研究者詳細 - 瀧澤　淳

論文 - 瀧澤　淳

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Safety and efficacy of acalabrutinib and obinutuzumab in treatment-naive chronic lymphocytic leukemia: a Japanese phase 1 study. 国際誌

Jun Takizawa, Takanori Teshima, Daisuke Ennishi, Satoshi Ichikawa, Ritsuro Suzuki, Akira Kojima, Yusuke Takahashi, Nobuya Hayashi, Hisashi Kawasumi, Kosho Murayama, Patricia Cheung, Toshio Kawata, Koji Izutsu

Leukemia & lymphoma 65 ( 11 ) 1586 - 1594 2024年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

DOI： 10.1080/10428194.2024.2370436

Alemtuzumab monotherapy for T-cell prolymphocytic leukemia: an observational study in Japan.

Motoko Yamaguchi, Noriko Fukuhara, Jun Takizawa, Kenji Ishitsuka, Akihiko Yokohama, Kana Miyazaki, Yuma Nato, Satoshi Ichikawa, Masaki Mitobe, Kodai Shima, Yuri Miyazawa, Koji Izutsu, Ritsuro Suzuki, Hirokazu Nagai, Naoya Nakamura

Journal of clinical and experimental hematopathology : JCEH 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Alemtuzumab is recommended as first-line and second-line therapies for T-cell prolymphocytic leukemia (T-PLL). This study retrospectively evaluated the efficacy and safety of alemtuzumab in nine Japanese patients with T-PLL at five participating institutions who were treated between January 2015 and August 2023. The median age at first administration of alemtuzumab was 72 years (range, 39 to 78). Two patients were treatment naïve, and seven had been treated with a median of one (range, 1 to 3) prior systemic therapy. Six patients were refractory to their most recent therapy. Three patients completed 12 weeks of treatment. The overall response rate and the complete response (CR) rate were 78% and 11%, respectively. Among the six patients who achieved a partial response, two achieved clinical CR but did not undergo bone marrow examination. One patient also achieved clinical CR but did not undergo CT or bone marrow examination for response evaluation. The median progression-free survival time was 8.1 months (95% confidence interval, 0.9 to 18.6). Three patients received readministration of alemtuzumab monotherapy after disease progression. There were no treatment-related deaths. The grade 3 or 4 nonhematologic adverse events included infusion reaction (grade 3, n = 2), cytomegalovirus reactivation (grade 3, n = 2), and pulmonary edema (grade 3, n = 1). One patient experienced Epstein‒Barr virus-positive diffuse large B-cell lymphoma 15 months after the last dose of alemtuzumab. These results confirm that the efficacy and safety of alemtuzumab monotherapy in Japanese patients are comparable to those previously reported.

DOI： 10.3960/jslrt.24028

Autologous HSCT with novel agent-based induction and consolidation followed by lenalidomide maintenance for untreated multiple myeloma. 国際誌

Yasuo Mori, Jun Takizawa, Yuna Katsuoka, Naoki Takezako, Koji Nagafuji, Hiroshi Handa, Junya Kuroda, Kazutaka Sunami, Tomohiko Kamimura, Ryosuke Ogawa, Yoshikane Kikushige, Mine Harada, Koichi Akashi, Toshihiro Miyamoto

Cancer science 2024年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20-65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high-dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent-to-treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1-year maintenance, respectively. With a median follow-up of 38 months, the 3-year progression-free survival (PFS) rate was 83.5% and the 3-year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment-related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high-risk cytogenetics showed a trend toward lower 3-year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra-high-risk cytogenetics (≥2 high-risk cytogenetics) had an even worse prognosis, with 61.2% 3-year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38-antibody should be assessed in future studies.

