受賞区分：国内学会・会議・シンポジウム等の賞  受賞国：日本国

受賞区分：国際学会・会議・シンポジウム等の賞 

受賞区分：国内学会・会議・シンポジウム等の賞  受賞国：日本国

記述言語：英語   出版者・発行元：Leukemia  

Peripheral T-cell lymphoma (PTCL) exhibits a diverse clinical spectrum, necessitating methods to categorize patients based on genomic abnormalities or tumor microenvironment (TME) profiles. We conducted an integrative multiomics study in 129 PTCL patients, performing whole-exome sequencing and identifying three genetic subtypes: C1, C2, and C3. C2 was characterized by loss of tumor suppressor genes and chromosomal instability, while C1 and C3 shared T follicular helper (TFH)-related genomic alterations, with C3 also showing a high incidence of IDH2 mutations and chromosome 5 gain. Compared to C1, survival was significantly worse in C2 (HR 2.52; 95% CI, 1.37–4.63) and C3 (HR 2.14; 95% CI, 1.17–3.89). We also estimated the proportions of immune cell fractions from the bulk RNA sequencing data using CIBERSORTx and classified TME signatures into the following hierarchical clusters: TME1 (characterized by increased B and TFH cells), TME2 (macrophages), and TME3 (activated mast cells). TME2 was associated with shorter survival (HR 3.4; 95% CI, 1.6–7.5) and was more frequent in C2 (64.3%) than in C1 (7.7%), whereas C1 had more TME3 signatures (80.8% vs. 28.6%). These findings highlight a significant relationship between genetic subtypes and TME signatures in PTCL, with important implications for clinical prognosis.

DOI： 10.1038/s41375-025-02563-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-025-02563-9.

記述言語：英語   出版者・発行元：Transplantation and Cellular Therapy  

Background: Patients with adult T-cell leukemia/lymphoma (ATL) are considered to have worse outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) than patients with other hematological malignancies, owing to high risk of relapse and immunocompromised status. However, no studies have compared transplant outcomes between patients with ATL and those with other hematological malignancies using a large-scale database. Objectives: To compare transplant outcomes between patients with ATL and those with other leukemias and to identify factors contributing to worse transplant outcomes in ATL patients. Study design: Using Japanese registry data, we retrospectively compared transplant outcomes between patients with ATL and those with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). As ATL often develops in patients in their 60s or older, patients with ATL, AML, or ALL aged ≥50 years were included in order to compare patients in the same age group. A total of 7764 patients (ATL, n = 1151; AML, n = 5393; ALL, n = 1220) who underwent their first allo-HSCT between January 1, 2006 and December 31, 2017 were included in this study. Results: Compared with AML, ATL showed significantly worse overall survival (OS) (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.14 to 1.34; P < .001) and higher risk of relapse (HR, 1.33; 95% CI, 1.2 to 1.47; P < .001), while there were no significant differences between AML and ALL. Among patients in complete remission (CR) at transplantation, ATL showed worse OS (HR, 1.30; 95% CI, 1.08 to 1.56; P = .006), higher risk of relapse (HR, 1.78; 95% CI, 1.48 to 2.14; P < .001), and higher risk of nonrelapse mortality (NRM) (HR, 1.38; 95% CI, 1.14 to 1.33; P = .001) in comparison with AML, whereas there were no significant differences between AML and ALL. Conclusion: We found that ATL patients have poor transplant outcomes compared with AML or ALL patients. In ATL patients, survival is poor, relapse is more frequent, and NRM is significantly higher, especially in cases of CR. These findings suggest that prevention of relapse and transplant-related complications is important for successful allo-HSCT in ATL.

DOI： 10.1016/j.jtct.2025.01.882

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Leukemia  

DOI： 10.1038/s41375-025-02541-6

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記述言語：英語   出版者・発行元：Leukemia  

Leukemic stem cells (LSCs) of acute myeloid leukemia (AML) can be enriched in the CD34⁺CD38^- fraction and reconstitute human AML in vivo. However, in acute promyelocytic leukemia (APL), which constitutes 10% of all AML cases and is driven by promyelocytic leukemia-retinoic acid receptor alpha (PML::RARα) fusion genes, the presence of LSCs has long been unidentified because of the difficulty in efficient reconstitution of human APL in vivo. Herein, we show that LSCs of the short-type isoform APL, a subtype of APL defined by different breakpoints of the PML gene, concentrate in the CD34⁺CD38⁻ fraction and express T cell immunoglobulin mucin-3 (TIM-3). Short-type APL cells exhibited distinct gene expression signatures, including LSC-related genes, compared to the other types of APL. Moreover, CD34⁺CD38⁻TIM-3⁺ short-type APL cells efficiently reconstituted human APL in xenograft models with high penetration, whereas CD34⁻ differentiated APL cells did not. Furthermore, CD34⁺CD38⁻TIM-3⁺ short-type APL cells reconstituted leukemia cells after serial transplantation. Thus, short-type APL was hierarchically organized by self-renewing APL-LSCs. The identification of LSCs in a subset of APL and establishment of an efficient patient-derived xenograft model may contribute to further understanding the APL leukemogenesis and devise individual treatments for the eradication of APL LSCs.

DOI： 10.1038/s41375-025-02530-9

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記述言語：英語   出版者・発行元：Cancer Science  

In this study, we investigated the measurable residual leukemic stem cell (MR-LSC) population after allogeneic stem cell transplantation (allo-SCT) for high-risk acute myeloid leukemia (AML), utilizing T-cell immunoglobulin mucin-3 (TIM-3) expression as a functional marker of AML leukemic stem cells (LSCs). Analysis of the CD34⁺CD38⁻ fraction of bone marrow cells immediately after achievement of engraftment revealed the presence of both TIM-3⁺LSCs and TIM-3⁻ donor hematopoietic stem cells (HSCs) at varying ratios. Genetic analysis confirmed that TIM-3⁺ cells harbored patient-specific mutations identical to those found in AML clones, whereas TIM-3⁻ cells did not, indicating that TIM-3⁺CD34⁺CD38⁻ cells represent residual AML LSCs. In 92 allo-SCT occasions involving 83 AML patients, we enumerated the frequencies of TIM-3⁺LSCs immediately after achieving hematologic complete remission with complete donor cell chimerism. Notably, only 22.2% of patients who achieved a TIM-3⁺MR-LSC^low status (<60%) experienced relapse, with a median event-free survival (EFS) of 1581 days (median follow-up duration was 2177 days among event-free survivors). Conversely, 87.5% of patients with TIM-3⁺MR-LSC^int/high (≥60%) relapsed, with a median EFS of 140.5 days. Furthermore, MR-LSC status emerged as a significant independent risk factor for relapse (hazard ratio, 8.56; p < 0.0001), surpassing the impact of patient disease status prior to allo-SCT, including failure to achieve complete remission (hazard ratio, 1.98; p = 0.048). These findings suggest that evaluating TIM-3⁺ MR-LSCs immediately after engraftment, which reflects the competitive reconstitution of residual TIM-3⁺ LSCs and donor HSCs, may be valuable for predicting outcomes in AML patients undergoing allo-SCT.

DOI： 10.1111/cas.16431

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記述言語：英語   出版者・発行元：Hematological Oncology  

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by a poor prognosis and frequent central nervous system (CNS) relapse. Sandwich therapy comprising dose-adjusted (DA)-EPOCH-R (etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, and rituximab) and high-dose methotrexate (HD-MTX) (DA-EPOCH-R/HD-MTX) showed excellent efficacy and manageable safety in a phase II study of patients diagnosed with stage II–IV CD5+ DLBCL. To validate the results of that study and elucidate the current state of treatment for CD5+ DLBCL, we retrospectively analyzed the outcomes of patients with CD5+ DLBCL diagnosed between 2016 and 2021 who received anthracycline-containing chemotherapy with rituximab. Among the 346 patients evaluated, 62 (18%) received DA-EPOCH-R/HD-MTX. The median follow-up time was 43 months. In 55 patients with stage II–IV disease treated with DA-EPOCH-R/HD-MTX, the 2-year overall survival (OS), progression-free survival, and cumulative incidence of CNS relapse were 87% (95% CI, 73%–94%), 76% (95% CI, 61%–86%), and 7.3% (95% CI, 2.4%–16%), respectively. There were no treatment-related deaths. Febrile neutropenia occurred in 18 (33%) patients. Multivariate analysis of the 346 patients identified elevated serum lactate dehydrogenase levels, multiple extranodal involvement, no intrathecal MTX (IT-MTX), and no DA-EPOCH-R/HD-MTX as independent risk factors for OS. Only one CNS relapse event was observed in 28 patients who received both HD-MTX and IT-MTX. Our study provides real-world data on the treatments and outcomes of a large number of patients. The favorable survival and manageable toxicity of DA-EPOCH-R/HD-MTX have been validated in clinical settings. The use of HD-MTX and IT-MTX might be effective for preventing CNS relapse in patients with CD5+ DLBCL.

DOI： 10.1002/hon.70047

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-025-02517-1.

記述言語：英語   出版者・発行元：Elsevier BV  

Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy has significantly improved management of relapsed or refractory multiple myeloma. However, manufacturing failure due to poor cell growth necessitates revision of treatment strategies that negatively impact patients. To identify risk factors for CAR-T manufacturing failure in patients with myeloma, a nationwide cohort study was performed, analyzing patients who underwent apheresis for idecabtagene vicleucel in Japan. Of 154 patients analyzed, 13 cases (8.4%) experienced manufacturing failure. We compared clinical factors between patients with manufacturing failure (failed group) and those who met specifications (successful group). Patients in the failed group had a higher prevalence of deletion 17p at diagnosis (38.5% vs 14.9%), were more likely to have been treated with alkylating agents within 6 months before apheresis (53.8% vs 23.4%), and had undergone more chemotherapy lines before apheresis (median, 6 vs 5). Additionally, patients with manufacturing failure exhibited significantly lower hemoglobin levels (8.6 vs 10.0 g/dL), platelet counts (5.9 × 10⁴/μL vs 13.8 × 10⁴/μL), and CD4/CD8 ratios (0.169 vs 0.474) than patient with successful manufacturing. Multivariate analysis revealed that low platelet counts (odds ratio [OR], 0.130 for every increase of 10⁵/μL; P = .041), or low CD4/CD8 ratios (OR, 0.100 for each doubling; P = .003) at apheresis increased the risk of manufacturing failure. Alkylating agents within 6 months before apheresis were associated with decreased platelet counts and CD4/CD8 ratios. Manufacturing failure remains an obstacle to CAR-T therapy for patients with myeloma. Avoiding risk factors, such as alkylating agents, and adopting risk-adapted strategies may optimize CAR-T therapy for patients with myeloma.

CiNii Research

記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

Therapeutic plasma exchange (TPE) is a strategy for treating cold agglutinin disease (CAD) in order to manage hemolytic complications. However, there are no reports of hemolysis during TPE. A 41-year-old man with secondary CAD was unable to undergo initial TPE because of red blood cell agglutination and hemolysis in his extracorporeal circulation. To avoid low temperatures, the patient and extracorporeal circulation were kept warm by covering and heating them, and finally, he was able to successfully receive TPE three times. Although our approach still has room for improvement, our management protocol appears to be an effective treatment modality for such cases.

DOI： 10.2169/internalmedicine.3606-24

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記述言語：英語   出版者・発行元：British Journal of Haematology  

This study retrospectively compared outcomes of various allogeneic haematopoietic cell transplantation (allo-HCT) platforms in patients with adult T-cell leukaemia/lymphoma. Platforms included human leukocyte antigen (HLA)-haploidentical-related donors using post-transplant cyclophosphamide (PTCY), HLA-matched related donors (MRD), HLA-matched unrelated donors (MUD) and cord blood transplantation (CBT). Patients who underwent their first allo-HCT between 2016 and 2021 were included. Outcomes analysed were overall survival (OS), relapse and non-relapse mortality (NRM). Seven hundred patients were included (PTCY, n = 121; MRD, n = 91; MUD, n = 160; CBT, n = 328). With a median follow-up of 794 days for survivors, 2-year OS was 48.1% (PTCY), 48.8% (MRD), 48.4% (MUD) and 34.6% (CBT); the respective 2-year cumulative incidence of relapse was 37.1%, 47.5%, 33.9% and 45.1% and that of NRM was 24.2%, 19.8%, 24.7% and 27.3%. PTCY was associated with delayed platelet engraftment relative to MRD and MUD. There was no increase in the incidence of severe acute or chronic graft-versus-host disease. In the PTCY group, poor performance status was a significant predictor of inferior OS, and infused CD34+ cell numbers of less than 5 × 10⁶/kg were associated with delayed neutrophil and platelet engraftment. These results suggest that allo-HCT with PTCY is a safe and effective platform for patients with adult T-cell leukaemia/lymphoma.

DOI： 10.1111/bjh.19835

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記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

DOI： 10.11406/rinketsu.66.303

PubMed

CiNii Research

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cytotherapy  

Background: The final manufactured tisagenlecleucel product should meet the commercial product release specifications to ensure the quality in terms of safety, purity, identity, and potency. However, it may occasionally fail to meet these specifications due to the nature of patient-derived cells with variable properties as starting material and the complex manufacturing process. The final product that does not meet at least one of the commercial release specifications is referred to as “out-of-specification” (OOS). However, the benefit-risk profile of OOS tisagenlecleucel has not yet been fully elucidated. Aims: To evaluate the safety and efficacy of OOS tisagenlecleucel in Japanese patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL). Methods: This is a single-arm, open-label, multicenter phase 3b study (NCT04094311). Patients consistent with label indication were enrolled and followed-up for 3 months. Results: Of the 29 patients enrolled between December 2019 and May 2022 across 13 qualified sites in Japan, 28 received tisagenlecleucel, and of these, 23 had r/r DLBCL and 5 had r/r B-ALL. The primary reasons for OOS were low cell viability (15 of 24 batches) and low dose (8 of 23 batches) tisagenlecleucel in the r/r DLBCL group, and high dose (4 of 5 batches) in the r/r B-ALL group. In patients with r/r DLBCL, the grade 3 or 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in 3 and 1 patients, respectively. Response assessments were performed for 15 of 23 patients with r/r DLBCL: 6 achieved a complete response, and 1 achieved a partial response as the best response within 3 months. Conclusions: Despite the limited patient sample size, our findings affirm that the infusion of OOS tisagenlecleucel is a viable option, with no observed increase in toxicity and outcomes comparable to those of in-specification products in clinical and real-world studies.

DOI： 10.1016/j.jcyt.2025.04.067

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記述言語：英語   出版者・発行元：International Journal of Hematology  

Prophylactic, diagnostic, and treatment strategies for acute graft-versus-host disease (aGVHD) may vary across medical centers and physicians. We aimed to investigate the relationship between center volume and the incidence and outcomes of aGVHD. This retrospective study included 28,786 patients who underwent their first hematopoietic stem cell transplantation (HSCT) (entire cohort) and 9498 patients who developed grade II–IV aGVHD (aGVHD cohort). Data were categorized into quartiles (very low, low, high, and very high) based on the number of HSCTs the treating center performed during the study period. We assessed the incidence of aGVHD using the entire cohort and overall survival (OS) using the aGVHD cohort. Higher center volume was associated with a higher incidence of grade II–IV aGVHD than very low center volume, with an adjusted hazard ratio of 1.07–1.11. Conversely, center volume was not associated with the incidence of grade III–IV aGVHD. OS after development of aGVHD was better in the higher center volume group than the very low-volume group, with an adjusted hazard ratio of 0.81–0.89. A very low-volume center was associated with a lower incidence of grade II–IV aGVHD in patients with allogeneic HSCT and poor survival in patients with aGVHD.

DOI： 10.1007/s12185-025-04003-2

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担当区分：最終著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本造血・免疫細胞療法学会  

<p> CD19標的キメラ抗原受容体T（CAR-T）細胞療法が再発/難治性大細胞型B細胞性リンパ腫の治療にパラダイムシフトをもたらした。CAR-T細胞療法のリアルワールドデータでは，欧州は米国に比べ治療成績が劣り，その一因としてリンパ球アフェレーシスから輸注までの期間（vein-to-vein interval）が米国より長いことが挙げられている。本邦でのvein-to-vein intervalは欧州よりもさらに長く，2022年以降はさらに延長傾向にあり，早急に対処すべき課題である。また，リンパ球アフェレーシス後に，病勢増悪や合併症により輸注に至らないケースも報告されている。アフェレーシス産物未使用により患者の治療機会が失われるだけでなく，コスト面でも重大な問題が生じている。これらの問題を解決するには，病床運用の改善，ブリッジング治療の向上，感染症の管理が必要である。</p>

DOI： 10.7889/tct-24-006

CiNii Research

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Bone Marrow Transplantation  

DOI： 10.1038/s41409-025-02616-z

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記述言語：英語   出版者・発行元：International Journal of Hematology  

Ruxolitinib, a Janus kinase (JAK1–JAK2) inhibitor, has demonstrated safety and efficacy in patients with graft-versus-host disease (GvHD). This phase 3 randomized trial (REACH3) evaluated the efficacy and the safety of ruxolitinib 10 mg twice daily compared with investigator-selected best available therapy (BAT) in a subgroup of Japanese patients (n = 37) with steroid-refractory or dependent (SR/D) chronic GvHD. At data cut-off, treatment was ongoing in 17 patients and discontinued in 20. The overall response rate (complete or partial) at week 24 was greater with ruxolitinib than BAT (50% vs. 20%; odds ratio, 4.13 [95% CI, 0.90–18.9]). The best overall response rate (complete or partial response at any time point up to week 24) was higher with ruxolitinib than BAT (68.2% vs. 46.7%; odds ratio, 2.69 [95% CI, 0.66–10.9]). Ruxolitinib led to longer median failure-free survival than BAT (18.6 months vs. 3.7 months; hazard ratio, 0.34; [95% CI, 0.14–0.85]). The most common grade ≥ 3 adverse events up to week 24 were anemia (ruxolitinib: 22.7%; BAT: 6.7%) and pneumonia (22.7% and 20.0%, respectively). Ruxolitinib showed a higher response rate and improvement in failure-free survival in Japanese patients with SR/D chronic GvHD, with a safety profile consistent with the overall study population.

DOI： 10.1007/s12185-024-03850-9

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

Background: KEYNOTE-A33 (NCT04317066) is an open-label, single-arm, phase 1 trial designed to evaluate the safety and efficacy of pembrolizumab in Japanese patients with relapsed or refractory (R/R) primary mediastinal large B-cell lymphoma (PMBCL). Methods: Patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary endpoints were safety and objective response rate (ORR) per International Working Group 2007 criteria by independent central review. The secondary endpoint was disease control rate (DCR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were exploratory. Results: Seven patients were enrolled and treated; the median age was 32 years (range 26–43) and 86% were female. The median time from the first dose to data cutoff (April 12, 2022) was 5.6 months (range 2.4–21.2). Grade 3–5 treatment-related adverse events (AEs) occurred in 2 patients (29%; 2 grade 4 neutropenia, 1 grade 3 febrile neutropenia); however, no patient discontinued pembrolizumab or died because of treatment-related AEs. The ORR was 43% [95% confidence interval (CI) 10–82]. DCR was 57% (95% CI 18–90). Median DOR was not reached (NR). Four (57%) patients had a reduction in target lesion size of ≥ 50%. The median PFS was 2.9 months (95% CI 2.6–NR). The median OS was 17.5 months (95% CI NE–NE), and the 12 months OS rate was 100%. Conclusion: Overall, pembrolizumab had manageable safety and clinically meaningful antitumor activity in Japanese patients with R/R PMBCL, results that were consistent with those observed in prior global studies. Trial Registry: Registry and the Registration No. of the study/trial: Clinicaltrials.gov: NCT04317066.

DOI： 10.1007/s10147-024-02627-8

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記述言語：英語   出版者・発行元：International Journal of Hematology  

Venetoclax was approved for relapsed/refractory chronic lymphocytic leukemia (R/R CLL) and small lymphocytic leukemia (SLL) in Japan in September 2019; however, clinical data in Japanese patients are limited. This all-case post-marketing surveillance assessed efficacy and safety in Japanese patients with R/R CLL/SLL who started venetoclax treatment between November 2019 and August 2020. Overall, the safety and efficacy analysis sets included 129 and 114 patients, respectively. The overall response rate (ORR) was 57.0%; ORRs were higher in patients with versus without concomitant rituximab (65.4% vs. 54.7%), and in patients with 1 versus ≥ 2 prior lines of therapies (72.5% vs. 44.4%). Adverse events (AEs) were reported in 66.7% of patients (86/129); the most common AEs were neutrophil count decreased (22.5%), white blood cell count decreased (7.8%), and tumor lysis syndrome (TLS; 6.2%). AEs of special interest (TLS, myelosuppression, and infection) were manageable in clinical practice in Japan. Venetoclax is efficacious and safe for R/R CLL/SLL patients in the real-world setting in Japan. ClinicalTrials.gov ID: NCT04198415.

DOI： 10.1007/s12185-024-03832-x

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記述言語：英語   出版者・発行元：Hematological Oncology  

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides durable remission for patients with adult T-cell leukemia/lymphoma (ATL); however, few studies have focused on post-transplant outcomes in ATL patients ≤49 years. To clarify prognostic factors in ATL among patients <40 years (adolescents and young adult [AYA]; n = 73) and 40–49 years (Young; n = 330), we conducted a nationwide retrospective study. Estimated 3-year overall survival (OS) rates were 61.8% and 43.1% in AYA and Young patients, respectively (p = 0.005). In the multivariate analysis, Young patients showed worse OS (Hazard ratio (HR) [95% confidential interval] 1.62 [1.10–2.39], p = 0.015), chronic graft-versus-host disease (GVHD)-free and relapse-free survival (CRFS) (HR 1.54 [1.10–2.14], p = 0.011), and GVHD-free and relapse-free survival (GRFS) (HR 1.40 [1.04–1.88], p = 0.026) than AYA patients. No significant differences were observed in OS, CRFS, or GRFS between the myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) regimens; however, non-relapse mortality was significantly lower in patients with the RIC regimen than those with the MAC regimen (HR 0.46 [0.24–0.86], p = 0.015). In summary, OS was worse in Young patients than in AYA patients in the allo-HSCT setting for ATL. Furthermore, the RIC regimen has potential as an alternative treatment option for ATL patients ≤49 years.

