Relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) has a poor prognosis, particularly in patients ineligible for autologous stem cell transplantation or cellular immunotherapy. This study evaluated the effectiveness of polatuzumab vedotin combined with rituximab and bendamustine (PBR) therapy in comparison to conventional chemotherapy in patients with R/R DLBCL. Of 86 patients with first relapse or primary refractory DLBCL, 32 received PBR in any subsequent line, while 54 received conventional chemotherapy alone. For comparison, 32 baseline-matched patients were selected from these 54 and defined as the conventional chemotherapy group. The median overall survival (OS) for all patients was 17.3 months (range, 1.5–85.7 months), with the PBR-treated group showing significantly improved outcomes (median OS 19.7 vs. 15.8 months, P = 0.025). Univariate and multivariate analyses identified PBR as a favorable prognostic factor for OS. In the second-line setting, 41.2

A comprehensive analysis of metabolites (metabolomics) has been proposed as a new strategy for analyzing liquid biopsies and has been applied to identify biomarkers predicting clinical responses or adverse events associated with specific treatments. Here, we aimed to identify metabolites associated with bortezomib (Btz)-related toxicities and response to treatment in newly diagnosed multiple myeloma (MM). Fifty-four plasma samples from transplant-ineligible MM patients enrolled in a randomized phase II study comparing two less-intensive regimens of melphalan, prednisolone and Btz (MPB) were subjected to the lipidomic profiling analysis. The amount of each lipid metabolite in plasma obtained prior to MPB therapy was compared to toxicity grades and responses to MPB therapy. High levels of 7 phospholipids (4 lysophosphatidylcholines and 3 phosphatidylcholines) were observed in cases with Btz-induced ≥ grade 2 peripheral neuropathy (BiPN) (n = 11). In addition, low levels of 3 fatty acids (FAs)—FA (18:2), FA (18:1), and FA (22:6)—were observed in patients who developed severe skin disorders ≥ grade 2 (n = 10). No metabolite significantly associated with treatment response was identified. We conclude that levels of specific plasma lipid metabolites are associated with the severity of BiPN and skin disorders in patients with MM. These metabolites may serve as candidate biomarkers to predict Btz-induced toxicity in patients with MM before initiating Btz-containing therapy.

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

Diarrhea is a frequently observed side effect of abemaciclib, and hepatotoxicity has also been reported as a serious side effect. In clinical trials, a higher incidence of hepatotoxicity has been reported in Japanese patients, so we conducted this study to determine the incidence of hepatotoxicity in clinical practice and to identify risk factors.

While the field of medical oncology has made tremendous progress, a variety of adverse events cannot be avoided. Among these, serious adverse events (SAEs) are required to be managed by the institution. Therefore, we have defined SAEs as "emergency hospitalization within one month after anticancer drug administration" and have launched a database system that ensures the collection of every object (presented in the 19th JSMO annual meeting). This database includes infrequent but important events such as hepatitis B virus reactivation and pneumocystis pneumonia (PCP) (presented in the 24th annual meeting of Japanese Society for Health Care Management).

Since the introduction of dose dense regimens, we observed an increase in Pneumocystis jiroveci Pneumonia (PCP) incidence in cases treated with dose dense Adriamycin/Cyclophosphamide (ddAC) regimen for adjuvant or neoadjuvant chemotherapy in our institution. We identified the incidence of PCP in this population and evaluated risk factors.