DOI： 10.1111/cas.16158

Characteristics of chronic lymphocytic leukemia in Japan: Comprehensive analysis of the CLLRSG-01 study

Jun Takizawa, Ritsuro Suzuki, Koji Izutsu, Toru Kiguchi, Hideki Asaoku, Yoshio Saburi, Taro Masunari, Atae Utsunomiya, Kengo Takeuchi, Naoya Nakamura, Koichi Ohshima, Michaela Gruber, Ulrich Jäger, Sadao Aoki, Junji Suzumiya

International Journal of Hematology 119 ( 6 ) 686 - 696 2024年3月

Clinicopathological comparison between PTCL-TBX21 and PTCL-GATA3 in Japanese patients. 国際誌

Yasumasa Shimasaki, Hiroaki Miyoshi, Keisuke Kawamoto, Noriaki Yoshida, Tatsuzo Mishina, Kazutaka Nakashima, Teppei Imamoto, Takeshi Sugio, Eriko Yanagida, Takeharu Kato, Kyohei Yamada, Mai Takeuchi, Takaharu Suzuki, Mayuko Moritsubo, Takuya Furuta, Yoshitaka Imaizumi, Jun Takizawa, Koji Kato, Junji Suzumiya, Ritsuro Suzuki, Koichi Ohshima

Cancer medicine 2024年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous disease that can be classified into the PTCL-TBX21 and PTCL-GATA3 subtypes. METHODS: In this study, we compared the clinicopathological features of PTCL-NOS in a Japanese cohort, classified using an IHC algorithm. RESULTS: One hundred patients with PTCL-NOS were categorized as having PTCL-TBX21 (n = 55), PTCL-GATA3 (n = 24), or PTCL-unclassified (n = 21). When comparing PTCL-TBX21 and PTCL-GATA3, PTCL-TBX21 showed significantly lower CD4 positivity (p = 0.047), lower counts of high endothelial venules (p = 0.032), and a tendency for a better response to initial treatment (p = 0.088). Gene expression analysis using the nCounter system showed higher expression of tumor immunity-related genes, such as PD-L1, LAG3, and IDO1, in PTCL-TBX21 than in PTCL-GATA3. PTCL-GATA3 had significantly worse overall survival (OS) than those with PTCL-TBX21 (p = 0.047), although a similar tendency was observed for progression-free survival (PFS) (p = 0.064). PTCL-GATA3 was a prognostic factor for OS in univariate analysis (HR 2.02; 95% CI, 1.09-3.77; p = 0.027), although multivariate analysis did not show significance (HR 2.07; 95% CI, 0.93-4.61; p = 0.074). In the PFS analysis, PTCL-GATA3 was an independent prognostic factor by univariate analysis (HR 1.96; 95% CI, 1.08-3.56; p = 0.027) and multivariate analysis (HR 2.34; 95% CI, 1.07-5.11; p = 0.032). CONCLUSION: The classification of PTCL-NOS into PTCL-TBX21 and PTCL-GATA3 is useful for predicting the prognosis of Japanese patients and stratifying the administration of tumor immune checkpoint inhibitors in clinical practice.

DOI： 10.1002/cam4.6793

YAP1/TAZ activity maintains vascular integrity and organismal survival. 国際誌

Shun Uemura, Masayuki Yamashita, Kazumasa Aoyama, Takako Yokomizo-Nakano, Motohiko Oshima, Miki Nishio, Masayoshi Masuko, Jun Takizawa, Hirohito Sone, Yasuhiro Yamada, Akira Suzuki, Atsushi Iwama

Biochemical and biophysical research communications 619 117 - 123 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Radiation therapy is one of the major treatment modalities for patients with cancers. However, ionizing radiation (IR) damages not only cancer cells but also the surrounding vascular endothelial cells (ECs). Hippo pathway effector genes Yap1 and Taz are the two transcriptional coactivators that have crucial roles in tissue homeostasis and vascular integrity in various organs. However, their function in adult ECs at the steady state and after IR is poorly understood. Here, we report sex- and context-dependent roles of endothelial YAP1/TAZ in maintaining vascular integrity and organismal survival. EC-specific Yap1/Taz deletion compromised systemic vascular integrity, resulting in lethal circulation failure preferentially in male mice. Furthermore, EC-specific Yap1/Taz deletion induced acute lethality upon sublethal IR that was closely associated with exacerbated systemic vascular dysfunction and circulation failure. Consistent with these findings, RNA-seq analysis revealed downregulation of tight junction genes in Yap1/Taz-deleted ECs. Collectively, our findings highlight the importance of endothelial YAP1/TAZ for maintaining adult vascular function, which may provide clinical implications for preventing organ injury after radiation therapy.

