Search Results (85)

Background/Objectives: Lisocabtagene maraleucel (liso-cel) is a CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). However, most published meta-analyses of CAR-T therapy in LBCL pool data across products, limiting product-specific interpretation. Methods: We conducted a systematic review and meta-analysis of clinical trials and retrospective real-world studies evaluating liso-cel monotherapy in R/R LBCL. The primary endpoint was the overall response rate (ORR). Secondary endpoints included complete response (CR), incidence of grade ≥ 3 adverse events, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), overall mortality rate (OMR), disease progression-related mortality, and adverse event-related mortality. Pooled proportions were estimated using random-effects models. Results: Eleven studies including 1206 patients were analyzed, comprising five clinical trials and six real-world retrospective cohorts. The pooled ORR was 78%, and the pooled CR rate was 60%. The pooled OMR was 38%, with a disease progression-related mortality of 28% and an adverse event-related mortality of 4%. Severe (grade ≥ 3) CRS and ICANS occurred in 2% and 8%, respectively. Severe (grade ≥ 3) hematologic toxicities were frequent, particularly neutropenia, thrombocytopenia, and anemia. Conclusions: Liso-cel monotherapy demonstrated high pooled response rates and low pooled incidences of severe CRS and ICANS across clinical trials and real-world settings in R/R LBCL. Severe ICANS, although uncommon, remains clinically meaningful, and severe hematologic toxicities were frequent and warrant careful monitoring and supportive care. These findings provide product-specific benchmarks for liso-cel in R/R LBCL. Full article

Background/Objectives: High-grade B-cell lymphomas (HGBCLs) with MYC and BCL2 or BCL6 translocations, colloquially referred to as double-hit lymphomas (and abbreviated here to DHL), are aggressive malignancies. Differentiating DHL from non-DHL HGBCLs is important, as DHL patients may benefit from more intensive treatment regimes. We aimed to identify predictive clinicopathological, morphological, and immunophenotypic features that could guide selection of HGBCLs for fluorescence in situ hybridization (FISH), which is expensive and less accessible in some centers. Methods: We conducted a PRISMA systematic review and meta-analysis on 29 studies identified from four databases (PubMed (MEDLINE), Ovid (Embase), Web of Science, and Scopus). We calculated risk ratios (RRs) to compare features between DHL and non-DHL HGBCL and between MYC/BCL2 and MYC/BCL6 DHL patients. Results: DHL patients were associated with higher Ann Arbor stage (RR 1.15, p = 0.028, I² = 38.7%), International Prognostic Index (IPI) score (RR 1.27, p = 0.047, I² = 37.9%), elevated lactate dehydrogenase (RR 1.26, p = 0.012, I² = 34.0%), and germinal center B-cell-like (GCB) immunophenotype (RR 1.21, p = 0.043, I² = 35.8%) compared to non-DHL HGBCL patients. c-Myc immunopositivity, extranodal disease, and bone marrow involvement were more likely in DHL, albeit not reaching statistical significance. Extranodal disease (p = 0.015, I² = 0.0%), central nervous system involvement (p = 0.044, I² = 0.0%), and non-GCB immunophenotype (p = 0.016, I² = 71.1%) were more likely in MYC/BCL6 compared to MYC/BCL2 DHL patients. BCL2 immunopositivity, CD10 immunopositivity, and MUM1 immunonegativity were more likely in MYC/BCL2 DHL, although the differences were not statistically significant. Conclusions: Our results have associated DHL with features of aggressive disease and found GCB immunophenotype as a histopathological feature with statistically significant predictive value for MYC/BCL2 DHL. Heterogeneity within the non-DHL HGBCL group and variation in immunohistochemical cut-off values between studies limited identification of other predictive features. Larger, consistently designed, prospective cohort studies could provide further evidence for a screening strategy for DHL. Full article

