Kana Miyazaki

Despite recent progress in improving patient survival, the outcomes in approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) remain poor. For many years, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard first-line treatment for DLBCL; however, pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone) has recently emerged as a new treatment option. In parallel, novel molecularly targeted therapies that target signaling pathways, cellular antigens, and epigenetic regulators associated with high-risk DLBCL are in development. Treatment strategies tailored to the cell of origin or to specific molecular subtypes are also being explored using subtype-specific targeted agents. In addition, agents that have demonstrated efficacy in patients with relapsed or refractory DLBCL—such as the anti-CD19 antibody tafasitamab and immunomodulatory drugs such as golcadomide—are currently under investigation for use in newly diagnosed patients. Immunotherapies, including anti-CD19-chimeric antigen receptor-T therapy and CD20×CD3 bispecific antibodies (BsAbs), have significantly improved outcomes in patients with relapsed or refractory disease and are now under evaluation as early-line therapies. BsAbs can enable more flexible treatment strategies, including combination regimens with cytotoxic or chemotherapy-free approaches. This review summarizes recent advances and ongoing trials that are investigating novel therapeutic strategies for newly diagnosed DLBCL that may soon be incorporated into clinical practice.

We analyzed the impact of the diagnosis-to-treatment interval (DTI) on survival in patients with CD5-positive diffuse large B-cell lymphoma (CD5 + DLBCL), using a data set of newly diagnosed patients. Among the 336 eligible patients, 247 (74%) received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), and 89 (26%) were treated with dose-adjusted (DA)-EPOCH-R (etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, and rituximab). The median DTI was 18 days (range 0–118). The short DTI (≤ 14 days) group included 135 patients (40%), and the long DTI (> 14 days) group included 201 patients (60%). Compared with the long DTI group, the short DTI group had more aggressive disease characteristics. Both the progression-free survival (PFS) ( P = 0.01) and the overall survival (OS) ( P < 0.01) were significantly inferior in the short DTI group compared with those in the long DTI group. Among 89 patients who received DA-EPOCH-R, no significant differences in PFS ( P = 0.92) or OS ( P = 0.86) were observed between the two groups. Multivariate analysis revealed that no DA-EPOCH-R was a risk factor for PFS in the short DTI group ( P = 0.06). A short DTI was a negative prognostic factor in our CD5 + DLBCL cohort. DA-EPOCH-R could be considered a potential treatment option for patients with a short DTI.

Background: Extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue (MALT lymphoma) with pulmonary involvement is a rare, indolent lymphoma with no standard treatment approaches. Methods: To clarify patient characteristics, treatment, and prognosis of pulmonary MALT lymphoma in the modern era, a multi‐institutional observational study of patients diagnosed between 2013 and 2022 was conducted. A modified Ann Arbor system was used for the analysis. Results: Among 186 eligible patients, 131 (70%) had stage IE/IIE disease, whereas 55 (30%) had stage IV disease. No patient had stage III disease. With a median follow‐up of 57 months, the 4‐year overall survival (OS) rates for the stage IE, IIE, and IV groups were 96%, 92%, and 90%, respectively. The stage IIE and IV groups had similar progression‐free survival (PFS) that was significantly worse than that of the stage IE group ( p < .001). In stage IE/IIE patients, no differences were found in OS ( p = .89) or PFS ( p = .90) among the first‐line treatment groups. In stage IV patients, the stomach was the most common synchronous extranodal site of involvement (36%). There were no differences in OS among the first‐line treatment groups ( p = .64). Conclusions: The OS of patients with MALT lymphoma with pulmonary involvement was favorable regardless of first‐line treatment modality, including watchful waiting. The short PFS in the stage IIE and IV groups indicates that these groups are candidates for therapeutic development.

This single-arm, phase 3 trial by the Japan Clinical Oncology Group evaluated the strategy of upfront allogeneic hematopoietic stem cell transplantation (allo-HSCT) after intensive chemotherapy for untreated aggressive adult T-cell leukemia-lymphoma (ATL). Patients ≤ 65 years old with aggressive ATL were eligible. The protocol-treatment was VCAP-AMP-VECP as induction-chemotherapy followed by allo-HSCT in first remission. Between 2010 and 2020, 110 patients were enrolled. Among all 92 transplantations, 41 under per-protocol (study transplantation) and 51 under off-protocol received allo-HSCT. The primary endpoint was met with 3-year OS of 44.0% (90% CI, 36.0–51.6 > 25.0). The median survival time of the study transplantation and all transplantation was 3.0 (95% CI, 1.5–5.8) and 2.5 years (95% CI, 1.4–4.8), respectively. Multivariable analysis with a time-dependent covariate for transplantation revealed that the hazard ratio for OS of study transplantation was 0.915 (95% CI, 0.554–1.512). In study transplantation, the rate of treatment-related death (TRD) in related and unrelated transplantation was 16.7% and 20.7%, respectively. Thirty-four deaths due to disease progression (PD) were observed. Upfront allo-HSCT can be recommended for aggressive ATL despite a relatively high rate of PD and TRD. However, the survival benefit of study transplantation remains unclear considering the immortal bias.

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].

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.

A retrospective study of extranodal natural killer/T-cell lymphoma (ENKL) patients diagnosed between 2014 and 2021 in Japan was conducted. Among 351 patients with sufficient data, 116 (33%) were in the advanced stage (5 in stage III and 111 in stage IV) at diagnosis, and were further analyzed. The median age was 60 years (range: 19–90), and 68 (59%) were male. Ninety-four (85%) of stage IV patients had two or more extranodal involvements. The most common first-line regimen was SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide; 52%). The 2-year overall survival (OS) for all patients was 38.5%, which was significantly improved after 2017 (25.2% for 2014–2017 vs. 50.7% for 2018–2021; P = 0.008). Patients treated with SMILE showed better OS than those treated with DeVIC or CHOP (2y-OS: 57.1%, 35.8%, and 0%, respectively; P < 0.001). The prognosis was significantly better in patients who received hematopoietic stem cell transplantation (HSCT) than in those who did not (2-year OS: 68.3% vs. 17.6%, P < 0.001). Multivariate analysis showed SMILE and HSCT were significant factors for OS. In conclusion, the prognosis of advanced-stage ENKL has improved in recent years. The L-asparaginase-containing chemotherapy and subsequent HSCT is considered the recommended strategy.

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