DOI： 10.1016/j.bbrc.2022.06.050

Long-term outcomes and central nervous system relapse in extranodal natural killer/T-cell lymphoma. 国際誌

Kana Miyazaki, Ritsuro Suzuki, Masahiko Oguchi, Senzo Taguchi, Jun Amaki, Takeshi Maeda, Nobuko Kubota, Dai Maruyama, Yasuhito Terui, Nodoka Sekiguchi, Jun Takizawa, Hiroyuki Tsukamoto, Tohru Murayama, Toshihiko Ando, Hiroshi Matsuoka, Masatoshi Hasegawa, Hideho Wada, Rika Sakai, Yoshihiro Kameoka, Norifumi Tsukamoto, Ilseung Choi, Yasufumi Masaki, Kazuyuki Shimada, Noriko Fukuhara, Takahiko Utsumi, Nobuhiko Uoshima, Yoshitoyo Kagami, Naoko Asano, Yasuo Ejima, Naoyuki Katayama, Motoko Yamaguchi

Hematological oncology 40 ( 4 ) 667 - 677 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.

DOI： 10.1002/hon.2977

A phase 2 study of polatuzumab vedotin + bendamustine + rituximab in relapsed/refractory diffuse large B‐cell lymphoma 査読国際誌

Yasuhito Terui, Shinya Rai, Koji Izutsu, Motoko Yamaguchi, Jun Takizawa, Junya Kuroda, Takayuki Ishikawa, Koji Kato, Youko Suehiro, Noriko Fukuhara, Ken Ohmine, Hideki Goto, Kazuhito Yamamoto, Nobuhiro Kanemura, Yasunori Ueda, Kenichi Ishizawa, Kyoya Kumagai, Atsuko Kawasaki, Tomohisa Saito, Misato Hashizume, Hirohiko Shibayama

Cancer Science 112 ( 7 ) 2845 - 2854 2021年7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：Wiley

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m2 , rituximab 375 mg/m2 (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography-computed tomography (PET-CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty-five patients (median age 71 [range 46-86] years) were enrolled. Twenty-three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow-up of 5.4 (0.7-11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1-52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression-free survival was 5.2 months (95% CI 3.6-not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3-4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1-2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI-184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.

DOI： 10.1111/cas.14937

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14937

A phase II Japanese trial of fludarabine, cyclophosphamide and rituximab for previously untreated chronic lymphocytic leukemia 査読

Koji Izutsu, Tomohiro Kinoshita, Jun Takizawa, Suguru Fukuhara, Go Yamamoto, Yasuo Ohashi, Junji Suzumiya, Kensei Tobinai

Japanese Journal of Clinical Oncology 51 ( 3 ) 408 - 415 2021年3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：Oxford University Press (OUP)

<title>Abstract</title>
<sec>
<title>Objective</title>
Fludarabine, cyclophosphamide and rituximab (FCR) is the standard regimen for fit patients with untreated CD20-positive chronic lymphocytic leukemia (CLL). However, this combination is unavailable in Japan because rituximab is not approved for CLL. We investigated the efficacy and safety of FCR in this single-arm, multicenter study designed as a bridging study to the CLL8 study by the German CLL Study Group.

</sec>
<sec>
<title>Methods</title>
The study enrolled previously untreated patients with CLL of Binet stage B or C with active disease. Patients with a Cumulative Illness Rating Scale score of ≤6 and creatinine clearance of ≥70 ml/min were eligible. Patients received 6 cycles of FCR every 28 days and were followed for up to 1 year.

</sec>
<sec>
<title>Results</title>
Seven patients were enrolled. The best overall response rate according to the 1996 NCI-WG Guidelines, the primary endpoint of the study, was 71.4% (95% confidence interval, 29.0–96.3%), with one patient achieving complete response. No deaths or progression occurred during follow-up. The main adverse event was hematotoxicity. CD4-positive T-cell count decreased in all patients; most patients showed no reduction in serum immunoglobulin G.

