BACKGROUND:Despite several attempts to improve the prognosis of patients with diffuse large B-cell lymphoma (DLBCL), the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen remains the standard of care in previously untreated DLBCL. A randomized phase II/III study (JCOG0601) was performed to investigate the efficacy of dose-dense weekly rituximab combined with standard CHOP (RW-CHOP). Herein, we report the final results of JCOG0601 as a post hoc assessment after an 8-year follow-up. METHODS:Patients aged 20-79 years with previously untreated DLBCL (stages I-IV, performance status 0-2) were randomized to either standard R-CHOP or RW-CHOP. RESULTS:Between December 2007 and December 2014, 421 patients were randomly assigned to R-CHOP (n = 213) or RW-CHOP (n = 208). With a median follow-up of 9.6 years, no meaningful differences were found in progression-free survival (PFS) and overall survival (OS) [hazard ratio (HR) in PFS, 0.94; 95% confidence interval (CI), 0.67-1.32; HR in OS, 0.94; 95% CI, 0.63-1.41]. The median PFS and OS were not estimable in both arms. Twenty-one (5.0%) cases of grade ≥ 3 cardiac toxicity were observed. The cumulative incidence rates of secondary malignancy were 14.6% and 16.8% in the R-CHOP and RW-CHOP arms, respectively. The median time from study enrollment to the onset of secondary malignancy was 4.5 years, and the incidence was time-dependent. No unexpected adverse events, including opportunistic infections, occurred. CONCLUSION:These final follow-up data confirmed the nonsuperiority of RW-CHOP in terms of PFS and OS. Standard R-CHOP remains the standard of care for untreated DLBCL.

Background Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma for which prognosis is typically poor without a timely diagnosis. To explore the safety and efficacy of standard chemotherapy combined with central nervous system (CNS)-directed therapy, we conducted a multicentre, single-arm, phase 2 trial in untreated IVLBCL patients without CNS involvement at diagnosis (PRIMEUR-IVL). In the primary analysis, the PRIMEUR-IVL study demonstrated 2-year progression-free survival (PFS) of 76% and 2-year overall survival (OS) of 92% with a low incidence (3%) of secondary CNS involvement (sCNSi). Methods We present a prespecified final analysis of the PRIMEUR-IVL study including 5-year PFS, OS and cumulative incidence of sCNSi. Participants were enrolled between June 2011 and July 2016, and the data cutoff date for the final analysis was 16 November 2021. The trial was registered in the UMIN Clinical Trial Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165). Findings With a median follow-up of 7.1 years (interquartile range 5.6-8.7), 5-year PFS in all 37 eligible patients was 68% (95% confidence interval [CI] 50%-80%) and OS was 78% (95% CI 61%-89%). No additional sCNSi was observed after the primary analysis. Severe adverse events after the primary analysis were grade 4 neutropenia (n = 1) and grade 4 myelodysplastic syndrome that did not require specific treatment (n = 1). Eight deaths occurred during the observation period after enrolment, due to primary disease (n = 6), sepsis (n = 1) and unknown sudden death (n = 1). Interpretation Long-term follow-up data demonstrated durable response for PFS and OS, and low cumulative incidence of sCNSi, indicating the efficacy of standard chemotherapy combined with CNS-directed therapy for untreated IVLBCL patients. Copyright (c) 2025 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

We encountered a patient with composite mantle cell lymphoma (MCL) and T-cell prolymphocytic leukemia (T-PLL) who presented with inactive disease to active T-PLL over 8 years. A 71-year-old man was diagnosed with MCL with an atypical T-cell population showing CD2+, CD3-, CD4+, CD7+, CD8-, and CD25+; however, the cause of the T-cell population could not be determined at the first MCL diagnosis. When MCL relapsed approximately 8 years after the initial treatment, T-PLL was definitively diagnosed using the T-PLL International Study Group criteria. MCL and T-PLL were determined to coexist in the lymph nodes and bone marrow by histological or flowcytometry analysis. Retrospective flow cytometry and T-cell receptor-polymerase chain reaction analysis of the stored samples suggested that the T-cell population noted at the time of initial MCL diagnosis eight years earlier was the same clone of T-PLL and the progression from inactive disease to active disease of his T-PLL. To the best of our knowledge, this is the first report of a composite MCL and T-PLL.

Abstract R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine [VCR], and prednisolone) is the standard of care for previously untreated patients with diffuse large B-cell lymphoma (DLBCL). However, some DLBCL survivors experience long-lasting VCR-related peripheral neuropathy (PN). VCR dose is usually reduced based on PN severity, but inconsistent results have been reported regarding the effect of VCR dose reduction on the prognosis of patients with DLBCL. To evaluate the clinical impact of the relative dose intensity (RDI) of VCR (RDIO), we conducted a supplementary analysis of JCOG0601, a randomized phase 2/3 trial in which R-CHOP and CHOP with 8 doses of weekly rituximab were compared for progression-free survival (PFS). Among 422 patients enrolled in JCOG0601, 401 who had received at least 6 courses of protocol treatment were eligible. PFS was not significantly different between patients with low RDIO (<95% [n = 161]) and high RDIO (≥95% [n = 240]; P = .0679), although those with low RDIO tended to have poor PFS (3-year PFS, 83.7% vs 78.2%). Multivariable analysis revealed that the presence of B symptoms and high-intermediate or high International Prognostic Index (IPI) risk, but not RDIO, were associated with poor PFS. To our knowledge, this is the first study revealing VCR dose reduction may not be associated with poor PFS as much as the presence of B symptoms and high-intermediate or high IPI risk, using data from a prospective trial with rituximab plus 21-day cycles of CHOP. If the patients with DLBCL can complete rituximab plus CHOP treatment, VCR dose reduction due to toxicity may not significantly impair treatment efficacy. JCOG0601 was registered at www.jcog.jp/en/trials as #jRCTs031180139.