DOI： 10.1002/hon.3315

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記述言語：英語   出版者・発行元：Cancer Science  

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare peripheral T-cell lymphoma characterized by cutaneous lesions and immunologic manifestations. The five-year survival rate of SPTCL has been reported to be over 80%, indicating a favorable prognosis. Recent studies have uncovered recurrent germline variants in HAVCR2, encoding an immunomodulator. In this study, we integrated whole-exome sequencing data from 60 samples collected from 36 SPTCL patients, encompassing six patients of our cohort and 30 patients of publicly available data. We identified 138 somatic mutations in skin tumors of 24 patients and HAVCR2 germline mutations in 23 of 29 patients. HAVCR2 p.Tyr82Cys mutations were identified in four of six Japanese patients. During the clinical courses of four patients, cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone were administered to all patients, but it resulted in incomplete responses in all four patients. However, disease conditions of all patients remained stable with additional treatment, including autologous peripheral blood stem cell transplantation. Over a 7.5-year median follow-up, one patient developed autoimmune-related diseases, while one developed other hematological malignancy, resulting in death. To our knowledge, this is the first report of recurrent HAVCR2 germline mutations in Japanese patients, suggesting the necessity for long-term follow-up.

DOI： 10.1111/cas.16345

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記述言語：英語   出版者・発行元：International Journal of Hematology  

Previously, we reported the efficacy and safety of tazemetostat in Japanese patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) harboring the EZH2 mutation in a multicenter, open-label, phase II study. Here, we present a follow-up analysis of tazemetostat at a long-term median follow-up of 35.0 months. Twenty patients were enrolled: 17 in the FL cohort and three in the DLBCL cohort. In the FL cohort, the objective response rate was 70.6%, consistent with the primary analysis, and the median progression-free survival (PFS) was not reached. The 24-month and 36-month PFS rates were 72.1% (95% confidence interval [CI] 41.5%–88.6%) and 64.1% (95% CI 33.7%–83.4%), respectively. The median duration of treatment was 30.2 months. After the primary analysis at a median follow-up of 12.9 months, grade 1–2 urinary tract infection, peripheral motor neuropathy, and hypogammaglobulinemia newly emerged, but the incidence of adverse events (AEs) did not increase notably during this follow-up period. No unexpected grade ≥ 3 treatment-related AEs were reported. Long-term oral monotherapy with tazemetostat showed favorable efficacy and safety profiles, indicating that it may be a useful third-line or later treatment option for patients with relapsed/refractory FL harboring the EZH2 mutation. Trial registration: ClinicalTrials.gov: NCT03456726.

DOI： 10.1007/s12185-024-03834-9

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PubMed

記述言語：英語   出版者・発行元：American Journal of Hematology  

Belumosudil mesylate is a selective Rho-associated coiled-coil kinase 2 inhibitor with immunomodulatory and antifibrosis effects. This multicenter, open-label, single-arm study evaluated belumosudil 200 mg once daily as second or subsequent line of therapy (LOT) in 21 Japanese patients ≥12 years of age with steroid-dependent/steroid-resistant chronic graft-versus-host disease (cGVHD). The primary endpoint of best overall response rate (ORR) at 24 weeks after enrollment of the last patient was 85.7% (95% confidence interval [CI]: 63.7–97.0), and the lower limit of the 95% CI exceeded the pre-defined threshold of 25%. The Kaplan–Meier estimate of duration of response rate at 24 weeks was 75% (95% CI: 46–90); 13/18 responders (72.2%) had a sustained response for ≥20 weeks. The median time to response was 4.1 weeks (range 3.90–8.10); ORR was 47.6% at 4 weeks and 75.0% at 24 weeks; best ORR was 80% for joints/fascia, 66.7% for the mouth, and 54.5% for skin. Overall, 57.1% of patients had clinically meaningful symptom improvement at least once; the median duration of symptom improvement was 22.2 weeks (range 4.0–51.3). Corticosteroid dose reductions were recorded for 57.1% of patients. Median failure-free and overall survival were not reached. Treatment-emergent adverse events occurred in 85.7% of patients (most commonly diarrhea, 19.0%), of which 38.1% were drug-related. There were no drug-related discontinuations or deaths. In summary, belumosudil 200 mg once daily as second or subsequent LOT in Japanese patients with steroid-dependent/steroid-resistant cGVHD was effective, with no new safety concerns.

DOI： 10.1002/ajh.27424

Scopus

PubMed

記述言語：英語   出版者・発行元：Cytotherapy  

This nationwide study retrospectively examined the center effect on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult B-cell acute lymphoblastic leukemia. The cohort analyses were separated into Philadelphia chromosome (Ph)-positive and -negative cases. The patients were divided into low- and high-volume groups according to the number of allo-HSCTs at each facility. The primary endpoint was 5-year overall survival (OS). This study included 1156 low-volume and 1329 high-volume Ph-negative and 855 low-volume and 926 high-volume Ph-positive cases. In Ph-negative cases, 5-year OS was significantly higher in the high-volume centers at 52.7% (95% confidence interval [CI]: 49.9–55.5) versus 46.8% (95% CI: 43.8–49.7) for the low-volume centers (P < 0.01). Multivariate analysis identified high volume as a favorable prognostic factor (hazard ratio [HR]: 0.81 [95% CI: 0.72–0.92], P < 0.01). Subgroup analysis in Ph-negative cases revealed that the center effects were more evident in patients aged ≥40 years (HR: 0.72, 95% CI: 0.61–0.86, P < 0.01) and those receiving cord blood transplantation (HR: 0.62, 95% CI: 0.48–0.79, P < 0.01). In Ph-positive cases, no significant difference was observed between the high and low-volume centers for 5-year OS (59.5% [95% CI: 56.2–62.7] vs. 54.9% [95% CI: 51.3–58.3], P = 0.054). In multivariate analysis, center volume did not emerge as a significant prognostic indicator. This study showed center effects on survival in Ph-negative but not in Ph-positive cases, highlighting the heterogeneity of the center effect in allo-HSCT for B-cell acute lymphoblastic leukemia. Collaborative efforts among transplant centers and further validation are essential to improve outcomes.

DOI： 10.1016/j.jcyt.2024.05.004

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PubMed

記述言語：英語  

DOI： 10.1016/j.bneo.2024.100033

PubMed

記述言語：英語   出版者・発行元：International Journal of Hematology  

Acute graft-versus-host disease (aGvHD) is a major complication after allogeneic hematopoietic stem cell transplantation in Japan and other countries. Nearly one-third of patients do not respond to standard systemic steroid therapy and no standard second-line treatment has been established in Japan. We report efficacy and safety findings of ruxolitinib versus best available therapy (BAT) from a subgroup analysis of the international, phase 3 REACH2 study in Japanese patients with steroid-refractory aGvHD. The primary endpoint was overall response rate (ORR) at day 28. Overall, 9 patients received ruxolitinib and 21 received BAT. The ORR at day 28 (88.9% vs 52.4%) and durable ORR at day 56 (66.7% vs 28.6%) were higher with ruxolitinib versus BAT. The estimated cumulative incidence of loss of response at 6 months was 12.5% with ruxolitinib and 18.2% with BAT. The median failure-free survival was longer with ruxolitinib versus BAT (2.73 vs 1.25 months). The most common adverse events up to day 28 in the ruxolitinib and BAT groups were anemia (55.6% vs 19.0%) and thrombocytopenia (44.4% vs 4.8%, respectively). Ruxolitinib showed better efficacy outcomes and a consistent safety profile compared with BAT in the Japanese subgroup, and the findings were consistent with overall study results.

DOI： 10.1007/s12185-024-03772-6

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PubMed

出版者・発行元：医歯薬出版  

DOI： 10.32118/ayu289090661

CiNii Research

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：Hla  

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for adult T-cell leukaemia/lymphoma (ATL). Specific HLAs are associated with outcomes of immunotherapy and allo-HSCT. We hypothesised that individual HLAs would affect the clinical outcomes of ATL patients after allo-HSCT. Using data from a Japanese registry, we retrospectively analysed 829 patients with ATL who received transplants from HLA-identical sibling donors or HLA-A, -B, -C or -DRB1 allele-matched unrelated donors between 1996 and 2015. We evaluated the overall mortality risk of HLA-A, -B and -DR antigens with frequencies exceeding 3%. Outcomes were compared between transplants with or without specific HLA antigens. Of the 25 HLAs, two candidates were identified but showed no statistically significant differences by multiple comparison. HLA-B62 was associated with a lower risk of mortality (hazard ratio [HR], 0.68; 95% confidence interval [CI]: 0.51–0.90; p = 0.008), whereas HLA-B60 was associated with a higher risk of mortality (HR, 1.64; 95% CI: 1.19–2.27; p = 0.003). In addition, HLA-B62 was associated with a lower risk of transplant-related mortality (TRM) (HR, 0.52; 95% CI: 0.32–0.85, p = 0.009), whereas HLA-B60 was associated with a higher risk of grades III–IV acute graft-versus-host disease (HR, 2.63; 95% CI: 1.62–4.27; p < 0.001). Neither HLA influenced relapse. The higher risk of acute GVHD in HLA-B60-positive patients and the lower risk of TRM in HLA-B62-positive patients were consistent with previously obtained results from patients with other haematological malignancies. Consideration of HLA in ATL patients may help to predict risk and outcomes after allo-HSCT.

DOI： 10.1111/tan.15555

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PubMed

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Hematology  

Response determined by 18[F]-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) positron emission tomography (PET)–CT after induction therapy can predict progression-free survival (PFS) in follicular lymphoma (FL). However, little prospective research has examined the significance of PET after second-line therapy. We conducted a prospective multicenter phase II trial (W-JHS NHL01) of bendamustine plus rituximab (BR) without rituximab maintenance for FL in first relapse. This study aimed to evaluate the usefulness of end-of-treatment (EOT)-PET for predicting PFS in FL patients in first relapse. EOT-PET examinations were performed between 6 and 8 weeks from the start of the last BR cycle. The primary endpoint was 1-year PFS. Key secondary endpoints were overall response rate (ORR), complete response rate (CRR), and 1-year overall survival (OS). Seventy-five patients were enrolled, and 8 were excluded from analysis. ORR was 86.6% and CRR was 59.7%. One-year PFS was 88.9% (95% confidence interval [CI] 80.7–94.3%) and 1-year OS in 75 patients was 97.3% (95% CI 89.6–99.3%). One-year PFS was significantly inferior in EOT-PET-positive patients (n = 9) compared with PET-negative patients (n = 58) (77.8% vs. 93.1%; p = 0.02). We confirmed that EOT-PET after second-line BR therapy could predict early progression in FL patients in first relapse.

DOI： 10.1007/s12185-024-03738-8

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PubMed

記述言語：英語  

DOI： 10.31547/bct-2023-033

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/blood.2023021567.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： https://doi.org/10.31547/bct-2023-032

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/FTD.0000000000001196.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-024-02222-5.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-023-02183-1.

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Bone Marrow Transplantation  

The “human leukocyte antigen (HLA) supertype” is a functional classification of HLA alleles, which was defined by structural features and peptide specificities, and has been reportedly associated with the clinical outcomes of viral infections and autoimmune diseases. Although the disparity in each HLA locus was reported to have no clinical significance in single-unit cord blood transplantation (sCBT), the clinical significance of the HLA supertype in sCBT remains unknown. Therefore, we retrospectively analyzed clinical data of 1603 patients who received sCBT in eight institutes in Japan between 2000 and 2017. Each HLA allele was categorized into 19 supertypes, and the prognostic effect of disparities was then assessed. An HLA-B supertype mismatch was identified as a poor prognostic factor (PFS: hazard ratio [HR] = 1.23, p = 0.00044) and was associated with a higher cumulative incidence (CI) of relapse (HR = 1.24, p = 0.013). However, an HLA-B supertype mismatch was not associated with the CI of acute and chronic graft-versus-host-disease. The multivariate analysis for relapse and PFS showed the significance of an HLA-B supertype mismatch independent of allelic mismatches, and other previously reported prognostic factors. HLA-B supertype-matched grafts should be selected in sCBT.

DOI： 10.1038/s41409-023-02183-1

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PubMed

記述言語：英語   出版者・発行元：Bone Marrow Transplantation  

This study aimed to address the prognostic impact of center experience based on the data of 7821 adults with acute myeloid leukemia who underwent allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2019 in Japan, where medical care was provided within a uniform healthcare system. Center experience was defined based on the number of allogeneic HCTs performed for any indication during the study period, by which centers were divided into low-, intermediate-, and high-volume centers. After adjusting for known confounding factors, the risk of overall mortality was lowest for the high-volume centers and highest for the low-volume centers, with the difference between the center categories attributed primarily to the risk of relapse. Patients transplanted at high-volume centers had higher risks of acute and chronic graft-versus-host diseases but without an increased risk of non-relapse mortality (NRM). These findings reveal the presence of a center effect in allogeneic HCT conducted during the past decade in Japan, highlighting the difference in relapse based on center experience. The weaker effect on NRM compared with that on relapse suggests that the transplantation care quality is becoming equalized across the country.

DOI： 10.1038/s41409-024-02222-5

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-023-02156-4.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-024-03738-8.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jtct.2024.01.056.

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Bone Marrow Transplantation  

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a currative treatment modality for diffuse large B-cell lymphoma (DLBCL) because of the intrinsic graft-versus-lymphoma effect. However, limited information is available regarding which patients with relapsed or refractory DLBCL are likely to benefit from allo-HSCT. We retrospectively analyzed data from 1268 DLBCL patients who received allo-HSCT. The overall survival and progression-free survival (PFS) rates were 30.3% and 21.6% at 3 years, respectively. Multivariate analysis revealed that stable or progressive disease at transplantation, male patient, poorer performance status at transplantation, and shorter intervals from previous transplantation were associated independently with a lower PFS. Four prognostic factors were used to construct a prognostic index for PFS, predicting 3-year PFS of 55.4%, 43.7%, 20.4% and 6.6%, respectively. The prognostic model predicted relapse rates following allo-HSCT accordingly (P < 0.0001), whereas did not predict transplantation-related mortality (P = 0.249). The prognostic index can identify a subgroup of DLBCL patients who benefit from allo-HSCT and it is worthwhile to evaluate whether this model is also applicable to patients undergoing allo-HSCT in cases of relapse after chimeric antigen receptor engineered T-cell therapy, although the application of allo-HSCT has been declining with the increase of novel immunotherapies.

DOI： 10.1038/s41409-023-02156-4

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PubMed

記述言語：英語   出版者・発行元：Blood Advances  

Immunomodulatory drugs (IMiDs) are key drugs for treating multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the interaction between cell-specific substrates and cereblon, a substrate receptor of the E3 ubiquitin ligase complex. Thus, identification of cell-specific substrates is important for understanding the effects of IMiDs. IMiDs increase the risk of thromboembolism, which sometimes results in fatal clinical outcomes. In this study, we sought to clarify the molecular mechanisms underlying IMiDs-induced thrombosis. We investigated cereblon substrates in human megakaryocytes using liquid chromatography–mass spectrometry and found that thrombospondin-1 (THBS-1), which is an inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, functions as an endogenous substrate in human megakaryocytes. IMiDs inhibited the proteasomal degradation of THBS-1 by impairing the recruitment of cereblon to THBS-1, leading to aberrant accumulation of THBS-1. We observed a significant increase in THBS-1 in peripheral blood mononuclear cells as well as larger von Willebrand factor multimers in the plasma of patients with myeloma, who were treated with IMiDs. These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.

DOI： 10.1182/bloodadvances.2023010080

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41375-023-02093-7.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.prp.2024.155117.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/cam4.6793.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/bloodadvances.2023010080.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10147-023-02443-6.

記述言語：英語   出版者・発行元：International Journal of Clinical Oncology  

Background: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. Methods: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. Results: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. Conclusion: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.

DOI： 10.1007/s10147-023-02443-6

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PubMed

記述言語：英語   出版者・発行元：Cancer Medicine  

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

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PubMed

記述言語：英語   出版者・発行元：Pathology Research and Practice  

Regulatory B cells (Bregs) suppress antitumor immunity by producing anti-inflammatory cytokines such as transforming growth factor β (TGF-β) and interleukin-10 (IL-10) and promoting tumor growth. It is unknown whether diffuse large B-cell lymphoma (DLBCL), a common subtype of B-cell malignancy, exhibits characteristics similar to those of Bregs. This study aimed to clarify the features of DLBCLs carrying Breg markers. In 123 DLBCL cases, we evaluated TGF-β and IL-10 expression in tumor biopsy samples using immunohistochemical staining and retrospectively analyzed their clinicopathological characteristics. Fifteen cases (12.2 %) classified as Breg-type DLBCL were positive for both TGF-β and IL-10. Breg-type DLBCL is mainly classified as having activated B cell-like cells of origin. Breg-type DLBCL cases showed significantly worse progression-free survival and overall survival (OS) than other DLBCL cases (P = 0.0016 and P = 0.042, respectively). In multivariate analysis, Breg-type DLBCL significantly affected OS (hazard ratio, 3.13; 95 % confidence interval 1.15–8.55; P = 0.025). Gene expression analysis showed that the expression of follicular dendritic cell-associated genes (FCER2, PIK3CD, FOXO1) was downregulated in Breg-type DLBCLs compared to other DLBCLs. These results suggest that the double expression of Breg markers, TGF-β and IL-10, in tumor cells indicates a poor prognosis in DLBCL patients. Further studies evaluating genomic abnormalities could confirm the characteristics of Breg-type DLBCL.

DOI： 10.1016/j.prp.2024.155117

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PubMed

記述言語：英語   出版者・発行元：Leukemia  

T follicular helper (T<inf>FH</inf>) cell lymphomas (TFHLs) are characterized by T<inf>FH</inf>-like properties and accompanied by substantial immune-cell infiltration into tumor tissues. Nevertheless, the comprehensive understanding of tumor-cell heterogeneity and immune profiles of TFHL remains elusive. To address this, we conducted single-cell transcriptomic analysis on 9 lymph node (LN) and 16 peripheral blood (PB) samples from TFHL patients. Tumor cells were divided into 5 distinct subclusters, with significant heterogeneity observed in the expression levels of T<inf>FH</inf> markers. Copy number variation (CNV) and trajectory analyses indicated that the accumulation of CNVs, together with gene mutations, may drive the clonal evolution of tumor cells towards T<inf>FH</inf>-like and cell proliferation phenotypes. Additionally, we identified a novel tumor-cell-specific marker, PLS3. Notably, we found a significant increase in exhausted CD8⁺ T cells with oligoclonal expansion in TFHL LNs and PB, along with distinctive immune evasion characteristics exhibited by infiltrating regulatory T, myeloid, B, and natural killer cells. Finally, in-silico and spatial cell-cell interaction analyses revealed complex networking between tumor and immune cells, driving the formation of an immunosuppressive microenvironment. These findings highlight the remarkable tumor-cell heterogeneity and immunoevasion in TFHL beyond previous expectations, suggesting potential roles in treatment resistance.

DOI： 10.1038/s41375-023-02093-7

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PubMed

出版者・発行元：医歯薬出版  

DOI： 10.32118/ayu28803199

CiNii Research

記述言語：英語   出版者・発行元：Cancer Diagnosis and Prognosis  

Background/Aim: Rash is a common adverse event (AE) observed during cytarabine and idarubicin induction therapy in patients with acute myeloid leukemia (AML). Previous studies have highlighted the challenge in predicting the onset and duration of rash. This study aimed to determine the factors that affect the onset of rash in patients receiving induction therapy for AML. Patients and Methods: This retrospective study involved 97 patients with AML who received induction chemotherapy with cytarabine and idarubicin at the Department of Hematology, Kyushu University Hospital between January 2008 and June 2022. The factors associated with rash were identified through a multivariate stepwise logistic regression analysis. Subsequently, the patient’s characteristics were compared between those with risk factors and those without risk factors using a matched pair analysis. Results: Pre-existing leukopenia [odds ratio (OR)=3.294; 95% confidence interval (CI)=1.272-8.531] and good performance status (PS=0) (OR=2.717; 95%CI=1.087-6.792) were significant risk factors for rash development. Conversely, the matched pair analysis indicated that patients with pre-existing leukopenia, excluding those with a PS score of 0, exhibited a significantly (p=0.015) higher incidence of rash than those without it. Conclusion: Both multivariate logistic regression analysis and matched pair analysis identified pre-existing leukopenia as a primary risk factor for rash development associated with cytarabine and idarubicin chemotherapy.

DOI： 10.21873/cdp.10372

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PubMed

記述言語：英語   出版者・発行元：Clinical Cancer Research  

Purpose: To determine, for patients with advanced or recurrent synovial sarcoma (SS) not suitable for surgical resection and resistant to anthracycline, the safety and efficacy of the infusion of autologous T lymphocytes expressing NY-ESO-1 antigen-specific T-cell receptor (TCR) gene and siRNA to inhibit the expression of endogenous TCR (product code: TBI-1301). Patients and Methods: Eligible Japanese patients (HLA-A^*02:01 or ^*02:06, NY-ESO-1-positive tumor expression) received cyclophosphamide 750 mg/m² on days -3 and -2 (induction period) followed by a single dose of 510⁹ (30%) TBI-1301 cells as a divided infusion on days 0 and 1 (treatment period). Primary endpoints were safety-related (phase I) and efficacy-related [objective response rate (ORR) by RECIST v1.1/immune-related RECIST (irRECIST); phase II]. Safety- and efficacy-related secondary endpoints were considered in both phase I/II parts. Results: For the full analysis set (N = 8; phase I, n = 3; phase II, n = 5), the ORR was 50.0% (95% confidence interval, 15.7–84.3) with best overall partial response in four of eight patients according to RECIST v1.1/irRECIST. All patients experienced adverse events and seven of eight patients (87.5%) had adverse drug reactions, but no deaths were attributed to adverse events. Cytokine release syndrome occurred in four of eight patients (50.0%), but all cases recovered with prespecified treatment. Immune effector cell-associated neurotoxicity syndrome, replication-competent retrovirus, and lymphocyte clonality were absent. Conclusions: Adoptive immunotherapy with TBI-1301 to selectively target NY-ESO-1-positive tumor cells appears to be a promising strategy for the treatment of advanced or recurrent SS with acceptable toxicity.

