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Akio Onishi,1 Yayoi Matsumura-Kimoto,1,2 Shinsuke Mizutani,1 Taku Tsukamoto,1 Takahiro Fujino,1 Akihiro Miyashita,1,3 Daichi Nishiyama,4 Kazuho Shimura,5 Hiroto Kaneko,5 Eri Kawata,6 Ryoichi Takahashi,7 Tsutomu Kobayashi,1,8 Hitoji Uchiyama,8 Nobuhiko Uoshima,3 Yoko Nukui,9 Yuji Shimura,1 Tohru Inaba,9 Junya Kuroda1 1Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Department of Hematology, Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center, Kyoto, Japan; 3Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan; 4Department of Hematology, Fukuchiyama City Hospital, Fukuchiyama, Japan; 5Department of Hematology, Aiseikai Yamashina Hospital, Kyoto, Japan; 6Department of Hematology, Matsushita Memorial Hospital, Moriguchi, Japan; 7Department of Hematology, Omihachiman Community Medical Center, Omihachiman, Japan; 8Department of Hematology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan; 9Division of Infection Control & Molecular Laboratory Medicine, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, JapanCorrespondence: Junya Kuroda, Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan, Tel +81-75-251-5740, Fax +81-75-251-5743, Email junkuro@koto.kpu-m.ac.jpBackground and Purpose: Anti-CD20 monoclonal antibodies (MoAbs), rituximab (RIT), and obinutuzumab (OBZ) are the central components of immunochemotherapy for B-cell lymphoma (BCL). However, these agents potentially cause B-cell depletion, resulting in the impairment of antibody (Ab) production. During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the optimal prediction of Ab response against anti–SARS-CoV-2 vaccination is critically important in patients with BCL treated by B-cell depletion therapeutics to prevent coronavirus disease 2019 (COVID-19).Patients and Methods: We investigated the effect of using RIT and/or OBZ on the Ab response in 131 patients with various types of BCL who received the second SARS-CoV-2 mRNA vaccine either after, during, or before immunochemotherapy containing B-cell–depleting moiety between June and November 2021 at seven institutes belonging to the Kyoto Clinical Hematology Study Group. The SARS-Cov-2 neutralizing Ab (nAb) was measured from 14 to 207 days after the second vaccination dose using the iFlash3000 automatic analyzer and the iFlash-2019-nCoV Nab kit.Results: Among 86 patients who received the vaccine within 12 months after B-cell depletion therapy, 8 (9.3%) were seropositive. In 30 patients who received the vaccine after 12 months from B-cell depletion therapy, 22 (73%) were seropositive. In 15 patients who were subjected to B-cell depletion therapy after vaccination, 2 (13%) were seropositive. The multivariate analysis indicated that an interval of 12 months between B-cell depletion therapy and the subsequent vaccination was significantly associated with effective Ab production. Receiver operating characteristic curve analysis identified the optimal threshold period after anti-CD20 MoAb treatment, which determines the seropositivity against SARS-CoV-2, to be 342 days.Conclusion: The use of anti-CD20 MoAb within 12 months before vaccination is a critical risk for poor Ab response against anti–SARS-CoV-2 vaccination in patients with BCL.Keywords: COVID-19, vaccine, B-cell lymphoma, anti-CD20 monoclonal antibody