The impact of achieving progression-free survival at 24 months (PFS24) on subsequent survival in patients with diffuse large B-cell lymphoma (DLBCL) relative to the general population remains debatable. We assessed the impact of achieving PFS24 in newly diagnosed DLBCL patients using data from JCOG0601, a prospective study of DLBCL patients treated with R-CHOP. Among 409 eligible patients (median follow-up: 5.3 years), 334 (82%) achieved PFS24, whereas 66 (16%) did not. Patients who achieved PFS24 had significantly better overall survival (OS) than those who did not (median OS, not reached vs. 1.3 years; p < 0.001). Similar results were observed for PFS12 and PFS60. The OS for patients after achieving PFS24 or PFS60 was not markedly different from that of the age-, sex-, and calendar period-matched Japanese general population (PFS24: standardized mortality ratio [SMR] 1.29, 95% confidence interval [CI] 0.72-2.12, p = 0.39; PFS60: SMR 1.43, 95% CI 0.47-3.33, p = 0.55). Conversely, the OS for patients after achieving PFS12 was significantly worse than that of the general population (SMR 2.30, 95% CI 1.59-3.22, p < 0.001). The primary cause of death among patients who achieved PFS12 was DLBCL, whereas the mortality rate from DLBCL among those who achieved PFS24 or PFS60 was less than 5%. Multivariable analysis showed that having two or more extranodal involvements (OR 2.76 [95% CI 1.39-5.46], p = 0.004) was the only significant risk factor for failing to achieve PFS24. Our findings suggest that PFS24 can serve as an early endpoint of OS in patients with DLBCL.

Secondary central nervous system involvement (sCNSi) in diffuse large B-cell lymphoma (DLBCL) is fatal. However, its features in patients with sCNSi who are categorized as lower risk by international prognostic index (IPI) or CNS-IPI are not yet fully understood. In the present analysis, we evaluated DLBCL patients who developed sCNSi at their first progression and who participated in JCOG0601, most of whom were lower risk by IPI. Of 409 patients, 21 (5.1

IntroductionThe objectives of this study are twofold. The first is to identify potential green infrastructure construction sites by building rooftops and sidewalks. The second is to analyze internal flooding for a wide range of drainage areas and to quantitatively evaluate the effectiveness of stormwater runoff control.MethodsThe target area has approximately 600 ha with a runoff coefficient of 0.71. Using Arc GIS Desktop 10.8.1, this study has identified green roofs and bioswales that would be highly beneficial in capturing large amounts of rainfall. In addition, Info Works ICM was used for the inundation analysis, which can simultaneously calculate the flow in sewer pipelines and above-ground inundation flow. Runoff coefficients were calculated for each land use using the urban land use subdivision mesh data with 100 m unit. This study targeted a 10-year probability rainfall (total rainfall: 86.3 mm, maximum hourly rainfall: 52.3 mm/h, duration: 3 h) with a middle concentrated rainfall waveform obtained from past experiments in the d4PDF database of ensemble climate prediction contributing to global warming.ResultsThe amount of land availability for green roofs and bioswales was about 1 and 0.1% of the drainage area, respectively. The runoff coefficients for green roofs only, bioswales only, with and without introduction of both green roofs and bioswales were 70.34, 70.87, 70.28, and 70.93%, respectively. The difference in runoff coefficients was about 0.65 percentage points even when both were constructed. As a result of inundation analysis, the reduction was 2.5% for the maximum waterlogged area, 1.5% for the flooded area, and 0.7% for the average depth of waterlogging divided by the maximum waterlogged area. The construction of green roofs and bioswales in the same area or downstream of the area shows little mitigation effect when flooding occurs in an area near the downstream end of the sewer network.DiscussionAlthough this study has mainly discussed the stormwater runoff control aspect, the most important feature of green infrastructure is its multifunctionality. In terms of utilizing and promoting green infrastructure, it is important to visualize its multifaceted effects and share them with many stakeholders.