Background/Objectives: Patients with high-risk diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBCL) have suboptimal outcomes with standard therapies. Dose-adjusted R-EPOCH (R-DA-EPOCH) is often used in selected high-risk settings and may also serve as an effective chemo-mobilizing strategy for autologous stem cell transplantation (ASCT). We aimed to evaluate the impact of first-line R-DA-EPOCH on stem cell mobilization and transplantation outcomes. Methods: We retrospectively analyzed 41 consecutive adult patients with high-risk DLBCL/HGBCL treated with first-line R-DA-EPOCH between 2016 and 2021. Stem cell collection was planned after cycle 5. The primary endpoint was the rate of poor mobilizers, defined as patients who collected <2 × 10⁶ CD34⁺ cells/kg or required plerixafor (PLX) to achieve this threshold. Results: The rate of poor mobilizers was 31.7% (13/41), with 22% (9/41) of patients requiring PLX. Overall, 68% of patients achieved ≥2 × 10⁶ CD34⁺ cells/kg at first mobilization, while 88% ultimately reached the target after remobilization. Mobilization failure occurred in 12% of patients. A total of 59% of patients proceeded to ASCT. Engraftment was achieved in all transplanted patients, with no transplant-related mortality. Conclusions: First-line R-DA-EPOCH enables effective stem cell mobilization in most high-risk DLBCL and HGBCL patients, although a substantial proportion require PLX support. These findings suggest that R-DA-EPOCH is a feasible platform for early mobilization and ASCT in selected patients. Full article

Background and Objectives: Comprehensive real-world data on dose-adjusted EPOCH-R (DA-EPOCH-R) incorporating molecular prognostic stratification remain limited. We evaluated the long-term efficacy, safety, and prognostic determinants of DA-EPOCH-R in a multicenter Turkish cohort. Materials and Methods: This retrospective study included 140 patients with aggressive B-cell lymphoma (diffuse large B-cell lymphoma [DLBCL], n = 81; primary mediastinal B-cell lymphoma [PMBL], n = 39; other, n = 20) treated with DA-EPOCH-R at five academic centers (2015–2020). Molecular profiling included immunohistochemistry (MYC, BCL-2, BCL-6) and fluorescence in situ hybridization (FISH). Survival was estimated by Kaplan–Meier analysis with Cox regression for prognostic factors. Results: At a median follow-up of 50.1 months, 5-year overall survival (OS) and event-free survival (EFS) rates were 71.3% and 66.3%, respectively (complete response rate: 68.6%). Molecular subtypes included double-expressor (DEL; n = 39), triple-expressor (TEL; n = 21), double-hit (DHL; n = 17), and triple-hit lymphoma (THL; n = 11). Five-year OS by IPI risk group ranged from 88.6% (low) to 49.4% (high) (p = 0.005). DEL status did not confer inferior OS (p = 0.738), whereas DHL and THL had markedly poor outcomes (p < 0.001). In multivariate analysis, IPI ≥ 3 (HR 2.54; p = 0.007) and MYC FISH rearrangement (HR 3.62; p < 0.001) independently predicted inferior OS. Grade 3–4 neutropenia occurred in 57.1%, with no grade 3–4 cardiotoxicity. Conclusions: DA-EPOCH-R provides favorable long-term outcomes in aggressive B-cell lymphomas. DEL status did not confer a survival disadvantage, an association that is hypothesis-generating and requires confirmation, as the present design cannot establish a causal mechanism. FISH-defined DHL/THL remain associated with dismal outcomes, warranting novel therapeutic strategies. Full article

