoue

Hematological oncology 40 ( 5 ) 1076 - 1085 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Chromosomal abnormalities in the role of prognostic factor for transplant patients with myelofibrosis (MF) are not fully investigated. Regarding complex karyotype (CK), we retrospectively analyzed 241 patients with primary and secondary MF who received a first allogeneic hematopoietic cell transplantation (HCT). Based on an unfavorable karyotype in the Dynamic International Prognostic Scoring System, we compared the outcomes in 3 groups: favorable karyotype, unfavorable karyotype including CK (unfavorable-CK(+)), and unfavorable karyotype not including CK (unfavorable-CK(-)). Overall survival was significantly shorter in the unfavorable-CK(+) group (hazard ratio (HR) 2.49, 95% CI: 1.46-4.24, P < 0.001), whereas there was no difference between the unfavorable-CK(-) group and the favorable group (HR 0.57, 95% CI: 0.20-1.59, P = 0.28). In addition, a significantly higher proportion of patients in the unfavorable-CK(+) group did not achieve complete remission after HCT (P = 0.007). The cumulative incidence of disease progression was significantly higher in the unfavorable-CK(+) group (HR 2.5, 95% CI 1.6-3.92, P < 0.001), whereas that in the unfavorable-CK(-) group was comparable to that in the favorable group (HR 0.49, 95% CI 0.12-1.94, P = 0.31). Further investigations will be needed to clarify the impact of CK on transplant outcomes in MF.

DOI： 10.1002/hon.3058

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Comparable survival outcomes with haploidentical stem cell transplantation and cord blood transplantation. 国際誌

Junichi Sugita, Yoshiko Atsuta, Hirohisa Nakamae, Yumiko Maruyama, Ken Ishiyama, Souichi Shiratori, Takahiro Fukuda, Mio Kurata, Naoki Shingai, Yukiyasu Ozawa, Masayoshi Masuko, Koji Nagafuji, Naoyuki Uchida, Masatsugu Tanaka, Makoto Onizuka, Junya Kanda, Takafumi Kimura, Tatsuo Ichinohe, Takanori Teshima

Bone marrow transplantation 57 ( 11 ) 1681 - 1688 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and umbilical cord blood transplantation (UCBT) are alternative to HLA-matched stem cell transplantation. We conducted a matched-pair analysis of PTCy-haplo and UCBT using the Japanese registry data. We identified 136 patients aged between 16 and 69 years who received PTCy-haplo as their first transplantation for acute leukemia or myelodysplastic syndromes. Control group included 408 UCBT recipients selected to match the PTCy-haplo group. Overall and relapse-free survival probabilities at 2 years were comparable between the PTCy-haplo and UCBT groups: 55% vs. 53% for overall survival (p = 0.46), and 47% vs. 48% for relapse-free survival (p = 0.79), respectively. The cumulative incidence of relapse was significantly higher (43% vs. 29%, respectively, p = 0.006), while the cumulative incidence of non-relapse mortality (NRM) was significantly lower (9% vs. 23%, respectively, p < 0.001) in the PTCy-haplo group. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was lower in the PTCy-haplo group compared to the UCBT group (29% vs. 41%, respectively, p = 0.016), while those of grade III-IV acute GVHD and chronic GVHD were not statistically different between the two groups. Our results suggest that both PTCy-haplo and UCBT are viable alternatives to HLA-matched stem cell transplantation.

DOI： 10.1038/s41409-022-01770-y

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Comparison of transplant outcomes between haploidentical transplantation and single cord blood transplantation in non‐remission acute myeloid leukaemia: A nationwide retrospective study

Kensuke Matsuda, Takaaki Konuma, Kyoko Fuse, Masayoshi Masuko, Koji Kawamura, Masahiro Hirayama, Naoyuki Uchida, Kazuhiro Ikegame, Atsushi Wake, Tetsuya Eto, Noriko Doki, Shigesaburo Miyakoshi, Masatsugu Tanaka, Satoshi Takahashi, Makoto Onizuka, Koji Kato, Takafumi Kimura, Tatsuo Ichinohe, Nobuyuki Takayama, Hikaru Kobayashi, Hirohisa Nakamae, Yoshiko Atsuta, Junya Kanda, Masamitsu Yanada

British Journal of Haematology 2022年10月

Salvage single-unit unrelated cord blood transplantation for graft failure following initial allogeneic transplantation in adult acute myeloid leukemia: trends in outcomes over the past 20 years. 国際誌

Takaaki Konuma, Kaito Harada, Tadakazu Kondo, Masayoshi Masuko, Naoyuki Uchida, Shingo Yano, Toshiro Kawakita, Makoto Onizuka, Shuichi Ota, Emiko Sakaida, Shigesaburo Miyakoshi, Yukiyasu Ozawa, Yutaka Imamura, Takafumi Kimura, Yoshinobu Kanda, Takahiro Fukuda, Yoshiko Atsuta, Masamitsu Yanada

Bone marrow transplantation 57 ( 12 ) 1848 - 1850 2022年10月

WT1ペプチドワクチン投与後10年間以上にわたり持続するWT1特異的な細胞傷害性T細胞

諏訪部達也, 柴崎康彦, 田村秀, 片桐隆幸, 井田桃里, 布施香子, 牛木隆志, 曽根博仁, 成田美和子, 増子正義

日本血液学会学術集会 84回 117 - 117 2022年10月

単一施設における節外性NK/T細胞リンパ腫、鼻腔(ENKL)における26例の後方視的解析 EBV-DNA定量の有用性

山田隆, 古山悠里, 水戸部正樹, 米沢穂高, 鈴木隆晴, 諏訪部達也, 片桐隆幸, 河本啓介, 布施香子, 柴崎康彦, 増子正義, 大島孝一, 曽根博仁, 瀧澤淳

日本血液学会学術集会 84回 294 - 294 2022年10月

同種移植後day30の末梢血CD8TN、CD4TEM割合は急性GVHD発症のバイオマーカーとなる

片桐隆幸, 古山悠里, 米沢穂高, 諏訪部達也, 布施香子, 柴崎康彦, 瀧澤淳, 曽根博仁, 増子正義

日本血液学会学術集会 84回 880 - 880 2022年10月

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