CD5-positive (CD5+) DLBCL is characterized by aggressive clinical characteristics and frequent CNS relapse.1 In 2020, we reported the results of the primary analysis of a phase 2 study of dose-adjusted (DA)-EPOCH-R combined with high-dose (HD)-MTX (DA-EPOCH-R/HD-MTX) (PEARL5 study) with a median follow-up of 3.1 years.2 In this letter, we report the results of our preplanned 5-year follow-up of this study. At a median follow-up time of 6.0 (range, 5.0–7.7) years, the 5-year PFS and OS of 47 eligible patients were 72% (90% CI, 57–83; 95% CI, 57–83) and 79% (90% CI, 67–87; 95% CI, 64–88), respectively (Figure 1A,B). One patient experienced a relapse in the cervical lymph nodes, Waldeyer's ring, and nasal cavity after the primary analysis. The 5-year PFS and OS of patients with CD5+ ABC DLBCL (n = 39) were 72% and 74%, respectively (Figure 2A,B). The 5-year CNS relapse rate was 9% (95% CI, 3–22) (Figure 3A). There were no CNS relapse events after the primary analysis. There was no significant difference in the CNS relapse rate among the CNS-IPI categories (data not shown). In our previous retrospective study of CD5+ DLBCL, CNS events occurred in 13% of the patients at the median follow-up of 6.8 years, and half of them were documented after 2 years of diagnosis.3 Given that no CNS events were observed in the present phase 2 study, the treatment protocol may have contributed to the prevention of late CNS relapse. No patients experienced grade 3 or higher late toxicity. There was no cardiovascular event and leukoencephalopathy during this follow-up. Second malignancies were reported in six patients (6%) and all were above 60 years of age (Table S1). Among them, two patients who had colon cancers were successfully treated with endoscopic resection. Among two patients who died during this follow-up, one died of a second malignancy. Our updated analysis confirmed that both excellent efficacy and safety of DA-EPOCH-R/HD-MTX were maintained for more than 5 years, indicating that DA-EPOCH-R/HD-MTX is one of the most reasonable first-line treatments for stage II–IV CD5+ DLBCL (UMIN000008507; jRCTs041180159). We wish to thank Takuya Matsunaga (Hokuou Hospital), Noriko Usui (The Jikei University School of Medicine), and Akiko Kada (Nagoya Medical Center) as members of the Data and Safety Monitoring Board. This study was supported by grants-in-aid from the Japan Agency for Medical Research and Development, AMED (JP15Ack0106157, JP16ck0106157, JP17ck0106157, JP18ck0106439), the Ministry of Labour, Health, and Welfare of Japan (201438142A), the director of Mie University Hospital (2012, 2013), and the National Cancer Center Research and Development Fund (26-A-4, 29-A-3). KMiyazaki reports research funding (Kyowa Kirin, Zenyaku). RSakai reports honoraria (Chugai, Takeda, Kyowa Kirin, Bristol Myers Squibb); research funding (Chugai, Kyowa Kirin). KS reports honoraria (Bristol Myers Squibb); research funding (Takeda, Bristol Myers Squibb, Chugai, Kyowa Kirin). IY reports honoraria (Chugai, Kyowa Kirin, Takeda); research funding (Chugai, Kyowa Kirin); NT reports honoraria (Takeda); research funding (Bristol Myers Squibb, Kyowa Kirin). YS reports honoraria (Chugai, Takeda, Kyowa Kirin, Bristol Myers Squibb, Pfizer); research funding (Chugai, Kyowa Kirin). NF reports honoraria (Bristol Myers Squibb, Chugai, Kyowa Kirin, Takeda, Zenyaku); research funding (Chugai). AA reports research funding (Chugai). YM reports research funding (Kyowa Kirin, Asahi Kasei, Takeda, Chugai). AY reports honoraria (Kyowa Kirin, Chugai, Takeda, Bristol Myers Squibb); research funding (Kyowa Kirin). KMiyawaki reports honoraria (Chugai). KI reports research funding (Bristol Myers Squibb, Pfizer, Kyowa Kirin, Chugai). RSuzuki reports honoraria (Chugai, Kyowa Kirin, Bristol Myers Squibb, Takeda); research funding (Chugai, Kyowa Kirin, Shionogi). KK reports honoraria (Kyowa Kirin, Chugai); research funding (Chugai, Takeda, Kyowa Kirin, Bristol Myers Squibb). NK reports research funding (Kyowa Kirin). MY reports research funding (Kyowa Kirin, Chugai). The other authors have nothing to disclose. Tomohiro Kinoshita, Koichi Ohshima, and Ritsuro Suzuki are editorial board members of Cancer Science. Approval of the research protocol by an Institutional Review Board: The study was approved by the protocol review committee of the study and the institutional review board of each institution in accordance with the Declaration of Helsinki. Informed consent: Written informed consent was obtained from all the patients. Registry and the registration no. of the study/trial: UMIN000008507; jRCTs041180159. Animal studies: N/A. Table S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Febrile neutropenia (FN) following chemotherapy is a potentially fatal complication, and subsequent treatment is often discontinued or reduced if FN occurs. A previous meta-analysis has demonstrated that reducing the dose of R-CHOP therapy less than the planned dose or prolonging the treatment interval implies a reduction in relative therapeutic intensity, resulting in poor treatment outcomes. In cases that developed FN after R-CHOP therapy but does not attenuate dose intensity (DI), the prognostic impact of FN has not been elucidated. Aims: We investigated whether the development of FN and relative DI (RDI) affect progression-free survival (PFS) and overall survival (OS) in JCOG0601 for untreated patients with diffuse large B-cell lymphoma. Methods: All eligible patients enrolled in JCOG0601 were included in the analysis (n=204 in arm A; 8 cycles CHOP-21 with 8 doses of rituximab once every 3 weeks and n=205 in arm B; 8 cylcles CHOP-21 with 8 doses of weekly rituximab). The entire cohort was divided into four groups according to the presence or absence of FN and RDI ≥ 85%. Group 1 (FN+, RDI of doxorubicin (DOX) or cyclophosphamide (CPA) < 85%) was used as the control arm for analysis with group 2 (FN+, RDI of DOX and CPA ≥ 85%), 3 (FN-, RDI of DOX or CPA < 85%), and 4 (FN-, RDI of DOX and CPA ≥ 85%). Results: RDI in arm A was CPA: 95.5% (range: 13.3-102.9%), DOX: 95.5% (range: 54.1-101.8%), and the RDI in arm B was CPA: 98.8% (range: 63.2-102.4%) and DOX: 98.8% (range: 62.5-102.4%). Forty-nine patients were classified in group 1, 67 in group 2, 27 in group 3, and 264 in group 4. There were no meaningful background differences among the four groups. The 5-year PFS were 73.5% (95% CI, 58.7-83.6%) in group 1, 80.6% (95% CI, 68.9-88.2%) in group 2, 61.0% (95% CI, 39.4-76.9%) in group 3, and 77.8% (95% CI, 72.2-82.5%) in group 4, respectively. The 5-year OS were 80.8% (95% CI, 66.2-89.5%) in group 1, 88.9% (95% CI, 78.0-94.6%) in group 2, 77.2% (95% CI, 56.0-89.1%) in group 3, and 86.1% (95% CI, 81.1-89.9%) in group 4, respectively. On univariable analysis, group 2 and group 4 had significantly better OS compared to group 1, while no significant difference was observed in PFS. There was no significant difference in groups 2, 3, and 4 compared to group 1 on multivariable analysis for PFS and OS. Summary/Conclusion: This study suggests that the attenuation of RDI rather than the presence of FN may have an impact on prognosis. Even in the presence of FN, the continuation of subsequent treatment without the attenuation of RDI may be associated with a better prognosis.Keywords: Febrile neutropenia, Cyclophosphamide, Doxorubicin, DLBCL

