Dai Maruyama

Background: Novel, accessible treatment options, are needed for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Mosunetuzumab, a T-cell–engaging bispecific antibody, plus polatuzumab vedotin, an antibody–drug conjugate, (Mosun-Pola), represents a novel fixed-duration outpatient therapy. The phase III SUNMO study (NCT05171647) demonstrated superior efficacy of Mosun-Pola versus rituximab plus gemcitabine-oxaliplatin (R-GemOx) in patients with R/R LBCL, with a manageable safety profile. We report outcomes of a Japan subgroup analysis of the SUNMO study. Methods: Patients were randomized 2:1 to receive Mosun-Pola or R-GemOx. Dual primary endpoints were centrally assessed overall response rate and progression-free survival (PFS). Results: At data cutoff (February 17, 2025), of 208 patients randomized (Mosun-Pola, n = 138; R-GemOx, n = 70), 16 were enrolled from Japan (Mosun-Pola, n = 9; R-GemOx, n = 7). All patients receiving Mosun-Pola achieved a response (100% [ n = 9]) versus 57.1% (n = 4/7) for those receiving R-GemOx. PFS was significantly prolonged with Mosun-Pola; median PFS of 16.2 months versus 3.8 months with R-GemOx (hazard ratio: 0.42; 95% confidence interval: 0.07–2.63). In the safety-evaluable population (Mosun-Pola, n = 9; R-GemOx, n = 7), overall incidence of adverse events was similar between the Japan subgroup and the overall population across both treatment arms. Cytokine release syndrome occurred in 5 patients who received Mosun-Pola; all events were grade 1, and all resolved. No incidence of immune effector cell-associated neurotoxicity syndrome was reported. Conclusions: Mosun-Pola demonstrated promising efficacy and manageable safety in patients with R/R LBCL enrolled from Japan, which was comparable with the overall population, supporting Mosun-Pola as a potential new treatment option in this patient population. Clinical trial registration: ClinicalTrials.gov, NCT05171647.

Background/Objectives: Multiple myeloma (MM) is an incurable plasma cell neoplasm in which diagnosis and prognostication rely on invasive bone marrow examinations that may not capture biological heterogeneity across different disease sites. There is a clinical need for non-invasive biomarkers that can accurately predict treatment outcomes. Methods: We performed a global proteomic profiling of bone marrow-derived extracellular vesicles (EVs) from nine MM patients and ten controls. A total of 8839 proteins were identified, of which 14 met predefined selection criteria. These candidates were quantified in serum-derived EVs using targeted proteomic analysis. Prognostic relevance of selected proteins was evaluated in newly diagnosed MM (NDMM) patients treated with daratumumab-containing frontline regimens (n = 26) and healthy individuals (n = 60). Progression-free survival (PFS) was analyzed using univariable and multivariable models. Results: IL5RA (p = 0.003) and BCMA (p < 0.001) were significantly elevated in serum EVs from MM patients compared with controls. Higher serum EV-IL5RA and EV-BCMA were associated with a trend toward shorter PFS. Combined assessment of these biomarkers enabled clear stratification of MM patients into three prognostic groups, including a cohort with markedly inferior outcomes, with a 20-month PFS of 0 (p = 0.001). In multivariable analysis, the combined serum EV-IL5RA and EV-BCMA signature suggests an independent prognostic potential (HR = 38.49 [95% CI, 1.51–47.79], p = 0.015). Conclusions: Serum EV-IL5RA and EV-BCMA are novel non-invasive biomarkers, measurable through routine blood testing, with strong potential to improve risk stratification in NDMM patients in the era of daratumumab-based frontline therapy.

Because primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (POAML) is rare, key clinical questions, including the best treatment strategy and the validity of watchful waiting (WW), remain unresolved. Although radiotherapy (RT) is the standard treatment for localized POAML, it is commonly associated with acute and late toxicities. Overall, 128 patients with localized POAML diagnosed and managed at our institution between 1998 and 2015 were retrospectively analyzed. Forty-two patients were initially managed with WW, and 86 received immediate RT. During a median follow-up of 7.2 years (range 0.1–18.4), no patients died of lymphoma progression. Seven patients in the WW group experienced disease progression at the primary site. In the RT group, almost all patients (97.7%) achieved a complete response after RT; however, 12 patients relapsed. Histological transformation occurred in one patient in each group. The 10-year cumulative incidence of progression was 24.9% (95% CI, 12.6–45.7%) with WW and 13.1% (95% CI, 6.9–23.9%) with RT (p = 0.27). The rate of freedom from systemic therapy at 10 years was 89.7 and 94.8%, respectively (p = 0.67). This observational study suggests that WW is an acceptable treatment option for selected patients with localized POAML, with no significant differences in long-term outcomes compared with RT.

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.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Central nervous system (CNS) relapse is an uncommon yet lethal event in patients with DLBCL. Polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisolone (pola-R-CHP) is a standard of care for patients with untreated DLBCL. In patients with DLBCL at high risk of CNS relapse, the intrathecal (IT) administration of methotrexate and cytarabine is widely adopted for CNS prophylaxis; however, the optimal treatment is unclear. The aim of this multicenter randomized phase III trial is to confirm the superiority of high-dose methotrexate administered during early cycles of pola-R-CHP in addition to IT chemotherapy for patients with untreated DLBCL at high risk of CNS relapse. A total of 390 patients from 52 institutions will be enrolled across a 4-year period. The primary endpoint is progression-free survival. This trial was registered in the Japan Registry of Clinical Trials as jRCTs031230505 [https://jrct.mhlw.go.jp/latest-detail/jRCTs031230505].

Peripheral T-cell lymphoma (PTCL) represents a heterogeneous group of lymphomas with a generally poor prognosis. With recent advances in our understanding of the cellular origins and genomic profiles of PTCL, lymphomas of follicular helper T-cell (TFH) origins with distinct markers and gene mutation profiles are categorized as a single entity, nodal TFH lymphomas—angioimmunoblastic type, follicular type, and not otherwise specified, in the fifth edition of the WHO classification. The standard treatment for PTCL has been CHOP or CHOP-like regimens for decades. The ECHELON-2 trial marked a significant advance in the treatment of PTCL by demonstrating significantly longer survival with BV-CHP than with CHOP for CD30-positive PTCL, establishing BV-CHP as the standard of care for this group of patients. However, attempts to integrate other novel agents into CHOP have largely been unsuccessful, primarily due to increased toxicity, and, thus, CHOP remains the standard treatment for CD30-negative PTCL. Upfront autologous stem cell transplantation is currently controversial, and ongoing randomized controlled trials are expected to clarify its role. With advances in our understanding of the molecular and genetic characteristics of PTCL and potential predictive biomarkers, the future development of treatment will focus on more stratified approaches, and ongoing trials are expected to provide further insights into optimizing these treatment strategies.

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.