Background and Objectives: Relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHL) remain associated with poor outcomes despite advances in chemoimmunotherapy and chimeric antigen receptor (CAR) T-cell therapy. Many patients are ineligible for or relapse after cellular therapies, highlighting the need for effective off-the-shelf immunotherapeutic approaches. CD20 × CD3 bispecific antibodies (BsAbs) redirect endogenous T cells against malignant B cells and have emerged as a promising therapeutic class in B-NHL. To summarize current clinical evidence regarding mosunetuzumab, glofitamab, epcoritamab, and odronextamab in B-NHL, focusing on efficacy, safety, and emerging therapeutic applications. Materials and Methods: A structured review of published phase I–III clinical trials evaluating the four currently approved CD20 × CD3 BsAbs in B-NHL was conducted. Efficacy outcomes, durability of response, and safety data were assessed across indolent and aggressive lymphoma subtypes. Results: CD20 × CD3 BsAbs demonstrated substantial and durable clinical activity in heavily pretreated B-NHL, including patients with prior CAR T-cell exposure. Mosunetuzumab showed high response rates and durable remissions in follicular lymphoma (FL), while glofitamab demonstrated significant efficacy in aggressive lymphomas, particularly diffuse large B-cell lymphoma (DLBCL). Epcoritamab exhibited consistent activity across lymphoma subtypes with favorable tolerability supported by subcutaneous administration and step-up dosing. Odronextamab also demonstrated clinically meaningful responses in both FL and DLBCL, including high-risk populations. Across studies, cytokine release syndrome (CRS) was the most common adverse event, predominantly low grade and manageable with established mitigation strategies. Immune effector cell-associated neurotoxicity syndrome (ICANS) was uncommon. Infections and hematologic toxicities, particularly neutropenia, represented clinically relevant adverse events across all treatment programs, highlighting the need for special supportive care. Conclusions: CD20 × CD3 BsAbs represent a major therapeutic advancement in R/R B-NHL, combining high clinical activity, manageable toxicity, and off-the-shelf availability. Their expanding integration into earlier treatment settings and combination strategies is expected to further reshape the therapeutic landscape of B-NHL. Full article