Lymphoplasmacytic lymphoma (LPL) is a type of low-grade B-cell lymphoma, with 90-95% of cases associated with Waldenström macroglobulinemia, characterized by the presence of IgM-type M-protein. We report, for the first time, a case of LPL-producing Bence Jones (BJ) protein kappa. The patient was a 78-year-old woman admitted to our department due to general fatigue and proteinuria that had persisted for 2 months. No M-protein was detected by blood immunofixation, but kappa-type BJ protein was detected in the urine. Light microscopy of a kidney biopsy sample revealed infiltration of lymphocytes and plasma cells into the perirenal adipose tissue and renal interstitium. The infiltrating cells exhibited kappa light chain restriction. Bone marrow examination revealed clusters of immature plasmacytoid lymphocytes that were CD20 positive, CD5 negative, and exhibited light chain restriction. Genetic analysis detected a MYD88 mutation, leading to the diagnosis of LPL in the patient. Six months after starting treatment with tirabrutinib, urinary protein levels improved to 0.2 g/gCr. Renal infiltration was identified due to urinary protein, and currently, no extramedullary lesions outside the kidneys are observed. Tirabrutinib has been extremely effective, but careful follow-up is still required., Competing Interests: Declarations. Conflict of interest: The authors have declared that no conflict of interest exists. Research involving human and animal participants: This article does not contain any studies with human participants performed by any of the authors. Informed consent: Informed consent was obtained from the patient for publication of this case report and accompanying images., (© 2025. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background: While R-CHOP has been one of the standard therapies for untreated high-tumor-burden (HTB) follicular lymphoma (FL) for over 2 decades, obinutuzumab plus bendamustine (OB) is also currently regarded as the standard of care since its approval in 2018 in Japan; however, the long-term efficacy and safety of OB in the daily clinical practice has not been thoroughly evaluated., Methods: We conducted a multicenter retrospective study for the clinical outcome of 53 patients with HTB FL treated by OB as the frontline therapy between 2018 and 2021 in the Kyoto Hematology Clinical Study Group (KOTOSG). All patients had at least 2-year follow-up period., Results: The median age was 67, and 60.4% were classified as high risk according to the Follicular Lymphoma International Prognostic Index. The overall and complete response rates after induction therapy with OB were 98% and 83%, respectively. With a median follow-up of 38.5 months, the 3-year progression-free survival (PFS) and overall survival (OS) were 77.3% and 91.2%, respectively. Grade 3-4 hematological adverse events (AEs) were common, including neutropenia (58.5%) and lymphopenia (98.1%). Non-hematological AEs included infections, such as lung infections, coronavirus disease 2019, and sepsis, with two cases (3.8%) being fatal. Finally, propensity score-matched analysis showed no significant difference in PFS between 46 FL patients treated by the frontline OB and 46 FL patients treated by R-CHOP between 2001 and 2019 in KOTOSG., Conclusion: This study highlighted the need for careful treatment selection based on patient background and disease condition in real-world practice with more elderly patients., Competing Interests: Declarations. Conflict of interest: TT has received honoraria from Bristol Myers Squibb (BMS), Janssen Pharmaceutical, Sanofi, Kyowa Kirin, and Chugai Pharmaceutical; TK has received honoraria from BMS, Chugai Pharmaceutical, Nippon Shinyaku, Ono Pharmaceutical, Sanofi, Nippon Kayaku, AstraZeneca, Abbvie, MSD, and Janssen Pharmaceutical; EK has received honoraria from Janssen Pharmaceutical, Chugai Pharmaceutical, Astra Zeneca, Alexion Pharmaceutical, BMS, Sanofi, Kyowa Kirin, Genmab, and Meiji Seika; NU has received honoraria from BMS, Janssen Pharmaceutical, and Abbvie; SF has received honoraria from Takeda Pharmaceutical, Sanofi, Janssen Pharmaceutical, Ono Pharmaceutical, and BMS; TF has received honoraria from Takeda Pharmaceutical; SM has received honoraria from Amgen, Astellas, Otsuka Pharmaceutical, Nippon Shinyaku, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi, and BMS; YS has received honoraria from Ono Pharmaceutical, BMS, Janssen Pharmaceutical, Sanofi, Kyowa Kirin, Takeda Pharmaceutical, and Chugai Pharmaceutical. JK is a consultant for Janssen Pharmaceutical, Pfizer, Abbvie, BeiGene, and BMS; has received research funding from Kyowa Kirin, Chugai Pharmaceutical, Asahikasei, Sumitomo Pharma, Otsuka Pharmaceutical, Mochida Pharmaceutical, Taiho Pharmaceutical, and Japan Blood Products Organization; and has received honoraria from Janssen Pharmaceutical, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi, Pfizer, Astra Zeneca, Astellas, Eisai, Abbvie, Novartis, Daiichi Sankyo, Amgen, Otsuka Pharmaceutical, and BMS. The other authors have no conflict of interest. Ethical approval and consent to participate: The ethics committee of each participating institute approved the study. Under this approval, the need to obtain informed consent from the study subjects was waived, and we disclosed information about the survey to the patients. Patient consent for publication: Not applicable., (© 2025. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Intranasal tumors in dogs are malignant solid tumors that are primarily treated with radiotherapy and often recur post-treatment. Combination therapy is pivotal in cancer therapy. Effective drugs include fluoropyrimidine 5-fluorouracil (5-FU) and toceranib phosphate. TS-1, an oral formulation containing the 5-FU prodrug tegafur and enzyme modulators gimeracil and oteracil, is proven to be safe in dogs with solid tumors. While the oral drug toceranib phosphate (Palladia ® ) is safely administered, the combined toxicity with TS-1 is unknown. We aimed to determine the dosage of this combination in dogs. In the preclinical/clinical trials conducted here, we used a standard 3+3 cohort design with fixed doses of toceranib phosphate (2.4 mg/kg) administered thrice weekly. TS-1 administration was initiated at a dose of 0.5 mg/kg (upper limit 2.0 mg/kg) thrice weekly. Four cohorts were included to confirm the safety of TS-1 and toceranib phosphate. Each cohort was followed up for 1 month. The intranasal tumor types included in the clinical trial (n=13) were adenocarcinoma (n=7), squamous cell carcinoma (n=1), non-epithelial malignancy (n=2), undifferentiated carcinoma (n=1), and transitional carcinoma (n=2). The TS-1 dosage could be increased up to its dose limit in the preclinical/clinical trials. The TS-1 dose to combine with toceranib phosphate thrice weekly was 2.0 mg/kg. This regimen was well-tolerated in dogs. Thus, combined TS-1 and toceranib phosphate therapy is safe for dogs with intranasal tumors.

