B‐cell non‐Hodgkin lymphoma (B‐NHL) is the most frequent hematological malignancy. Although refined chemotherapy regimens and several new therapeutics including rituximab, a chimeric anti‐CD20 monoclonal antibody, have improved its prognosis in recent decades, there are still a substantial number of patients with chemorefractory B‐NHL. Anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy is expected to be an effective adoptive cell treatment and has the potential to overcome the chemorefractoriness of B‐cell leukemia and lymphoma. Recently, several clinical trials have shown remarkable efficacy of anti‐CD19 CAR T‐cell therapy, not only in B‐acute lymphoblastic leukemia but also in B‐NHL. Nonetheless, there are several challenges to overcome before introduction into clinical practice, such as: (i) further refinement of the manufacturing process, (ii) further improvement of efficacy, (iii) finding the optimal infusion cell dose, (iv) optimization of lymphocyte‐depleting chemotherapy, (v) identification of the best CAR structure, and (vi) optimization of toxicity management including cytokine release syndrome, neurologic toxicity, and on‐target off‐tumor toxicity. Several ways to solve these problems are currently under study. In this review, we describe the updated clinical data regarding anti‐CD19 CAR T‐cell therapy, with a focus on B‐NHL, and discuss the clinical implications and perspectives of CAR T‐cell therapy.

This study analysed incidence, patient outcome, immunophenotype and prognostic factors of histological transformation (HT) from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) to diffuse large B-cell lymphoma (DLBCL) in 467 patients (median age, 61 years). The primary sites of MALT lymphoma were the stomach (43%), ocular adnexa (25%), lung (8%), systemic (8%) and other tissues (16%). HT occurred in 8% of MALT lymphomas. Risk of HT by 15 years was 5%: 4% in limited-stage diseases (n = 385) and 16% in advanced-stage diseases (n = 56) (P = 0·02). The median time to HT was 48 months (range, 4-139). Five-year progression-free survival (PFS) and overall survival (OS) rates after HT were 80% and 94%, respectively. Immunohistochemical results of DLBCL were as follows: germinal centre B-cell (GCB)/non-GCB, 37%/63%; CD10, 9%; BCL6, 59%; MUM1, 38%; MYC, 42%; BCL2, 35%; Ki67 ≥ 90%, 23%; and CD5, 3%. The majority (75%, 9/12) of GCB-type DLBCLs exhibited CD10(-) , BCL6(+) and MUM1(-) immunophenotypes; the remainder had CD10(+) immunophenotypes. Multivariate analysis revealed that only advanced stage at HT was a significant adverse factor for PFS (P = 0·037). Thus, overall risk of HT was low and prognosis after HT was favourable; however, in advanced-stage cases, risk of HT was relatively high and prognosis was unfavourable.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive non-Hodgkin lymphoma with poor prognosis and few treatment options for patients with relapsed, recurrent, or refractory disease. We evaluated the efficacy and safety of valemetostat, a potent EZH1 and EZH2 inhibitor, in treating relapsed/refractory (R/R) ATL. This multicenter phase 2 trial (NCT04102150; https://clinicaltrials.gov/ct2/show/NCT04102150; DS3201-A-J201) enrolled patients with R/R aggressive ATL (acute, lymphoma, unfavorable chronic type). Patients received valemetostat 200 mg/day until progressive disease or unacceptable toxicity. The primary endpoint was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Twenty-five patients (median age, 69.0) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. The primary endpoint was met with a centrally reviewed ORR of 48.0% (90% CI, 30.5% to 65.9%), including 5 complete and 7 partial remissions. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). IEAC-assessed median DOR was not reached (NR; 95% CI, 1.87 months to NR). Treatment-emergent adverse events (TEAEs) were manageable. TEAEs that occurred in ≥20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. Grade ≥3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL.

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We identified increased staining of PD-L1 in cHL and that of PD-L2 in PMBL. GZL had a pattern similar to that of cHL.

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B-cell non-Hodgkin lymphoma (NHL) is the most frequent hematologic malignancy. Despite the refinement of chemoimmunotherapy, a substantial number of patients experience chemorefractory disease. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is considered the most promising and effective therapy to overcome chemorefractory B-cell NHL. Based on the promising results obtained from pivotal trials, the US Food and Drug Administration and European Medicines Agency approved anti-CD19 CAR T-cell therapy for relapsed/refractory diffuse large B-cell lymphoma. Nonetheless, there remain several controversial issues and problems awaiting solutions, including optimal management of toxicities, overcoming relapsed/refractory disease after CAR T-cell therapy, and improving CAR-T manufacturing platform. Definite unmet medical needs among patients with chemorefractory B-cell NHL still exist. CAR T-cell therapy might be a game changer that can defeat chemorefractory B-cell NHL, and further clinical development is warranted. In this review, we summarize the recent clinical developments, clinical implications, and perspectives of CAR T-cell therapy, focusing on B-cell NHL.