</sec>
<sec>
<title>Conclusion</title>
Although the number of patients was limited, FCR appears to be effective with manageable toxicity for treatment-naïve fit Japanese patients with CD20-positive CLL.

</sec>
<sec>
<title>Clinical trial number</title>
JapicCTI-132285.

</sec>

DOI： 10.1093/jjco/hyaa215

Consolidation with 90 Yttrium-ibritumomab tiuxetan after bendamustine and rituximab for relapsed follicular lymphoma. 国際誌

Katsuhiro Miura, Hideki Tsujimura, Yasufumi Masaki, Masaki Iino, Jun Takizawa, Yoshinobu Maeda, Kazuhiko Yamamoto, Shinobu Tamura, Akiyo Yoshida, Hideo Yagi, Isao Yoshida, Koichi Kitazume, Taro Masunari, Ilseung Choi, Yasutaka Kakinoki, Ritsuro Suzuki, Tadashi Yoshino, Shigeo Nakamura, Yoshihiro Hatta, Takashi Yoshida, Masatoshi Kanno

Hematological oncology 39 ( 1 ) 51 - 59 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Bendamustine and rituximab (BR) are widely used in patients with follicular lymphoma (FL) previously treated with conventional immunochemotherapy, but the role of consolidation radioimmunotherapy in these patients is unknown. This study evaluated the efficacy and safety of consolidation with 90 Yttrium-ibritumomab tiuxetan (90 Y-IT) after re-induction therapy with BR in patients with previously treated FL. This study included adult patients with relapsed FL who had undergone one or two prior therapies. Re-induction therapy with BR was administered every 4 weeks up to 4-6 cycles. If patients achieved at least partial response, 90 Y-IT was administered as consolidation therapy. The primary endpoint was 2-year progression-free survival (PFS) after consolidation. A total of 24 FL patients (median age 60 years) who had undergone one (n = 17) or two (n = 7) prior treatments received BR. After BR therapy, 22 patients proceeded to consolidation with 90 Y-IT, resulting in an overall 88% response rate to the protocol treatment. Within a median observation period of 46.8 months, the estimated 2-year PFS rate after the consolidation among the 22 patients receiving 90 Y-IT was 59% (95% confidence interval [CI], 38%-77%). Patients whose remission after previous treatment had lasted ≥2 years had a significantly higher 2-year PFS rate than patients whose remission after previous treatment had been <2 years (68% vs. 33%, Wilcoxon p = 0.0211). Major adverse events during the protocol treatment and within 2 years after the consolidation were hematological toxicities, but they were generally acceptable. Consequently, the estimated 2-year overall survival after the consolidation was 95% (95% CI, 74%-99%). In conclusion, in a subset of patients with previously treated FL, 90 Y-IT consolidation after BR re-induction conferred a durable remission, indicating that consolidation therapy using 90 Y-IT may be a novel therapeutic option for patients with relapsed FL (UMIN000008793).

DOI： 10.1002/hon.2809

DA-EPOCH-R therapy for high-grade B-cell lymphoma with <i>MYC</i> and <i>BCL2</i> and/or <i>BCL6</i> rearrangements in a patient with renal dysfunction 査読

Masaki Mitobe, Keisuke Kawamoto, Takaharu Suzuki, Tatsuya Suwabe, Yasuhiko Shibasaki, Masayoshi Masuko, Kanako Inoue, Hiroaki Miyoshi, Koichi Ohshima, Hirohito Sone, Jun Takizawa

Journal of Clinical and Experimental Hematopathology 61 ( 1 ) 42 - 47 2021年

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Society for Lymphoreticular Tissue Research

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit lymphoma, has been reported as refractory to R-CHOP therapy and requires more intensive regimens. However, intensive and safe regimens for patients with renal dysfunction are unknown. Herein, we report the successful use of DA-EPOCH-R therapy for double-hit lymphoma in a 64-year-old man with renal dysfunction. The patient had lymphoma-induced bilateral ureteral obstruction. Although renal dysfunction remained after removing the obstruction using R-CHOP therapy, we completed six cycles of DA-EPOCH-R therapy without any major adverse events. DA-EPOCH-R therapy may be a safe regimen for renal dysfunction patients.