We conducted a multi-institutional retrospective study in 100 transplant-ineligible (TI) patients with diffuse large B-cell lymphoma (DLBCL) that relapsed or progressed after first-line R-CHOP (or -like) therapy to develop a robust predictive model for TI relapsed/refractory (r/r) DLBCL, which has a heterogeneous but poor prognosis by currently available treatment modalities other than chimeric antigen receptor T-cell (CAR-T) therapy or bispecific antibodies. The median age at relapse or progression was 76 years. The median progression-free survival (PFS) and overall survival (OS) from the first progression were 11.5 months and 21.9 months, respectively. Multivariate analysis identified low lymphocyte-to-monocyte ratio (LMR), elevated high lactate dehydrogenase, and elevated C-reactive protein at progression as independent predictors of OS. A predictive model based on these three factors, here designated as the Kyoto Prognostic Index for r/r DLBCL (KPI-R), successfully stratified their OS and PFS with statistical significance. In addition, event-free survival less than 24 months for R-CHOP and low LMR were identified as significant predictive factors for non-response in any sequence of salvage therapy. We concluded that LMR is a bonafide predictor of treatment response and prognosis in patients with TI r/r DLBCL, and may be helpful in treatment decision-making., (© 2024. Japanese Society of Hematology.)

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

Multiple myeloma reduces cellular and humoral immunity. Optimal prediction of antibody response to anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients with MM and related disorders is essential to prevent coronavirus disease 2019 (COVID-19) during the SARS-CoV-2 pandemic. This study analyzed the humoral response to the anti-SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine and its associated factor in 83 patients from June to November 2021 at seven member institutions of the Kyoto Clinical Hematology Study Group. SARS-CoV-2 neutralizing antibody (nAb) was measured from 12 to 210 days. The result revealed that 40 (48.2%) patients with MM and 59 (100%) healthy controls became seropositive after vaccination. Receiver operating characteristic curve analysis identified serum immunoglobulin (Ig) M of > 18 mg/dL at vaccination as the optimal threshold level associated with seropositivity in the whole cohort. Moreover, the multivariate analysis identified serum IgM of > 18 mg/dL as the independent predictor for a favorable response. Serum IgA level was positively associated with vaccine response in a sub-cohort. Our findings indicate a significant association between immunoparesis and impaired humoral response against mRNA vaccination, including that against SARS-CoV-2, and that serum non-M-protein Ig levels can serve as surrogate biomarkers of nAb production ability., (© 2023. Japanese Society of Hematology.)

Introduction: Skeletal muscle mass is considered a prognostic factor for survival in patients with cancer. In this study, we investigated the associations between skeletal muscle mass, physical function, fatigue, and quality of life(QOL)at diagnosis in patients with hematological malignancies., Methods: In this study, we included 27 untreated patients with newly diagnosed hematological malignancies who visited our hospital. The patients were assessed during the period from diagnosis to the start of chemotherapy. Data regarding age, white blood cell count, hemoglobin level, platelet count, and body mass index(BMI)were obtained from the patients' medical records. In addition, skeletal muscle mass index(SMI), phase angle (PhA), grip strength, knee extension strength, and short physical performance battery, brief fatigue inventory, EuroQol 5 dimensions 5-levels, and mini nutritional assessment short-form scores were calculated., Results: The mean SMI value was 6.6±1.3 kg/m2(7.4±1.2 kg/m2 in men and 5.7±0.6 kg/m2 in women). SMI showed significant correlations with platelet count(r=-0.42, p=0.03), BMI(r=0.61, p≤0.01), PhA(r=0.54, p≤0.01), grip strength(r=0.81, p≤0.01), and knee extension strength(r=0.49, p=0.01). Multiple regression analysis, conducted using SMI as the dependent variable, revealed that BMI and grip strength were significant variables(p≤0.01)., Discussion: In untreated patients with newly diagnosed hematological malignancies, SMI was associated with BMI and grip strength but not with fatigue or QOL. Assessment of BMI and grip strength at diagnosis may help predict skeletal muscle mass.

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS., Competing Interests: TF has received honoraria from Takeda Pharmaceutical; TT has received honoraria from Bristol Myers Squibb (BMS), Janssen Pharmaceutical, Sanofi, Kyowa Kirin and Chugai Pharmaceutical; YS has received honoraria from Ono Pharmaceutical, BMS, Janssen Pharmaceutical, Sanofi, Kyowa Kirin, Takeda Pharmaceutical and Chugai Pharmaceutical; SM has received honoraria from Sanofi and Ono Pharmaceutical; and NU has received honoraria from BMS and Takeda. JK is a consultant for Janssen Pharmaceutical, Abbvie and BMS; has received research funding from Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Shionogi and BMS; and has received honoraria from Janssen Pharmaceutical, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi and BMS. None of the pharmaceutical companies aforementioned benefited from the present research or played any role in our study. All other authors declare that they have no competing interests., (Copyright: © Inoue et al.)