Background: Despite several attempts of randomized phase III trial to overcome R-CHOP in overall survival (OS), R-CHOP has been continued to be a standard of care in previously untreated DLBCL. We conducted a randomized phase II/III study (JCOG0601, jRCTs031180139) that investigated the efficacy of dose-dense weekly rituximab combined with standard CHOP regimen (RW-CHOP) during the early treatment period for previously untreated DLBCL and published the results (Ohmachi K, et al. Blood Adv. 2021). Here in, we report the long-term efficacy and safety of the JCOG 0601 trial after 8 years follow-up from the end of accrual. Methods: Patients aged 20-79 years with previously untreated CD20-positive DLBCL (stage I-IV, performance status 0-2) were randomized to standard R-CHOP (CHOP-21 with eight doses of rituximab, once every 3 weeks) or RW-CHOP (CHOP-21 with eight doses of weekly rituximab). The primary endpoint of phase III part was progression-free survival (PFS). Required sample size was 422 patients, an accrual period of 7 years, and a follow-up period of 3 years with the primary analysis. An additional follow-up period was added to assess long-term outcomes, for a total of 8 years of follow-up. Results: Between December 2007 and December 2014, 422 patients were enrolled, but primary analysis was performed on 421 patients after one patient withdrew consent: 213 in the R-CHOP arm and 208 in the RW-CHOP arm. The baseline characteristics were as follows (R-CHOP arm vs. RW-CHOP arm): median age, 61 vs. 62 years; male sex, 54.5% vs. 55.8%; Ann Arbor stage I/II/III/IV, 14.6/32.9/26.8/25.8% vs. 16.3/42.8/20.2/20.7%; and International Prognostic Index score ≤2, 77.0% vs. 87.5%. At a primary analysis, there was no significant difference in PFS between the arms. At the time of final analysis with a median follow-up of 9.6 years (range: 0.3-14.9) among all patients, meaningful differences were not found in PFS and OS as well as the primary analysist (hazard ratio [HR] in PFS of RW-CHOP against R-CHOP, 0.94; 95% confidence interval [CI], 0.67 to 1.32, one-sided log-rank, P = 0.36 and HR in OS, 0.94; 95% CI, 0.63 to 1.41). Median PFS and OS were not estimable in both arms. Estimated 10 years PFS and OS of all patients was 66.9% (95% CI, 62.1 to 71.3) and 78.0% (95% CI, 73.6 to 81.7). After the first relapse or refractoriness, 126 patients received post-protocol salvage therapy: 66 in the R-CHOP arm and 60 in the RW-CHOP arm. In each arm, 3 patients received high-dose chemotherapy followed by autologous stem cell transplantation. One patient in the R-CHOP arm proceeded to allogeneic stem cell transplantation from a sibling donor. Ann Arbor stage I to II disease tended to have more favor prognosis than Ann Arbor stage III to IV disease, and no sustained relapse was observed in either stage. Of the 401 patients who underwent central pathological review, 125 were diagnosed with germinal center B-cell-like (GCB) type and 216 with non-GCB type by immunohistochemistry analysis. There was no remarkable difference in PFS between the arms for GCB type and non-GCB type. Death occurred in 95 patients: 56 from DLBCL, 2 from treatment-related cardiac toxicity, 9 from treatment-related mortality caused by salvage treatment, 14 from secondary malignancies, and 11 from other diseases or reasons. There were 34 secondary malignancies in 31 patients (14.6%) in the R-CHOP arm, and 39 cases in 35 patients (16.8%) in the RW-CHOP arm. The most common secondary malignancies were lung cancer (2.6%), colon cancer (1.9%), prostate cancer (1.7%) and gastric cancer (1.9%). Three cases of acute myeloid leukemia (0.7%) and three of myelodysplastic syndromes (0.7%) were observed. The median age of patients who developed secondary malignancy was 72 years (range: 49-84) at the onset. The median time from study enrollment to the onset of secondary malignancy was 4.5 (range: 0.1-13.1) years and the incidence was time dependent. There were no unexpected adverse events, including late opportunistic infections. Conclusion: This final-follow up data demonstrated again no superiority of RW-CHOP in PFS and OS. Standard R-CHOP remains a standard of care for untreated DLBCL.