Background: Secondary central nervous system involvement (sCNSi) during the clinical course of diffuse large B-cell lymphoma (DLBCL) develops in approximately 5% of patients, and has a poor prognosis. The features of sCNSi in patients identified as higher risk according to international prognostic index (IPI) and CNS-IPI have been well evaluated, however those in patients with sCNSi who are lower risk by IPI or CNS-IPI are not yet fully understood. Aims: To explore the characteristics of sCNSi in patients who participated in JCOG0601 and were considered mainly low risk according to IPI. Methods: Of 409 eligible patients in the JCOG0601 randomized controlled trial, we evaluated patients who developed sCNSi at their first progression. The JCOG0601 trial compared standard R-CHOP-21 (arm A, n = 204) and RW-CHOP-21 in which rituximab is administered 8 times per week from the commencement of treatment (arm B, n = 205) for untreated patients with DLBCL (Ohmachi K, et al. Blood Adv. 2021;5:984). Patients were grouped according to IPI as follows: in arm A, 92 in lower risk (L), 67 in low-intermediate risk (L-I), 33 in high-intermediate risk (H-I), and 15 in high risk (H); in arm B, 112 in L, 67 in L-I, 18 in H-I, and 8 in H. Patients at lower risk of IPI accounted for 82% of the total. The risk of CNS-IPI in each arm was as follows: in arm A, 91 in L, 96 in intermediate (I), and 17 in H; in arm B, 112 in L, 84 in I, and 9 in H. The protocol did not allow CNS prophylaxis. The cumulative incidence (CI) of sCNSi was calculated with consideration to competing risks of death and non-CNS progression or relapse. Results: Median follow-up was 4.9 years, during which 21 patients (5.1%) developed sCNSi. The 5-year overall CI of sCNSi was 5.1%, and that in L, I, and H of CNS-IPI was 4.0%, 5.3%, and 11.5%, respectively. Five-year CI of sCNSi was 7.3% in arm A and 2.9% in arm B (Gray’s test, p = 0.11). The CI of sCNSi by CNS-IPI was 5.6% in L, 6.8% in I, and 17.6% in H in arm A; and 2.7% in L, 3.6% in I, and 0% in H in arm B. Of the 21 patients with sCNSi, 8, 10, and 3 were categorized as L, I, and H of CNS-IPI, respectively. Common locations of extranodal lesions at the time of registration in patients with sCNSi were stomach (n = 4), paranasal cavity (n = 3), and bone marrow (n = 2). In particular, 2 of 3 patients with paranasal cavity lesions were categorized as L or I of CNS-IPI. In univariable analysis, paranasal cavity lesion was a high-risk factor for sCNSi (subdistribution hazard ratio, 4.34 [95% confidence interval, 1.28–14.73], p = 0.018). Kidney and adrenal gland, which are high-risk organs in CNS-IPI, were not high risk in this analysis. Median overall survival (OS) after sCNSi was 1.3 years, with 2-year OS of 39.3%. Summary/Conclusion: sCNSi in DLBCL patients at lower risk of CNS-IPI was low, as previously reported, but those with paranasal cavity lesions developed sCNSi despite the lower risk of CNS-IPI.

Introduction Copy number alterations (CNAs) of chromosome 9p24.1 are frequently observed in patients (pts) with classic Hodgkin lymphoma (cHL), which result in increased expression of programmed death ligand-1 on Reed-Sternberg (RS) cells. The amplification of 9p24.1 was found in approximately 50% of pts with advanced-stage cHL, and was an independent prognostic factor for worse progression-free survival (PFS) (Roemer MG, et al. JCO. 2016). In addition, 9p24.1 CNAs is thought to be one of the potential predictive markers for response of immune checkpoint blockade for cHL (Gerhard-Hartmann E, et al. BJH. 2022). However, the incidence or prognostic impact of 9p24.1 CNAs in elderly pts with newly diagnosed advanced-stage cHL remains unclear. In this ancillary analysis of a multi-center retrospective study (HORIZON study, UMIN000033264), we evaluated clinical impact of 9p24.1 CNAs in elderly pts with newly diagnosed advanced-stage cHL who received a doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Methods The key eligibility criteria of the current analysis were as follows: 1) pts with histologically diagnosed cHL between 2007 and 2016 in each institution; 2) advanced-stage cHL (stage III, IV or IIB with bulky or extranodal lesion); 3) age at diagnosis > 60 years; 4) had received at least one cycle of ABVD as initial treatment including a modified ABVD regimen (dacarbazine dose reduced to 250 mg/m2); and 5) had available specimen for tissue fluorescence in situ hybridization (FISH) analysis. All specimens were centrally reviewed by 3 experienced hematopathologists and confirmed the diagnosis of cHL. In the tissue FISH analysis, CNAs of the 9q24.1 loci along with the expression of CD30 were simultaneously detected using a combination of immunofluorescence with Fluorescence Immunophenotyping and interphase Cytogenetics as a Tool for Investigation of Neoplasia (FICTION), as described previously (Martínez-Ramírez A, et al. Leukemia. 2004). A median number of 50 RS cells (range: 30 to 74 RS cells) per case were analyzed. According to the previous report (Roemer MG, et al. JCO. 2016), nuclei with a target:control probe ratio of ≥ 3:1 were defined as amplification, and those with a probe ratio of > 1:1 but , < 3:1 were classified as relative copy gain. Nuclei with a probe ratio of 1:1 but more than two copies of each probe were defined as polysomic for chromosome 9p. In each case, the percent and magnitude of 9p24.1 amplification, copy gain, polysomy, and normal copy numbers (disomy) were noted. Cases were classified by the highest observed level of 9p24.1 CNAs. As survival analysis, overall survival (OS), PFS, and event-free survival (EFS; defined as the time from a diagnosis of cHL to disease progression or relapse, subsequent systemic chemotherapy for cHL, or death due to any cause), were evaluated. Results Among 99 eligible pts, the median age was 71 years (interquartile range [IQR] 65-77). The numbers of pts with an ECOG performance status (PS) 2 or more and B symptoms were 17 (17%) and 50 (51%), respectively. Sixty pts (61%) had mixed cellularity cHL, and 28 pts (28%) had nodular sclerosis cHL. Forty-five pts (45%) were positive for EBV-encoded small RNA (EBER) in situ hybridization. Hypoalbuminemia [serum albumin <4 g/dL] and anemia [hemoglobin <10.5 g/dL], were observed in 84 (85%), and 37 pts (37%), respectively. All the 99 pts had 9p24.1 CNAs; 67 pts (68%) had amplification, and the remaining 32 pts (32%) had copy gain (Figure 1). Hypoalbuminemia and anemia were significantly more frequent among pts with 9p24.1 amplification. The incidence of 9p24.1 amplification in EBER-positive cases tend to be higher than that of EBER-negative cases (78% in pts with EBER- positive vs. 59% in pts with EBER-negative, P=0.056). With a median follow-up duration of 52 months, the estimated OS, PFS, and EFS at 5 years in pts with 9p24.1 amplification were 80.1%, 64.2%, 59.9%, respectively. The estimated 5-year OS, PFS, and EFS of pts with 9p24.1 copy gain were 71.2%, 58.4%, 55.7%, respectively. No statistical differences were observed regarding these survival parameters between those pts with amplification and copy gain. Conclusion This ancillary analysis showed that hypoalbuminemia and anemia were significantly more frequent among pts with 9p24.1 amplification. Nevertheless, 9p24.1 amplification was not a prognostic factor for OS, PFS, and EFS in elderly pts with advanced-stage cHL treated with ABVD in the present study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