DOI： 10.3960/jslrt.20043

Real World Treatment Practices for Chronic Lymphocytic Leukemia in Japan: An Observational Database Research Study (CLIMBER-DBR)

Jun Takizawa, Koji Izutsu, Hirokazu Nagai, Kenjiro Fukase, Maki Nakamura, Masahisa Jinushi, Junji Suzumiya

Journal of Clinical and Experimental Hematopathology 61 ( 3 ) 126 - 134 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Society for Lymphoreticular Tissue Research

There are limited real-world data on the treatment practices and healthcare resource utilization associated with chronic lymphocytic leukemia (CLL) in Japan. In this study (CLIMBER-DBR), we performed retrospective analyses of the Japanese Medical Data Vision database, and extracted data for 2562 patients with newly diagnosed CLL (CLL-1 cohort) and 930 patients receiving CLL treatment (CLL-2 cohort) registered between March 1, 2013 and February 28, 2018. The median follow-up in the CLL-1 cohort was 721 (quartile 1-3: 363-1267) days and the median time to initial (first-line) treatment was 1331 (quartile 1-3: 189-not reached) days. In the CLL-2 cohort, the most frequently used regimens were fludarabine alone (17.7%), cyclophosphamide alone (13.7%), and bendamustine/rituximab (8.2%). The median (quartile 1-3) times to second-line and third-line treatments were 1066 (273-not reached) and 1795 (631-not reached) days, respectively. The CLIMBER-DBR was the first database research study to assess current treatment practices for CLL in Japan, where the treatment patterns were driven by the approval/reimbursement status of drugs in the study period. Our study provides an important benchmark for future studies of CLL in Japan.

DOI： 10.3960/jslrt.20044

Real World Treatment Practices for Mantle Cell Lymphoma in Japan: An Observational Database Research Study (CLIMBER-DBR)

Koji Izutsu, Junji Suzumiya, Jun Takizawa, Kenjiro Fukase, Maki Nakamura, Masahisa Jinushi, Hirokazu Nagai

Journal of Clinical and Experimental Hematopathology 61 ( 3 ) 135 - 144 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Society for Lymphoreticular Tissue Research

Mantle cell lymphoma (MCL) accounts for approximately 3% of all cases of malignant lymphoma in Japan. The CLIMBER-DBR (Treatment practices and patient burden in chronic lymphocytic leukemia and mantle cell lymphoma patients in the real world: An observational database research in Japan) study examined the clinical characteristics, treatment patterns, and health-care resource utilization of MCL in a real-world clinical setting in Japan. Using the Japanese Medical Data Vision database, we extracted data for 1130 patients with MCL (ICD-10 code C83.1) registered between March 1, 2013 and February 28, 2018. The date of first MCL diagnosis was taken as the index date. The mean (standard deviation) age, body weight, and modified Charlson Comorbidity Index were 71.4 (10.9) years, 58.3 (11.7) kg, and 1.9 (1.6). respectively, and 24.6% were <= 65 years old. The median follow-up period was 654 days (first-third quartile 290.5-1049 days). A total of 802 patients (71.0%) underwent first-line treatment. The most common first-line treatment was bendamustine/rituximab (BR; 27.8%), followed by rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP; 15.6%) and rituximab/tetrahydropyranyl-adriamycin/cyclo-phosphamide/vincristine/prednisolone (R-THP-COP; 6.5%). The median (95% confidence interval) times to initial (first-line), second-line, and third-line treatments were 45 (36-62), 687 (624-734), and 1188 (1099-1444) days, respectively. Treatment practices for MCL in Japan are consistent with trends observed in Western countries. Our study can serve as a benchmark to assess future MCL treatments in Japan.