Introduction: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity of extranodal large B-cell lymphoma characterized by selective growth of lymphoma cells in the lumina of small vessels. The prognosis of IVLBCL is typically poor without timely diagnosis. Based on the promising efficacy of rituximab-containing chemotherapy and a high incidence of secondary central nervous system (CNS) involvement after rituximab-chemotherapy, we conducted the PRIMEUR-IVL study to explore the efficacy of CNS-oriented therapy with rituximab-chemotherapy whose primary analysis demonstrated 2-year progression-free survival (PFS) of 76% and 2-year overall survival (OS) of 92% with a low incidence of secondary CNS involvement of 3%. Patients and Methods: The PRIMEUR-IVL study is a multicenter, single-arm, phase 2 trial at 22 hospitals in Japan for untreated histologically confirmed IVLBCL patients without apparent CNS involvement at diagnosis. The treatment regimen includes three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) followed by two cycles of rituximab with high-dose methotrexate and additional three cycles of R-CHOP. Intrathecal chemotherapy including methotrexate, cytarabine, and prednisolone was administered four times during the R-CHOP phase. We present a preplanned final analysis of the PRIMEUR-IVL study including 5-year PFS, OS and secondary CNS involvement. Results: A total of 38 patients were enrolled, of whom 37 patients were eligible. One patient with a history of testicular lymphoma was excluded. As of July 2021, with a median follow-up of 7.1 years (interquartile range 5.6–8.7), 5-year PFS in all eligible patients was 68% (95% confidence interval [CI] 50%–80%) and OS was 78% (95% CI 61%–89%). Median PFS and OS were not reached. No additional secondary CNS involvement was observed after primary analysis with 3% of cumulative incidence. Severe adverse events after the primary analysis were grade 4 neutropenia (n = 1) and grade 4 myelodysplastic syndrome that did not require specific treatment (n = 1). During the observation period after enrollment, there were a total of eight deaths due to following reasons: primary disease (n = 6), sepsis (n = 1), and unknown sudden death (n = 1). Conclusions: In this 5-year, long-term follow-up analysis of the PRIMEUR-IVL study, frontline treatment of CNS-oriented therapy with standard R-CHOP for untreated IVLBCL patients without apparent CNS involvement provided durable response and clinically meaningful results for PFS, OS, and low incidence of secondary CNS involvement with manageable toxicity. Our result provides one of active treatment for untreated IVLBCL patients. The research was funded by: The Practical Research for Innovative Cancer Control, the Japan Agency for Medical Research and Development (AMED), Japan, JP19ck0106511 and the National Cancer Center Research and Development Fund, 23-A-17 and 26-A-4. The research was supported by the Center for Supporting Hematology-Oncology Trials (C-SHOT). Keyword: chemotherapy Conflicts of interests pertinent to the abstract K. Shimada Honoraria: AstraZeneca, Chugai, Eisai, Kyowa Kirin, Symbio M. Yamaguchi Honoraria: AbbVie, Bristol Myers Squibb, Chugai, Janssen, Kyowa Kirin, Meiji Seika, MSD, Nippon Shinyaku, SymBio, Takeda Research funding: AstraZeneca, Chugai Pharma, Genmab, Incyte, Eisai, Takeda, Nippon Shinyaku, Otsuka, Asahi Kasei, Kyowa Kirin, Chugai H. Nagai Honoraria: Kyowa Kirin, Takeda, Chugai, Bristol Myers Squibb, Eisai, Novartis, Janssen, Mundi Pharma, Lilly, AstraZeneca, Ono, Meiji, AbbVie, Nippon Shinyaku, GSK, Sumitomo Pharma, Genmab, CSL Behring Research funding: Kyowa Kirin, Takeda, Chugai, Bristol Myers Squibb, Janssen, AstraZeneca, Ono, AbbVie, Nippon Shinyaku, Daiichi-Sankyo, Zenyaku Kogyo, Solasia J. Takizawa Honoraria: Chugai, Kyowa Kirin N. Fukuhara Honoraria: Chugai, Genmab, AbbVie, Takeda, Eli Lilly, AstraZeneca, Meiji Seika, Ono, Janssen, Bristol-Myers Squibb, Eisai, Kyowa Kirin, Symbio, Novartis Research funding: Chugai, Genmab, AbbVie, Takeda, Eli Lilly, Incyte, Chordia Therapeu D. Ennishi Honoraria: Eisai, Kyowa Kirin, Chugai Research funding: Nippon Shinyaku, Chugai Y. Minami Consultant or advisory role: Takeda, Novartis Honoraria: Bristol-Myers Squibb, Novartis, Pfizer, Daiichi Sankyo, Astellas Research funding: CMIC, Bristol-Myers Squibb, Novartis, Takeda, Chugai, Ono Y. Atsuta Consultant or advisory role: Meiji Seika, JCR Pharmaceuticals, Kyowa Kirin Honoraria: Novartis, AbbVie H. Kiyoi Honoraria: Novartis, Astellas, AbbVie, Chugai Research funding: Zenyaku Kogyo, Nippon Shinyaku, Chugai, Astellas, Kyowa Kirin, Takeda, Sumitomo Pharma, Sanofi, Eisai, Ono, FUJIFILM, Kyowa Kirin, Otsuka, Perseus Proteomics, Daiichi Sankyo, CURED, Bristol-Myers Squibb, AbbVie