We conducted a randomized phase II study to determine a more promising modified MPB regimen for TI-NDMM (JCOG1105, jRCTs031180097). The primary analysis in JCOG1105 revealed that Arm A (known as PETHEMA/GEM05 MPB) showed a higher CR rate and longer PFS without intolerable toxicities compared with Arm B (a further less intensive MPB) at a median follow-up period of 26 months, suggesting that the twice-weekly dosing of bortezomib in the first cycle along with a higher dose of melphalan and higher cumulative dose of both bortezomib and melphalan influenced the efficacy of the modified MPB regimen in patients with TI-NDMM1 (Appendix S1). Here, we report the updated results from preplanned analysis of JCOG1105 with a 3-year follow-up from the end of accrual. Between July 2013 and April 2016, in total 91 patients were randomized to Arm A (45 patients) and Arm B (46 patients). As for the data cut-off (June, 2019), the median follow-up period of all eligible patients was 47.3 months (range 10.4–71.1). The PFS rates at 1, 3, and 5-years (95% CI) were 86.0% (71.6%–93.5%), 27.9% (15.6%–41.6%), and 16.4% (5.8%–31.8%) in Arm A, and 73.3% (57.8%–83.9%), 13.3% (5.4%–24.9%) and not estimable in Arm B with the HR of Arm B to Arm A being 1.69 (95% CI 1.06–2.68; Figure 1A). Predefined subgroup analyses of PFS are shown in Figure 2. Female patients seemed to have better PFS in Arm A (HR in Arms B to A, 2.87 [95% CI 1.34–6.61]) compared with male patients (HR in Arms B to A, 1.18 [95% CI 0.66–2.13]; Figure 2A,B), and patients with PS 2-3 also showed a tendency to have better PFS in Arm A (HR in Arms B to A, 4.32 [95% CI 1.42–13.1]), unlike patients with PS 0–1 (HR in Arms B to A, 1.44 [95% CI 0.85–2.45]; Figure 2C,D). The OS rate at 5 years was 73.4% (95% CI 54.8%–85.3%) in Arm A and 56.8% (95% CI 31.2%–76.0%) in Arm B, respectively (HR in Arms B to A, 1.58 [95% CI 0.71%–3.53]) (Figure 1B). The OS was similar between Arms A and B. In total, 25 patients (10 in Arm A and 15 in Arm B) died during the follow-up period, with a tendency toward numerical imbalance regarding death from myeloma (six in Arm A and 11 in Arm B). In comparison with AEs reported in the primary analysis,1 there were no marked changes in the incidence and severity of AEs reported in the final analysis. There are no reports regarding the influence of gender on the survival of patients with TI-NDMM who were treated with a bortezomib-containing regimen, and the reason why female patients seemed to have a better PFS in Arm A in the present study seemed to be unclear. Although there was a slight imbalance in the number of patients with International Staging System (ISS) stage III (14 males and two females) and expression of adverse chromosomal translocation-associated genes (FGFR3 or MAF mRNA; three males and seven females), other patient characteristics, treatment exposure including percentage planned dose of bortezomib, melphalan, and prednisolone and incidence of AEs were similar between female and male patients. Among patients with PS 2–3 at study enrollment (10 patients each in both arms), the long-term PFS in Arm A also tended to be better compared with that in Arm B. As our eligibility criteria permitted the enrollment of patients with PS 3 only resulting from osteolytic lesions (six patients in Arm A and eight patients in Arm B), rapid responses to treatment and improvement of patients' condition could have resulted in better PFS in Arm A. In JCOG1105, although a higher median cumulative dose of melphalan was administered in Arm A (324 mg/m2) compared with in Arm B (252 mg/m2), a lower incidence of second primary malignancies was observed in Arm A (one patient) compared with in Arm B (five patients; Table 1). This result was consistent with the long-term follow-up findings of the VISTA study2 