DOI： 10.1158/1078-0432.CCR-23-1456

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PubMed

記述言語：英語   出版者・発行元：Molecular Therapy  

Stem cell gene therapy using the MFGS-gp91^phox retroviral vector was performed on a 27-year-old patient with X-linked chronic granulomatous disease (X-CGD) in 2014. The patient's refractory infections were resolved, whereas the oxidase-positive neutrophils disappeared within 6 months. Thirty-two months after gene therapy, the patient developed myelodysplastic syndrome (MDS), and vector integration into the MECOM locus was identified in blast cells. The vector integration into MECOM was detectable in most myeloid cells at 12 months after gene therapy. However, the patient exhibited normal hematopoiesis until the onset of MDS, suggesting that MECOM transactivation contributed to clonal hematopoiesis, and the blast transformation likely arose after the acquisition of additional genetic lesions. In whole-genome sequencing, the biallelic loss of the WT1 tumor suppressor gene, which occurred immediately before tumorigenesis, was identified as a potential candidate genetic alteration. The provirus CYBB cDNA in the blasts contained 108 G-to-A mutations exclusively in the coding strand, suggesting the occurrence of APOBEC3-mediated hypermutations during the transduction of CD34-positive cells. A hypermutation-mediated loss of oxidase activity may have facilitated the survival and proliferation of the clone with MECOM transactivation. Our data provide valuable insights into the complex mechanisms underlying the development of leukemia in X-CGD gene therapy.

DOI： 10.1016/j.ymthe.2023.09.004

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ymthe.2023.09.004.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1158/1078-0432.CCR-23-1456.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1007/s12185-023-03646-3.

記述言語：英語   出版者・発行元：International Journal of Hematology  

DOI： 10.1007/s12185-023-03646-3

Web of Science

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/anticanres.16596.

記述言語：英語   出版者・発行元：Anticancer Research  

Background/Aim: Adverse events (AEs) must be managed during cancer therapy. We had previously developed a medication guidance sheet (MGS) to monitor AEs after conditioning therapy with allogeneic hematopoietic stem cell transplantation (HSCT). However, it remains unclear whether this sheet can accurately predict the type, onset, and duration of AEs in clinical practice. In this study, we evaluated the clinical utility of the original MGS in patients receiving total body irradiation (TBI) and cyclophosphamide (CY). Patients and Methods: Fifty-eight patients who underwent TBI/CY were included. The types, onsets, and durations of AEs observed during real monitoring were compared with those listed in the original MGS. Results: A total of 361 subjective AE symptoms were observed, all of which were predictive, as listed in the MGS. However, the durations of several AEs were longer than expected. Thus, the prediction accuracy for all AEs was 67.0%. The accuracy rate was the lowest for anorexia (6.7%), followed by diarrhea (42.6%), and nausea/vomiting (55.6%). Acute graft versus host disease (GVHD) most likely caused the prolongation of AEs. Subsequently, the original MGS was revised to account for the possible occurrence of acute GVHD. Conclusion: When monitoring AEs in patients receiving a TBI/CY conditioning regimen for HSCT, the involvement of acute GVHD-associated AEs should be considered. In this respect, the present modified MGS is particularly useful for rapid and accurate monitoring of AEs.

DOI： 10.21873/anticanres.16596

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記述言語：英語   出版者・発行元：Ferrata Storti Foundation (Haematologica)  

The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and high-risk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] =5.46; P<0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR=2.33; P=0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATLPI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (−4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (−2), and GATA3 (−3).

DOI： 10.3324/haematol.2022.281510

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記述言語：英語   出版者・発行元：Cancer Science  

Metabolic alterations, especially in the mitochondria, play important roles in several kinds of cancers, including acute myeloid leukemia (AML). However, AML-specific molecular mechanisms that regulate mitochondrial dynamics remain elusive. Through the metabolite screening comparing CD34⁺ AML cells and healthy hematopoietic stem/progenitor cells, we identified enhanced lysophosphatidic acid (LPA) synthesis activity in AML. LPA is synthesized from glycerol-3-phosphate by glycerol-3-phosphate acyltransferases (GPATs), rate-limiting enzymes of the LPA synthesis pathway. Among the four isozymes of GPATs, glycerol-3-phosphate acyltransferases, mitochondrial (GPAM) was highly expressed in AML cells, and the inhibition of LPA synthesis by silencing GPAM or FSG67 (a GPAM-inhibitor) significantly impaired AML propagation through the induction of mitochondrial fission, resulting in the suppression of oxidative phosphorylation and the elevation of reactive oxygen species. Notably, inhibition of this metabolic synthesis pathway by FSG67 administration did not affect normal human hematopoiesis in vivo. Therefore, the GPAM-mediated LPA synthesis pathway from G3P represents a critical metabolic mechanism that specifically regulates mitochondrial dynamics in human AML, and GPAM is a promising potential therapeutic target.

DOI： 10.1111/cas.15835

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

急性骨髄性白血病(AML)に特異的なミトコンドリア機能の制御に関与する分子メカニズムを検討した。CD34陽性AML細胞と健常な造血幹/前駆細胞を比較した代謝物スクリーニングを通じて、AMLにおけるリゾホスファチジン酸(LPA)合成活性の亢進を同定した。LPAは、LPA合成経路の律速酵素であるグリセロール-3-リン酸アシルトランスフェラーゼ(GPAT)によってグリセロール-3-リン酸から合成される。GPATの4つのアイソザイムのうち、グリセロール-3-リン酸アシルトランスフェラーゼ、ミトコンドリア(GPAM)がAML細胞で高発現していた。GPAMサイレンシングまたはFSG67(GPAM阻害剤)でLPA合成を阻害すると、ミトコンドリア分裂が誘導され、その結果、酸化的リン酸化が抑制され、活性酸素種が増加することで、AMLの増殖が著しく阻害された。さらに、FSG67によるGPAM阻害は、in vivoでの正常な造血に影響を与えることなく、AMLに対して有効であることが示された。以上より、GPAMを介したグリセロール-3-リン酸からのLPA合成経路は、AMLにおけるミトコンドリア動態を特異的に制御する重要な代謝機構であり、GPAMは有望な治療標的であることが示唆された。

記述言語：日本語   出版者・発行元：(有)科学評論社  

慢性リンパ性白血病/小リンパ球性リンパ腫(CLL/SLL)に対するvenetoclax投与後の腫瘍崩壊症候群(TLS)の発現状況と、適切な予防措置および対応が施行されているかについて検討した。調査票回収対象症例の登録期間はvenetoclax販売開始日の2019年11月22日から2020年8月31日、観察期間はvenetoclax投与開始日から用量漸増期間終了後32週間である。主治医がCLL/SLLと診断した解析可能症例数は112例で、年齢中央値は72.5歳、男性は79例であった。TLS予防として、飲水または補液による水分負荷を107例(95.5%)、血液検査を109例(97.3%)、薬物療法を75例(67.0%)に施行していた。TLS予防として投与された主な薬剤はfebuxostatが65例、rasburicaseが9例であった。TLSは7例(6.3%)8件に発現し、全例に飲水または補液による水分負荷、5例にfebuxostatまたはrasburicaseが投与されていた。venetoclax投与前に適切なTLS予防措置を実施した上で投与を開始することにより、TLSが発現した場合にも管理可能であることが示唆された。

記述言語：英語   出版者・発行元：Blood Advances  

Cancer-specific metabolic activities play a crucial role in the pathogenesis of human malignancies. To investigate human acute leukemia–specific metabolic properties, we comprehensively measured the cellular metabolites within the CD34⁺ fraction of normal hematopoietic stem progenitor cells (HSPCs), primary human acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) cells. Here, we show that human leukemia cells are addicted to the branched-chain amino acid (BCAA) metabolism to maintain their stemness, irrespective of myeloid or lymphoid types. Human primary acute leukemias had BCAA transporters for BCAA uptake, cellular BCAA, α-ketoglutarate (α-KG), and cytoplasmic BCAA transaminase-1 (BCAT1) at significantly higher levels than control HSPCs. Isotope-tracing experiments showed that in primary leukemia cells, BCAT1 actively catabolizes BCAA using α-KG into branched-chain α-ketoacids, whose metabolic processes provide leukemia cells with critical substrates for the trichloroacetic acid cycle and the synthesis of nonessential amino acids, both of which reproduce α-KG to maintain its cellular level. In xenogeneic transplantation experiments, deprivation of BCAA from daily diet strongly inhibited expansion, engraftment and self-renewal of human acute leukemia cells. Inhibition of BCAA catabolism in primary AML or ALL cells specifically inactivates the function of the polycomb repressive complex 2, an epigenetic regulator for stem cell signatures, by inhibiting the transcription of PRC components, such as zeste homolog 2 and embryonic ectoderm development. Accordingly, BCAA catabolism plays an important role in the maintenance of stemness in primary human AML and ALL, and molecules related to the BCAA metabolism pathway should be critical targets for acute leukemia treatment.

DOI： 10.1182/bloodadvances.2022008242

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Anticancer Research  

Background/Aim: For quick and accurate monitoring of potential adverse events (AEs) during concurrent chemotherapy, we had previously developed innovative medication instruction sheets (MIS) for a variety of chemotherapy regimens. However, it is still unclear whether these sheets correctly predict the type and time course of the onset and recovery of AEs. Therefore, we monitored AEs in patients with acute myeloid leukemia (AML) receiving high-dose cytarabine (HD-AraC) using the original MIS. Patients and Methods: Patients who received HD-AraC following remission induction chemotherapy were included in this study. Data obtained from AE monitoring were evaluated, and the original MIS was modified as appropriate. Results: Among 41 patients, a total of 203 AEs (139 non-hematological and 64 hematological) were observed after chemotherapy. By contrast, all but one patient (97.6%) experienced 102 AEs (43 nonhematological and 59 hematological) before chemotherapy. The AEs that appeared after chemotherapy were all predicted items described in the original MIS; however, their onset and duration were not consistent with the predicted data, in which the prediction accuracy was 69.1% for non-hematological AEs and 1.6% for hematological events. Based on these monitoring data, the original MIS was revised, which led to an increase in the prediction accuracy to 94.2% for nonhematological events and 100% for hematological events. Conclusion: Preexisting AEs should be considered when preparing MIS for consolidation therapy with HD-AraC. The modified MIS based on AE monitoring exhibited a sufficiently high prediction accuracy.

DOI： 10.21873/anticanres.16508

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記述言語：英語   出版者・発行元：Medical Mycology  

Breakthrough candidemia (BrC) is a significant problem in immunocompromised patients, particularly those with hematological disorders. To assess the characteristics of BrC in patients with hematologic disease treated with novel antifungal agents, we collected clinical and microbiological information on said patients from 2009 to 2020 in our institution. Forty cases were identified, of which 29 (72.5%) received hematopoietic stem cell transplant (HSCT)-related therapy. At BrC onset, the most administered class of antifungal agents were echinocandins, administered to 70% of patients. Candida guilliermondii complex was the most frequently isolated species (32.5%), followed by C. parapsilosis (30%). These two isolates were echinocandin-susceptible in vitro but had naturally occurring FKS gene polymorphisms that reduced echinocandin susceptibility. Frequent isolation of these echinocandin-reduced-susceptible strains in BrC may be associated with the widespread use of echinocandins. In this study, the 30-day crude mortality rate in the group receiving HSCT-related therapy was significantly higher than in the group not receiving it (55.2% versus 18.2%, P =. 0297). Most patients affected by C. guilliermondii complex BrC (92.3%) received HSCT-related therapy and had a 30-day mortality rate of 53.8%; despite treatment administration, 3 of 13 patients had persistent candidemia. Based on our results, C. guilliermondii complex BrC is a potentially fatal condition in patients receiving HSCT-related therapy with echinocandin administration.

DOI： 10.1093/mmy/myad056

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/mmy/myad056.

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

CD19特異的キメラ抗原受容体T細胞療法であるチサゲンレクロイセルを受けた再発・難治性B細胞リンパ腫患者の転帰を後ろ向きに検討した。2019年10月から2021年10月までに5施設でチサゲンレクロイセルを処方された89例(年齢20～72歳)を対象とした(び漫性大細胞型B細胞リンパ腫患者71例、形質転換濾胞性リンパ腫患者18例)。その結果、追跡期間中央値6.6ヵ月で、65例が臨床的奏効を得た。12ヵ月時点の全生存率(OS)は67.0%、無イベント生存率(EFS)は46.3%であった。患者80例にサイトカイン放出症候群が認められ、6例はグレード3以上であった。免疫エフェクター細胞関連神経毒性症候群は5例に発生した。代表的な感染症イベントは、サイトメガロウイルスウイルス血症、菌血症、敗血症であった。その他の有害事象では、ALT上昇、AST上昇、下痢、浮腫、クレアチニン上昇が多かった。多変量解析により、高い代謝腫瘍体積(≧80mL)、およびチサゲンレキュセル注入前のSD(安定)/PD(進行)はEFSおよびOSの不良と有意に関連していた。さらに、それら二つの因子の組み合わせは患者の予後を効率的に層別化した(ハザード比6.87、95%CI 2.4～19.65、P<0.05)。以上より、チサゲンレクロイセルは後期治療においても実行可能であり、有効であった。

記述言語：英語   出版者・発行元：Cancer Science  

DOI： 10.1111/cas.15784

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記述言語：英語   出版者・発行元：International Journal of Clinical Oncology  

Background: Tisagenlecleucel, an autologous CD19-directed T-cell immunotherapy, can induce a durable response in adult patients with relapsed/refractory (r/r) B-cell lymphoma. Methods: To elucidate the outcome of chimeric antigen receptor (CAR) T-cell therapy in Japanese, we retrospectively analyzed the outcomes of 89 patients who received tisagenlecleucel for r/r diffuse large B-cell lymphoma (n = 71) or transformed follicular lymphoma (n = 18). Results: With a median follow-up of 6.6-months, 65 (73.0%) patients achieved a clinical response. The overall survival (OS) and event-free survival (EFS) rates at 12 months were 67.0% and 46.3%, respectively. Overall, 80 patients (89.9%) had cytokine release syndrome (CRS), and 6 patients (6.7%) had a grade ≥ 3 event. ICANS occurred in 5 patients (5.6%); only 1 patient had grade 4 ICANS. Representative infectious events of any grade were cytomegalovirus viremia, bacteremia and sepsis. The most common other adverse events were ALT elevation, AST elevation, diarrhea, edema, and creatinine elevation. No treatment-related mortality was observed. A Sub-analysis showed that a high metabolic tumor volume (MTV; ≥ 80 ml) and stable disease /progressive disease before tisagenlecleucel infusion were both significantly associated with a poor EFS and OS in a multivariate analysis (P < 0.05). Notably, the combination of these 2 factors efficiently stratified the prognosis of these patients (HR 6.87 [95% CI 2.4–19.65; P < 0.05] into a high-risk group). Conclusion: We report the first real-world data on tisagenlecleucel for r/r B-cell lymphoma in Japan. Tisagenlecleucel is feasible and effective, even in late line treatment. In addition, our results support a new algorithm for predicting the outcomes of tisagenlecleucel.

DOI： 10.1007/s10147-023-02334-w

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記述言語：英語   出版者・発行元：Blood Advances  

The activation of β-catenin plays critical roles in normal stem cell function, and, when aberrantly activated, the maintenance and enhancement of cancer stemness in many solid cancers. Aberrant β-catenin activation is also observed in acute myeloid leukemia (AML), and crucially contributes to self-renewal and propagation of leukemic stem cells (LSCs) regardless of mutations in contrast with such solid tumors. In this study, we showed that the AML-specific autocrine loop comprised of T-cell immunoglobulin mucin-3 (TIM-3) and its ligand, galectin-9 (Gal-9), drives the canonical Wnt pathway to stimulate self-renewal and propagation of LSCs, independent of Wnt ligands. Gal-9 ligation activates the cytoplasmic Src homology 2 domain of TIM-3 to recruit hematopoietic cell kinase (HCK), a Src family kinase highly expressed in LSCs but not in HSCs, and HCK phosphorylates p120-catenin to promote formation of the LDL receptor–related protein 6 (LRP6) signalosome, hijacking the canonical Wnt pathway. This TIM-3/HCK/p120-catenin axis is principally active in immature LSCs compared with TIM-3–expressed differentiated AML blasts and exhausted T cells. These data suggest that human AML LSCs constitutively activates β-catenin via autocrine TIM-3/HCK/p120-catenin signaling, and that molecules related to this signaling axis should be critical targets for selective eradication of LSCs without impairing normal HSCs.

DOI： 10.1182/bloodadvances.2022008405

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Bone Marrow Transplantation  

This Japanese nationwide retrospective study investigated the impact of HLA-mismatched unrelated transplantation for adult T-cell leukemia-lymphoma (ATL) patients who received transplantation between 2000 and 2018. We compared 6/6 antigen-matched related donor (MRD), 8/8 allele-matched unrelated donor (8/8MUD), and 1 allele-mismatched unrelated donor (7/8MMUD) in the graft-versus-host direction. We included 1191 patients; 449 (37.7%) were in the MRD group, 466 (39.1%) in the 8/8MUD group, and 276 (23.7%) in the 7/8MMUD group. In the 7/8MMUD group, 97.5% of patients received bone marrow transplantation, and no patients received post-transplant cyclophosphamide. The cumulative incidences of non-relapse mortality (NRM) and relapse at 4 years, and the probabilities of overall survival at 4 years in the MRD group were 24.7%, 44.4%, 37.5%, in the 8/8MUD group were 27.2%, 38.2%, and 37.9%, and in the 7/8MMUD group were 34.0%, 34.4%, and 35.3%, respectively. The 7/8MMUD group had a higher risk of NRM (hazard ratio (HR) 1.50 [95% CI, 1.13–1.98; P = 0.005]) and a lower risk of relapse (HR 0.68 [95% CI, 0.53–0.87; P = 0.003]) than the MRD group. The donor type was not a significant risk factor for overall mortality. These data suggest that 7/8MMUD is an acceptable alternative donor when an HLA-matched donor is unavailable.

DOI： 10.1038/s41409-023-02002-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cas.15835.

記述言語：英語   出版者・発行元：Journal of Infection and Chemotherapy  

Aim: Data on the pharmacokinetics (PK) and area under the curve (AUC)-based dosing strategy of vancomycin (VCM) in hematologic malignancies are limited. According to our preliminary narrative review, only a few population PK analyses in hematologic malignancies have been performed. Therefore, we aimed to develop a population PK model, investigate the factors influencing VCM PK, and propose an optimal dosing regimen for hematologic malignancies. Methods: A retrospective study was conducted in patients with underlying hematologic malignancies treated with VCM. A total of 148 patients were enrolled for population PK modeling. Simulation analyses were performed to identify dosing regimens achieving a target exposure of AUC<inf>0-24</inf> of 400–600 mg h/L at the steady-state. Results: The VCM PK data were best described with a one-compartment model. Significant covariates included creatinine clearance (Ccr), diagnosis of acute myeloid leukemia (AML) and neutropenia on VCM clearance (CL), and body weight (WT) on the volume of distribution (Vd). The typical values of CL and Vd were 3.09 L/h (normalized to Ccr value of 90 mL/min) and 122 L/70 kg, respectively. Concerning the effect on VCM dosing, AML patients required 15% higher doses than non-AML patients, independently of renal function. In contrast, for neutropenic patients, only those with augmented renal clearance (ARC, Ccr value ≥ 130 mL/min) required a 10% dose increase compared to non-neutropenic patients. Conclusion: AML patients with neutropenia and ARC represent a critical population with a higher risk of VCM underexposure. Thus, individualized dosing adjustment and therapeutic drug monitoring are strongly recommended.

DOI： 10.1016/j.jiac.2023.01.010

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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：Bone Marrow Transplantation  

DOI： 10.1038/s41409-023-01919-3

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本血液学会  

日本人再発性/難治性大細胞型B細胞リンパ腫(LBCL)患者を対象に、CD19標的自家キメラ抗原受容体(CAR)T細胞療法であるアキシカブタゲンシロルユーセル(axi-cel)の1年間の有効性と安全性を検討する多施設共同非盲検単群第2相試験を実施した。患者16例(年齢44～70歳)がaxi-celの投与を受け、安全性解析セットに含まれた。患者1例では投与量が目標量の半分以下であったため、残りの15例が有効性解析セットに含まれた。その結果、追跡期間中央値13.4ヵ月の時点で、客観的奏効率は86.7%で、response conversionにより完全奏効率(CR)は53.3%に改善した。7例が進行(PD)を経験し、1例がaxi-celによる再治療後にCRを達成した。安全性に関する新たな懸念は認められなかった。axi-celに対して推定される耐性機序は患者により異なり、CD19の発現低下、プログラム細胞死リガンド1の発現亢進、マクロファージと血管新生のシグネチャーの増加などが考えられた。

記述言語：英語   出版者・発行元：International Journal of Hematology  

Axicabtagene ciloleucel (axi-cel) is an autologous, CD19-targeting chimeric antigen receptor T‑cell therapy. We recently reported the 3-month follow-up results of a phase 2, multicenter, open‑label, single-arm study of axi-cel in Japanese patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) (JapicCTI-183914). Here, we present 1-year efficacy and safety data and biomarker analysis data regarding mechanisms of resistance to axi-cel. Primary and secondary endpoints included investigator-assessed objective response rate (ORR), serious adverse events, and treatment-emergent adverse events. Axi-cel pharmacokinetics were also examined. Biomarker analysis was performed by cytokine measurement, immunohistochemistry, RNA sequencing, and whole-exome sequencing. At a median follow-up of 13.4 months, ORR was 86.7% (13/15 patients), and the complete response (CR) rate improved to 53.3% (8/15 patients) due to response conversion. Seven patients experienced disease progression, and one achieved CR after re-treatment with axi-cel. No new safety concerns were detected. Plausible resistance mechanisms to axi-cel varied among patients but included CD19 downregulation, programmed death-ligand 1 upregulation, and increased macrophage and angiogenesis signatures. The 1-year efficacy and safety of axi-cel were confirmed in Japanese patients with R/R LBCL. Resistance to treatment may involve multiple factors, including target antigen loss and an unfavorable tumor environment. Clinical trial registration: Japan Clinical Trials Information; JapicCTI-183914.