Introduction The impact of progression-free survival status at 24 months (PFS24) or event-free survival status at 24 months (EFS24) on subsequent survival has been evaluated in patients with various lymphoma subtypes. Patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who achieve PFS24 or EFS24 generally have excellent outcomes. It has been observed that the overall survival (OS) after achieving EFS24 was not significantly different from that of the general population (M.J. Maurer. J Clin Oncol, 2014). However, the OS after achieving PFS24 was significantly worse than that of the general population (M.J. Maurer. Ann Oncol, 2018). Consequently, the impact of achieving PFS24 for DLBCL patients remains controversial. In this supplementary analysis, we evaluated the impact of achieving PFS24 on the subsequent survival of untreated DLBCL patients by using data from JCOG0601, a randomized phase2/3 study assessing the schedule of rituximab administration in combination with tri-weekly CHOP (Ohmachi K. Blood Adv, 2021). Methods Among 422 patients enrolled between Dec 2007 and Dec 2014 in JCOG0601, 409 patients were eligible for this analysis (Data cutoff date: Dec 19, 2017). PFS24 was defined as being alive without progression or relapse for 24 months from randomization. The protocol treatment was initiated within 7 days after randomization. OS from PFS24 was defined as the time from achieving PFS24 or the date of progression or relapse to death from any cause. We compared OS from PFS24 with that of age-, sex-, and calendar period-matched Japanese general population using standardized mortality ratios (SMRs). Similarly, PFS12 and PFS60, as well as OS from PFS12 and PFS60, were defined in the same manner as PFS24 and OS from PFS24. The log-rank P-values for OS were calculated. Results The baseline characteristics of the 409 patients were as follows: a median age of 62 years (range, 20-79), with males accounting for 56% (n=227) of the patients. At diagnosis, 46% (n=188) of the patients were Ann Arbor stage III or IV. The majority of patients (82%; n=335) were classified as international prognostic index low or low-intermediate risk. Based on the Hans algorithm for cell-of-origin, 51% (n=210) of the patients were categorized as non-germinal center B-cell type (non-GCB). At a median follow-up of 5.3 years among all patients, a total of 334 patients (82%) achieved PFS24, while 66 patients (16%) failed to achieve PFS24. Five patients died without progression within 24 months, and four patients were lost to follow-up within 24 months. Multivariable analysis revealed that risk factors for failing to achieve PFS24 included serum LDH levels higher than the upper normal limit and two or more extranodal lesions. Patients who achieved PFS24 had a significantly better OS than those who failed to achieve PFS24 (median OS, not reached vs. 1.3 years; P < 0.001). Similar results were observed when using PFS12 and PFS60, regardless of the cell-of-origin. Among the patients who failed to achieve PFS24, non-GCB type patients more frequently had relapsed or refractory diseases in extranodal sites (72%: n=26/36) compared to GCB type patients (43%; n=6/14). The OS after achieving PFS24 or PFS60 was not remarkably different from that of the general population (PFS24: SMR 1.29, 95% confidence interval [CI] 0.72-2.12, P = 0.39; PFS60: SMR 1.43, 95% CI 0.47-3.33, P = 0.55). However, the OS after achieving PFS12 was significantly worse than that of the general population (SMR 2.30, 95%CI 1.59-3.22, P < 0.001). The primary cause of death for patients achieving PFS12 was DLBCL with the cumulative incidence of more than 5% at 5 years, while the incidence of death due to DLBCL was less than 5% for those achieving PFS24. The primary cause of death for the patients achieving PFS24 was other diseases except for DLBCL and treatment-related toxicity, including secondary malignancies (n=4/7) and pneumonia (n=3/7). Conclusion Newly diagnosed DLBCL patients treated with R-CHOP who achieved PFS24 exhibited an excellent subsequent outcome, which did not differ from those of age-, sex-, calendar-period matched individuals in the general population. Our findings suggest that PFS24 achievement could serve as a surrogate endpoint for OS in DLBCL patients. Further research is warranted to establish the utility of PFS24 achievement as a reliable milestone in clinical practice.

Introduction R-CHOP (rituximab, cyclophosphamide [CY], doxorubicin [DXR], vincristine [VCR], and prednisolone) is the standard of care for diffuse large B-cell lymphoma (DLBCL) and cures around 60% of patients. However, some DLBCL survivors suffer from long-lasting peripheral neuropathy (PN) caused by VCR, and the dose of VCR is usually decreased to prevent severe PN. Though, there is a lack of information regarding the effect of VCR dose reduction on DLBCL prognosis, especially based on data from prospective clinical trials. Recently, VCR dose reduction was not associated with poor prognosis in patients with aggressive B-cell lymphomas, based on the results of the RICOVER-60 trial (NCT00052936) (Bewarder et al., Haematologica 2023). In this trial, R-CHOP was administered in 14-day cycles. To evaluate the clinical impact of relative dose intensity (RDI) of VCR (RDI O) in patients with DLBCL treated with tri-weekly R-CHOP (R-CHOP21), we conducted a supplemental analysis of the JCOG0601: randomized phase II/III trial of the Japan Clinical Oncology Group (jRCTs031180139). In the JCOG0601 trial, RW-CHOP21 (CHOP21 with eight doses of weekly rituximab) and R-CHOP21 were compared for progression-free survival (PFS) (Ohmachi et al., Blood Adv. 2021). Methods Between 2007 and 2014, 422 patients were enrolled in the JCOG0601 trial. Among them, 401 patients who received at least six courses of R-CHOP21 (n=206) or RW-CHOP21 (n=195) were eligible for this supplemental analysis. Those who could not complete six courses of chemotherapy were excluded because their treatment outcomes might be impaired mainly due to their disease aggressiveness and not the dose intensity of chemotherapy. As PFS was not significantly different between the two treatment arms, these 401 patients were analyzed together (Figure A). The impact of decreased RDI O on PFS was assessed using the Cox proportional hazard model and two-sided log-rank p-values with several cutoff values of RDI O (95, 90, 85, 80, 70, 60, or 50%). The VCR dose was reduced according to the protocol. As a subgroup analysis, the impact of RDI O was evaluated in patients whose RDI of CY and DXR (RDI C+H) were retained, defined as RDI C+H were both ≥85% (high RDI C+H), or not retained, defined as either or both of RDI C+H were <85% (low RDI C+H). Clinical factors, including the cell of origin (COO), as defined by the Hans algorithm, were evaluated for their association with poor PFS. Result The baseline clinical characteristics of the 401 patients were as follows: median age, 62 years (range, 20-79), male sex (54.6%); performance status of 0 or 1 (97.5%); Ann Arbor stage Ⅰ or Ⅱ (53.4%); and International Prognostic Index (IPI) of low or low-intermediate (82.6%). The median RDI O of the 401 patients was 97% (interquartile range [IQR], 89-100). The median RDI of CY and DXR were as high (96% each). At the data cut-off date (Dec 2017), the median follow-up time was 59.4 months, and the 3-year PFS was 81.5% (95% confidence interval [CI], 77.3-85.0). Among the cutoff values investigated, 95% of RDI O (<95% [n=161], ≥95% [n=240]) showed the smallest p value (log-rank test, p = 0.0679), and the hazard ratio (HR) of low RDI O against high RDI O was 1.452 (95% CI, 0.971-2.171) (Figure B); RDI O <95% clinically means VCR dose was reduced in one or more times. A cutoff value of 95% was used for further analyses. Patients with RDI O <95% tended to have low RDI C+H. According to RDI O of <95% vs. ≥95%, there was a similar difference in the subgroup of patients with high RDI C+H as in the whole population (n=324, HR 1.508, 95% CI 0.934-2.434), but no remarkable difference in low RDI C+H (n=77, HR 0.932, 95% CI 0.432-2.009). Multivariable analysis revealed that the presence of B symptoms (HR 1.859, 95% CI 1.078-3.207) and high-intermediate or high IPI scores (HR 1.721, 95% CI 1.031-2.873) were risk factors for PFS. However, neither RDI O <95%, low RDI C+H, nor COO subtypes showed no remarkable impact on poor PFS in this patient population. Conclusion Our study demonstrated that among patients with DLBCL who completed six or more courses of R-CHOP21, VCR dose reduction was not associated with poor PFS as much as the presence of B symptoms and high IPI risk. VCR dose reduction driven by toxicity might not impair its efficacy if patients can complete R-CHOP21 therapy.