that showed no increased risk of second primary malignancies with MPB. In summary, the final analysis of JCOG1105 demonstrated that twice-weekly dosing of bortezomib in the first cycle along with higher dose of melphalan and higher cumulative dose of both bortezomib and melphalan (Arm A) confers sustained PFS benefit with no new AE-related concerns. However, a continued risk of relapse was observed in both arms because maintenance therapy was not recommended and all patients except two did not receive maintenance therapy in JCOG1105. Based on the results of this study, we are now conducting a next clinical trial incorporating anti-CD38 antibody and fixed-duration maintenance therapy combined with a modified MPB regimen and assessment of high-risk cytogenetics and MRD (JCOG1911; jRCTs031200320). DM, SI, and RM conceived and designed the study; all authors provided study materials and recruited patients; DM, SI, and RM collected, analyzed, and interpreted the data; DM, SI, and RM wrote the manuscript; all authors gave final approval of the manuscript. We thank the JCOG Data Center/Operations Office for their support in data and study management. This work was supported in part by the National Cancer Center Research and Development Funds (26-A-4, 29-A-3, and 2020-J-3), a Grant-in-Aid for Clinical Cancer Research (H26-kakushin-teki-gan-ippan-074) from the Ministry of Health, Labour and Welfare of Japan, and by the Japan Agency for Medical Research and Development under grant nos. JP16ck0106077, JP19ck0106348 and 21ck0106685h0001 (DM). DM reports honoraria (Janssen, Mundhipharma, Eisai, Chugai); research funding (Celgene, Novartis, Chugai, Ono, Takeda, Janssen, MSD). SI, an editorial board member of Cancer Science, reports honoraria (Celgene, Sanofi, Janssen, Takeda, Ono, Bristol Myers Squibb); research funding (Bristol Myers Squibb, Celgene, Janssen, Daiichi Sankyo, Amgen, Ono, AbbVie, GlaxoSmithKline, Eli Lilly, Caelum, Pfizer, Takeda, Sanofi). RM has nothing to disclose. SK reports honoraria (Chugai, Kyowa Kirin, Janssen, Daiichi Sankyo); research funding (Chugai, Kyowa Kirin, Janssen, Daiichi Sankyo). NF reports honoraria (Chugai, Kyowa Kirin, Huya Japan); research funding (AbbVie, Bayer, Chugai, Celgene, Eisai, Gilead, Incyte, Ono, Solasia). NY, KM, and MY have nothing to disclose. JK reports honoraria (Janssen). NT and HT have nothing to disclose. KU reports honoraria (Novartis Pharma); research funding (Astellas Pharma, AbbVie, Apellis, Symbio, Daiichi Sankyo, Novartis, Janssen, Otsuka, Astellas-Amgen-Biopharma, Takeda, Nippon Shinyaku, Bristol Myers Squibb). TY reports honoraria (Janssen). TU and IM have nothing to disclose. YT reports honoraria (Takeda, Janssen, Celgene); scholarship (Chugai, Takeda, Taiho, Astellas, Ono). YN has nothing to disclose. SO reports honoraria (Novartis, Bristol Myers Squibb); research funding (Kyowa Kirin). EO has nothing to disclose. IH reports honoraria (Bristol Myers Squibb, Takeda, Celgene, Sanofi, Janssen); research funding (Bristol Myers Squibb, Celgene). YS, SY, SY, YS, YK, and SF have nothing to disclose. KT reports honoraria (Daiichi Sankyo, Chugai, Byer, Kyowa Kirin, HUYA BIO, Bristol Myers Squibb). HN reports honoraria (Celgene, Esai, Chugai, Ono, Mundipharma); research funding (Bayer, AstraZeneca, Zenyaku Kogyo, Takeda, Mundipharma, SymBio, Chugai); scholarship (Chugai). Approval of the research protocol: The study protocol was approved by the Protocol Review Committee of JCOG, and was reviewed and approved by the National Cancer Center Hospital Certified Review Board (CRB3180008). Informed consent: Written informed consent was obtained from all the patients. Registry and registration No. of the trial: jRCTs031180097. Animal studies: N/A. Appendix 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.