DOI： 10.1007/s12185-022-03494-7

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記述言語：英語   出版者・発行元：In Vivo  

Background/Aim: To monitor adverse events rapidly and accurately during combination chemotherapy, we established an innovative medication instruction sheet (MIS) including cytarabine and idarubicin induction therapy. However, it is unclear whether this MIS allows for the accurate prediction of adverse events and their onset timing in a clinically significant manner. We therefore evaluated the clinical usefulness of our MIS for monitoring adverse events. Patients and Methods: Patients who received cytarabine and idarubicin induction therapy for acute myeloid leukemia (AML) at the Department of Hematology, Kyushu University Hospital between January 2013 and February 2022 were included. The real-world clinical data were compared to the MIS to determine the accuracy of the MIS for predicting the onset and duration of adverse events in patients with AML during induction chemotherapy. Results: Thirty-nine patients with AML were included in this study. Overall, 294 adverse events were noted, all of which were predicted items in the MIS. Among the 192 non-hematological adverse events, 131 (68.2%) occurred during a similar period as that listed in the MIS, whereas among the 102 hematological adverse events, 98 (96.1%) appeared earlier than expected. For the non-hematological events, the onset and duration of elevated aspartate aminotransferase levels and nausea/vomiting coincided well with those listed in the MIS, whereas the predictive accuracy for rashes was the lowest. Conclusion: Hematological toxicity was not predicted because of the bone marrow failure associated with AML. Our MIS was useful for rapidly monitoring non-hematological adverse events in patients with AML receiving cytarabine and idarubicin induction therapy.

DOI： 10.21873/invivo.13164

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3324/haematol.2022.281510.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Hematology  

Background: Tisagenlecleucel yielded a high durable response rate in patients with relapsed/refractory (r/r) follicular lymphoma (FL) in the global phase 2 ELARA trial. Here, we report the efficacy, safety, and cellular kinetics of tisagenlecleucel in a subgroup of Japanese patients with r/r FL from ELARA. Methods: ELARA (NCT03568461) is a global single-arm trial of tisagenlecleucel in patients with r/r FL who received ≥ 2 prior lines of therapy. The primary endpoint was the complete response rate (CRR), and the secondary endpoints were the overall response rate, duration of response, progression-free survival, overall survival, safety, and cellular kinetics. Results: As of March 29, 2021, nine Japanese patients were enrolled and received tisagenlecleucel with a median follow-up of 13.6 months (range, 10.5‒19.3). Per independent review committee, CRR was 100% (95% CI 63.1‒100). Within 8 weeks of infusion, cytokine release syndrome (CRS) of any grade was reported in 6 patients (66.7%); however, no grade ≥ 3 CRS or any grade serious neurological events or treatment-related deaths were observed. Conclusion: Tisagenlecleucel showed high efficacy and manageable safety in adult Japanese patients with r/r FL. Moreover, the clinical outcomes were similar to the global population, which supports the potential of tisagenlecleucel in Japanese patients with r/r FL.

DOI： 10.1007/s12185-022-03481-y

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

症例は31歳女性で、inv(16)(p13.1q22)を有する急性骨髄性白血病(AML)と診断された。臨床試験で自家造血幹細胞移植(ASCT)後に大量化学療法を受けたが、ASCTから2年後に再発した。そこで、HLA一致の非血縁者男性ドナーから、強度減弱前処置を用いた同種造血幹細胞移植(HSCT)を受けた。タクロリムス(Tac)とメトトレキサートによる予防下で急性移植片対宿主病(GVHD)発症したため、プレドニゾロン(PSL)で対処した。その後、中等度の慢性GVHDに進行したため、PSLとリツキシマブによる追加の免疫抑制剤、および修正フルチカゾン/アリスロマイシン/モンテルカスト(mFAM)併用療法を施行した。慢性GVHDに対してTac療法とmFAM療法を継続していたが、同種HSCT後9年目に食欲不振、寝汗、右下腹部痛を呈した。ドナー由来のバーキットリンパ腫と診断した。リツキシマブ併用集中化学療法により部分奏効が得られた。再発リスクの低減と化学療法の反復による臓器毒性を回避するため、アップフロント大量化学療法後にドナー由来のCD34+細胞を用いた幹細胞救済療法(疑似自家造血幹細胞移植[pASCT])を施行し、免疫抑制剤を適切に調整した。pASCT後23ヵ月間、cGVHDの増悪もなく、無病状態が維持された。

記述言語：英語   出版者・発行元：International Journal of Hematology  

Donor-derived hematological malignancies have been recognized as rare but serious late complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Most cases in the literature were diagnosed as myelodysplastic syndrome or acute leukemia, with very few malignant lymphoma reported. We herein present another case of donor-derived Burkitt lymphoma that occurred 9 years after allo-HSCT under continued administration of immunosuppressants for chronic graft-versus-host disease (GVHD). The patient achieved a partial response after rituximab-combined intensive chemotherapy. To reduce the risk of relapse and to avoid organ toxicities due to repeated chemotherapies, we performed upfront high-dose chemotherapy followed by stem cell rescue using donor-derived CD34⁺ cells, called pseudo-autologous HSCT (pASCT), and adjusted immunosuppressants appropriately. The patient remained disease-free for 23 months after pASCT without exacerbation of cGVHD. Although the observation period has been relatively short and longer follow-up is needed, pASCT may be a feasible option for donor-derived lymphoma even in patients with active cGVHD.

DOI： 10.1007/s12185-022-03458-x

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

再発・難治性(r/r)濾胞性リンパ腫(FL)患者を対象に、CD19抗原を標的とした自家キメラ抗原受容体発現T(CAR-T)細胞であるチサゲンレクルユーセルの有効性と安全性を評価する国際共同第2相試験(ELARA試験)が実施された。本研究では、日本人r/r FL患者のサブグループ解析を行った。ELARA試験では2ライン以上の前治療を受けたr/r FL患者を対象とした。主要評価項目は完全奏効率(CRR)、副次評価項目は全奏効率、奏効期間、無増悪生存期間、全生存期間、安全性、細胞動態であった。2021年3月29日時点で日本人患者9例(年齢47～71歳)が登録され、チサゲンレクルユーセルの輸注を受け、追跡期間中央値は13.6ヵ月(範囲10.5～19.3ヵ月)であった。独立審査委員会により、CRRは100%(95%CI 63.1～100)であった。輸注後8週間以内に、いずれかのグレードのサイトカイン放出症候群(CRS)が6例(66.7%)に報告されたが、グレード3以上のCRSや重篤な神経系イベントや治療関連死は観察されなかった。以上より、チサゲンレクルユーセルは、日本人成人r/r FL患者において、高い有効性と管理可能な安全性を示した。試験成績は全体の集団と同様であり、日本人r/r FL患者におけるチサゲンレクルユーセルの可能性が支持された。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Pediatrics International  

DOI： 10.1111/ped.15399

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

症例は10歳男児。最終ライン治療としてチサゲンレクルユーセルを投与された。生後4ヵ月時にMLL-ENL融合を呈する小児白血病と診断され、初回導入療法にてCRが得られたが化学療法施行中に骨髄再燃をきたし、14ヵ月時、HLAミスマッチ非血縁ドナーから臍帯血移植を受けて2回目のCRを獲得した。しかし、8ヵ月後に再燃を認めたため、2歳時に母親から骨髄ハプロ移植を受けるも7歳時に再燃を呈した。9歳時、左脚骨にも再燃をきたし、免疫抑制剤の中止によって増悪コントロールを図ったが軽度肺慢性GVHDの発症を認め、ブリナツモマブの5コース投与により4回目のCRが得られた。10歳時、チサゲンレクルユーセル療法のアフェレーシス後に骨髄再燃と骨病変の再発をきたし、慢性GVHDは免疫抑制剤の投与なく消失していた。チサゲンレクルユーセルは従来のリンパ球枯渇化処理後に投与し、脚部サイズはリンパ球枯渇化により一過性に減少したものの、CAR-T細胞療法施行の3日後にグレード2のサイトカイン放出症候群の発症に伴って増大を呈した。トシリズマブとメチルプレドニゾロンを開始したところ全身症状と局所症状のコントロールが得られたが、9ヵ月後に進行性肺病変のため死亡した。

記述言語：日本語   出版者・発行元：一般社団法人 日本臨床薬理学会  

<p>【目的】</p><p>ポサコナゾールは、造血器腫瘍患者における深在性真菌症の予防及び真菌症の治療に適応を有するアゾール系抗真菌薬である。ポサコナゾールは、本邦では治療薬物モニタリング（TDM）の対象薬剤ではないが、海外では真菌症の発症予防としてトラフ値＞0.7μg/mL、治療としてトラフ値＞1.0μg/mLがそれぞれ推奨されている。一方、市販後の実臨床データを用いたポサコナゾールの薬物動態学的検討はほとんどなされておらず、血中濃度に影響する因子に関する情報は不足している。そこで本研究では、母集団薬物動態解析法を用いてポサコナゾール血中濃度に及ぼす影響因子を明らかにすることを目的とした。</p><p>【方法】</p><p>九州大学病院にて2021年7月から2022年11月までにポサコナゾール錠を内服した造血器腫瘍患者を対象とし、通常診療より得られた血液検体の残余を用いてLC-MS法によりポサコナゾール血中濃度を測定した。母集団薬物動態モデルの構築には、Nonlinear Mixed Effect Model（NONMEM）ver. 7.4を用いた。電子カルテより患者情報、検査値、診療記録を後ろ向きに抽出し、ポサコナゾールクリアランス（CL）に対する影響因子を探索した。なお、本研究は九州大学臨床研究倫理審査委員会の承認を得て実施した。</p><p>【結果・考察】</p><p>ポサコナゾール血中濃度130検体（28例）を用いて、母集団薬物動態モデルを構築した。最終モデルは、1次吸収過程を含む1-コンパートメントモデルで記述した。見かけのCL（CL/F）に影響する因子として、体重、血清総タンパク値、下痢が同定された。また、体重増加及び血清総タンパク値低下に伴いCL/Fが上昇すること、下痢症状を有する患者では正常便の患者と比較してCL/Fが平均26%高くなることが示された。造血器腫瘍患者では、化学療法による粘膜炎や造血幹細胞移植後の消化管移植片対宿主病により重度の下痢症状を呈することから、粘膜障害や腸管異常によるポサコナゾールの吸収不良が下痢によるCL/F上昇の要因となっている可能性が示唆された。</p><p>【結論】</p><p>実臨床データを用いた解析により、高体重、血清総タンパク低値、下痢によりポサコナゾール血中濃度が低下することが示された。これらの因子を有する造血器腫瘍患者では、TDMの実施が有用である可能性が考えられる。</p>

DOI： 10.50993/jsptsuppl.44.0_1-c-o03-5

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：International Journal of Hematology  

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). However, TKI-related chronic renal toxicity has been reported, particularly in patients with hypertension. We assessed whether incidental use of specific types of antihypertensive drugs, including renin–aldosterone–angiotensin system inhibitors (RAASis), affects the change in estimated glomerular filtration rate (eGFR) during TKI treatment. We retrospectively analyzed all eGFR measurements during TKI treatment for 142 CML patients at Kyushu University Hospital, estimating the rate of eGFR change using a mixed-effects model. Overall, a significant interaction was found between the type of antihypertensive medication used and the yearly change in eGFR (P < 0.01), with RAASi users exhibiting the most rapid decrease in eGFR (− 5.5%/year). The analysis by TKI used showed that the interaction was significant only in imatinib and bosutinib users (P < 0.01 and P = 0.04, respectively). The yearly rate of eGFR decrease was the most notable in RAASi users, at − 5.7 (− 6.6, − 4.9) and − 10.1 (− 12.3, − 7.9) for imatinib and bosutinib users, respectively. Our findings indicate that eGFR should be carefully monitored in patients taking these TKIs.

DOI： 10.1007/s12185-022-03433-6

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記述言語：英語   出版者・発行元：Annals of Hematology  

We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity conditioning between 2002 and 2017 to investigate longitudinal changes in outcomes and the optimal melphalan dose and graft-versus-host disease (GVHD) prophylaxis regimen. Outcomes were compared between FM80/100 (melphalan dose: 80 or 100 mg/m²) and FM140 (melphalan dose: 140 mg/m²), as well as between calcineurin inhibitor (CNI) plus methotrexate (MTX), CNI plus mycophenolate mofetil (MMF), and CNI alone. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates improved over time (OS: 27% in 2000s vs. 42% in 2010s, p < 0.001; NRM: 43% in 2000s vs. 26% in 2010s, p < 0.001). Multivariable analysis showed that in the 2000s, melphalan dose and GVHD prophylaxis regimen did not affect any outcomes. In the 2010s, FM80/100 (vs. FM140) related to better OS (hazard ratio [HR] 0.62, p = 0.01) and NRM (HR 0.52, p = 0.016). MTX + CNI and CNI alone (vs. CNI + MMF) related to worse OS (CNI + MTX, HR 2.01, p < 0.001; CNI alone, HR 2.65, p < 0.001) and relapse/progression (CNI + MTX, HR 2.40, p < 0.001; CNI alone, HR 2.13, p = 0.023). In recent years, the use of FM80/100 and CNI + MMF significantly reduced the risk of NRM and relapse/progression, respectively, and resulted in better OS after UCBT for lymphoma.

DOI： 10.1007/s00277-022-04990-w

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記述言語：英語   出版者・発行元：International Journal of Hematology  

The selective phosphatidylinositol 3-kinase δ inhibitor zandelisib demonstrated favorable safety and efficacy [objective response rate (ORR) 79%] in patients with B-cell malignancies in a phase 1b study in the US and Switzerland. In this phase 1 dose-escalation study (NCT03985189), 9 Japanese patients with relapsed/refractory indolent non-Hodgkin’s lymphoma (R/R iNHL) received zandelisib on a continuous daily schedule (45 or 60 mg) until progressive disease/unacceptable toxicity. No dose-limiting toxicities were observed. The maximum tolerated dose was not reached. At a median follow-up of 17.5 months, Grade ≥ 3 treatment-emergent adverse events that occurred in 2 or more patients were neutrophil count decreased (55.6%; 5/9) and diarrhea (33.3%; 3/9). Immune-related toxicities, including hepatobiliary disorder, aspartate/alanine aminotransferase increased, diarrhea/colitis, organizing pneumonia, stomatitis, and rash, led to zandelisib discontinuation in 4 patients. The investigator-assessed ORR, based on modified Lugano criteria, was 100%, including 2 complete responses (22.2%; in follicular lymphoma patients receiving 60 mg/day). Median duration of response, progression-free survival, and time to response were 7.9, 11.1, and 1.9 months, respectively. Zandelisib demonstrated a manageable safety profile at 60 mg, the recommended phase 2 dose (RP2D) in Japanese patients. The RP2D resulted in favorable pharmacokinetics and anti-tumor efficacy in Japanese patients with R/R iNHL. Trial registration. NCT03985189 (ClinicalTrials.gov).

DOI： 10.1007/s12185-022-03450-5

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

ザンデリシブ(ZAN)の第1相用量漸増試験で、再発性/難治性の無痛性非ホジキンリンパ腫(R/R iNHL)患者9名を対象として、疾患進行や非許容毒性の発現までZAN(45または60mg)を連日継続投与した。本試験では用量制限毒性は観察されず、最大耐量には達しなかった。追跡期間中央値の17.5ヵ月で2名以上の患者に発生したグレード3以上の治療下発現有害事象は、好中球数減少(55.6%)と下痢(33.3%)であった。肝胆道障害、AST/ALT増加、下痢/大腸炎、器質化肺炎、口内炎、発疹などの免疫関連毒性により、患者4名でZAN中止となった。研究者評価の客観的奏効率は100%で2例の完全奏効(22.2%)を含み、奏効期間、無増悪生存率、奏効までの期間の中央値は、それぞれ7.9、11.1、1.9ヵ月であった。以上より、ZANは日本人患者の第2相推奨用量である60mgにて、R/R iNHL日本人患者に良好な薬物動態と抗腫瘍効果をもたらすと考えられた。

記述言語：英語   出版者・発行元：(一社)日本血液学会  

レニン-アルドステロン-アンジオテンシン系阻害剤(RAASi)を含む特定の降圧薬の偶発的使用が、TKI治療中の慢性骨髄性白血病(CML)の推算糸球体濾過量(eGFR)の変化に及ぼす影響を評価した。対象は当院のCML患者142名で、混合効果モデルを用いてeGFR変化率を推定し、TKI治療中の全てのeGFR測定値を遡及的に分析した。全体的に、使用した降圧薬の種類とeGFRの年間変化との間に有意な相互作用を認め、RAASi使用者が最も急速なeGFR減少(-5.5%/年)を示した。TKI別の分析では、イマチニブ(IMA)とボスチニブ(BOS)の間でのみ相互作用が有意であった。eGFRの年間減少率はRAASi使用者で最も顕著で、IMAとBOSでは-5.7と-10.1であった。以上より、上記TKIを服用している患者はeGFRを監視する必要があると考えられた。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/blood-2022-158024

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DOI： 10.1182/blood-2022-164913

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DOI： 10.1182/blood-2022-159804

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記述言語：英語   出版者・発行元：Lancet Haematology  

Background: The prognosis for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia remains poor. UCART19, an allogeneic genome-edited anti-CD19 chimeric antigen receptor (CAR) T-cell product derived from healthy donors and available for immediate clinical use, offers a potential therapeutic option for such patients. The CALM trial is a first-in-human study evaluating the safety and antileukaemic activity of UCART19 in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. Methods: This phase 1, open-label study was conducted at eight centres across France, the UK, the USA, and Japan. Adult patients aged 16–70 years with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukaemia who had morphological relapse or a minimal residual disease level of at least 1 × 10^–3 and had exhausted standard treatment options were enrolled in the study, which comprised a dose-escalation phase of up to three UCART19 doses followed by a safety expansion phase. Patients underwent lymphodepletion with fludarabine (30 mg/m² per day intravenously for 3 days) and cyclophosphamide (500 mg/m² per day intravenously for 3 days) with or without alemtuzumab (1 mg/kg or 40 mg or 60 mg over 5 days) and received UCART19 doses of 6 × 10⁶, 6–8 × 10⁷, or 1·8–2·4 × 10⁸ total CAR T cells intravenously, followed by safety evaluation and disease response assessments. The primary endpoint was incidence and severity of adverse events. Secondary endpoints were the overall response rate, duration of response, relapse-free survival, progression-free survival, and overall survival. This trial is registered with ClinicalTrials.gov (NCT02746952) and is complete. Findings: Between Aug 1, 2016, and June 30, 2020, 25 patients were enrolled in the study and treated with UCART19. Median duration of follow-up was 12·8 months (IQR 2·8–24·8). Median age was 37 years (IQR 28–45). 14 (56%) patients were male and 11 (44%) female. 17 (68%) patients were White, two (8%) Black, two (8%) Asian, and four (16%) from other racial or ethnic groups. Three patients developed dose-limiting toxicities (one at each dose level); one had grade 4 cytokine release syndrome and two had grade 4 prolonged cytopenias. Grade 3 or higher cytokine release syndrome was reported in six (24%) patients and grade 3 or higher neurological toxicity in one (4%) patient. Grade 3 or higher infections occurred in seven (28%) patients, and grade 4 prolonged cytopenia in four (16%) patients. Two (8%) patients developed grade 1 acute cutaneous graft-versus-host disease. 14 patients died, nine from progressive disease and five from infections or other complications, of which four were considered to be related to UCART19 or lymphodepletion, or both. After a median of follow-up of 12·8 months (IQR 2·8–24·8), overall response rate was 48% (95% CI 28–69; 12 of 25 patients), duration of response and median relapse-free survival were 7·4 months (95% CI 1·8 to not calculable), progression-free survival was 2·1 months (95% CI 1·2–2·8), and overall survival was 13·4 months (95% CI 4·8–23·0). Interpretation: UCART19 had a manageable safety profile, and showed evidence of antileukaemic activity in heavily pretreated adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. This study shows that allogeneic off-the-shelf CAR T cells can be used safely to treat patients with relapsed B-cell acute lymphoblastic leukaemia. Funding: Servier.

DOI： 10.1016/S2352-3026(22)00245-9

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記述言語：英語   出版者・発行元：BMJ Open  

Introduction Adoptive cell transfer of genetically engineered T cells is a promising treatment for malignancies; however, there are few ideal cancer antigens expressed on the cell surface, and the development of chimeric antigen receptor T cells (CAR-T cells) for solid tumour treatment has been slow. CAR-T cells, which recognise major histocompatibility complex and peptide complexes presented on the cell surface, can be used to target not only cell surface antigens but also intracellular antigens. We have developed a CAR-T-cell product that recognises the complex of HLA-A∗02:01 and an epitope of the MAGE-A4 antigen equipped with a novel signalling domain of human GITR (investigational product code: MU-MA402C) based on preclinical studies. Methods and analysis This is a dose-escalation, multi-institutional, phase 1 study to evaluate the tolerability and safety of MU-MA402C for patients with MAGE A4-positive and HLA-A∗02:01-positive unresectable advanced or recurrent solid cancer. Two dose cohorts are planned: cohort 1, MU-MA402C 2×10 8 /person; cohort 2, MU-MA402C 2×10 9 /person. Prior to CAR-T-cell infusion, cyclophosphamide (CPA) and fludarabine (FLU) will be administered as preconditioning chemotherapy. Three evaluable subjects per cohort, for a total of 6 subjects (maximum of 12 subjects), will be recruited for this clinical trial. The primary endpoints are safety and tolerability. The severity of each adverse event will be evaluated in accordance with Common Terminology Criteria for Adverse Events V.5.0. The secondary endpoint is efficacy. Antitumour response will be evaluated according to Response Evaluation Criteria in Solid Tumours V.1.1. Ethics and dissemination This clinical trial will be conducted in accordance with the current version of Good Clinical Practice. The protocol was approved by the Clinical Research Ethics Review Committee of Mie University Hospital (approval number F-2021-017). The trial results will be published in peer-reviewed journals and/or disseminated through international conferences. Trial registration number jRCT2043210077.