Supplementary Data. 1. Supplementary Methods 2. Supplementary Data Supplementary Table 1, Patient information at sampling. Supplementary Figure 1, A: Genomic alterations of both tumor and normal samples in Cases A-16, A-20, and A-35. B: Analysis of TCR-γ gene rearrangement in a case. Supplementary Figure 2, Re-expression of INK4a or ARF into ATL cell lines. Supplementary Table 2, Status of CD58 and B2M in ATL samples. Supplementary Table 3, Genetic alterations related to acute transformation of chronic type ATL. 3. References

The cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen, containing doxorubicin (DXR), which is a key drug for aggressive non-Hodgkin lymphoma (NHL), is a standard chemotherapeutic regimen; however, its administration in elderly patients is often intolerable. Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracycline developed in Japan. We have conducted a phase II trial of a full-dose THP-COP (modified CHOP regimen with DXR replaced by THP) regimen for elderly patients with newly diagnosed, advanced-stage, aggressive NHL. Patients aged 70–79 years old with previously untreated NHL according to the Working Formulation (D through H and J), disease stage I with a bulky mass or stage II–IV, and performance status of 0–1 were eligible. The THP-COP regimen, which consisted of 750-mg/m2 cyclophosphamide, 50-mg/m2 THP, 1.4-mg/m2 vincristine (capped at 2.0 mg) on day 1, and 100-mg prednisolone daily on days 1 to 5, was delivered every 3 weeks for 6 cycles. The primary endpoint was complete response (CR) rate. Twenty-nine patients were enrolled in the study. The CR rate was 65.5% (95% confidence interval, 45.7–82.1%). The 3-year failure-free and overall survival rates were 54.1% and 53.9%, respectively. The most frequent observed grade 3 or 4 toxicity was neutropenia, which occurred in 80% of the patients. Grade 3 cardiac dysfunction was observed in one patient. The full-dose THP-COP regimen exhibited similar efficacy and safety, and a tendency for less cardiac toxicity, when compared with the standard CHOP regimen in elderly Japanese patients with newly diagnosed, advanced-stage, aggressive NHL.

The clinical characteristics of B-cell lymphoma (BCL) were studied through the combined analysis of six clinical trials conducted by the Japan Clinical Oncology Group - Lymphoma Study Group (JCOG-LSG) for aggressive lymphoma in the 1990s, before the introduction of rituximab. Through a central pathological review, 829 patients were diagnosed with BCL according to the World Health Organization classification and treated with doxorubicin-containing combination chemotherapies. Of these patients, 642, 104, 30, and 24 patients were diagnosed with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL), respectively. The overall survival (OS) of FL and MZL patients was higher than that of patients with DLBCL and MCL. The OS of the MCL patients was higher than that of DLBCL patients in the first 5 years, but MCL had the lowest survival after 5 years. The OS of DLBCL patients was clearly stratified by the international prognostic index and showed data compatible with that of aggressive lymphoma in the pre-rituximab era. These results established the clinical aspects of BCL in a large number of patients treated in prospective studies during the pre-rituximab era in Japan.

A labscale continuous CO2 capture system for coalfired power plants with amine-impregnated solid sorbents was optimized using process simulation. The system comprises three-column fixed-bed sorbents, and a steam-aided vacuum swing absorption (SA-VSA) was used as the CO2 capture/recovery process. The simulation was performed using Aspen Adsorption V10. First, the effect of three sensitive parameters, namely, regeneration steam volume, rinsing time, and feed-gas moisture, was simulated and the obtained results were compared with the experimental values. As a result, the simulated values agreed well with those of the experimentals. After the reliability of the simulator has been demonstrated, a cycle time and each process time was optimized by the simulation. As a result, the potential for further reduction of the regeneration heat without lowering the amount of CO2 capture was measured by simulation. Finally, the simulation-suggested process was experimentally confirmed and then optimized with 540 s of cycle time, which successfully demonstrated a minimum regeneration heat of 1.2 GJ/t-CO2 (not including electric energy of vacuum pump) with high recovery rate (>= 90%), purity (>= 99%), and continuous CO2 capturing. Therefore, this simulation-based optimization technique would be useful for optimizing the CO2 capture process with an amine-impregnated solid sorbent.