To evaluate the specific prognostic value of CAs, we conducted an analysis of 923 symptomatic multiple myeloma patients. Among this cohort, 480 patients had complete data set of high-risk CAs by interphase fluorescent in situ hybridization at diagnosis. In the high-risk group analysis, the median OS of patients without CAs ( n  = 338, 72 %) was 6.5 years, patients with del(17p) ( n  = 42, 9 %) was 4.4 years, patients with t(4;14) or t(14;16) ( n  = 72, 15 %) was 4.4 years, and patients with double-positive CAs(del(17p) and t(4;14) or t(14;16)) ( n  = 18, 4 %) was 2.1 years ( p  = 0.032). Patients with double-positive CAs had a significantly worse prognosis., Competing Interests: All authors received research funding from ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb Company. JKU is appointed as an officer or advisor at Kansai Medical Net. JKU received lecture honoraria from Bristol-Myers Squibb Company, Janssen Pharmaceutical K. K., Sanofi K.K., ONO PHARMACEUTICAL CO., LTD., AbbVie GK., Takeda Pharmaceutical Company Limited, and Novartis Pharma KK. AT received lecture honoraria from Bristol-Myers Squibb Company, Novartis Pharma KK, Kyowa Kirin Co., Ltd., Astellas Pharma Inc., Nippon Shinyaku Co., Ltd., JANSSEN PHARMACEUTICAL K.K., Otsuka Pharmaceutical Co., Ltd. MH received lecture honoraria from Novartis Pharma K.K., Takeda Pharmaceutical Company, Limited, Bristol-Myers Squibb., Otsuka Pharmaceutical Co., Ltd. IM received lecture honoraria from Novartis Pharma KK, Bristol-Myers Squibb Company, Pfizer Japan Inc., DAIICHI SANKYO COMPANY, LIMITED., Otsuka Pharmaceutical Co., Ltd., Astellas Pharma Inc., Janssen Pharmaceutical K.K, AbbVie GK., Takeda Pharmaceutical Company Limited, ONO PHARMACEUTICAL Co., Ltd., SymBio Pharmaceuticals Limited. HS received lecture honoraria from Takeda Pharmaceutical Company, Limited., ONO PHARMACEUTICAL CO., LTD., Novartis Pharma K.K., Bristol-Myers Squibb K.K., JANSSEN PHARMACEUTICAL K.K., CHUGAI PHARMACEUTICAL CO., LTD., Sanofi K.K., AstraZeneca K.K. TI received lecture honoraria from Bristol-Myers Squibb, Mundipharma K.K., Novartis Pharma K.K., Pfizer Japan Inc., Takeda Pharmaceutical Company, Limited., AbbVie GK., CHUGAI PHARMACEUTICAL CO., LTD., Sanofi K.K., Nippon Shinyaku Co., Ltd., CSL Behring K.K., Otsuka Pharmaceutical Co., Ltd., NIHON PHARMACEUTICAL CO., LTD., JANSSEN PHARMACEUTICAL K.K.. SF received lecture honoraria from Takeda Pharmaceutical Company, Ltd., Sanofi K.K., JANSSEN PHARMACEUTICAL K.K., ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb K.K. TT received lecture honoraria from Sanofi K.K.. JKU received writing fees from JANSSEN PHARMACEUTICAL K.K., Bristol-Myers Squibb K.K. JKU received grants for research from Bristol-Myers Squibb Company, ONO PHARMACEUTICAL CO., LTD., Sysmex Corporation, Takeda Pharmaceutical Company, Limited, Otsuka Pharmaceutical Co., Ltd., Incyte Corporation, JANSSEN PHARMACEUTICAL K.K., Pfizer Japan Inc., CHUGAI PHARMACEUTICAL Co., Ltd., Kyowa Kirin Co., Ltd., IQVIA Services Japan K.K. AT received grants for research from ONO PHARMACEUTICAL Co., Ltd., COGNANO, Inc., DKS Co., Ltd.. IM received grants for research from Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., Astellas Pharma Inc., AbbVie GK., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited., Alexion, Otsuka Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K. NH received grants for research from Otsuka Pharmaceutical Co., Ltd. HS received grants for research from JANSSEN PHARMACEUTICAL K.K., ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb K.K., Novartis Pharma K.K., AstraZeneca K.K., AbbVie GK., Eisai Co., Ltd., HUYABIO International, CHUGAI PHARMACEUTICAL CO., LTD., PharmaEssentia Japan KK. TI received grants for research from Bristol-Myers Squibb. JKU recieved scolarship grant from Kyowa Kirin Co., Ltd., CHUGAI PHARMACEUTICAL CO., LTD., DAIICHI SANKYO COMPANY, LIMITED, ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Eisai Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Takeda Pharmaceutical Company, Limited., Nippon Shinyaku Co., Ltd. AT received scholarship grants from Takeda Pharmaceutical Company, Limited, Nippon Shinyaku Co., Ltd., Kyowa Kirin Co., Ltd., CHUGAI PHARMACEUTICAL CO., LTD., Sanofi K.K., Otsuka Pharmaceutical Co., Ltd., Astellas Pharma Inc., Eisai Co., Ltd., OHARA Pharmaceutical Co., Ltd., Popuri, Kinshikouraininjin, AbbVie, SHIONOGI & CO., LTD., Asahi Kasei Pharma Corporation., the Japanese Society of Hematology. MH recieved scholarship grants from CHUGAI PHARMACEUTICAL CO., LTD., Kyowa Kirin Co., Otsuka Pharmaceutical Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., Takeda Pharmaceutical Company, Limited., ONO PHARMACEUTICAL CO., LTD. IM received scholarship grants from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited., Shionogi & Co., Ltd., ASAHI KASEI PHARMA CORPORATION, Eisai Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., NIPPON SHINYAKU CO.,LTD., Otsuka Pharmaceutical Co., Ltd, AbbVie GK., ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. IM received scholarship grants from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited., Shionogi & Co., Ltd., ASAHI KASEI PHARMA CORPORATION, Eisai Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., NIPPON SHINYAKU CO.,LTD., Otsuka Pharmaceutical Co., Ltd, AbbVie GK., ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. HS received scholarship grants from Astellas Pharma Inc., TEIJIN PHARMA LIMITED, SHIONOGI & CO., LTD., Eisai Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., Nippon Shinyaku Co., Ltd. CS received lecture honoraria from Sanofi K.K., JANSSEN PHARMACEUTICAL K.K., Bristol-Myers Squibb K.K., (© 2023 The Author(s).)