DOI： 10.1136/bmjopen-2022-065109

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記述言語：英語   出版者・発行元：Cancer Research Communications  

Background: UCART19¹ is an “off-the-shelf” genome-edited anti-CD19 chimeric antigen receptor (CAR)-T cell product, manufactured from unrelated healthy donor cells. Methods: UCART19 was administered to 25 adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) in the CALM trial. All patients underwent lymphodepletion with fludarabine and cyclophosphamide ± alemtuzumab and received one of three ascending doses of UCART19. Given the allogeneic nature of UCART19, we analyzed the impact of lymphodepletion, HLA disparities, and host immune system reconstitution on its kinetics, along with other factors known to affect autologous CAR-T cell clinical pharmacology. Results: Responder patients (12/25) had higher UCART19 expansion (Cmax) and exposure (AUCT<inf>last</inf>) than nonresponders (13/25), as measured by transgene levels in peripheral blood. The persistence of CAR⁺ T cells did not exceed 28 days in 10/25 patients and lasted beyond 42 days in 4/25. No significant correlation was found between UCART19 kinetics and administered cell dose, patient and product characteristics or HLA disparities. However, the number of prior lines of therapy and absence of alemtuzumab negatively impacted UCART19 expansion and persistence. Alemtuzumab exposure positively affected IL7 and UCART19 kinetics, while negatively correlating with host T lymphocyte AUC0-28. Conclusions: UCART19 expansion is a driver of response in adult patients with R/R B-ALL. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on IL7 and host-versus-graft rejection. Significance: First description of the clinical pharmacology of a genome-edited allogeneic anti-CD19 CAR-T cell product showing the crucial role of an alemtuzumab-based regimen in sustaining UCART19 expansion and persistence through increased IL7 availability and decreased host T lymphocyte population.

DOI： 10.1158/2767-9764.CRC-22-0175

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Hematology  

Relapsed and refractory aggressive lymphoma have a poor prognosis. High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is effective in chemosensitive patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is among the few options for non-chemosensitive patients. ¹⁸Fluoro-2-deoxy-d-glucose positron emission tomography–computed tomography (¹⁸FDG-PET/CT) is the standard tool for evaluating response to chemotherapy and residual tumor volume. However, accurate assessment of residual tumor volume is not currently being achieved in clinical practice, and its value in prognostic and therapeutic stratification remains unclear. To answer this question, we investigated the efficacy of quantitative indicators, including total metabolic tumor volume (TMTV), in predicting prognosis after auto-HSCT and allo-HSCT. We retrospectively analyzed 39 patients who received auto-HSCT and 28 who received allo-HSCT. In the auto-HSCT group, patients with a higher TMTV had a poor prognosis due to greater risk of relapse. In the allo-HSCT group, patients with a higher TMTV had a lower progression-free survival rate and a significantly higher relapse rate. Neither Deauville score nor other clinical parameters were associated with prognosis in either group. Therefore, pre-transplant TMTV on PET is effective for prognostic prediction and therapeutic decision-making for relapsed or refractory aggressive lymphoma.

DOI： 10.1007/s12185-022-03394-w

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本血液学会  

造血幹細胞移植(HSCT)施行前の再発・難治性(R/R)悪性リンパ腫患者において、18フルオロ-2-デオキシ-グルコース陽電子放出断層撮影法(18FDG-PET/CT)による総代謝腫瘍体積(TMTV)の評価が予後に与える影響を後方視的に検討した。2007年1月～2015年12月に当院においてHSCT施行前の3ヵ月以内にPET/CT検査を実施したR/R悪性リンパ腫患者67例を対象とした。39例(年齢20～65歳)が自家HSCTを受け、28例(年齢22～69歳)が同種HSCTを受けた。その結果、自家HSCT群のTMTVが大きい患者は、再発リスクが高く、予後が不良であった。同種HSCT群では、TMTVが大きい患者は無増悪生存率が低く、再発率も有意に高かった。Deauvilleスコアやその他の臨床パラメータはいずれも両群の予後と関連しなかった。以上より、HSCT前のPET/CTで評価したTMTVはR/Rアグレッシブリンパ腫の予後予測や治療方針の決定に有効であった。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-022-03458-x.

記述言語：英語   出版者・発行元：American Journal of Ophthalmology Case Reports  

Purpose: This article presents a case of panuveitis that occurred after unrelated allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a patient with lymphoma-type human T-cell leukemia virus type-1 (HTLV-1)-associated adult T-cell leukemia (ATL). Observations: A 45-year-old man developed unilateral panuveitis 18 months after undergoing allo-HSCT. He underwent vitrectomy, and depositions of grey-white granules localized on the retinal artery were observed in the eye. Cytological examination of the vitreous aspirates showed that the atypical lymphoid cells stained positive for CD3 and CD8, but negative for CD4, B-cell markers, and cytomegalovirus antigen. Interphase fluorescence in situ hybridization using X‐ and Y‐chromosome probes revealed complete donor chimerism in CD8⁺ T cells in the vitreous aspirates. Conclusions and importance: Donor-derived CD8⁺ T lymphocytes can induce panuveitis like HTLV-1-assiciated uveitis after allo-HSCT in patients with ATL. Pathological diagnosis of vitreous infiltration by vitrectomy is helpful in patients with ATL. Donor-derived CD8⁺ T lymphocytes-induced panuveitis is recurrent but susceptible to regional corticosteroid treatment.

DOI： 10.1016/j.ajoc.2022.101673

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出版者・発行元：東京医学社  

DOI： 10.24479/endo.0000000301

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blood Advances  

DOI： 10.1182/bloodadvances.2021006193

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/bloodadvances.2022008242.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

再発または難治性の成人T細胞白血病/リンパ腫(R/R ATLL)患者を対象に、ヒストン脱アセチル化酵素を阻害することによって抗腫瘍効果を発揮するツシジノスタットの有効性と安全性を評価するため、多施設共同前向き第IIb相試験を実施した。モガムリズマブによる前治療またはモガムリズマブに対する不耐性・禁忌のために化学療法による全身治療を受けたR/R ATLL患者23例(年齢60～89歳)に対してツシジノスタット40mgの週2回経口投与を行った。主要評価項目の客観的奏効率は30.4%(95%CI 13.2～52.9)であった。無増悪生存期間中央値は1.7ヵ月(95%CI 0.8～7.4)、奏効期間中央値は9.2ヵ月(95%CI 2.6～未達)、全生存期間中央値は^7.9ヵ月(95%CI 2.3～18.0)であった。全例で有害事象が発現し、その主なものは血液系および消化器系であった。グレード3以上の有害事象の発生率は78.3%で、その殆どが臨床検査値異常(血小板、好中球、白血球、ヘモグロビンの減少)であった。以上より、ツシジノスタットの忍容性は良好であり、有害事象は支持療法や用量変更によってほぼ管理可能であった。

記述言語：英語   出版者・発行元：(一社)日本血液学会  

早期に臨床的に意義のあるサイトメガロウイルス(csCMV)感染がなく、レテルモビル(LMV)予防投与を完了した同種造血細胞移植(allo-HCT)レシピエントにおいて、晩期csCMV感染に関連する危険因子を後方視的に検討した。2018年6月から2021年2月までに当院でallo-HCTを受け、csCMV感染予防のための予防的LMVを受けた患者81例(年齢18～70歳)を対象とした。そのうち23例(28.4%)はCMV再活性化を起こし、抗CMV薬による初回介入までの期間の中央値はallo-HCT後で131日(範囲103～166日)、LMV中止後で30日(範囲5～67日)であった。晩期csCMV初回感染の治療期間中央値は21日(範囲12～43日)であった。晩期csCMVは免疫再構成の遅れと明らかに相関していた。HLA不一致ドナー(HR 13.0、p=0.011)またはCMVに対するIgG陰性ドナー(HR 2.39、p=0.043)からのallo-HCTはリスクが有意に高かった。また、晩期CMV感染の有無による移植成績に差は認められなかった。以上より、より多くのallo-HCTレシピエント、特に「高リスク」ドナーから移植を受けるレシピエントにおいて、LMV長期投与の晩期csCMV感染予防に対する効果を明らかにする必要性が示唆された。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1056/NEJMoa2201817.

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI-8000) in patients with relapsed or refractory (R/R) adult T-cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty-three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end-point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression-free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.

DOI： 10.1111/cas.15431

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Hematology  

Prophylactic use of letermovir (LMV) markedly reduces the incidence of early clinically significant cytomegalovirus (csCMV) infection within the first 100 days after allogeneic hematopoietic cell transplantation (allo-HCT), which improves transplant outcomes. However, some patients eventually develop late-csCMV infection (beyond day 100) after completing LMV prophylaxis. To assess the incidence of late-csCMV infection as well as its risk factors and impacts on transplant outcome, a total of 81 allo-HCT recipients who had not developed early csCMV infection during LMV prophylaxis were retrospectively analyzed. Among them, 23 (28.4%) patients developed late-csCMV infection (until day 180) at a median time of 131 days after transplantation and 30 days after LMV discontinuation, respectively. Late-csCMV infection was correlated with apparent delayed immune reconstitution: patients transplanted from HLA-mismatched donors (hazard ratio [HR] = 13.0, p = 0.011) or CMV-IgG-negative donors (HR = 2.39, p = 0.043) had a significantly higher risk. In this study, transplant outcomes did not differ between patients with and without late-csCMV infection. This suggests a need to clarify the efficacy of extended administration of LMV for preventing late-csCMV infection in a larger number of allo-HCT recipients, especially those with “high-risk” donors.

DOI： 10.1007/s12185-022-03348-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：In Vivo  

Background/Aim: High-dose chemotherapy is frequently administered to patients with hematologic malignancies, thereby causing severe adverse drug reactions (ADRs) at a relatively high frequency. To precisely monitor ADRs, we developed a medication instruction sheet (MIS) for patients who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) combination therapy for non-Hodgkin’s lymphoma (NHL). Herein, we evaluated the usefulness of the MIS for managing ADRs in patients who received R-CHOP therapy. Patients and Methods: We included patients aged ≥20 years who received R-CHOP therapy as first-line treatment for NHL at the Department of Hematology, Kyushu University Hospital, between August 2014 and December 2018. Medical professionals evaluated the possible occurrence of ADRs according to the present MIS and ADRs were graded according to the Common Toxicity Criteria, version 4.0 (National Cancer Institute, Bethesda, MD, USA). Finally, the accuracy of the MIS in predicting the occurrence of ADRs of different grades and during definite periods was evaluated. Results: Seventy-five patients with NHL were included in the present study. Overall, 359 ADR events were monitored, which were predicted ADR items listed in the MIS. Among these, 254 (71%) events occurred during the same period as those listed in the MIS. The onset timing of any grade of an infusion reaction and peripheral neuropathy precisely matched those listed in the MIS. However, the accuracy of the MIS was reduced in patients with thrombocytopenia (42%). Conclusion: The present MIS could be useful for monitoring ADRs in patients with cancer undergoing R-CHOP therapy.

DOI： 10.21873/invivo.12852

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記述言語：英語   出版者・発行元：Leukemia  

Fit patients with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) in relapsed or refractory (R/R) disease status often receive salvage chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHCT) or allogeneic HCT (alloHCT). However, there is no consensus on the type of HCT that should be applied for such patients. Herein, we retrospectively evaluated the survival outcome of 760 adult R/R PTCL-NOS or AITL patients who underwent the first HCT. Among them, 318 relapsed after first remission (REL) and 442 were refractory to the primary therapy (PIF). The 4-year overall survival (OS) of autoHCT and alloHCT was 50 and 50% for REL patients, and 52 and 49% for PIF patients, respectively. In the multivariable analysis, alloHCT tended to be associated with better progression-free survival (PFS) in REL (hazard ratio [HR] 0.74; 95% confidence interval [CI]: 0.53–1.03), and significantly better PFS in PIF (HR 0.64; 95% CI: 0.46–0.88) compared with autoHCT. The subgroup analysis with propensity-score matching showed that alloHCT was associated with better OS for REL-sensitive and PIF-nonremission disease. This study suggested that the advantage of alloHCT for R/R PTCL-NOS or AITL is different, depending on the disease status at HCT.

DOI： 10.1038/s41375-022-01545-w

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記述言語：英語   出版者・発行元：Blood Advances  

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy, with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin (COO), genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of “unfavorable” molecular signatures.

DOI： 10.1182/bloodadvances.2021004618

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/bloodadvances.2021004618.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：Anticancer Research  

Background/Aim: The occurrence of chemotherapy-related serious adverse events (AEs) is associated with a poor prognosis of hematopoietic malignancies. We have developed a medication guidance sheet (MGS) for monitoring AEs occurring when combining chemotherapy with etoposide, methylprednisolone, cisplatin, cytarabine, and rituximab (ESHAP±R). In this study, the usefulness of MGS was investigated in non-Hodgkin’s lymphoma patients. Patients and Methods: The MGS was used to monitor AEs in 48 adult patients receiving ESHAP±R. The prediction accuracy of the MGS was estimated before and after modification based on practical data. Results: A total of 246 AEs developed, all of which were predicted by the MGS. Among them, 149 events (61%) occurred during the same period as those predicted by the MGS. After modification of MGS for the onset and duration of AEs, the accuracy increased to 84%. Conclusion: The accuracy of the original MGS for ESHAP±R was insufficient but greatly improved after the AEs duration modification.

DOI： 10.21873/anticanres.15686

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記述言語：英語   出版者・発行元：Frontiers in Cardiovascular Medicine  

Chimeric antigen receptor T (CAR-T) cell therapy has been shown to have substantial efficacy against refractory hematopoietic malignancies. However, it frequently causes cytokine release syndrome (CRS) as a treatment-specific adverse event. Although cardiovascular events associated with CAR-T cell therapy have been increasingly reported recently, pericardial disease is a rare complication and its clinical course is not well characterized. Here, we report a case of acute pericardial effusion with cardiac tamponade after CAR-T cell therapy. Case Summary: A 59-year-old man with refractory diffuse large B-cell lymphoma underwent CAR-T cell therapy. Grade 2 CRS was observed on day 0; it progressed to grade 4 on day 7 and was accompanied by a fever over 39°C, hypoxia requiring intubation, hypotension requiring the use of a vasopressor agent, and supraventricular tachycardia. Although cardiac function was preserved, marked pericardial effusion with the collapse of the right heart was detected on echocardiography. Since pericardiocentesis was considered to have a high complication risk due to severe myelosuppression, medications for CRS were prioritized. Tocilizumab, an interleukin-6 inhibitor, and high-dose methylprednisolone (1 g/day for 3 days) were administered for the management of severe CRS. On day 8, the pericardial effusion decreased, and the hemodynamic status markedly stabilized. CRS did not exacerbate after the steroid dose was reduced. Further, lymphoma size reduced after the induction of CAR-T cell therapy, and tumor regrowth was not noted at 3 months after CAR-T cell infusion. Conclusion: Interleukin-6 pathway inhibitors and corticosteroid therapy should be considered in the context of CRS for significant pericardial effusion after CAR-T cell therapy in the acute phase.

DOI： 10.3389/fcvm.2022.848091

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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  

Clonal hematopoiesis (CH) refers to the disproportionate expansion of hematopoietic stem cell clones and their corresponding progeny following the acquisition of somatic mutations. CH is common at the time of diagnosis in patients with blood cancers, including multiple myeloma (MM) and lymphoma. The presence of CH mutations correlates with IL-6 mediated inflammation and may result in lymphoma or MM modulation through microenvironment effects or by manifestations of the mutations themselves within the founding tumor clone. As might be expected with a variety of mutations and multiple potential mechanisms, CH exerts context-dependent effects, being protective in some settings and harmful in others. Though CH is very common in patients with hematologic malignancies, how it intersects with therapy and the natural disease course of these cancers are active areas of investigation. In lymphomas and MM specifically, patients have high rates of CH at diagnosis and are subsequently exposed to therapies, such as cytotoxic chemotherapy, that can cause CH progression to overt hematologic malignancy. The expanding diversity of treatment modalities for these cancers also increases the opportunities for CH to impact clinical outcome and modulate clinical responses. Here we review the basic biology and known health effects of CH, and we focus on the clinical relevance of CH in lymphoma and MM.

DOI： 10.1016/j.jaccao.2022.01.098

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Bone Marrow Transplantation  

We retrospectively compared the outcomes of reduced-intensity conditioning (RIC) transplantation from matched related donors (MRD; n = 266), matched unrelated donors (MUD; n = 277), and umbilical cord blood (UCB; n = 513) for mature lymphoid malignancies. The 3-year overall survival rates for the MRD, MUD, and UCB groups were 54%, 59%, and 40%, respectively (P < 0.001). Multivariate analysis showed no differences in survival between the MRD group and the MUD or UCB group. However, survival was significantly affected by the conditioning regimen and graft-versus-host disease (GVHD) prophylaxis in the UCB group, but not in the MRD and MUD groups. Notably, multivariate analysis showed that the risk of overall mortality in the UCB recipients who received the optimal conditioning regimen and GVHD prophylaxis (n = 116) was lower than that in the MRD group (relative risk [RR], 0.69; P = 0.03) and tended to be lower than that in the MUD group (RR, 0.75; P = 0.09). Our results suggest that UCB transplantation performed with the optimal conditioning regimen and GVHD prophylaxis is highly effective. Moreover, UCB is readily available. Thus, UCB transplantation with the optimal conditioning regimen and GVHD prophylaxis is preferable to MUD transplantation when MRD are not available in the setting of RIC transplantation for mature lymphoid malignancies.

DOI： 10.1038/s41409-021-01525-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Human Pathology  

Lymphoproliferative disorder (LPD) can occur in patients with inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD). On rare occasions, patients with IBD develop myeloid neoplasms; however, the frequency and clinicopathological features of IBD-associated lymphoid and myeloid proliferative disorder (LMPD) in Japanese patients are still unclear. In this study, we reviewed 2474 Japanese patients with IBD and found that LMPD occurred in 12 (0.5%) patients with UC (n = 7) or CD (n = 5). Together with an additional 3 cases, we analyzed a total of 15 cases of LMPD for clinicopathological and histological features. Based on the status of using immunosuppressants such as biologics and immunomodulators, Epstein–Barr virus (EBV) infection, and histopathology, the 15 cases were classified into Group I (high-grade LPD; n = 7), Group II (low-grade LPD; n = 5), and Group III (myeloid neoplasms; n = 3). Most patients in Group I were undergoing strong immunosuppressive therapy, and the LPD lesions corresponded to high-grade B-cell or T cell/natural killer cell lymphoma often with EBV infection. Discontinuation of immunosuppressive drugs alone did not resolve these LPDs; Group I patients required chemotherapy, and eventually 4 of them (57%) died of the tumor. Most cases in Group II were low-grade B-cell lymphoma without EBV infection and had an indolent clinical course with excellent prognosis. All patients in Group III developed acute myeloid leukemia (AML) during the course of CD. Two (67%) of these patients died of AML. Our study suggests that IBD-associated LMPD is very rare but can follow an aggressive clinical course.

DOI： 10.1016/j.humpath.2021.12.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Bone Marrow Transplantation  

DOI： 10.1038/s41409-021-01412-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Medicine  

Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor-T cell therapy with clinically meaningful outcomes demonstrated in patients with relapsed/refractory (r/r) B-cell lymphoma. In a previous pilot study of tisagenlecleucel in r/r follicular lymphoma (FL), 71% of patients achieved a complete response (CR). Here we report the primary, prespecified interim analysis of the ELARA phase 2 multinational trial of tisagenlecleucel in adults with r/r FL after two or more treatment lines or who relapsed after autologous stem cell transplant (no. NCT03568461). The primary endpoint was CR rate (CRR). Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival, overall survival, pharmacokinetics and safety. As of 29 March 2021, 97/98 enrolled patients received tisagenlecleucel (median follow-up, 16.59 months; interquartile range, 13.8–20.21). The primary endpoint was met. In the efficacy set (n = 94), CRR was 69.1% (95% confidence interval, 58.8–78.3) and ORR 86.2% (95% confidence interval, 77.5–92.4). Within 8 weeks of infusion, rates of cytokine release syndrome were 48.5% (grade ≥3, 0%), neurological events 37.1% (grade ≥3, 3%) and immune effector cell-associated neurotoxicity syndrome (ICANS) 4.1% (grade ≥3, 1%) in the safety set (n = 97), with no treatment-related deaths. Tisagenlecleucel is safe and effective in extensively pretreated r/r FL, including in high-risk patients.

DOI： 10.1038/s41591-021-01622-0

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：New England Journal of Medicine  

BACKGROUND: Patient outcomes are poor for aggressive B-cell non-Hodgkin's lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines. METHODS: We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety. RESULTS: A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P = 0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standardcare group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events. CONCLUSIONS: Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach.

DOI： 10.1056/NEJMoa2116596

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Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

Background: Axicabtagene ciloleucel (axi-cel) is an autologous chimeric antigen receptor T-cell based anti-CD19 therapy. The ZUMA-1 study, multicenter, single-arm, registrational Phase 1/2 study of axi-cel demonstrated high objective response rate in patients with relapsed/refractory large B-cell lymphoma. Here, we present the results of the bridging study to evaluate the efficacy and safety of axi-cel in Japanese patients (JapicCTI-183914). Methods: This study was the phase 2, multicenter, open-label, single-arm trial. Following leukapheresis, axi-cel manufacturing and lymphodepleting chemotherapy, patients received a single infusion of axi-cel (2.0 × 10⁶ cells/kg). Bridging therapy between leukapheresis and conditioning chemotherapy was not allowed. The primary endpoint was objective response rate. Results: Among 17 enrolled patients, 16 received axi-cel infusion. In the 15 efficacy evaluable patients, objective response rate was 86.7% (95% confidence interval: 59.5–98.3%); complete response/partial response were observed in 4 (26.7%)/9 (60.0%) patients, respectively. No dose-limiting toxicities were observed. Grade ≥ 3 treatment-emergent adverse events occurred in 16 (100%) patients—most commonly neutropenia (81.3%), lymphopenia (81.3%) and thrombocytopenia (62.5%). Cytokine release syndrome occurred in 13 (81.3%) patients (12 cases of grade 1 or 2 and 1 case of grade 4). No neurologic events occurred. Two patients died due to disease progression, but no treatment-related death was observed by the data-cutoff date (October 23, 2019). Conclusion: The efficacy and safety of axi-cel was confirmed in Japanese patients with relapsed/refractory large B-cell lymphoma who have otherwise limited treatment options. Trial registration: JapicCTI-183914.