Synchronous double cancers are an infrequent finding. The focus of this study was a case of diagnosed synchronous double breast cancer (BC) and axillary (Ax) follicular lymphoma (FL). The patient was a 73-year-old woman who had been visiting her local doctor for follow-up of a fibroadenoma of the left breast, and was referred to our hospital after being diagnosed with invasive ductal carcinoma (IDC) of the left breast. Ultrasonography (US) revealed enlarged Ax lymph nodes (LNs) and US-guided core needle biopsy (CNB) was performed. CNB revealed no metastasis of IDC; however, a diagnosis of FL was made. Therefore, the patient was diagnosed with synchronous double BC and Ax FL and underwent partial surgical resection of the BC and close monitoring of the FL. To the best of our knowledge, this is the first case of malignant lymphoma diagnosed by CNB of Ax LNs during preoperative BC screening. CNB allows for a shorter waiting time for the examination, and it is considered to be minimally invasive, cost-effective and non-inferior to surgical resection in terms of specimen volume. Therefore, active preoperative evaluation of Ax LNs using US-guided CNB may contribute to BC staging, and may also help diagnose synchronous cancers.

The BLd regimen, which is a triplet regimen of bortezomib (Bor), lenalidomide (Len), and dexamethasone (Dex), is effective against newly diagnosed multiple myeloma (NDMM). However, non-hematological toxicities, such as peripheral neuropathy (PN), often hamper long-term continuation of the regimen, particularly in older adult patients. In this study, we examined the efficacy and safety of the modified BLd regimen with reduced-intensity Bor and standard-dose Len. The chemotherapy regimen consisted of 1.3 mg/m2 Bor administered subcutaneously on days 1 and 8, 25 mg Len administered on days 1–14, and 20 mg Dex on days 1–2 and 8–9 of a 3 week cycle for 8 cycles, followed by a 4 week cycle of Dex (40 mg weekly). Among the 30 patients enrolled, 60.0% (95% CI 40.6–77.3) had a very good partial response or better, and the best overall response rate was 96.7% (95% CI 82.8–99.9). Eight patients (26.7%) achieved a complete response. Grade 3 or higher PN was not observed and hematological toxicity was the most common adverse event. The modified BLd regimen showed favorable efficacy with a manageable safety profile, which suggests it could be a treatment option for transplant-ineligible NDMM.