The prognostic impact of patient-related factors, including age, nutritional parameters, and inflammation status, in higher-risk myelodysplastic syndromes (HR-MDS) has been largely unexplored. This multicenter retrospective study aimed to establish a real-world practice-based prognostic model for HR-MDS by considering both disease- and patient-related parameters in 233 patients treated with AZA monotherapy at seven institutions. We found that anemia, presence of circulating blasts in peripheral blood, low absolute lymphocyte count, low total cholesterol (T-cho) and albumin serum levels, complex karyotype, and del(7q) or  - 7 were poor prognostic factors. Therefore, we developed a new prognostic model called the Kyoto Prognostic Scoring System (KPSS) by incorporating the two variables with the highest C-indexes (complex karyotype and serum T-cho level). The KPSS classified patients into the following three groups: good (0 risk factors), intermediate (1), and poor (2). Median overall survival for these groups was 24.4, 11.3, and 6.9, respectively (p < 0.001). The discriminatory power of the KPSS was higher than that of the traditional International Prognostic Scoring System. In conclusion, we identified several nutritional parameters with prognostic relevance in patients with HR-MDS and generated a prognostic model consisting of complex karyotype and serum T-cho level that enabled excellent risk stratification., (© 2023. Japanese Society of Hematology.)

We systematically investigate functional and molecular measures of stemness in patients with acute myeloid leukemia (AML) using a cohort of 121 individuals. We confirm that the presence of leukemic stem cells (LSCs) detected through in vivo xenograft transplantation is associated with poor survival. However, the measurement of leukemic progenitor cells (LPCs) through in vitro colony-forming assays provides an even stronger predictor of overall and event-free survival. LPCs not only capture patient-specific mutations but also retain serial re-plating ability, demonstrating their biological relevance. Notably, LPC content represents an independent prognostic factor in multivariate analyses including clinical guidelines of risk stratification. Our findings suggest that LPCs provide a robust functional measure of AML, enabling quantitative and rapid assessment of a wide range of patients. This highlights the potential of LPCs as a valuable prognostic factor in AML management., Competing Interests: Declaration of interests The authors declare no competing interests., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease, which presents with features of myelodysplastic syndromes with ring sideroblasts and essential thrombocythemia, as well as anemia and marked thrombocytosis. SF3B1 and JAK2 mutations are often found in patients, and are associated with their specific clinical features. This study was a retrospective analysis of 34 Japanese patients with MDS/MPN-RS-T. Median age at diagnosis was 77 (range, 51-88) years, and patients had anemia (median hemoglobin: 9.0 g/dL) and thrombocytosis (median platelet count: 642 × 109/L). Median overall survival was 70 (95% confidence interval: 68-not applicable) months during the median follow-up period of 26 (range: 0-91) months. A JAK2V617F mutation was detected in 46.2% (n = 12) of analyzed patients (n = 26), while an SF3B1 mutation was detected in 87.5% (n = 7) of analyzed patients (n = 8). Like those with myelodysplastic syndromes or myeloproliferative neoplasms, patients often received erythropoiesis-stimulating agents and aspirin to improve anemia and prevent thrombosis. This study, which was the largest to describe the real-world characteristics of Japanese patients with MDS/MPN-RS-T, showed that the patients had similar characteristics to those in western countries., (© 2023. Japanese Society of Hematology.)