DOI： 10.1007/s10147-021-02033-4

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Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人 日本造血・免疫細胞療法学会  

<p> Background: Cord blood is an alternative donor source for patients without HLA-matched donors. Calcineurin inhibitors (CNIs) alone, as prophylaxis for graft-versus-host disease (GVHD) in cord blood transplantation (CBT) patients, reportedly increase the incidence of severe pre-engraftment immune reaction (PIR), leading to transplant-related mortality (TRM) with primary engraft failure and multiple organ dysfunctions. Therefore, additional immunosuppressive agents are needed. Reportedly, short-term methotrexate (sMTX) plus CNIs improved outcomes in patients receiving CBT with full-intensity conditioning (FIC) regimens; however, safety and efficacy of sMTX plus cyclosporine have not been assessed in patients receiving CBT with reduced-intensity conditioning (RIC) regimens. Methods: We retrospectively analyzed 43 patients who received single-unit CBT and were treated with sMTX plus cyclosporine (RIC group, 15; FIC group, 28). Results: Neutrophil engraftment rate was significantly lower in RIC group (53.3%) than in FIC group (78.6%, <i>P</i>=0.04). Cumulative incidence of TRM tended to be higher in the RIC group than in the FIC group (<i>P</i>=0.12); the leading cause of death in the RIC group was bacterial infections. Conclusions: sMTX plus cyclosporine does not seem feasible for treating patients receiving single-unit CBT following RIC. MTX dose optimization or alternative immunosuppressive agent application should be considered in such patients.</p>

DOI： 10.7889/tct-21-001

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Hematology  

Post-transplant cytomegalovirus (CMV) disease can be almost completely avoided by current infection control procedures. However, CMV reactivation occurs in more than half of patients, and some patients can develop clinically resistant CMV infections. Whether resistance is due to the host’s immune status or a viral resistance mutation is challenging to confirm. Therefore, a prospective observational analysis of refractory CMV infection was conducted in 199 consecutive patients who received allogeneic hematopoietic stem cell transplantation at a single institution. Among them, 143 (72%) patients received anti-CMV drugs due to CMV reactivation, and only 17 (8.5%) exhibited refractory CMV infection. These patients had clinically refractory infection. However, viral genome analysis revealed that only one patient exhibited a mutation associated with the anti-CMV drug resistance. Clinical resistance was mainly correlated with host immune factors, and the incidence of resistance caused by gene mutations was low at the early stage after a transplantation.

DOI： 10.1007/s12185-021-03218-3

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PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本造血・免疫細胞療法学会  

強度減弱前処置後に単一ユニット臍帯血移植(CBT)を施行した患者の移植片対宿主病(GVHD)予防におけるメトトレキサート(sMTX)+シクロスポリン短期併用療法の安全性と有効性を後方視的に検討した。2007年1月から2013年7月までに血液悪性腫瘍に対して単一ユニットCBTを受けた患者43例のうち、15例(年齢57～72歳)が強度減弱前処置(RIC)、28例(年齢18～64歳)が通常強度前処置(FIC)を受けた。RIC群の好中球生着率は53.3%(95%CI:24.2～75.7)であり、FIC群の78.6%(95%CI:57.0～90.2、p=0.04)に比べて有意に低値であった。生存者の追跡期間の中央値854日(範囲60～1738日)において、FIC群とRIC群の全生存期間(p=0.57)と無増悪生存期間(p=0.89)には統計学的な有意差はなかった。移植2年後の移植関連死亡率はFIC群に比べてRIC群で高い傾向にあった(p=0.12)。移植2年後の再発率はFIC群で46.4%、RIC群で20.0%であった(p=0.06)。死亡原因の第1位は、RIC群で細菌感染、FIC群では再発であった。以上より、sMTXとシクロスポリンの併用は、RIC後に単一ユニットCBTを受けた患者の治療に実行可能でないと考えられた。

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：シュプリンガー・ジャパン(株)  

日本人再発・難治性大細胞型B細胞リンパ腫患者を対象に、CD19に対するキメラ抗原受容体(CAR)-T細胞であるアキシカブタゲンシロルユーセル(Axi-Cel)の有効性と安全性を評価するためのブリッジング試験として多施設共同非盲検単群第2相試験を実施した。患者16例(年齢44～70歳)がAxi-Cel注入を受けた。有効性の評価対象である15例の客観的奏効率は86.7%(95%CI 59.5～98.3)で、完全奏効または部分奏効はそれぞれ4例(26.7%)または9例(60.0%)に認められた。用量制限毒性は認められなかった。グレード3以上の有害事象は16例(100%)で出現し、好中球減少症(81.3%)、リンパ球減少症(81.3%)、血小板減少症(62.5%)が多く認められた。サイトカイン放出症候群は13例(81.3%)に出現した(グレード1または2が12例、グレード4が1例)。神経学的イベントは発生しなかった。病勢進行により2例が死亡したが、データカットオフ日までに治療関連死亡は認められなかった。以上より、日本人の再発・難治性大細胞型B細胞リンパ腫患者において、Axi-Celの有効性と安全性が確認された。

記述言語：英語   出版者・発行元：(一社)日本血液学会  

同種造血幹細胞移植を受けた患者199例を対象に、サイトメガロウイルス(CMV)pp65抗原陽性細胞数や抗CMV薬への反応性を前向きに検討した。早期死亡(好中球生着前の死亡と定義)は8例に認められた。患者36例は、臨床経過中および移植後1年までCMV抗原血症(pp65抗原陽性細胞を染色して検査)を発症しなかった。患者155例は、移植後の中央値34日(範囲9～97)で少なくとも1回、CMV抗原血症の検査結果が陽性であった。追跡期間中の白血球5万個あたりのCMV pp65抗原陽性細胞の最大数の中央値は5個(範囲1～332)であった。患者143例(72%)はCMV再活性化により抗CMV薬を投与され、17例(8.5%)は臨床的に難治性CMV感染症であった。ウイルスゲノム解析の結果、抗CMV薬耐性に関連する変異を有する患者は1例のみであった。以上より、CMV感染症の臨床抵抗性は主に宿主の免疫因子と相関しており、遺伝子変異による抗CMV薬抵抗性の発生は移植後早期には少ないことが示された。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-021-01445-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.cpccr.2021.100108

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-021-03191-x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/S1470-2045(21)00375-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/bloodadvances.2021004932

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/10428194.2021.1941937

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/bjh.17456

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1056/NEJMoa2033122

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jtct.2021.07.010.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cas.14886

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1200/JCO.20.01366.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cas.14937.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cas.14906.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-020-03024-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-020-00996-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-020-01192-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/bloodadvances.2020003639

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00277-020-04310-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/hon.2816

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1346-8138.15600

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi:10.1111/cas.14536

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi:10.1007/s12185-020-02929-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1007/s12185-020-02911-z.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1007/s10147-020-01699-6.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1111/cas.14437.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1111/cas.14424.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1182/blood.2019003749.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1182/blood.2019002194.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.3324/haematol.2019.231076.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Schizophyllum commune, a basidiomycete fungus, is a quite rare cause of invasive sinusitis for which no standard treatment has yet been established. We report herein a 59-year-old woman who developed S. commune rhinosinusitis after remission induction chemotherapy for her acute myeloid leukemia. No causative microorganisms were identified in the sinus lavage fluid culture, whereas nucleotide sequencing of the internal transcribed spacer region using endoscopic sinus biopsy specimen could confirm the pathogen as S. commune. Liposomal amphotericin B and voriconazole (VRCZ) treatment ameliorated both her clinical symptoms and laboratory findings. The patient was successfully treated with allogeneic stem cell transplantation, under continuous VRCZ administration, without aggravation of S. commune sinusitis. Molecular diagnosis and prompt intervention with suitable antifungal drugs may be crucial to manage this rare infectious complication.

DOI： 10.1016/j.jiac.2019.12.013

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only available curative treatment option for patients with aggressive adult T cell leukemia-lymphoma (ATL). Donor human T cell leukemia virus (HTLV) 1 seropositivity is a critical concern when choosing relative donors, as they are not usually recommended due solely to the occurrence of donor-derived ATL. A previous report suggested that allo-HCT with an HTLV-1-seropositive donor increased ATL-related mortality. We updated the risk assessment for choosing an HTLV-1-seropositive allo-HCT donor for ATL. Our current registry data, which include larger numbers of HTLV-1-seropositive donors and longer observation periods, revealed no significant difference in overall survival (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.70-1.24; P = .61) or cumulative incidence of either ATL-related (HR, 0.96; 95% CI, 0.64 to 1.45; P = .80) or non-ATL-related mortality (HR, 0.91; 95% CI, 0.61 to 1.37; P = .66). Similarly, when considering only patients with ATL in complete remission, there was no significant difference in overall survival (HR, 1.02; 95% CI, 0.70 to 1.49; P = .91) or cumulative incidence of either ATL-related (HR, 1.20; 95% CI, 0.66 to 2.20; P=0.54) or non-ATL-related mortality (HR, 0.86; 95% CI, 0.52-1.42; P = .66). These data indicate that selecting HTLV-1-seropositive donors might not be contraindicated for patients with ATL receiving allo-HCT if alternative donors are unavailable. Further risk assessment remains to be performed.

DOI： 10.1016/j.bbmt.2019.12.004

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Graft failure (GF) is a life-threatening complication after allogeneic stem cell transplantation (SCT). Although salvage SCTs can be performed with haploidentical donor (HID) or cord blood (CB), no study has compared the performances of these two sources. Using nationwide registration data, we compared the transplant outcomes of patients who developed GF and underwent salvage transplantation from HID (n = 129) and CB (n = 570) from 2007 to 2016. The HID group demonstrated better neutrophil recovery (79.7 vs. 52.5% at 30 days, P < 0.001). With a median follow-up of 3 years, both groups demonstrated similar overall survival (OS) and nonrelapse mortality (NRM; 1-year OS, 33.1 vs. 34.6% and 1-year NRM, 45.1 vs. 49.8% for the HID and CB groups). After adjustments for other covariates, OS did not differ in both groups. However, HID was associated with a lower NRM (hazard ratio, 0.71; P = 0.038) than CB. The incidence of acute graft-versus-host disease (GVHD)-related deaths was significantly higher in the HID group, although infection-related deaths were observed more frequently in the CB group. HID may be a promising salvage SCT option after GF due to its faster engraftment and low NRM.

DOI： 10.1038/s41409-020-0821-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The effects of stem cell transplantation (SCT) in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) remain controversial. We analyzed the feasibility of SCT and risk factors associated with outcomes of PTCL-NOS and AITL patients to identify the potential clinical efficacy of SCT. We retrospectively analyzed the data of PTCL-NOS (n = 83) and AITL (n = 112) patients who received autologous (n = 10 and 16, respectively) or allogeneic (n = 12 and 4, respectively) SCT, or no SCT (n = 61 and 92, respectively) between 2008 and 2018. All PTCL-NOS and AITL diagnoses were reconfirmed by an experienced hematopathologist. Median age at PTCL-NOS and AITL diagnoses in the SCT group was younger than that in the no SCT group. Significant risk factors for lower overall survival were intermediate–high and high-risk international prognostic indexes in PTCL-NOS patients (P = 0.0052), and a > 2 modified prognostic index for T-cell lymphoma (P = 0.0079) and no SCT (P = 0.028) in AITL patients. Autologous or allogeneic SCT compared with no SCT in AITL patients resulted in 3-year overall survival of 68.6% and 100% vs. 57.2% (P = 0.018). Strategies should be developed to improve selection of PTCL-NOS and AITL patients suitable for SCT and/or additional novel therapies.

DOI： 10.1007/s12185-020-02879-w

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Immune tolerance against alloantigens plays an important role in the success of clinical organ and allogeneic hematopoietic stem cell transplantation. The mechanisms of immune tolerance to alloantigens have gradually been elucidated over time. Although there have been numerous reports to date on the induction of tolerance to alloantigens, the establishment of mixed chimerism is well-known to be crucial in the induction and maintenance of immune tolerance for either of the methods. Since the early 1980s, the murine system of cyclophosphamide (Cy)-induced tolerance has also been examined extensively. The present review focuses on studies conducted on Cy-induced immune tolerance. Clinical data of patients with allogeneic transplantation suggest that the posttransplant Cy method to induce immune tolerance has been successfully translated from basic studies into clinical practice.

DOI： 10.3389/fimmu.2019.03138

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a retrospective analysis of 38 patients (age ≤ 30 years) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) for relapsed or refractory anaplastic large-cell lymphoma (ALCL). Median follow-up for survivors after undergoing allo-SCT was 72 months (range, 35–96 months). Eight patients received reduced-intensity conditioning (RIC) regimens, including three patients with fludarabine plus melphalan-based regimens and five patients with fludarabine plus busulfan-based regimens. The remaining 30 patients received myeloablative conditioning (MAC) regimens. Median ages in the RIC and MAC groups were 24 and 15 years, respectively. The 5-year overall survival rates in the RIC and MAC groups were 100% and 49%, respectively (P = 0.018). The 5-year event-free survival rates in the RIC and MAC groups were 88% and 43%, respectively (P = 0.039). In the RIC group, four of the eight patients showed residual disease at allo-SCT, but all eight patients survived with complete remission (CR), including one patient with relapse. This result suggests that allo-SCT using the RIC regimen may be effective for relapsed or refractory ALCL in children, adolescents, and young adults, even in non-CR cases.

DOI： 10.1007/s12185-019-02748-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/bjh.16050

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vaccination against vaccine-preventable diseases (VPDs) is highly recommended for hematopoietic stem cell transplantation (HSCT) recipients by several guidelines; however, the safety and seropositivity after live attenuated vaccines remain unclear in adult HSCT recipients. We analyzed titers of antibodies against measles, rubella, mumps, and varicella zoster virus (VZV) from Japanese adult patients who underwent allogeneic HSCT (allo-HSCT) (n = 74), autologous HSCT (auto-HSCT) (n = 39), or chemotherapy (n = 93). The seropositive rates for measles, rubella, mumps, and VZV in allo-HSCT recipients were 20.2%, 36.4%, 5.4%, and 55.4%, respectively. These rates were equivalent to those in auto-HSCT recipients but were significantly lower than those in patients receiving chemotherapy. Antibody titers tended to gradually decrease with time. Twenty-nine allo-HSCT recipients and 8 auto-HSCT recipients received live attenuated vaccines against VPDs for which they tested seronegative. The titers of antibodies against measles, rubella, and mumps significantly increased after 2 shots of vaccine, and the seropositive rate increased up to 19%, 30%, and 27%, respectively. Three patients (8.1%) experienced mild adverse events, which resolved promptly, indicating safe administration of the live attenuated vaccines. In multivariate analysis, history of chronic graft-versus-host disease was significantly associated with high seropositivity for measles as well as high seroconversion rate for measles after vaccination. Live attenuated vaccines against VPDs were safely administered in seronegative adult HSCT recipients. A further observational study is crucial to evaluate the efficacy of vaccination in seronegative HSCT patients.

DOI： 10.1016/j.bbmt.2019.04.006

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Methotrexate (MTX) carries a risk of lymphoproliferative disorders (LPDs), but MTX-associated LPDs (MTX-LPDs) can resolve spontaneously after MTX withdrawal. However, the precise clinicopathologic features of MTX-LPD remain unclear. We aimed to investigate the clinicopathologic characteristics, outcomes, and prognostic factors for histologic types of MTX-LPD. Paraffin-embedded tissue samples of 219 patients with MTX-LPD were analyzed. In total, 30,33,106, and 26 had reactive lymphoid hyperplasia (RH), polymorphic-LPD (Poly-LPD), diffuse large B-cell lymphomas (DLBCLs), and classic Hodgkin lymphoma (CHL), respectively. The clinicopathologic features of RH, Poly-LPD, DLBCLs, and CHL were as follows: extranodal involvement: 13.8% (4/29), 36.4% (12/33), 69.5% (73/105), and 15.4% (4/26); Epstein-Barr virus encoded RNA positivity: 55.2% (16/29), 71.9% (23/32), 45.3% (48/106), and 76.9% (20/26); necrosis: 0% (0/29), 51.5% (17/33), 34.3% (36/105), and 12.0% (3/25); and Hodgkin Reed-Sternberg-like cells: 17.2% (5/29), 50% (14/28), and 19.8% (21/106). The median duration from MTX withdrawal to the time of disease regression was 10.4, 3.0, 4.2, and 2.7 months for RH, Poly-LPD, DLBCLs, and CHL. After MTX withdrawal, progression-free survival was the greatest for RH, followed by for Poly-LPD, DLBCL, and CHL (all P<0.05). Overall survival did not differ significantly between the groups. On univariate analysis, the predictive factors for progression-free survival included plasma cell infiltrate for CHL, eosinophil infiltrate, age above 70 years, and extensive necrosis for Poly-LPD, while they were Epstein-Barr virus encoded RNA positivity and International Prognostic Index risk for DLBCL on multivariate analysis. In conclusion, histologic categorization and histology-specific factors could be useful for predicting MTX-LPD progression after MTX withdrawal.

DOI： 10.1097/PAS.0000000000001271

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sinusoidal obstruction syndrome (SOS) is a lethal complication after hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is the only drug internationally recommended for SOS treatment in Western countries. Recombinant human soluble thrombomodulin (rhTM), which is promising for the treatment of patients with disseminated intravascular coagulation, is also reported to be potentially effective for SOS. To clarify the safety and efficacy of DF and rhTM, we conducted a retrospective survey of these agents in Japan. Data from 65 patients who underwent allogeneic HSCT and received DF (n = 24) or rhTM (n = 41) for SOS treatment were collected. The complete response rates for SOS on day 100 were 50% and 54% in the DF and rhTM groups, respectively. The 100-day overall survival rates were 50% in the DF group, and 48% in the rhTM group. Several severe hemorrhagic adverse events were observed in one patient in the DF group and five patients in the rhTM group. The main causes of death were SOS-related death, and no patient died of direct adverse events of DF or rhTM. Our results suggest that rhTM, as well as DF, can be effective as a novel treatment option for SOS.

DOI： 10.1038/s41409-018-0304-4

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ajh.25438

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The hepatitis C virus (HCV) is a single-stranded RNA virus which is thought to be involved in the onset of B cell lymphoma. HCV-positive diffuse large B cell lymphoma (DLBCL) has been reported to clinically manifest in extranodal lesions (e.g., in the liver, spleen, and stomach). Here, we investigated HCV-positive and -negative primary splenic DLBCL (p-spDLBCL) and non-primary splenic DLBCL (ordinary DLBCL). Furthermore, to examine HCV lymphomagenesis, RNA in situ hybridization (ISH), RT-PCR (reverse-transcription polymerase chain reaction), and NS3 immunostaining of HCV viral nonstructural proteins were performed. HCV-positive p-spDLBCL patients presented fewer B symptoms (asymptomatic) and better performance status, with elevated presence of splenic macronodular lesions and more germinal center B cell (GCB) sub-group cases than HCV-negative p-spDLBCL patients. However, HCV-positive ordinary DLBCL patients were found to have more non-GCB sub-group cases than HCV-negative ordinary DLBCL patients. HCV-positive DLBCL patients showed 20.6% (7/34) NS3 positivity, 16.7% (1/6) HCV-RNA in situ positivity, and 22.2% (2/9) detection of HCV-RNA in tumor tissue by RT-PCR. Splenic samples were found to have a higher frequency of HCV detection than lymph node samples, thus suggesting that HCV may be closely related to lymphomagenesis, especially in splenic lymphoma.

DOI： 10.1007/s00277-019-03628-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Treatment options for patients with adult T cell leukemia/lymphoma (ATLL) who have relapsed disease after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are limited. To clarify which patients with ATLL are likely to benefit from these treatment options and to define patient populations for novel treatments, we performed a nationwide retrospective analysis of 252 Japanese patients who had relapsed ATLL after allo-HSCT. Some long-term survivors remained after tapering and withdrawal of immunosuppressive agents. Thirty-six patients who received donor lymphocyte infusion had a better overall survival (OS) in comparison to those who did not [hazard ratio (HR), 0.63; 95% confidence interval (CI), 0.43-0.93; P =.02], suggesting the efficacy of a graft-versus-ATLL (GvATLL) effect even after relapse. Multivariate analysis demonstrated that skin lesions at initial relapse of ATLL were independently associated with higher OS (HR, 0.41; 95% CI, 0.22-0.74; P =.003), indicating that the skin is a susceptible target organ of GvATLL. This study suggested that enhancement of a GvATLL effect is a potential therapeutic option for relapsed disease after allo-HSCT. Further investigations of incorporation of immune-based approaches with new molecular target drugs into the therapeutic options of patients with ATLL before and after transplantation are warranted.

DOI： 10.1002/hon.2558

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas. Methods: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m ² and doxorubicin 50 mg/m ² on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m ² and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152. Findings: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2–not evaluable) in the A+CHP group and 20·8 months (12·7–47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54–0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group. Interpretation: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile. Funding: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

DOI： 10.1016/S0140-6736(18)32984-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients receiving cancer chemotherapy may experience a number of potentially severe adverse drug reactions. It is crucial for all members of the health care team to monitor the effect of medicines on the patient to ensure the safety and efficacy of the chemotherapy. The present study prepared medication instruction sheets (MISs) on hematological malignancy and conducted a questionnaire survey to verify their usefulness among physicians, dentists, and nurses. MISs were prepared for 103 chemotherapy and 44 pretreatment regimens for hematopoietic stem cell transplantation in the Department of Hematology at Kyushu University Hospital. Eight questions were prepared to investigate whether MISs could help physicians, dentists, and nurses manage cancer chemotherapy more safely, effectively, and efficiently, as well as in the sharing of information. A total of 35 medical staff working in inpatient wards, including 8 physicians, 3 dentists, and 24 nurses, participated in the questionnaire survey. All of the staff responded to the questionnaire survey, which showed that the MISs were favorably accepted by the participants. There was no negative opinion on the management of chemotherapy using the MISs. The MIS was a useful tool for sharing information on cancer chemotherapy between patients and medical staff and for enabling efficient management, thereby improving the safety and efficacy of treatment.

