The advent of T-cell-redirecting therapies has considerably reshaped the treatment landscape for relapsed/refractory multiple myeloma (RRMM), particularly in patients with triple-class exposed or refractory disease. Chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies (BsAbs), which primarily target B-cell maturation antigen (BCMA), have shown remarkable efficacy in pivotal trials and real-world settings. More recently, G protein-coupled receptor class C group 5 member D-targeted agents have emerged as promising options, particularly for patients who relapse after undergoing BCMA-directed therapy. CAR T-cell therapies can induce deep and durable responses with the potential for long-term remission. However, their use is limited because of manufacturing delays, center certification requirements, and severe toxicity risks. BsAbs offer the advantage of being off-the-shelf, enabling immediate treatment initiation and generally manageable safety profiles, making them the preferred option for frail patients or those with rapidly progressing disease. Nevertheless, continuous dosing and cumulative immunosuppression remain a clinical challenge. Although no direct comparative trials exist between CAR T-cell therapies and BsAbs, each modality has distinct advantages and limitations. Treatment decisions should be individualized based on disease characteristics, patient conditions, and institutional capabilities. Future directions include integrating these agents into earlier lines of therapy, developing novel targets, and exploring multi-antigen strategies to overcome antigen escape. As this field rapidly evolves, real-world evidence and personalized treatment approaches will become critical for optimizing outcomes in patients with RRMM. This review provides an up-to-date summary of the current T-cell-redirecting therapies, including their clinical profiles and safety considerations.

Adult T-cell leukemia/lymphoma (ATLL) is a T-cell malignancy with poor prognosis caused by human T-cell leukemia virus type 1 (HTLV-1). ATLL is characterized by the emergence of abnormal lymphocytes, represented by the so called “flower cell”. However, the mechanisms by which these cells contribute to tumorigenic processes associated with HTLV-1 infection are not well understood. Recent reports have suggested that CD30, tumor necrosis factor receptor superfamily 8 plays a role in the generation of these abnormal lymphocytes, providing insight into the involvement of CD30 in the tumorigenic process of HTLV-1-infected cells. Since CD30 can be targeted with brentuximab vedotin (BV), an anti-CD30 antibody linked with monomethyl auristatin E, a tubulin toxin, it is essential to gain a deeper understanding of the functions of CD30 in HTLV-1-infected cells in order to develop effective strategies for treating and preventing ATLL. This review describes the current understanding of how CD30 impacts the development of ATLL in cells infected with HTLV-1, with a specific emphasis on the connection between CD30 and the generation of abnormal lymphocytes.

The expression of CD30 in diffuse large B-cell lymphoma (DLBCL) has long been debated regarding its clinical significance. This report synthesizes the conflicting findings on CD30 and proposes a new paradigm. Central to this concept is that the prognostic value and biological function of CD30 are critically dependent on the lymphoma cell-of-origin (COO) and tumor microenvironment (TME) it shapes. Analysis of large-scale public gene expression datasets revealed that high CD30 expression is an independent favorable prognostic factor in DLBCL, but this effect is exclusively confined to the germinal center B-cell-like subtype. In contrast, CD30 expression showed no prognostic significance in the activated B-cell-like subtype. This specificity is attributable to CD30’s role as a key architect of the TME, inducing an immune-tolerant environment, particularly through CD4+ T-cell infiltration and recruitment of regulatory T-cells. This understanding provides a strong rationale for COO- and TME-guided therapeutic strategies, such as combining the anti-CD30 antibody-drug conjugate brentuximab vedotin with immunomodulatory agents. This report elucidates the enigma of CD30 and outlines a path towards personalized medicine for DLBCL.

Patients with follicular lymphoma are expected to have relatively long survival due to slow disease progression, but the disease generally relapses repeatedly and remains incurable. Therefore, development of treatments for relapsed or refractory follicular lymphoma is an urgent issue. The recent introduction of cellular immunotherapy has significantly changed treatment of B-cell malignancies. Clinical development of anti-CD19 chimeric antigen receptor (CAR)-T cell therapy and CD20×CD3 bispecific antibody therapy for follicular lymphoma is underway. Multiple studies have also reported the effectiveness of CAR-T cell and bispecific antibody therapies for relapsed or refractory follicular lymphoma, and some cellular immunotherapies have already been approved in Japan. While CAR-T therapy is highly effective and may offer a functional cure in some patients, it faces challenges such as limited access, high cost, and high toxicities. Bispecific antibodies, in contrast, have relatively mild toxicities and can be widely used in patients with poor general conditions, including elderly patients, but have problems such as the burden of long-term administration. Optimal patient selection, management of unique toxicities, and high costs remain issues to be resolved for cellular immunotherapy. This review summarizes the recent clinical data on cellular immunotherapy for follicular lymphoma.