Background: Erythrocytosis, most often measured as an increase in hemoglobin and/or hematocrit, is a common reason for referral to internal medicine and hematology clinics and a rational approach is required to effectively identify patients with polycythemia vera while avoiding over-investigation., Aim: We aimed to develop and validate a simple rule to predict JAK2 mutation positivity based on complete blood count parameters to aid in the diagnostic approach to patients referred for elevated hemoglobin., Setting: Internal medicine and hematology clinics at an academic tertiary referral center., Participants: The JAK2 Prediction Cohort (JAKPOT), a large retrospective cohort (n = 901) of patients evaluated by internal medicine and hematology specialists for elevated hemoglobin., Design: JAK2 mutation analysis was performed in all patients and clinical and laboratory variables were collected. Patients were randomly divided into derivation and validation cohorts. A prediction rule was developed using data from the derivation cohort and tested in the validation cohort., Key Results: The JAKPOT prediction rule included three variables: (i) red blood cell count >6.45×10 12 /L, (ii) platelets >350×10 9 /L, and (iii) neutrophils >6.2×10 9 /L; absence of all criteria was effective at ruling out JAK2-positivity with sensitivities 94.7% and 100%, and negative predictive values of 98.8% and 100% in the derivation and validation cohorts, respectively, with an overall low false negative rate of 0.4%. The rule was validated for three different methods of JAK2 testing. Applying this rule to our entire cohort would have resulted in over 50% fewer tests., Conclusion: In patients with elevated hemoglobin, the use of a simple prediction rule helps to accurately identify patients with a low likelihood of having a JAK2 mutation, potentially limiting costly over-investigation in this common referral population., (© 2022. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1-mutated AML. Although patients with NPM1-mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3A R882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1-mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3A R882 mutations and the co-occurrence of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3A R882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3A R882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3A R882 mutations and triple mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3A R882 /FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3A R882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3A R882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: This case report describes the successful management of rehabilitation therapy for a hematological malignancy patient who was receiving chemotherapy and had coronavirus disease 2019 (COVID-19)., Case: A 76-year-old man receiving chemotherapy for relapsed refractory multiple myeloma (MM) presented to our hospital with fever and dyspnea and was hospitalized with a diagnosis of COVID-19. Physical therapy (20 min/day, 5 days/week) was started on day 6 of hospitalization while the patient was receiving oxygen therapy. Conditioning exercises and movement exercises were performed in an isolation room, and blood counts, fracture susceptibility, and respiratory status were monitored. The patient was severely immunocompromised and required 34 days of isolation due to persistent severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2) infection. Physical function was assessed by manual muscle testing of the lower extremities and by the extent of lower extremity fatigue and dyspnea on exertion, as assessed using the Borg scale. Motor capacity was assessed using the de Morton Mobility Index (DEMMI) score and the Barthel Index (BI). Muscle weakness and severe dyspnea developed 4 days after physical therapy was started. However, physical therapy led to improvements in DEMMI score and BI. The patient was discharged home on day 43 with home medical care., Discussion: Careful management of MM and COVID-19 facilitated safe treatment with physical therapy. The patient's physical function improved with a carefully planned physical therapy program. Moreover, the patient required prolonged isolation due to persistent viral shedding; however, as a result of the treatment, which was coordinated between physicians and nurses, the patient could be discharged home., Competing Interests: CONFLICTS OF INTEREST: The authors have no conflicts of interest to declare., (2023 The Japanese Association of Rehabilitation Medicine.)