DOI： 10.1691/ph.2019.9467

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Conditioning regimens for stem cell transplantation (SCT) involving total body irradiation (TBI) are generally preferred over busulfan (BU)-based ones for lymphoid malignancies. However, reports of favorable results using BU against lymphomas have recently emerged. This study sought to compare the effectiveness of BU and TBI regimens for SCT against lymphomas. We retrospectively analyzed 893 lymphoma patients who underwent primary SCT in Japan between 1980 and 2015. The median age of all patients was 18 years (range, 0–30 years) with 589 males, 303 females, and 1 patient whose sex was unknown. Overall survival (OS) was not different between those receiving BU and TBI (P = 0.672). OS in patients receiving autologous SCT was significantly better with BU over TBI regimens (P = 0.038), particularly in children (0–15 years) (P = 0.024). Conversely, OS in adolescents and young adults (AYAs; 16–30 years) receiving allogeneic SCT was significantly worse with BU over TBI regimens (P = 0.035). Overall, BU regiments had comparable effectiveness to TBI conditioning regimens, and, although less effective for AYAs with allogeneic SCT, were particularly more effective than TBI regimens for children who received autologous SCT.

DOI： 10.1002/pbc.27918

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/10428194.2018.1466295

記述言語：英語   掲載種別：研究論文（学術雑誌）  

To assess compliance with the Japanese antiemetic guidelines for chemotherapy-induced nausea and vomiting (CINV), the frequencies of CINV occurrence and use of antiemetic rescue medications were examined in patients with hematological malignancy. A total of 40 patients with hematologic malignancy were eligible in this study. This study was performed in the Department of Hematology, Kyushu University Hospital, as a subgroup analysis from a nationwide, multicenter prospective cohort study conducted by the CINV Study Group of Japan. In the patients with hematological malignancy, the guideline compliance rate was 45 %. Five patients (22.7 %) experienced vomiting during the observation period after receiving non-guideline-consistent antiemetic prophylaxis, whereas no patient experienced vomiting after receiving guideline-consistent antiemetic prophylaxis. The study was not sufficiently powered to reach a statistical significance in its frequency of occurrence between the compliance and non-compliance groups. In the entire study period, 8 out of 40 patients required rescue medication, but there was no association between the status of compliance and the antiemetic guidelines. A total of 22 (55.0 %) patients achieved complete response, which was defined as no vomiting and no use of antiemetic rescue medication, during the study period. The rate of compliance with the prophylactic antiemetic treatment guidelines seemed to be low in patients with hematological malignancy, although the status of the guideline compliance did not always influence the antiemetic effects.

DOI： 10.1691/ph.2019.8889

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Reactivation of human herpesvirus (HHV)-6B is relatively common after allogeneic hematopoietic stem cell transplantation (HSCT) and HHV-6B diseases may consequently develop. Among them, HHV-6B encephalitis is a serious and often fatal complication. The aim of these clinical practice recommendations is to provide diagnostic and therapeutic guidance for HHV-6B encephalitis after allogeneic HSCT. In this evidence-based review, we critically evaluated data from the published literature. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assist in generating recommendations. We have summarized the findings that contribute to decision-making and we have provided our recommendations. In cases where rigorous clinical data are unavailable, recommendations have been developed in discussions with physicians who have relevant expertize.

DOI： 10.1038/s41409-019-0752-5

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1056/NEJMoa1804980

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-019-0486-4

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-019-0491-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41409-018-0248-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor–induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve–related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve–related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; P =.049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; P =.036), whereas there was no significant difference among the latter 2 groups (P =.889). The development of HHV6-associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve–related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication.

DOI： 10.1016/j.bbmt.2018.07.017

記述言語：英語   掲載種別：研究論文（学術雑誌）  

GNA13 is a G protein involved in modulating tumor proliferative capacity, infiltration, metastasis, and migration. Genomic alteration of GNA13 was frequently observed in follicular lymphoma (FL). In this study, we examined 167 cases of FL by immunostaining of GNA13 using tissue microarray to evaluate the clinical significance. There were 26 GNA13-positive cases (15.6%) and 141 GNA13-negative cases (84.4%). GNA13-positive cases had a higher incidence of early progression of disease for which disease progression was recognized within 2 years compared with GNA13-negative cases (P=0.03). There were no significant differences in other clinicopathologic factors including histological grade, BCL2-IGH translocation, immunohistochemical phenotype, and Follicular Lymphoma International Prognostic Index. In addition, overall survival and progression-free survival were poorer in GNA13-positive cases than in GNA13-negative cases (P=0.009 and 0.005, respectively). In multivariate analysis, GNA13 positivity was found to be a poor prognostic factor for overall survival and progression-free survival. Thus, GNA13 protein expression was an independent prognostic factor and may affect disease progression in FL.

DOI： 10.1097/PAS.0000000000000969

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P =.013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P <.0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P <.001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants.

DOI： 10.1016/j.bbmt.2018.06.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell neoplasm, and the outcome of patients with ATL after chemotherapy is poor. Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment modality for ATL, and four factors, namely, age > 50 years, male recipient, lack of complete remission at transplantation, and transplantation of cord blood, were previously shown to be associated with poor survival. We retrospectively analyzed the outcome of 21 patients with ATL who had undergone allo-HSCT at our hospital during a 3-year period. Of 21 patients, all had at least one of the above risk factors, and 18 had two or more. With a median follow-up of 19.7 months for living patients, the 1- and 2-year overall survival (OS) rates after transplantation were 34% and 27%, respectively. All relapse/progression events occurred within 1 year after allo-HSCT, and the cumulative incidence of relapse/progression at 1 year after allo-HSCT was 46.9%. The 100-day and 1-year nonrelapse mortality (NRM) rates were 19% and 42%, respectively. No significant difference in OS was observed between myeloablative and reduced-intensity conditioning regimens. The 3-year OS (27%) of ATL patients who received allo-HSCT and who had at least one adverse factor was somewhat poorer than the 3-year OS of 33% identified in a nationwide study of allo-HSCT in ATL patients in Japan. The high relapse/progression and NRM rates are major problems to be solved to achieve better outcome.

DOI： 10.1002/hon.2549

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Peripheral T-cell lymphoma (PTCL), not otherwise specified (PTCL-NOS) is among the most common disease subtypes of PTCL, one that exhibits heterogeneous clinicopathological features. Although multiple disease-stratification models, including the cell-of-origin or gene-expression profiling methods, have been proposed for this condition, their clinical significance remains unclear. To establish a clinically meaningful stratification model, we analyzed gene-expression signatures of tumors and tumor-infiltrating immune cells using the nCounter system, which enables accurate quantification of low abundance and/or highly fragmented transcripts. To do so, we assessed transcripts of 120 genes related to cancer or immune cells using tumor samples from 68 newly diagnosed PTCL-NOS patients and validated findings by immunofluorescence in tumor sections. We show that gene-expression signatures representing tumor-infiltrating immune cells, but not those of cancerous T cells, dictate patient clinical outcomes. Cases exhibiting both B-cell and dendritic cell (DC) signatures (BD subgroup) showed favorable clinical outcomes, whereas those exhibiting neither B-cell nor DC signatures (non-BD subgroup) showed extremely poor prognosis. Notably, half of the non-BD cases exhibited a macrophage signature, and macrophage infiltration was evident in those cases, as revealed by immunofluorescence. Importantly, tumor-infiltrating macrophages expressed the immune-checkpoint molecules programmed death ligand 1/2 and indoleamine 2, 3-dioxygenase 1 at high levels, suggesting that checkpoint inhibitors could serve as therapeutic options for patients in this subgroup. Our study identifies clinically distinct subgroups of PTCL-NOS and suggests a novel therapeutic strategy for 1 subgroup associated with a poor prognosis. Our data also suggest functional interactions between cancerous T cells and tumor-infiltrating immune cells potentially relevant to PTCL-NOS pathogenesis.

DOI： 10.1182/pbloodadvances.2018018754

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cord blood transplantation (CBT) is a distinct risk factor for human herpesvirus-6 (HHV-6) reactivation and HHV-6 encephalitis. In a prospective multicenter trial we investigated the effects of prophylactic foscarnet (90 mg/kg i.v. infusion from days 7 to 27 after CBT) on the occurrence of HHV-6 reactivation, HHV-6 encephalitis, and acute graft-versus-host disease (aGVHD) in CBT recipients. Between 2014 and 2016, 57 patients were included in a foscarnet-prophylaxis group. Outcomes were compared with an historical control group who received CBT between 2010 and 2014 (standard-treatment group, n = 63). The cumulative incidence of high-level HHV-6 reactivation, defined as plasma HHV-6 DNA ≥ 10⁴ copies/mL, at 60 days after CBT was significantly lower in the foscarnet-prophylaxis group than in the standard-treatment group (18.3% versus 57.3%, P <.001). Multivariate analysis revealed that myeloablative preconditioning and standard treatment were significant risk factors for high-level HHV-6 reactivation. The cumulative incidence of HHV-6 encephalitis at 60 days after CBT was not different between the groups (foscarnet-prophylaxis group, 12.4%; standard-treatment group, 4.9%; P =.14). The cumulative incidences of grades II to IV and grades III to IV aGVHD at 60 days after CBT were not different between the groups (grades II to IV aGVHD: foscarnet-prophylaxis group, 42.0%; standard-treatment group, 40.5%; P =.96; grades III to IV aGVHD: foscarnet-prophylaxis group, 14.5%; standard-treatment group, 14.5%; P = 1.00). In the setting of this study foscarnet significantly suppressed systemic HHV-6 reactivation in CBT recipients but failed to prevent the development of HHV-6 encephalitis. Suppression of HHV-6 reactivation by foscarnet did not show any effects against the incidence of aGVHD.

DOI： 10.1016/j.bbmt.2018.02.008

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (esti-mated age of onset <15 years). We compared the prognosis of adult-onset chronic active Epstein-Barr virus infection with that of patients with nasal-type (n=37) and non-nasal-type (n=45) extranodal NK/T-cell lymphoma. The median estimated age of onset of these lymphomas was 39 years (range, 16–86 years). Compared to patients with pediatric-onset disease, those in whom the chronic active Epstein-Barr virus infection developed in adulthood had a significantly decreased incidence of fever (P=0.005), but greater frequency of skin lesions (P<0.001). Moreover, hypersensitivity to mosquito bites and the occurrence of hydroa vacciniforme were less frequent in patients with adult-onset disease (P<0.001 and P=0.0238, respectively). Thrombocytopenia, high Epstein-Barr virus nuclear antigen antibody titer, and the presence of hemophagocytic syndrome were associated with a poor prognosis (P=0.0087, P=0.0236, and P=0.0149, respective-ly). Allogeneic hematopoietic stem cell transplantation may improve survival (P=0.0289). Compared to pediatric-onset chronic active Epstein-Barr virus infection and extranodal NK/T-cell lymphoma, adult-onset chronic active Epstein-Barr virus infection had a poorer prognosis (P<0.001 and P=0.0484, respectively). Chronic active Epstein-Barr virus infection can develop in a wide age range, with clinical differences between adult-onset and pediatric-onset disease. Adult-onset chronic active Epstein-Barr virus infection is a disease with a poor prognosis. Further research will be needed.

DOI： 10.3324/haematol.2017.174177

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.3324/haematol.2017.174177.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Disease status at allogeneic hematopoietic cell transplantation (HCT) is an important pretransplant prognostic factor of HCT in adult T cell leukemia/lymphoma (ATL); however, other prognostic factors, including comorbidities, were not predictive in small cohort analyses. Several scoring systems (HCT-specific comorbidity index [HCT-CI]/modified European Group for Blood and Marrow Transplantation risk score [mEBMT]) have been adopted to predict HCT outcomes in other hematologic malignancies. We retrospectively evaluated HCT-CI and mEBMT to predict nonrelapse mortality (NRM) in 824 ATL patients registered in the Japan Society for Hematopoietic Cell Transplantation TRUMP database, from 2008 until 2013. A higher HCT-CI was associated with greater NRM when comparing HCT-CI 0 versus HCT-CI 1 to 3 and HCT-CI 0 versus HCT-CI ≥ 4. A higher mEBMT score was not associated with higher NRM when comparing mEBMT 0 to 3 with 4 to 6. Because ATL patients are older and consequently at risk of additional complications, we developed an optimized prognostic index for ATL (ATL-HCT-PI) using known risk factors: age, HCT-CI, and donor–recipient sex combination. The ATL-HCT-PI scores effectively predicted the 2-year NRM (22.0%, 27.7%, and 44.4%, respectively). Therefore, the newly developed ATL-HCT-PI, in combination with other risk factors, is more useful for predicting NRM in HCT for ATL patients.

DOI： 10.1016/j.bbmt.2017.11.005

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/leu.2017.251

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00277-017-3146-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

There has recently been remarkable progress in immunosuppressive agents, such as tacrolimus and cyclosporine. Therefore, the rate of organ establishment has improved in transplantation. However, immunosuppressive agents generally suppress the function of T cells. Thus, opportunistic infections, such as cytomegalovirus infection, are still a major problem in kidney transplantation. Induction of specific tolerance to avoid immunosuppressive drug therapy after kidney transplantation is considered as the ultimate goal of transplantation. Various factors induce tolerance that involves establishment of hematopoietic chimerism and various cell subsets. In particular, we have carried out various studies regarding the cyclophosphamide-induced tolerance system. Tolerance is induced after establishment of hematopoietic chimerism after donor bone marrow transplantation. At the clinical stage, kidney transplantation before administration of cyclophosphamide after transfusion of bone marrow to create hematopoietic chimera is considered to be one of the most successful protocols. Furthermore, recent studies have shown the involvement of multiple populations of immune cells in preserving immunological tolerance and promoting long-term renal grafts. The present review focuses on how cyclophosphamide and other immune factors induce tolerance in kidney transplantation.

DOI： 10.1111/iju.13474

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/bjh.15123

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Shorter duration of infusion of monoclonal antibody treatments May reduce treatment burden and improve healthcare resource utilization. Methods: This phase II study recruited Japanese patients with previously untreated CD20+ B-cell non-Hodgkin lymphoma. Patients received intravenous obinutuzumab 1000 mg by regular infusion on Days 1, 8 and 15 of Cycle 1, followed by 90-min shorter duration of infusion in up to seven subsequent cycles, provided they received ≥3 regular infusions without any grade ≥3 infusion-related reactions and had a lymphocyte count <5.0 × 10
⁹
cells/l. Standard cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy was given in Cycles 1–6. The primary endpoints were as follows: incidence of grade ≥3 infusion-related reactions in Cycle 2 in patients who started shorter duration of infusion in Cycle 2, serum obinutuzumab concentrations and phar-macokinetic parameters and the time course of cytokine release. Adverse events and serious adverse events were monitored. Results: Of 35 patients treated, 28 completed eight cycles; 31 started shorter duration of infusion in Cycle 2 and two patients in subsequent cycles. Two patients discontinued before starting shorter duration of infusion. No grade ≥3 infusion-related reactions occurred in Cycle 2. Twenty-one infusion-related reactions (all grades 1–2) were reported in 17/35 (49%) patients overall, mostly in Cycle 1 (18/21 infusion-related reactions [86%]). Grade ≥3 AEs occurring in ≥10% of patients included neutropenia/neutrophil count decreased (66%) and leukopenia/white blood cell count decreased (23%). Steady-state pharmacokinetics of obinutuzumab were attained in Cycle 2 and were not affected by shorter duration of infusion. No relevant cytokine elevations were reported with shorter duration of infusion. Conclusions: Regular infusion and shorter duration of infusion of obinutuzumab have comparable tolerability and pharmacokinetics in Japanese patients.

DOI： 10.1093/jjco/hyy087

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT), post-transplant lung infection is critical for their prognosis. Mycobacterium abscessus complex is not fully recognized as a nontuberculous mycobacteria (NTM) pathogen of post-SCT lung infection. Here, we present three post-allogeneic SCT patients who developed pulmonary infection caused by M. abscessus complex including M. abscessus and M. massiliense. In all three cases, macrolide antibiotics had been administered for bronchiolitis obliterans syndrome (BOS) before the confirmation of their infection, and macrolide resistance was noted in the M. abscessus isolates, one of which resulted in an unfavorable treatment outcome. It is important to consider M. abscessus lung infection as well as other NTM in patients receiving allo-SCT, particularly those receiving macrolide therapy for BOS.

DOI： 10.1016/j.jiac.2017.08.011

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The antiemetic effects and safety of granisetron and palonosetron against chemotherapy-induced nausea and vomiting (CINV) were retrospectively evaluated in patients with non-Hodgkin lymphoma receiving bendamustine-based chemotherapy. A total of 61 patients were eligible for this study. Before starting the bendamustine-based chemotherapy, granisetron or palonosetron were intravenously administered with or without aprepitant and/or dexamethasone. The proportions of patients with complete control (CC) during the overall (during the 6 days after the start of the chemotherapy), acute (up to 2 days), and delayed (3 to 6 days) phases were assessed. CC was defined as complete response with only grade 0–1 nausea, no vomiting, and no use of antiemetic rescue medication. Granisetron or palonosetron alone were administered to 9 and 19 patients, respectively. Aprepitant and/or dexamethasone were combined with granisetron and palonosetron in 28 and 5 patients, respectively. Acute CINV was completely controlled in all patients. Both granisetron monotherapy and palonosetron combination therapy could provide good control of delayed CINV, although the CC rates during the delayed and overall phases were not significantly different among mono- and combination therapy of the antiemetics. There was no significant difference in the frequencies of adverse drug events between the granisetron and palonosetron treatment groups. The present study showed that the antiemetic efficacy and safety of granisetron-based therapy were non-inferior to those of palonosetron-based therapy. Taken together with treatment costs, granisetron monotherapy would be adequate to prevent CINV in patients with non-Hodgkin lymphoma receiving bendamustine-based chemotherapy.

DOI： 10.1691/ph.2018.7948

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chemotherapy-induced nausea and vomiting (CINV) are generally evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE). The Multinational Association for Supportive Care in Cancer (MASCC) developed the MASCC Antiemesis Tool (MAT) to facilitate recognition for CINV between patients and oncology specialists. In the present study, MAT and CTCAE were comparatively assessed in Japanese patients with hematological malignancies. A total of 61 patients were eligible for this study. The CTCAE data were collected from an electronic medical record system. The patients were asked to complete the Japanese version of MAT in the hospital, on the first and fourth days after the start of chemotherapy. The percentages of patients in whom nausea was completely controlled, with severity scores of zero, ranged from 70.5 to 82.0% for CTCAE and from 59.0 to 75.4% for MAT, during the first five days after the chemotherapy. The percentages of patients who had no vomiting ranged from 93.4 to 96.7% for CTCAE and from 90.2 to 98.4% for MAT. During the observation periods, the day-to-day response profiles of patients who received antiemetic treatment were comparable between CTCAE and MAT cohorts, and these two assessment tools showed good, positive correlations for nausea severity scores. The present study shows that the MAT is a useful tool for assessing the severity of CINV in patients with hematological malignancy, is comparable to CTCAE, and facilitates the identification of poor cancer care conditions by medical staff.

DOI： 10.1248/bpb.b18-00336

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Currently, allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only available curative modality for patients with adult T-cell leukemia–lymphoma (ATL). When used in conjunction with posttransplantation cyclophosphamide (PTCY) for graft-versus-host disease prophylaxis, allo-HCT from an HLA haplo-identical donor yields promising outcomes for many diseases other than ATL. However, appropriate comparisons with other donor sources, especially cord blood and conventional HLA haplo-identical donors, are needed to validate the safety and efficacy of this modality. In this study, we retrospectively evaluated the outcome of allo-HCT without PTCY in patients with ATL registered in the Japan Society for Hematopoietic Cell Transplantation TRUMP database between 1985 and 2015. During that period, 46 patients received allo-HCT without PTCY and survivors were followed for a median of 2316.5 days (range: 220–3884 days). Although the estimated 1- and 5-year overall survival rates of the entire cohort were 34.5% and 17.7%, respectively, the cumulative 1- and 5-year non-ATL mortality rates of 41.3% and 55.8%, respectively, were high. The results of our study will serve as a platform for discussions of the safety and efficacy of haplo-HCT for future clinical trials in patients with ATL.

DOI： 10.1038/s41409-018-0400-5

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1056/NEJMoa1708984.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatitis C virus (HCV) is a single-stranded RNA virus that not only affects hepatocytes, by B cells as well. It is thought that HCV is involved in the onset of B-cell lymphoma. The clinicopathological characteristics of HCV-positive diffuse large B-cell lymphoma (DLBCL) and HCV-positive splenic marginal zone lymphoma (SMZL) are known, but there has been no report on HCV-positive follicular lymphoma (FL). In this study, the clinicopathological characteristics of HCV-positive FL were examined in 263 patients with FL who were classified into a HCV-positive group with HCV antibody and negative groups without one. The number of patients with HCV-positive FL and HCV-negative FL was 10 (3.8%) and 253 (96.2%), respectively. The patients with HCV-positive FL commonly had more than one region of lymphadenopathy, Ann Arbor stage III/IV, hemoglobin < 120 g/l, elevated lactate dehydrogenase level, and highrisk categorization of Follicular Lymphoma International Prognostic Index (FLIPI) than in patients with HCV-negative FL. Overall survival and progression-free survival were poorer in patients with HCV-positive FL than in those with HCV-negative FL (p < 0.0001 and 0.006, respectively). Also, multivariate analysis revealed that positive HCV antibody was a poor prognostic factor of OS. In conclusion, HCV-positive FL has unique clinical features and may have a great impact on the overall survival of affected patients.