The efficacy of chemotherapy for relapsed/refractory diffuse large B-cell lymphoma remains inadequate. Recent advances in T-cell engaging therapies, including chimeric antigen receptor T-cell therapy and bispecific antibodies (BsAbs), aim to overcome chemotherapy resistance. BsAbs targeting CD20/CD3, such as epcoritamab, glofitamab, mosunetuzumab, and odronextamab, are rapidly progressing toward widespread clinical application. This review summarizes the clinical efficacy of each BsAb and highlights the need for careful management of adverse events, such as cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome. Although monotherapy remains the standard approach, clinical trials are exploring earlier-line use and combination strategies to further enhance outcomes. Particular attention is given to predictive biomarkers of response and mechanisms of resistance, including target antigen loss, tumor histology, prior therapies, intratumoral and peripheral T-cell status, and the emerging role of minimal residual disease monitoring.

Chimeric antigen receptor T-cell (CAR T-cell) therapy has become an established treatment option for relapsed or refractory large B-cell lymphoma, offering durable remission in some previously incurable cases. However, the effective management of immune-mediated toxicities, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remains critical to ensure safety. Treatment algorithms have been proposed based on the American Society for Transplantation and Cellular Therapy consensus grading system by the Joint Accreditation Committee of the International Society for Cellular Therapy and the European Group for Blood and Marrow Transplantation, as well as the National Comprehensive Cancer Network guidelines. Recently, early intervention to ensure that CAR T-cell therapy is performed safely has also been proposed. This review provides an update and overview of the treatment strategies for CRS and ICANS in CAR T-cell therapy for malignant lymphoma.

Accurate detection of M-proteins in multiple myeloma (MM) patients treated with daratumumab (DARA) is challenging because DARA, an IgG-κ monoclonal antibody, produces immunofixation electrophoresis (IFE) bands that mimic disease-derived M-proteins. Although the Daratumumab-Specific Immunofixation Reflex Assay (DIRA) can resolve this interference, it is not always feasible in routine practice, highlighting the need for alternative methods. D-Clean is a novel reagent designed to neutralize DARA interference and is compatible with standard IFE systems without specialized equipment. We evaluated the performance of D-Clean compared with DIRA and examined clinical factors influencing DARA interference, including the interval since the last administration and serum IgG levels. Serum samples from 20 DARA-treated patients, 32 untreated patients, and normal serum spiked with DARA were analyzed.

D-Clean eliminated DARA-derived IgG-κ bands in 19 of 20 patients, yielding results comparable to DIRA. Notably, in two cases, D-Clean detected small Bence Jones-type M-proteins that were missed by DIRA, suggesting slightly higher sensitivity. Among 76 samples from DARA-treated patients, DARA-derived bands appeared only within 33 days after the last dose and were more frequent in patients with low polyclonal IgG levels. To our knowledge, this is the first study to demonstrate that serum IgG levels significantly affect the detectability of DARA-derived bands on IFE. These findings indicate that D-Clean is a reliable and practical alternative to DIRA, although the results are preliminary and require validation in multicenter studies. For clinicians, awareness of DARA dosing intervals and patients’ IgG status is essential for accurate response assessment and treatment decision-making.

Terminal deoxynucleotidyl transferase (TdT)-positive high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements (“double/triple-hit” lymphoma) is a rare, aggressive malignancy that often mimics B-lymphoblastic lymphoma (B-LBL), making accurate diagnosis challenging but clinically critical. We report the case of a 63-year-old female with triple-hit HGBCL involving the duodenum, initially presenting with blastoid morphology and a B-LBL-like immunophenotype: TdT(+), CD10(+), CD20(-), BCL6(-), and CD45dim. However, negativity for CD34 and other features inconsistent with B-LBL, such as MUM-1 positivity and cytoplasmic immunoglobulin expression, were also present. Fluorescence in situ hybridization confirmed MYC, BCL2, and BCL6 rearrangements. Despite an initial response to the hyper-CVAD/MA regimen, the patient subsequently relapsed. Relapse biopsies confirmed persistent triple-hit status and clonal identity via IgH gene rearrangement analysis. Unexpectedly, however, the immunophenotype at relapse had changed significantly, with tumor cells becoming TdT(-), CD20(+), and BCL6(+), while remaining CD10(+). Ultimately, the patient died of the disease despite receiving salvage therapies. To our knowledge, this is the first reported case of TdT-positive HGBCL demonstrating loss of TdT expression alongside other immunophenotypic changes at relapse. This case highlights the potential for significant phenotypic change in this rare HGBCL subtype and the importance of comprehensive immunophenotypic and genetic analysis at both diagnosis and relapse for accurate classification and management, particularly in distinguishing it from B-LBL.