DOI： 10.3960/jslrt.20056

Combination of CD47 and signal‐regulatory protein‐α constituting the “don’t eat me signal” is a prognostic factor in diffuse large B‐cell lymphoma 査読国際誌

Ryo Kazama, Hiroaki Miyoshi, Mai Takeuchi, Kohta Miyawaki, Kazutaka Nakashima, Noriaki Yoshida, Keisuke Kawamoto, Eriko Yanagida, Kyohei Yamada, Takeshi Umeno, Takaharu Suzuki, Koji Kato, Jun Takizawa, Masao Seto, Koichi Akashi, Koichi Ohshima

Cancer Science 111 ( 7 ) 2608 - 2619 2020年7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：Wiley

The interaction between CD47 and signal-regulatory protein-α (SIRPα) inhibits phagocytosis, thus affecting the clinical outcomes of neoplastic diseases. Although CD47 upregulation is associated with poor prognosis in several malignancies, the effect of SIRPα expression and its coexpression with CD47 remains unclear. This study aimed to investigate the clinicopathologic effect of CD47 and SIRPα expression in diffuse large B-cell lymphoma (DLBCL). Immunostaining of 120 biopsy samples showed that CD47 is primarily expressed in tumor cells, whereas SIRPα is expressed in nonneoplastic stromal cells, mostly macrophages. CD47high cases showed higher MYC protein expression and lower MYC translocation. The SIRPαhigh cases presented significantly shorter overall survival (OS) and progression-free survival (PFS) than SIRPαlow cases in the activated B-cell (ABC) subtype of DLBCL (P = .04 and P = .02, respectively). Both CD47high and SIRPαhigh presented significantly shorter OS and PFS than other cases among all DLBCL patients (P = .01 and P = .004, respectively), and the ABC type (P = .04 and P = .008, respectively) but not the germinal center B-cell type. Both CD47high and SIRPαhigh yielded a constant independent prognostic value for OS and PFS in multivariate analysis (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.20-7.43; P = .02; and HR, 2.87; 95% CI, 1.42-5.85; P = .003, respectively). To the best of our knowledge, this is the first study to report that combinatorial CD47 and SIRPα expression is a potential independent prognostic factor for DLBCL. Evaluation of CD47 and SIRPα expression could be useful before CD47 blockade therapy.

DOI： 10.1111/cas.14437

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14437

Evolution in the management of chronic lymphocytic leukemia in Japan: should MRD negativity be the goal? 査読

Junji Suzumiya, Jun Takizawa

International Journal of Hematology 111 ( 5 ) 642 - 656 2020年5月

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): a multicentre, single-arm, phase 2 trial 査読国際誌

Kazuyuki Shimada, Motoko Yamaguchi, Yoshiko Atsuta, Kosei Matsue, Keijiro Sato, Shigeru Kusumoto, Hirokazu Nagai, Jun Takizawa, Noriko Fukuhara, Koji Nagafuji, Kana Miyazaki, Eiichi Ohtsuka, Masataka Okamoto, Yasumasa Sugita, Toshiki Uchida, Satoshi Kayukawa, Atsushi Wake, Daisuke Ennishi, Yukio Kondo, Tohru Izumi, Yoshihiro Kin, Kunihiro Tsukasaki, Daigo Hashimoto, Masaaki Yuge, Atsumi Yanagisawa, Yachiyo Kuwatsuka, Satoko Shimada, Yasufumi Masaki, Nozomi Niitsu, Hitoshi Kiyoi, Ritsuro Suzuki, Takashi Tokunaga, Shigeo Nakamura, Tomohiro Kinoshita

The Lancet Oncology 21 ( 4 ) 593 - 602 2020年4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 BV

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. METHODS: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. FINDINGS: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. INTERPRETATION: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. FUNDING: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.

DOI： 10.1016/s1470-2045(20)30059-0

Clinicopathological analysis of splenic red pulp low-grade B-cell lymphoma. 査読国際誌

Takaharu Suzuki, Hiroaki Miyoshi, Joji Shimono, Keisuke Kawamoto, Fumiko Arakawa, Takuya Furuta, Kyohei Yamada, Eriko Yanagida, Mai Takeuchi, Masao Seto, Hirohito Sone, Jun Takizawa, Koichi Ohshima