Abstract Introduction The prognosis of classic Hodgkin lymphoma (cHL) in young adults has improved following advances in current therapeutics. However, evidence of elderly patients with cHL has limited due to its rarer. To analyze clinical outcomes and risk factors in elderly patients with advanced-stage cHL who received a doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen, we conducted a nationwide multi-center retrospective study in Japan (UMIN000033264). Methods The key eligibility criteria of the current study were as follows: 1) patients with histologically diagnosed cHL between 2007 and 2016 in each institution; 2) advanced-stage cHL (stage III, IV or IIB with bulky or extranodal lesion); 3) age at diagnosis > 60 years; and 4) had received at least one cycle of an ABVD regimen as initial treatment including a modified ABVD regimen (dacarbazine dose reduced to 250 mg/m 2 at first cycle). Patients with human immunodeficiency virus infection or methotrexate-associated cHL were excluded. The primary endpoint was 5-year overall survival (OS). Secondary endpoints included progression-free survival (PFS) and event-free survival (EFS), the latter defined as the time from a diagnosis of cHL to disease progression or relapse, subsequent systemic chemotherapy for cHL, or death due to any cause in this study. The average relative dose intensity (ARDI) of ABVD was calculated as the sum of the relative dose intensity of each drug divided by four. Results A total of 171 patients from 45 institutions were included in this study. The central pathological review could be performed in 140 cases (82%), in which histological subtypes of cHL were determined as follows: mixed cellularity, 89 (64%); nodular sclerosis, 33 (24%); lymphocyte-deleted, 4 (3%); lymphocyte-rich, 2 (1%); not otherwise specified, 12 (9%). The median age was 71 years (interquartile range [IQR] 65-76). The number of patients in each 10-year age group was 79 (46%) for 61-70 years, 78 (46%) for 71-80 years, and 14 (8%) for > 81 years. The numbers of patients with ECOG performance status (PS) ≥2 and B symptoms were 33 (19%) and 85 (50%), respectively. Bulky mediastinal diseases were found in four patients (2%). The risk factors used for the International Prognostic Score (IPS), including male sex, stage IV, hypoalbuminemia, anemia, leukocytosis, and lymphopenia, were not significantly different among these age groups. The median number of cycles of ABVD was 6 (IQR:5-7), and 66% of patients completed at least 6 cycles. The median ARDI was 77%. The median ARDI in each 10-year age group was 88% for 61-70 years, 71% for 71-80 years, and 54% for > 81 years. With a median follow-up time of 52 months (IQR:31-76), the estimated OS, PFS, and EFS at 5 years were 72%, 59%, and 54%, respectively. Among 131 patients whose Epstein-Barr virus (EBV) status was analyzed using EBV-encoded small RNA1 (EBER1) in situ hybridization, 61 (46%) were positive for EBER1. The OS was not significantly different between EBV-positive and EBV-negative patients (75% and 76% at 5 years, respectively). Univariate analysis for OS revealed that age, PS ≥ 2, hypoalbuminemia, anemia, lymphopenia, and the presence of B symptoms were significantly associated with short OS. In multivariate analysis, age (hazard ratio [HR] 1.568 per 10-year increase, 95% confidence interval [CI] 1.020-2.411) was only an independent risk factor for OS, whereas lymphopenia (HR 1.967, 95% CI 1.196-3.235) was an independent risk factor for EFS. Higher ARDI was significantly associated with improved OS and EFS. Bleomycin-induced lung toxicity (BLT), observed in 41 (24%) patients, was not associated with OS. In this study, we found that 55 patients died: 23 within two years after diagnosis mainly due to cHL progression (n = 10, 43%) and treatment-related toxicity (infection [n = 4, 17%] and BLT [n = 4, 17%]). The remaining 32 patients died more than two years after diagnosis mainly due to second primary malignancies (n = 14, 44%), including solid tumors (n = 6), other types of lymphoma (n = 4), and myelodysplastic syndrome/acute myeloid leukemias (n = 4). Conclusions The HORIZON study showed relatively good prognosis for elderly patients with advanced-stage cHL who received an ABVD regimen (estimated five-year OS rates was 72%). Age and lymphopenia were an independent risk factors for OS and EFS, respectively. The development of novel therapies is warranted to improve the outcomes of such patients. Disclosures Makita: SymBio: Honoraria; Novartis: Honoraria; Eisai: Honoraria; Daiichi-Sankyo: Consultancy; CSL Behring: Honoraria; Chugai: Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kusumoto: Kyowa Kirin: Honoraria; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Research Funding. Tsujimura: Takeda: Honoraria; Chugai: Honoraria; Kyowa Kirin: Honoraria; Eisai: Honoraria; Janssen: Honoraria. Takayama: Chugai: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding. Kuroda: Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Shionogi: Research Funding; Asahi Kasei: Research Funding; Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Shimada: BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Otsuka: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; SymBio: Honoraria. Okamoto: Chugai: Research Funding; Kyowa Kirin: Research Funding; Ono: Research Funding; Taiho: Research Funding; Takeda: Research Funding. Asano: Takeda: Honoraria. Maruyama: Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Research Funding; MSD: Honoraria, Research Funding; Otsuka: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma,: Research Funding; Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Mundipharma: Honoraria; Kyowa Kirin: Honoraria; Zenyaku: Honoraria; AstraZeneca: Honoraria; Nippon: Honoraria; SymBio: Honoraria. Yamaguchi: Chugai: Honoraria, Research Funding; Genmab: Research Funding; MSD: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Takeda: Honoraria; Ono: Honoraria; Celgene: Honoraria; Otsuka: Honoraria; Sumitomo Dainippon: Honoraria; Eisai: Honoraria; AstraZeneca: Consultancy. Nagai: AbbVie: Research Funding; AstraZeneca: Honoraria, Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Chordia Therapeutics: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Mundipharma: Honoraria, Research Funding; Nippon Shinyaku: Research Funding; Novartis: Honoraria; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Sumitomo Dainippon Pharma: Honoraria; SymBio Pharmaceuticals: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Zenyaku Kogyo: Research Funding.