BACKGROUND:The occurrence of transfusion-transmitted hepatitis B virus (HBV) infection has fallen dramatically due to continuous improvements in pre-transfusion laboratory testing. However, the characteristics of transfusion-transmitted HBV infection caused by individual donor nucleic acid amplification test (ID-NAT)-negative blood products are unclear.CASE PRESENTATION:A 76-year-old woman with acute myeloid leukemia was diagnosed with transfusion-transmitted HBV infection after receiving apheresis platelets derived from an ID-NAT-negative blood donation. This case was diagnosed definitively as transfusion-mediated because complete nucleotide homology of a 1556 bp region of the HBV Pol/preS1-preS2-S genes and a 23 bp region of the HBV core promoter/precore between the donor and recipient strains was confirmed by PCR-directed sequencing. The case is uncommon with respect to the unexpectedly prolonged HBV-DNA incubation period of nearly 5 months after transfusion (previously, the longest period observed since the recent implementation of ID-NAT pre-transfusion laboratory testing in Japan was 84 days). Slow-replicating HBV genotype A2 may contribute to the prolonged incubation period; also, the quantity of apheresis platelets delivered in a large volume of plasma, and/or the immune response of the recipient suffering from a hematological neoplasm, may have contributed to establishment of HBV infection in the recipient. This was supported by analysis of three previously documented cases of transfusion-transmitted HBV infection by blood products derived from ID-NAT-negative donations in Japan.CONCLUSION:Continuous monitoring of HBV infection for longer periods (>3 months) may be required after transfusion of blood components from an ID-NAT-negative HBV window donation.

Rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) is the standard of care for untreated diffuse large B-cell lymphoma (DLBCL). However, the schedule for rituximab administration has not been optimized. To compare standard R-CHOP with CHOP plus dose-dense weekly rituximab (RW-CHOP) in patients with untreated DLBCL, we conducted a phase 2/3 study (JCOG0601, jRCTs031180139). Patients were randomly assigned to R-CHOP (CHOP-21 with 8 doses of rituximab once every 3 weeks [375 mg/m2]) or RW-CHOP (CHOP-21 with 8 doses of weekly rituximab [375 mg/m2]) groups. The primary end point of the phase 2 component was percent complete response (%CR) of the RW-CHOP arm, whereas that of the phase 3 component was progression-free survival (PFS). Between December 2007 and December 2014, 421 untreated patients were randomly assigned to R-CHOP (213 patients) or RW-CHOP (208 patients). The %CR in the RW-CHOP arm was 85.3% and therefore met the prespecified decision criteria for the phase 2 component. With a median follow-up of 63.4 months, the 3-year PFS and overall survival were 79.2% and 88.7% in the R-CHOP arm and 80.3% and 90.4% in the RW-CHOP arm, respectively. There was no significant difference in PFS (hazard ratio, 0.95; 90.6% confidence interval, 0.68-1.31). Although the safety profile and efficacy of RW-CHOP was comparable with R-CHOP and its tolerability was acceptable, weekly rituximab in combination with CHOP during the early treatment period did not improve PFS in untreated patients with DLBCL. This trial was registered at jrct.niph.go.jp as #jRCTs031180139.

7551 Background: CD5+ DLBCL is characterized by a poor prognosis and frequent central nervous system (CNS) relapse after standard immunochemotherapy. In the primary analysis of our multicenter phase II study of DA-EPOCH-R/HD-MTX for newly diagnosed stage II-IV CD5+ DLBCL, the 2-year (yr) progression-free survival (PFS) was 79% and the 2-yr CNS relapse rate was 9% at a median follow-up of 3.1 yrs (Miyazaki, et al. 2020). The aim of this preplanned 5-yr follow-up was to assess PFS, overall survival (OS), the CNS relapse rate, and late toxicity. Methods: A total of 47 patients (pts) with newly diagnosed stage II-IV CD5+ DLBCL between 20-75 yrs old and ECOG PS of 0-3 were enrolled. The treatment included 4 cycles of DA-EPOCH-R followed by 2 cycles of HD-MTX (3.5 g/m 2 ) and 4 additional cycles of DA-EPOCH-R. Intrathecal administration of MTX and/or cytarabine was not allowed. 45 (96%) pts completed the protocol treatment. The data were updated as of December 1, 2020. Results: The median follow-up of alive pts was 6.0 yrs (range, 5.0-7.7). The pts’ characteristics were as follows: age, 37-74 yrs (median, 62); male, 38%; ECOG PS > 1, 4%; stage III/IV, 57%; IPI HI/H, 47%; CNS-IPI high, 21%; and ABC/GCB/unclassified (n = 46), 85%/9%/7%. The 5-yr PFS and OS were 72% (95% CI, 57-83%) and 79% (95% CI, 64-88%), respectively. The 5-yr PFS and OS of pts with CD5+ ABC DLBCL (n = 39) were 72% and 74%, respectively. The 5-yr CNS relapse rate in all 47 pts was 9% (95% CI, 3-22%). There were no CNS relapse events after the primary analysis. Neither grade 3/4 late adverse events nor cardiac events of any grade were observed. Possible second malignancies were recorded in 6 (13%) pts. Among them, one pt who received R-ICE as salvage therapy experienced acute myeloid leukemia. The other 2 pts had colon cancers treated with endoscopic polypectomy/mucosal resection. Conclusions: Both the survival benefit and safety of DA-EPOCH-R/HD-MTX were maintained during a 5-yr follow-up, indicating the excellent efficacy, and safety of this approach as a first-line therapy for CD5+ DLBCL. Clinical trial information: UMIN000008507.