Pathology international 70 ( 5 ) 280 - 286 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Primary splenic low-grade B-cell lymphoma of the red pulp comprises hairy cell leukemia (HCL) and splenic B-cell lymphoma/leukemia, unclassifiable (SPLL-U). SPLL-U is a rare disease that includes subtypes of a hairy cell leukemia-variant (HCL-v), splenic diffuse red pulp small B-cell lymphoma (SDRPL) and other types that are known as narrow sense SPLL-U (SPLL-U-NS). Notably, limited information is available regarding the BRAF mutation (V600E) and cyclin D3 expression in subtypes of SPLL-U. Therefore, we performed a pathological analysis of the BRAF mutation (V600E) and characterized pathological features of SPLL-U. We reviewed the pathological findings of 12 SPLL-U cases. The 12 cases considered included two cases of HCL-v, six cases of SPLL-U-NS and four undetermined cases. The BRAF mutation (V600E) was detected in three cases, which were all SPLL-U-NS. Cases with the BRAF mutation (V600E) have increased levels of CD103 expression and decreased cyclin D3 and cyclin D1 expression compared with cases that lacked the BRAF mutation. These findings suggest that the BRAF mutation might play a significant role in SPLL-U. Therefore, the significance of the BRAF mutation should be evaluated via genomic or transcriptional analyses of a large cohort of SPLL-U patients.

DOI： 10.1111/pin.12909

The natural course of IgG4-related ophthalmic disease after debulking surgery: a single-centre retrospective study 査読国際誌

Jun Ominato, Tokuhide Oyama, Hiroyuki Cho, Naoya Shiozaki, Hajime Umezu, Jun Takizawa, Takeo Fukuchi

BMJ Open Ophthalmology 4 ( 1 ) e000295 - e000295 2019年8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：BMJ

<sec><title>Objective</title>This study aimed to examine the natural course and relapse rate of IgG4-related ophthalmic disease (IgG4-ROD) after debulking surgery in Japanese patients.

</sec><sec><title>Methods and analysis</title>This retrospective review included patients with IgG4-ROD who did not undergo further treatment following debulking surgery. The patients were diagnosed between January 2009 and December 2018 at the Department of Ophthalmology and Pathology, Niigata University Medical and Dental Hospital. The main outcome measures included postoperative IgG4-ROD recurrence rate and differences between patients with and without recurrent disease.

</sec><sec><title>Results</title>Fifteen patients (six male, 9 female; 61.8±16.2 years) were included. Twelve patients (80.0%) had dacryoadenitis disease and three patients (20.0%) had orbital fat tissue disease. About 70%–100% of the lesion was resected in the debulking surgery and the pathological diagnosis was rendered. A definitive diagnosis was made in 13 cases (86.7%) and a probable diagnosis in 2 cases (13.3%). Patients were followed up for 39.0±25.5 months following operation. All patients had lesion volume reduction and patients with dacryoadenitis had eyelid swelling improvement after surgery. Two patients (13.3%) had disease recurrence and six patients (40.0%) had extraophthalmic lesions. There was no statistically significant difference in clinical features between relapsed and non-recurring cases.

</sec><sec><title>Conclusion</title>We observed a 13.3% relapse rate following debulking surgery in patients with IgG4-ROD who did not undergo further treatment. This rate is lower than the documented relapse rate of 30%–70% following oral prednisolone therapy. Therefore, debulking surgery may be a treatment option for IgG4-ROD.

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DOI： 10.1136/bmjophth-2019-000295

Improved prognosis of extranodal NK/T cell lymphoma, nasal type of nasal origin but not extranasal origin. 査読国際誌

Yamaguchi M, Suzuki R, Miyazaki K, Amaki J, Takizawa J, Sekiguchi N, Kinoshita S, Tomita N, Wada H, Kobayashi Y, Niitsu N, Ando T, Maeda T, Saito B, Matsuoka H, Sakai R, Kubota N, Masaki Y, Kameoka Y, Asano N, Oguchi M, Katayama N

Annals of hematology 98 ( 7 ) 1647 - 1655 2019年7月

Memory B cell pool of autoimmune pulmonary alveolar proteinosis patients contains higher frequency of GM-CSF autoreactive B cells than healthy subjects. 査読国際誌

Nei T, Urano S, Motoi N, Hashimoto A, Kitamura N, Tanaka T, Nakagaki K, Takizawa J, Kaneko C, Tazawa R, Nakata K

Immunology Letters 212 22 - 29 2019年6月

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