Background: Primary ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma (POAML) is the most common subtype of indolent ocular adnexal lymphomas. Although radiotherapy (RT) is the standard of care for localized POAML, it can occasionally lead to permanent side effects. Other treatment strategies, such as rituximab (R) monotherapy and immunochemotherapy, have been used for POAML treatment, but their long-term benefits and relative merits remain unclear. While watchful waiting (WW) is a potential option for some indolent lymphomas, the benefits of WW for POAML patients are also unclear., Methods: We here retrospectively analyzed 75 patients who were diagnosed with POAML between 2008 and 2019 in the institutions of the Kyoto Clinical Hematology Study Group., Results: Commonly involved sites were conjunctiva (42.7%), orbit (36.0%), and lacrimal gland (12.0%), and most patients (92.0%) presented with Ann Arbor stage IE disease. The treatment strategy was selected at the physicians' discretion. More patients without subjective symptoms by tumor mass were subjected to WW (29 patients), while more patients with tumor-derived subjective symptoms were treated by tumor-directed therapy (24 received focal RT, and 19 received R monotherapy). Complete response rates were 79.2% and 42.1% in the RT and R groups, respectively. At 60 months of follow-up, the estimated proportions of POAML patients not requiring new treatment were 69.4%, 85.2%, and 53.8% in the WW, RT, and R groups, respectively. There were no significant differences in the time to start a new treatment between WW and RT groups (median: both not reached [NR], p = 0.187) and between WW and R groups (median: NR vs. 69.0 months, p = 0.554). No specific predictive factor for the future need of treatment was identified in the WW group., Conclusion: Our results demonstrate WW may be an acceptable treatment option for POAML, especially for asymptomatic patients., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Molecular testing for JAK2 mutations is part of the standard diagnostic workup for patients with suspected polycythemia vera. We sought to characterize evolving practice patterns in the investigation of erythrocytosis and the prevalence of secondary causes, including use of medications such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, among patients who underwent molecular testing., Methods: We reviewed charts of all consecutive patients investigated for erythrocytosis (hemoglobin > 160 g/L for women, > 165 g/L for men) with JAK2 testing between 2015 and 2021 at London Health Sciences Centre, a tertiary referral centre in Ontario, Canada, to assess changes in rates of JAK2 mutation positivity, average hemoglobin levels and the prevalence of secondary causes of erythrocytosis., Results: A total of 891 patients with erythrocytosis underwent JAK2 mutation testing with an increase in number of tests (particularly from 2017 to 2018), a decrease in the rate of JAK2 positivity and similar average hemoglobin levels over the study period. We observed a high proportion of patients with secondary causes of erythrocytosis, ranging from 59% to 74% over the study period, including medications associated with erythrocytosis, namely testosterone (6%-11%) and SGLT2 inhibitors (2%-19%). Stopping SGLT2 inhibitors was associated with a significant decrease in hemoglobin levels (mean -14.7 g/L, 95% confidence interval -18.9 to -10.5 g/L) compared with continuation., Interpretation: Use of SGLT2 inhibitors may be a common and underrecognized secondary cause of elevated hemoglobin levels in patients investigated for erythrocytosis. Our findings underscore the importance of a detailed medical history to support judicious use of molecular testing, in adherence with the current guideline on the investigation of erythrocytosis., Competing Interests: Competing interests: None declared., (© 2022 CMA Impact Inc. or its licensors.)

Recent studies have reported that measurable residual disease (MRD) analysis using NPM1 mutations helps determine whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in acute myeloid leukemia (AML) patients. However, the optimal timing and cutoff value for measuring MRD using genomic DNA remain undetermined. This study aimed to investigate the optimal timing and cutoff value to ascertain the value of NPM1 mutation in MRD assessment. NPM1-mutated MRD was quantified by real-time polymerase chain reaction of bone marrow samples from 56 patients with NPM1-positive AML who achieved hematological remission. The area under the receiver-operating characteristic curve was greatest when MRD was assessed after two courses of post-remission therapy with a cutoff value of 0.010% (specificity, 68.4%; sensitivity, 87.0%). Patients whose MRD was below the cutoff value throughout the course of treatment had significantly better overall survival and relapse-free survival rates. Of the 33 patients who did not undergo transplantation during the first remission, all of the 11 who were never MRD-negative at any point experienced a relapse. Evaluating MRD with a cutoff value of 0.010% after two courses of post-remission therapy helps predict prognosis and determine the indication for allo-HSCT., (© 2022. Japanese Society of Hematology.)

Purpose: It is well studied that physical function and social background affect the quality of life (QoL) of cancer patients. However, differences in QoL by age and factors affecting health state utility values (HSUV) of patients with hematological malignancies have not yet been sufficiently investigated. Our aim is to investigate the factors that affect QoL and HSUV in such patients., Methods: A total of 32 patients with hematological malignancies on outpatient chemotherapy were included. QoL and HSUV were evaluated using the EuroQol-5 Dimension 5-level (EQ-5D-5L). Physical function was assessed using grip strength, knee extension strength, 6-min walking distance, and Short Physical Performance Battery (SPPB). Fatigue was assessed using Brief Fatigue Inventory (BFI), and nutritional status was assessed using Mini Nutritional Assessment-Short Form (MNA-SF)., Results: In the EQ-5D-5L, a high percentage of the patients were aware of mobility problems and pain/discomfort, and mobility problems were more common in the older-aged group (≥ 65 years old, n = 16) than in the middle-aged group (< 65 years old, n = 16). In addition, the older-aged group showed lower HSUV and physical function. SPPB (β = 0.38, p < 0.01), BFI (β =  - 0.58, p < 0.01), and MNA-SF (β = 0.29, p = 0.02) were independent factors affecting HSUV (adjusted R 2  = 0.65, p < 0.01). BFI was correlated with HSUV in both older and middle-aged groups., Conclusion: Comprehensive supports, to improve lower extremity function, fatigue, and nutritional status, are required to augment QoL and HSUV in patients with hematological malignancies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: In most laboratories, next generation sequencing (NGS) has been added without consideration for redundancy compared to conventional cytogenetics (CG). We tested a streamlined approach to genomic testing in patients with suspected myeloid and plasma cell neoplasms using next generation sequencing ("NGS first") as the primary testing modality and limiting cytogenetics (CG) to samples with morphologic abnormalities in the marrow aspirate., Methods: Based on morphologic interpretation of bone marrow aspirate and flow cytometry, samples were triaged into four groups: (a) Samples with dysplasia or excess blasts had both NGS and karyotyping; (b) Samples without excess blasts or dysplasia had NGS only; (c) Repeat samples with previous NGS and/or CG studies were not retested; (d) Samples for suspected myeloma with less than 5% plasma cell had CG testing cancelled., Results: Seven hundred eleven adult bone marrow (BM) samples met the study criteria. The NGS first algorithm eliminated CG testing in 229/303 (75.6%) of patients, primarily by reducing repeat testing. Potential cost avoided was approximately $124 000 per annum. Hematologists overruled the triage comment in only 11/303 (3.6%) cases requesting CG testing for a specific indication., Conclusions: Utilizing NGS as the primary genomic testing modality NGS was feasible and well accepted, reducing over three quarters of all CG requests and improving the financial case for adoption of NGS. Key factors for the success of this study were collaboration of clinical and genomic diagnostic teams in developing the algorithm, rapid turnaround time for BM interpretation for triage, and communication between laboratories., (© 2021 John Wiley & Sons Ltd.)