We conducted a nationwide retrospective analysis of 116 hepatitis B virus (HBV) surface antigen (HBsAg)‐positive patients with diffuse large B‐cell lymphoma (DLBCL) and 278 HBsAg‐negative patients with DLBCL, as a control cohort, who received rituximab‐containing regimens as an induction chemotherapy at 30 Japanese medical centers between January 2004 and December 2014. Hepatitis was defined as an absolute serum alanine aminotransferase (ALT) level of ≥100 U/L. HBV reactivation‐related hepatitis was defined as hepatitis with an absolute serum HBV DNA level of ≥3.3 log IU/mL or an absolute increase of ≥2 log compared with the baseline value. HBsAg‐positive patients were divided into three groups based on anti–HBV prophylactic therapy: no nucleos(t)ide analogue (non–NA, n = 9), lamivudine (LAM, n = 20), and entecavir (ETV, n = 87). The 4‐year cumulative incidence (CI) of hepatitis in HBsAg‐positive and HBsAg‐negative patients was 21.1% and 14.6% ( P = .081), respectively. The 4‐year CI of HBV reactivation‐related hepatitis was higher in HBsAg‐positive patients than in HBsAg‐negative patients (8.0% vs 0.4%; P < .001). Among HBsAg‐positive patients, the 4‐year CI of HBV reactivation‐related hepatitis was the highest in the non–NA group (33.3%), followed by the LAM (15.0%) and ETV (3.8%) groups ( P < .001). Of note, 3 non–NA patients (33%) and 1 LAM patient (5%) (but no ETV patients) died due to HBV hepatitis. Based on Cox multivariate analysis, HBsAg positivity was not associated with poor overall survival. Prophylactic use of ETV would reduce the occurrence of HBV reactivation‐related hepatitis and mortality in HBsAg‐positive DLBCL patients receiving rituximab‐containing chemotherapy.

Bortezomib (Btz) shows robust efficacy in patients with multiple myeloma (MM); however, some patients experience suboptimal responses and show specific toxicities. Therefore, we attempted to identify specific HLA alleles associated with Btz-related toxicities and response to treatment. Eighty-two transplant-ineligible patients with newly diagnosed MM enrolled in a phase II study (JCOG1105) comparing two less intensive melphalan, prednisolone, plus Btz (MPB) regimens were subjected to HLA typing. The frequency of each allele was compared between the groups, categorized based on toxicity grades and responses to MPB therapy. Among 82 patients, the numbers of patients with severe peripheral neuropathy (PN; grade 2 or higher), skin disorders (SD; grade 2 or higher), and pneumonitis were 16 (19.5%), 15 (18.3%), and 6 (7.3%), respectively. Complete response was achieved in 10 (12.2%) patients. Although no significant HLA allele was identified by multiple comparisons, several candidates were identified. HLA-B*40:06 was more prevalent in patients with severe PN than in those with less severe PN (odds ratio [OR] = 6.76). HLA-B*40:06 and HLA-DRB1*12:01 were more prevalent in patients with SD than in those with less severe SD (OR = 7.47 and OR = 5.55, respectively). HLA-DRB1*08:02 clustered in the group of patients with pneumonitis (OR = 11.34). Complete response was achieved in patients carrying HLA-DQB1*03:02, HLA-DQB1*05:01, and HLA-DRB1*01:01 class II alleles. HLA genotyping could help predict Btz-induced toxicity and treatment efficacy in patients with MM, although this needs further validation.