Solitary plasmacytoma (SP) of the bone is a localized neoplasm of plasma cells that can involve the jaw. Epstein-Barr virus (EBV)-positive SP has been documented in immunocompetent individuals; however, its clinicopathological features and prognostic implications remain to be fully clarified. We report a case of EBV-positive SP of the maxilla in a 74-year-old partially edentulous man who presented with swelling in the left posterior maxilla. The lesion measured approximately 30 mm and was covered by intact mucosa. Histopathological examination and systemic evaluation confirmed EBV-positive SP localized to the maxilla. The patient initially received radiotherapy without effect. Subsequently, chemotherapy with ixazomib, lenalidomide, and dexamethasone was administered, resulting in a complete response. No local recurrence was observed after 2 years and 6 months of follow-up. This case highlights the potential for chemotherapy in managing radiotherapy-resistant EBV-positive SP. Further studies are warranted to better understand the pathogenesis and treatment strategies for this rare condition.

Mixed-phenotype acute leukemia (MPAL) is an uncommon hematological malignancy, and cases exhibiting trilineage differentiation are extraordinarily rare. Here, we report the case of a 63-year-old male patient who presented with severe dyspnea secondary to a massive anterior mediastinal mass and pleural effusion, in the absence of detectable abnormal cells in the peripheral blood. Immunophenotypic analysis of pleural fluid and tumor biopsy revealed an unprecedented trilineage phenotype with concurrent expression of T-lymphoid (cytoplasmic CD3⁺ and CD7⁺), B-lymphoid (CD19⁺ and CD22⁺), myeloid (cytoplasmic MPO⁺ and CD33⁺) markers, along with stem cell (CD34⁺ and HLA-DR⁺), and lymphoblastic (TdT⁺) markers. B-lineage commitment was further confirmed by immunoglobulin heavy chain gene rearrangement. These findings established a diagnosis of T/B/myeloid triphenotypic MPAL presenting as an aleukemic disease with minimal bone marrow infiltration (<1%). Initial treatment with acute myeloid leukemia-directed induction therapy (daunorubicin plus cytarabine) proved refractory. However, the hyperCVAD regimen, which is an acute lymphoblastic leukemia (ALL)-directed approach, achieved a complete metabolic response. Subsequent consolidation with cord blood transplantation resulted in durable remission lasting 2 years before a late relapse, which occurred in the mediastinal region. This is the first reported case of non-leukemic, triphenotypic MPAL presenting as a primary mediastinal tumor, highlighting the diagnostic complexity and therapeutic challenges associated with this rare malignancy. Based on our experience, intensive ALL-directed chemotherapy followed by allogeneic stem cell transplantation may offer an effective therapeutic strategy for this exceptionally rare clinical entity.

Primary central nervous system large B-cell lymphoma (PCNS-LBCL) is a rare extranodal non-Hodgkin lymphoma that typically affects the brain parenchyma. Spinal cord involvement as an initial manifestation is extremely uncommon and poses considerable diagnostic challenges, often mimicking inflammatory demyelinating diseases. We report the case of a man in his late 50s who initially presented with steroid-responsive cervical myelitis, resulting in a provisional diagnosis of multiple sclerosis. Despite treatment with corticosteroids and ofatumumab, the patient experienced neurological deterioration and developed cerebellar lesions. Stereotactic brain biopsy confirmed PCNS-LBCL. Although the initial spinal lesion may have represented a definite lymphoma, it was also considered a sentinel lesion, a non-neoplastic inflammatory precursor occasionally observed in PCNSL. This case highlights the diagnostic complexity of PCNS-LBCL presenting with isolated spinal involvement and steroid responsiveness, both of which may delay appropriate treatment. Notably, cerebrospinal fluid analysis at the time of initial presentation of spinal lesions revealed elevated interleukin-10 levels, which declined substantially following chemotherapy, correlating with clinical improvement. Clinicians should maintain a high index of suspicion for central nervous system lymphoma in cases of relapsing myelitis unresponsive to conventional immunotherapy and consider timely biopsy when clinically feasible. Heightened awareness of sentinel lesions may facilitate early recognition and improve outcomes in patients with PCNSL.

We report a case of spindle-cell variant of diffuse large B-cell lymphoma (Sp-DLBCL) occurring in the uterine cervix of a 50-year-old female patient. A review of the literature revealed that most reported cases of Sp-DLBCL arise in the skin, with only seven previously documented cases occurring in the uterine cervix. This report highlights the importance of considering Sp-DLBCL in the differential diagnoses of spindle-cell tumors of the uterine cervix, although lymphoid neoplasia is relatively rare in this organ. We also emphasize the importance of deep tissue biopsy to minimize artifacts caused by tissue damage and careful interpretation of immunostaining results.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive matured T-cell lymphoma caused by human T-lymphotropic virus type I. In advanced stage, multiple organs including bone marrow, skin, liver, spleen, gastrointestinal tract and lung may be involved, in addition to the lymph nodes and peripheral blood. However, to our best of knowledge, no case of primary testicular ATLL has been previously reported: namely primary ATLL of immune privileged site. In this paper, we present a case of primary testicular ATLL case with a poor prognosis despite being in limited stage (Stage I). The report of primary testicular T-cell lymphoma is scant, and accumulation of cases is required.