We conducted a post hoc analysis of our previous pilot observational study on the efficacy and safety of carfilzomib (CFZ)-containing therapy in 50 patients with relapsed/refractory multiple myeloma in routine practice to clarify the relationships between three major criteria for vulnerability (frailty, poor performance status [PS], and advanced age [≥ 75 years]) and their clinical impact on efficacy and adverse events (AEs). Sixteen patients fulfilled at least one and five patients fulfilled all three criteria. The overall response rate was not significantly affected by frailty, poor PS, and/or advanced age; however, frailty and advanced age were significantly associated with shorter progression-free survival (PFS). In contrast, no significant difference in PFS was observed between patients with PS0-1 or PS2-4. The three criteria for vulnerability were associated with more frequent hematologic AEs: frailty, poor PS, and/or advanced age significantly increased the risk of grade 3-4 anemia and lymphopenia. However, these criteria were not associated with increased risk of other non-hematologic AEs except infection. Collectively, these results demonstrate the need to carefully manage severe hematologic AEs in vulnerable patients and perform disease-specific assessment of frailty to predict prognosis., (© 2022. Japanese Society of Hematology.)

Mutations of CCAAT/enhancer-binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBPAmu for prognosis in 1028 patients with AML, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (P < .001), better overall survival (OS; P < .001) and a lower risk of relapse (P < .001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients: OS, P = .008; the cumulative incidence of relapse, P = .063; patients aged ≤70 years and with intermediate-risk karyotype: OS, P = .008; cumulative incidence of relapse, P = .026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio, 0.3287; P < .001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA-mutated AML., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Bone marrow (BM) involvement is associated with prognosis in diffuse large B-cell lymphoma (DLBCL), the most prevalent disease subtype of malignant lymphoma. We conducted this multi-institutional retrospective study to investigate the functional association and prognostic values of four BM tests (BM biopsy, BM clot, flow cytometry (FCM), and BM smear). A total of 221 DLBCL patients were enrolled. BM involvement was detected in 17 (7.7%), 16 (7.2%), 27 (12.2%), and 34 (15.4%) patients by BM biopsy, BM clot, FCM, and BM smear, respectively. The consistency between BM biopsy and clot examination was favorable, with a κ coefficient of 0.705, whereas the consistencies among other modalities were poor. In 184 patients treated with the first-line R-CHOP (-like) regimen, BM involvement was associated with shorter progression-free survival (PFS) irrespective of the type of modality for a positive result. Intriguingly, among various single and combinatory modalities, the combination of BM biopsy and FCM had the highest hazard ratio of 3.33 and a c-index of 0.712. In conclusion, our study suggested that the combination of BM biopsy and FCM is the prognostically relevant central approach for BM involvement detection. The other BM examinations also may provide complementary information in clinical settings.

The plateau phase emerging during the treatment of multiple myeloma (MM) is known to last steadily for a certain period, even without treatment. Therefore, the treatment started at plateau phase is expected to be associated with a better outcome. In this study, this hypothesis was evaluated retrospectively for previously treated MM patients in Kansai Myeloma Forum database who received lenalidomide (LEN) with or without dexamethasone for the first time. Disease stability index (DSI) was defined as (maximum - minimum values of M protein during the 90 days before the start of LEN) divided by M-protein values at the start of LEN. The patients were classified into three groups: stable (S), DSI ≤ 0.25; increasing (I), DSI > 0.25 with increasing M protein; decreasing (D), DSI > 0.25 with decreasing M protein. In univariate analysis of 352 patients, DSI group "I", non-IgG type, serum albumin<3.5 g/dL, and age≥70 were statistically significant prognostic factors for both progression-free survival and overall survival. In multivariate analysis, the former 3 risk factors were statistically significant for poor overall survival. Thus, DSI is an independent prognostic factor for the treatment with LEN for previously treated MM., (© 2021 John Wiley & Sons Ltd.)