DOI： 10.18632/oncotarget.23138

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/10428194.2017.1403021

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The developmental pathway for human megakaryocytes remains unclear, and the definition of pure unipotent megakaryocyte progenitor is still controversial. Using single-cell transcriptome analysis, we have identified a cluster of cells within immature hematopoietic stem- and progenitor-cell populations that specifically expresses genes related to the megakaryocyte lineage. We used CD41 as a positive marker to identify these cells within the CD34⁺CD38⁺IL-3Rα^dimCD45RA^- common myeloid progenitor (CMP) population. These cells lacked erythroid and granulocyte-macrophage potential but exhibited robust differentiation into the megakaryocyte lineage at a high frequency, both in vivo and in vitro. The efficiency and expansion potential of these cells exceeded those of conventional bipotent megakaryocyte/erythrocyte progenitors. Accordingly, the CD41⁺ CMP was defined as a unipotent megakaryocyte progenitor (MegP) that is likely to represent the major pathway for human megakaryopoiesis, independent of canonical megakaryocyte-erythroid lineage bifurcation. In the bone marrow of patients with essential thrombocythemia, the MegP population was significantly expanded in the context of a high burden of Janus kinase 2 mutations. Thus, the prospectively isolatable and functionally homogeneous human MegP will be useful for the elucidation of the mechanisms underlying normal and malignant human hematopoiesis. (Blood. 2017;129(25): 3332-3343).

DOI： 10.1182/blood-2016-09-741611

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary hypertension (PH) is a rare, but life-threatening, adverse event in patients treated with tyrosine kinase inhibitors (TKIs), such as dasatinib, but has not been fully evaluated in patients treated with imatinib or nilotinib. We used echocardiography to noninvasively assess the incidence of PH in 105 patients with chronic myeloid leukaemia (CML) treated with imatinib (n = 37), nilotinib (n = 30) or dasatinib (n = 38). The mean triscupid regurgitation peak gradient (TRPG), which reflects pulmonary arterial pressure, was 22·7 mmHg in the imatinib group, 23·1 mmHg in the nilotinib group and 23·4 mmHg for dasatinib group. These values were not significantly different, but higher than those (19·0 mmHg) in newly diagnosed CML patients. A TRPG > 31 mmHg, marking possible PH onset, was detected in 9 of 105 patients: one (2·7%) treated with imatinib, three (10·0%) with nilotinib and five (13·2%) with dasatinib. Only three patients complained of dyspnoea, whereas the other six were asymptomatic. In addition, there was a tendency toward correlation of TRPG value and age or TKI treatment duration. These results suggested that treatment with not only dasatinib, but also imatinib and nilotinib, can be associated with subclinical PH. Noninvasive echocardiography is useful for screening, especially in older patients with long-term TKI treatment.

DOI： 10.1111/bjh.14608

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jtho.2016.12.023

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: T-cell prolymphocytic leukemia (T-PLL) is a very rare, aggressive T-cell neoplasm. Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is also a highly aggressive lymphoma. These two diseases can often be confused with each other; therefore, we aimed to determine the clinical and pathological differences between T-PLL and PTCL-NOS. Methods: We analyzed 15 T-PLL and 91 PTCL-NOS patients and also compared clinical features between T-PLL and PTCL-NOS with leukemic presentation. Peripheral blood images and biopsy specimens were analyzed, and treatment responses were determined via imaging modalities. The clinicopathological characteristics were statistically compared. Results: T-PLL cells were smaller in size than those of PTCL-NOS with leukemic presentation (P=.0068); moreover, PTCL-NOS cells with leukemic presentation were smaller than those of PTCL-NOS without leukemic presentation (P=.0017). Immunophenotypic patterns in T-PLL and PTCL-NOS were similar. Five-year overall survival rates of T-PLL and all PTCL-NOS patients were 57.5% and 36.8%, respectively. No significant differences were found in clinical manifestations or prognoses; T-PLL and PTCL-NOS with leukemic presentation had essentially equivalent characteristics. Conclusion: T-PLL and PTCL-NOS may share common biological and clinical characteristics in Japanese patients.

DOI： 10.1111/ejh.12856

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Combination use of the proteasome inhibitor bortezomib and the immunomodulatory drugs lenalidomide or thalidomide has provided superior outcomes in multiple myeloma over their single use; however, these combinations can produce significant toxicities. Unexpectedly, we found a small but significant increase in the population of immature granulocytes and erythrocytes/megakaryocytes in peripheral blood in 16 of 22 patients (73%) treated with dexamethasone in combination with bortezomib and immunomodulatory drugs (triplet), but not in any of 25 patients treated with either bortezomib or immunomodulatory drugs with dexamethasone (doublet). These immature cells gradually increased to a peak level (mean 2.6% per white blood cells) with triplet therapy, and disappeared immediately after therapy cessation. The numbers of circulating CD34⁺ cells and colony-forming cells derived from peripheral blood mononuclear cells increased after triplet therapy compared with those in patients treated by either bortezomib or immunomodulatory drugs plus dexamethasone. Furthermore, triplet regimen downregulated the expression of CXCR4, a chemokine receptor essential for bone marrow retention, on CD34⁺ cells, suggesting an unexpected effect on normal hematopoietic stem/progenitor cells through the reduced interaction with the bone marrow microenvironment. Our observations suggest that combination use should be carefully evaluated to exert synergistic anti-myeloma effects while avoiding unexpected adverse events.

DOI： 10.1007/s12185-016-2148-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/bmt.2016.313

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Infertility associated with ovarian failure is a serious late complication for female survivors of allogeneic hematopoietic stem cell transplantation (SCT). Although pretransplant conditioning regimen has been appreciated as a cause of ovarian failure, increased application of reduced-intensity conditioning allowed us to revisit other factors possibly affecting ovarian function after allogeneic SCT. We have addressed whether donor T-cell-mediated graft-versus-host disease (GVHD) could be causally related to female infertility in mice. Histological evaluation of the ovaries after SCT demonstrated donor T-cell infiltration in close proximity to apoptotic granulosa cells in the ovarian follicles, resulting in impaired follicular hormone production and maturation of ovarian follicles. Mating experiments showed that female recipients of allogeneic SCT deliver significantly fewer newborns than recipients of syngeneic SCT. GVHD-mediated ovary insufficiency and infertility were independent of conditioning. Pharmacologic GVHD prophylaxis protected the ovary from GVHD and preserved fertility. These results demonstrate for the first time that GVHD targets the ovary and impairs ovarian function and fertility and has important clinical implications in young female transplant recipients with nonmalignant diseases, in whom minimally toxic regimens are used.

DOI： 10.1182/blood-2016-07-728337

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-016-2093-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Allogeneic hematopoietic stem cell transplantation (allo-SCT) has a curative potential for myelofibrosis (MF) patients; however, its association with a high therapy-related mortality (TRM) remains a big obstacle that needs to be overcome. Ruxolitinib (RUXO), a novel JAK1/2 inhibitor, can be used as a bridging therapy until allo-SCT can be performed to reduce TRM. We herein report a RUXO-treated MF patient who developed recurrent subcutaneous Sweet’s disease (SSD) that was successfully treated by the administration of systemic glucocorticoids. We performed allo-SCT as previously scheduled, resulting in a good clinical course without deterioration of SSD. RUXO administration, as well as MF itself, might therefore sometimes cause this rare non-infectious event.

DOI： 10.2169/internalmedicine.8491-16

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In the present study, the antiemetic effect of palonosetron, not combined with dexamethasone and aprepitant, on chemotherapy-induced nausea and vomiting was evaluated in patients with malignant lymphoma receiving first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, and was compared to that of granisetron. A total of 74 patients with non-Hodgkin lymphoma were included in this study (April 2007 to December 2015). Palonosetron (0.75 mg) or granisetron (3 mg) was intravenously administered before R-CHOP therapy. The proportions of patients with complete response (CR) during the overall (0-120 h after the start of R-CHOP therapy), acute (0-24 h) and delayed (24-120 h) phases were evaluated. CR was defined as no vomiting and no use of antiemetic rescue medication. A total of 32 and 42 patients were treated with palonosetron and granisetron, respectively. The CR rate in the palonosetron group was significantly higher than that in the granisetron group during the delayed phase (90.6 and 61.9%, respectively; p=0.007). Logistic regression analysis showed that use of palonosetron improved the CR rate during the delayed phase, compared to use of granisetron. Female sex, age less than 60 years, no habitual alcohol intake, and Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 1 were significant risk factors associated with non-CR. The findings of this study suggested the superiority of palonosetron to granisetron, without accompanying dexamethasone and aprepitant, for chemotherapy-induced nausea and vomiting in patients with malignant lymphoma.

DOI： 10.1248/bpb.b17-00318

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/blood-2016-02-698936

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.stemcr.2016.07.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.55.5987

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.55.5241

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-015-1883-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-015-1778-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ajh.23897

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various hematopoietic disorders. Graft-versus-host disease (GVHD) and infections are the major obstacles of HSCT, and their close relationship has been suggested. Although roles of bacterial and viral infections in the pathophysiology of GVHD are well described, impacts of fungal infection on GVHD remain to be elucidated. In mouse models of GVHD, injection of α-mannan (Mn), a major component of fungal cell wall, or heat-killed Candida albicans exacerbated GVHD, particularly in the lung. Mn-induced donor T-cell polarization toward Th17 and lung-specific chemokine environment in GVHD led to accumulation of Th17 cells in the lung. The detrimental effects of Mn on GVHD depended on donor IL-17A production and host C-type lectin receptor Dectin-2. These results suggest a previously unrecognized link between pulmonary GVHD and fungal infection after allogeneic HSCT.

DOI： 10.1182/blood-2014-12-615781

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbmt2014.08.012

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/bmt.2014.189

記述言語：英語  

DOI： 10.1016/j.exphem.2014.07.267

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語  

DOI： 10.1007/s12185-014-1611-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbmt.2013.09.014

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-013-1430-9

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-013-1410-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-013-1402-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語  

DOI： 10.1007/s12149-012-0676-2

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4049/jimmunol.1202971

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4049/jimmunol.1202820

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12185-013-1278-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.52.8390

記述言語：英語  

DOI： 10.2146/ajhp120363

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/blood-2012-02-409607

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/blood-2012-03-414490

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/ajh.23247

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In our institute, tacrolimus was started at a dose of 0.03 mg/kg/day and adjusted to maintain a blood concentration between 10 and 20 ng/mL combined with short term methotrexate after bone marrow transplantation from an unrelated donor. Dose adjustment was performed strictly, in order to prevent grade II-IV acute graft-versus-host disease (GVHD)while avoiding renal toxicity of tacrolimus. Then, in this study, we retrospectively evaluated the tacrolimus blood concentration during the first 4 weeks after transplantation. The mean tacrolimus concentration of the eligible 52 patients was 17.41+/-4.84(range, 9.5-33.4)ng/mL in the 1st week after transplantation, but declined to 13.7+/- 4.0(range, 8.1-25.6)ng/mL in the 2nd week. The dose of tacrolimus was decreased as follows: 0.022+/-0.005 mg/ kg/day(range 0.011-0.039)in the 1st week, and 0.018+/-0.007 mg/kg/day(range 0.004-0.040)in the 2nd week. The incidence of grade II-IV GVHD was 63.0% and grade III-IV was 13.9%. The individual variations of tacrolimus blood concentration did not affect the incidence of grade II-IV acute GVHD, as far as the concentration being maintained in the range of 14.82+/-4.22 ng/mL during the first 4 weeks after transplantation. In addition, the variations of tacrolimus concentration didn?t associate statistically with renal toxicity.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/sj.bmt.1705715

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/sj.bmt.1705660

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Reduced-intensity stem cell transplantation (RIST) has opened a new era for hematopoietic stem cell transplantation (HSCT). It was developed based on the knowledge that graft-versus-tumor (GVT) effect is the main anti-tumor effect in allogeneic HSCT. Because RIST is associated with less morbidity and mortality, it can be applied to many patients who could not undergo conventional HSCT. Experiences in the last decade clarified many issues related to RIST. For example, graft-versus-host disease (GVHD) in RIST may differ in character compared to conventional HSCT. Also, it is now known that intensity of conditioning is important in disease control, and the optimal regimens may be different for each disease or for each disease status. There are still many unsolved questions, and large prospective randomized trials are necessary to resolve these.

DOI： 10.2174/157488807780599248

記述言語：英語   掲載種別：研究論文（学術雑誌）  

To investigate effects of the preautografting administration of rituximab on the mobilization and engraftment of peripheral blood stem cells (PBSC), we retrospectively analyzed the outcomes of 43 newly diagnosed diffuse-large B-cell lymphoma patients who received CHOP chemotherapy with or without rituximab as a first-line treatment before autologous PBSC transplantation (PBSCT). There was no difference in the number of CD34⁺ cells among PBSC between the non-rituximab and the rituximab groups. Although B-cells were completely depleted from PBSC in the rituximab group, we found no difference in the expression of CXCR-4, VLA-4 and c-Kit on PBSC, indicating that rituximab did not affect the expression of these adhesion molecules, which might be involved in the mechanism of mobilization. There was no significant difference in the recovery of neutrophils and platelets, transplant-related toxicity and post-transplant complications between the two groups. Despite the short follow-up, there was no significant difference in progression-free survival between the two groups. These results indicated no adverse effect of rituximab on the mobilization and engraftment of PBSC. Larger studies are required to determine the impact of rituximab on the mobilization and function of PBSC as well as whether a survival advantage exists in patients who undergo auto-PBSCT with rituximab.

DOI： 10.1038/sj.bmt.1705649

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We describe the case of a 38-year-old male patient who had acute myeloid leukemia and developed prolonged neutropenia after induction chemotherapy. He developed thrombotic complications at multiple sites. Thrombophlebitis of the hemorrhoidal plexus became exacerbated and developed into critical cellulitis. Because the patient had no human leukocyte antigen-identical sibling, we considered an alternative donor. Because of the necessity for early neutrophil recovery to resolve the critical infection, we proceeded with allogeneic peripheral blood stem cell transplantation (PBSCT) from a microchimeric haploidentical sibling donor. We infused peripheral blood mononuclear cells directly into the patient without cryopreservation and thawing procedures. We aimed for the contaminating granulocytes to act as a granulocyte transfusion. Actually, the neutrophils increased to 1.6 × 10⁹/L on day 1, when the patient showed a temporary resolution of infection. Engraftment was achieved shortly after neutropenic nadir, and acute graft-versus-host disease (GVHD) has been well controlled. Although the patient experiences extensive chronic GVHD, he has been well as an outpatient with a 90% Karnofsky performance status score. The leukemia has been in complete remission for more than 1 year. These findings suggest the clinical utility of a salvage therapy with allogeneic PBSCT from a microchimeric haploidentical donor to treat refractory leukemia concurrent with life-threatening infection.

DOI： 10.1532/IJH97.06168

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an HLA-matched related donor has been suggested to improve the poor prognosis of adult T-cell leukemia/lymphoma (ATLL). However, the infusion of HTLV-I-infected cells from HTLV-I-positive related donors could lead to the development of donor-derived ATLL under immunosuppressive conditions. Although most ATLL patients lack a suitable HLA-matched related donor and require an HTLV-I-negative unrelated donor, little information is currently available regarding the outcome of unrelated bone marrow transplantation (UBMT) for ATLL. To evaluate the role of UBMT in treating ATLL, we retrospectively analyzed data from 33 patients with ATLL treated by UBMT through the Japan Marrow Donor Program (JMDP). Overall survival (OS), progression-free survival, and cumulative incidence of disease progression and progression-free mortality at 1 year after UBMT were 49.5%, 49.2%, 18.6%, and 32.3%, respectively. Multivariate analysis identified recipient age as an independent prognostic factor for OS (P = .044). Patients age ≥50 years who showed nonremission at transplantation tended to have higher rates of treatment-related mortality. Our observations suggest that UBMT could represent a feasible treatment option for ATLL patients and warrant further investigation based on these risk factors.

DOI： 10.1016/j.bbmt.2006.09.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 42-year-old woman was referred to us for the treatment of relapsed Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL), which had been maintained in complete remission for seven years after an allogeneic bone marrow transplantation (allo-BMT) from an unrelated donor. She received remission-reinduction chemotherapy combined with imatinib mesylate. After the documentation of the molecular remission of Ph+ALL, she underwent the second allo-BMT from another unrelated donor. GVHD prophylaxis consisted of tacrolimus (TAC) and short-term methotrexate. On day 21, she suddenly suffered from an intermittent severe, cramp-like pain in the right lower limb. The typical pain profile and exclusion of other causative diseases suggested calcineurin-inhibitor induced pain syndrome (CIPS) as a possible cause of pain. The pain was gradually relieved after discontinuation of TAC and administration of several analgesic drugs. CIPS is rarely seen following allogeneic stem cell transplantation (allo-SCT); only three cases have been so far reported to our knowledge. Thus, physicians should be alert to this complication in patients receiving allo-SCT.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/sj.bmt.1705170

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/sj.bmt.1705169

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hemopoietic stem and progenitor cells ordinarily residing within bone marrow are released into the circulation following G-CSF administration. Such mobilization has a great clinical impact on hemopoietic stem cell transplantation. Underlying mechanisms are incompletely understood, but may involve G-CSF-induced modulation of chemokines, adhesion molecules, and proteolytic enzymes. We studied G-CSF-induced mobilization of CD34 ⁺CD10⁺CD19^-Lin^- and CD34 ⁺CD10⁺CD19⁺Lin^- cells (early B and pro-B cells, respectively). These mobilized lymphoid populations could differentiate only into B/NK cells or B cells equivalent to their marrow counterparts. Mobilized lymphoid progenitors expressed lymphoid- but not myeloid-related genes including the G-CSF receptor gene, and displayed the same pattern of Ig rearrangement status as their bone marrow counterparts. Decreased expression of VLA-4 and CXCR-4 on mobilized lymphoid progenitors as well as multipotent and myeloid progenitors indicated lineage-independent involvement of these molecules in G-CSF-induced mobilization. The results suggest that by acting through multiple trans-acting signals, G-CSF can mobilize not only myeloid-committed populations but a variety of resident marrow cell populations including lymphoid progenitors.

DOI： 10.4049/jimmunol.175.4.2647

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 38-year-old woman was admitted with superior mesenteric vein (SMV) thrombosis, which was refractory to anticoagulation therapy. The plasma antithrombin activity was decreased and hardly compensated by concentrated antithrombin preparation due to high consumption rate. However, successful anticoagulation was achieved by administration of direct thrombin inhibitor, argatroban. Family studies of antithrombin activity revealed that she had type I congenital antithrombin deficiency. A novel heterozygous mutation in the gene for antithrombin (single nucleotide T insertion at 7916 and 7917, Glu 272 to stop in exon 4) was identified. Argatroban administration would be effective in the treatment of congenital antithrombin deficiency with SMV thrombosis.

DOI： 10.1111/j.1600-0609.2005.00480.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/naika.94.1281

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1074/jbc.M408442200

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/sj.bmt.1704770

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1532/IJH97.04126

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1532/IJH97.04109

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/sj.bmt.1704682

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a 72-year-old man with Waldenström's macroglobulinemia (WM) in whom diffuse large B-cell lymphoma (DLCL) occurred 17 years after the diagnosis of WM. The malignant cells of both DLCL and WM expressed CD20 on their surface. CHOP plus anti-CD20 monoclonal antibody, rituximab, were effective for both diseases, and the patient remains disease-free 17 months later.

DOI： 10.2169/internalmedicine.43.131

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1046/j.0902-4441.2003.00160.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1046/j.1365-2141.2003.04650.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

IFN-α inhibits B lymphocyte development, and the nuclear protein Daxx has been reported to be essential for this biological activity. We show in this study that IFN-α inhibits the clonal proliferation of B lymphocyte progenitors in response to IL-7 in wild-type, but not in tyk2-deficient, mice. In addition, the IFN-α-induced up-regulation and nuclear translocation of Daxx are completely abrogated in the absence of tyk2. Therefore, tyk2 is directly involved in IFN-α signaling for the induction and translocation of Daxx, which may result in B lymphocyte growth arrest and/or apoptosis.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 51-year-old man with non-Hodgkin's lymphoma (NHL) was treated with high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT). Although he had HLA-DRB1 0405 and a positive rheumatoid factor, he was unlikely to develop rheumatoid arthritis (RA) according to diagnostic criteria. However, the patient developed RA 40 days after transplantation. Our experience suggests that the systemic autoimmune disease, RA, may occur in patients with predisposing factors after autologous PBSCT.

DOI： 10.1038/sj.bmt.1703664

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cytomegalovirus (CMV) antigenemia and quantitative real-time polymerase chain reaction (PCR) were compared for monitoring of CMV reactivation after allogeneic stem cell transplantation. The number of CMV antigen-positive cells by the antigenemia assay and the level of CMV DNA by real-time PCR correlated well. The sensitivity and specificity of the antigenemia assay was 55.4% and 95.5%, respectively, using real-time PCR as the reference standard. The probability of positive antigenemia at day 100 was 76.5%, with a median of first detection at day 37 in 51 patients, compared with a positive PCR of 84.3% and day 33, respectively. When HLA-identical sibling donor transplant recipients and other donor transplant recipients were analyzed separately, there was no difference between the two tests. However, temporal patterns of first detection of CMV antigen-positive cells and CMV DNA differed between HLA-identical and alternative recipients; patients without CMV (29%) or with sporadic positive PCR results (14%) were more common in HLA-identical sibling transplants, wereeas patients with simultaneous antigenemia and positive PCR occurred more in alternative transplants (48%). Two of 51 patients (4%) developed CMV colitis despite antigenemia-guided prophylaxis, but both were successfully treated with ganciclovir. Although PCR is more sensitive than antigenemia, both tests are useful in the early detection of CMV after allogeneic stem cell transplantation.

DOI： 10.1038/sj/bmt/1703513

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 17-year-old Japanese woman with Ewing's sarcoma was initially treated with conventional chemotherapy and local irradiation, and then with high-dose chemotherapy supported by autologous peripheral blood stem cell transplantation. Four years later she was diagnosed with chronic myelogenous leukaemia (CML). The BCR/ABL fusion gene was detected in both peripheral blood and bone marrow cells by reverse transcription-polymerase chain reaction, but not in the harvest product of peripheral blood stem cells which were infused at the time of transplantation. This case adds to the accumulating evidence of therapy-related CML developing after high-dose chemotherapy and autologous stem cell transplantation.

DOI： 10.1046/j.1365-2141.2002.03517.x

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1182/blood.V99.6.2094