Introduction: Recent studies based on next-generation sequencing revealed the genetic landscape of diffuse large B cell lymphoma (DLBCL). A new genetic classification system was proposed, including four groups; the BCL2 and SGK1 groups that were both associated with germinal center B-cell like (GCB) DLBCL, an MYD88 group that was associated with non-GCB DLBCL, and a NOTCH2 group that was not associated with a specific cell-of-origin (COO). Unfortunately, this classification method is somewhat complex and thus not fully accepted in clinical practice. Furthermore, part of all cases remained unclassified; as such, it is clear that the diversity of the genetic landscape of DLBCL is not yet fully understood. In this study, we performed a retrospective analysis of genetic abnormalities and their correlations with clinical characteristics in a Japanese cohort of patients diagnosed with DLBCL. Materials and Methods: We collected clinical data from 224 of a total of 234 patients who were diagnosed with DLBCL between 2013 and 2018 at Chiba University Hospital. We also collected formalin-fixed paraffin-embedded (FFPE) specimens obtained from 204 patients via standard diagnostic procedures. The COO for each sample was assessed using the Hans algorithm with immunohistochemical staining; rearrangements of BCL2, BCL6, and MYC were evaluated by fluorescence in situ hybridization. Targeted DNA sequencing was performed using a 144-gene custom panel. Results: Of the 224 DLBCL patients evaluated in our study, the median age at diagnosis was 69 years (range, 18 - 92 years). The median follow-up time was 34 months; three-year progression-free survival (PFS) was 63.2%, and three-year overall survival was 78.0%. COO was determined in 218 cases; 93 of these cases (41.5%) were classified as GCB type and 125 cases (55.8%) as non-GCB type. We successfully performed targeted DNA sequencing in 167 of the 204 FFPE samples. Compared to previous reports, our cohort included relatively higher frequencies of mutations in PIM1 (44.3%), KMT2D (40.7%), MYD88L265P (37.7%), and CD79B (24.5%); by contrast, we detected comparatively lower mutation frequencies in B2M (6.6%), ETV6 (5.4%), CDKN2A (4.7%), and TNFAIP3 (4.1%). Multivariate adjustment of genes extracted by univariate analysis and factors identified by International Prognostic Index score revealed that genetic mutations of MYD88L265P (Hazard ratio [HR] = 2.045), IL16 (HR = 4.848), and BCOR (HR = 6.295) were significant prognostic factors. Mutations in IL16 and BCOR are novel factors that will be used to predict poor prognosis. In the 167 sequenced cases, 110 were classified into the aforementioned four subtypes based on mutations detected in 23 genes together with rearrangements of BCL2 and BCL6; specifically, 47 cases were classified as members of the MYD88 group, 28 in the BCL2 group, 19 in the NOTCH2 group, and 16 in the SGK1 group. We identified a trend toward differential PFSs among the four groups (p = 0.18); three-year PFS was 51.2% among patients with MYD88 group, 59.6% in the BCL2 group, 63.2% in the NOTCH2 group, and 75.0% for the SGK1 group. When compared outcomes of patients in the BCL6 group, patients in the MYD88 group had significantly inferior PFS (p = 0.043) among the non-GCB DLBCL patients; those in the BCL2 group revealed a trend toward inferior PFS compared with those in the SGK1 group (p = 0.34) among the GCB DLBCL patients. We next focused on 28 cases of CD5-positive DLBCL; this is a distinct DLBCL subtype with poor prognosis that is identified more frequently among Asians. We observed significantly higher frequencies of frameshift or nonsense mutations in CD58 and missense mutations in MYD88L265P. Furthermore, evaluation of gene expression data for CD5-positive DLBCL reported in a published database (Miyazaki K et al. Int J Hematol. 2015) revealed diminished expression of CD58 (p = 0.01) and augmented expression of MYD88L265P (p < 0.001). These results suggest that there may be a specific correlation between genetic mutations and gene expression. Intriguingly, these specific genes are key regulators of the immune response, suggesting that inflammation contribute to the unfavorable outcome of CD5-positive DLBCL. Conclusion: Our study provides support for the genetic classification of DLBCL using targeted DNA sequencing to evaluate outcomes in our Japanese cohort. We also identified mutations in novel candidate genes that may be used to predict clinical outcomes. Disclosures Nakaseko: Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau. Kaneda:SRL Inc.: Research Funding; SCRUM Inc.: Research Funding; Tsubakimoto Chain Co.: Research Funding; Takeda Foundation: Research Funding; Princess Takamatsu Cancer Research Fund.: Research Funding; Wedge Co Ltd: Research Funding.

The efficiency of upfront consolidation with high-dose chemotherapy/autologous stem-cell transplantation (HDCT/ASCT) for newly diagnosed high-risk diffuse large B-cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high-risk DLBCL patients having an age-adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R-CHOP-14 (arm A) or 3 cycles of R-CHOP-14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2-y progression-free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow-up of 40.3 mo, 2-y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%-81.2%) and 66.7% (95% CI: 48.8%-79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%-85.7%) and 83.3% (95% CI: 66.6%-92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non-hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R-CHOP-14 showed higher 2-y PFS and less toxicity compared with R-CHOP-14/CHASER in patients with high-risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN-CTR, UMIN000003823).