Background: Primary thyroid lymphoma (PTL) is a rare malignancy, accounting for less than 5% of thyroid cancers and less than 2% of extranodal lymphomas. It predominantly affects older women and is strongly associated with autoimmune thyroiditis, particularly Hashimoto’s thyroiditis. Diagnosis is often challenging due to non-specific clinical, imaging, and cytological findings, and the role of surgery has progressively shifted from therapeutic to primarily diagnostic. Methods: We conducted a retrospective single-center case series including nine patients treated for PTL between 2015 and 2025 at a tertiary referral endocrine surgery center. An analysis was conducted on clinical presentation, pre-existing thyroid disease, diagnostic work-up, histopathological subtypes, treatment strategies and outcomes. All patients underwent preoperative ultrasound and fine-needle aspiration cytology (FNAC); surgical intervention was performed to confirm cytology results, when cytology was inconclusive or when compressive symptoms were present. Results: The cohort included six females and three males, with a median age of 65.2 years. Four patients had Hashimoto’s thyroiditis and three had multinodular goiter. FNAC was diagnostic or suggestive of lymphoma in three cases only, and surgical biopsy or thyroidectomy for a definitive diagnosis was performed in eight cases. One case started follow-up after cytology and flow cytometry. Histological subtypes were heterogeneous, including diffuse large B-cell lymphoma, Burkitt’s lymphoma, Hodgkin lymphoma, follicular lymphoma, high-grade B-cell lymphoma, and MALT lymphoma. Seven patients received combined chemoimmunotherapy. A complete response was obtained in eight patients, with a minimum follow-up of three years; one patient died of unrelated causes. Conclusions: PTL remains a rare and diagnostically challenging thyroid malignancy. FNAC alone is frequently insufficient, and surgical biopsy retains an important role in cases with high clinical suspicion or compressive symptoms. While surgery has limited therapeutic value, a multidisciplinary approach and timely, tailored treatment are crucial to achieving favorable outcomes. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is molecularly heterogeneous, and approximately 30-50% of patients fail to achieve cure with standard R-CHOP. Genotype-directed first-line therapy may improve outcomes by targeting subtype-specific oncogenic pathways. This study evaluated the feasibility, efficacy, and safety of a molecularly adapted R-CHOP-X strategy with two-year follow-up. Methods: In this single-center, prospective, non-randomized study conducted between September 2023 and the data cut-off (16 September 2025), 43 adults with newly diagnosed DLBCL (excluding high-grade B-cell lymphoma, primary immune-privileged, and primary mediastinal large B-cell lymphomas) underwent tumor genotyping using the LymphGen classification after targeted sequencing: a 19-gene Sanger panel (Cohort 1, n = 35) or an expanded 60-gene panel (Cohort 2, n = 8; proof-of-concept). All patients received one initial cycle of R-CHOP as bridge therapy pending molecular profiling results, followed by five cycles of R-CHOP-X, with the additional agent (vorinostat, acalabrutinib, decitabine, or lenalidomide) selected according to molecular subtype. Response was assessed by PET/CT per Lugano criteria; adverse events were graded per NCI CTCAE v5.0. Results: The overall study population was predominantly high-risk: 72% had an IPI of 3–5, 58% had stage III–IV disease, and 67% exhibited a non-GCB immunophenotype. Expansion from the 19-gene to the 60-gene panel reduced unclassifiable (NOS) cases from 34% to 12%. The overall response rate was 100% (43/43); complete response among patients completing therapy was 100% (35/35). At two years, overall survival was 92% (95% CI 83–100%) and progression-free survival was 94% (95% CI 86–100%). Two early relapses occurred (NOS and N1 subtypes), both resulting in death. Grade 3–4 neutropenia, thrombocytopenia, and anemia occurred in 26%, 12%, and 7% of patients, respectively; no dose reductions or treatment discontinuations were recorded. Conclusions: Molecularly adapted R-CHOP-X is feasible and associated with high response rates and favorable two-year survival in newly diagnosed DLBCL, comparing favorably with historical R-CHOP outcomes in high-risk populations. Expanded genomic panels substantially improve molecular classifiability. These findings warrant validation in larger, multicenter, randomized clinical trials. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) and high-grade follicular lymphoma (FL) are aggressive B-cell malignancies predominantly affecting older adults. R-CHOP remains the frontline standard of care, with frail and elderly patients requiring attenuated regimens such as R-mini-CHOP. Real-world comparative data in elderly and Hispanic populations remain limited. We aimed to evaluate outcomes of R-mini-CHOP versus R-CHOP in elderly patients and to explore potential differences by ethnicity. Methods: Single-center retrospective analysis of adult patients older than 70 years with DLBCL and high-grade FL, treated between January 2014 and June 2025. Clinical characteristics, treatment responses, and survival outcomes were analyzed. The overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Results: A total of 136 patients were included (72 R-mini-CHOP; 64 R-CHOP). Patients receiving R-mini-CHOP were older (median 82 vs. 74 years) and had higher-risk features. Overall response rates were 88.7% and 92.6% in the R-mini-CHOP and R-CHOP groups, respectively. Two-year OS was 79.3% for R-mini-CHOP and 76.7% for R-CHOP. Median OS and PFS were not reached in either group. Elevated lactate dehydrogenase (LDH) was associated with an inferior response. We identified a trend toward better response with R-CHOP in Hispanic patients, although this was not statistically significant. Conclusions: In this real-world cohort, R-mini-CHOP achieved response and survival outcomes comparable to R-CHOP despite worse baseline characteristics. These findings support the use of dose-attenuated therapy in frail and elderly patients and suggest that equitable access to care may mitigate ethnic disparities in outcomes. Full article

Background: Mediastinal ectopic pancreas (EP) is an exceptionally rare entity that can mimic malignancy. Diagnosis is typically established post-operatively; pre-operative confirmation is challenging. Case Presentation: We describe a 28-year-old man presenting with life-threatening airway obstruction due to a progressive mediastinal mass, requiring emergency tracheal stenting. Diagnostic workup revealed a critical discordance: while CT-guided core biopsy confirmed benign ectopic pancreatic tissue, concurrent flow cytometry identified a monoclonal B-cell population with a high Ki-67 index (~86%), raising concern for a high-grade lymphoid process. However, no morphological evidence of lymphoma was found, and PET-CT showed only moderate metabolic activity (SUVmax 4.6), making an untreated aggressive lymphoma less consistent. The patient declined surgical resection. Management proceeded with a conservative strategy of structured clinical surveillance based on the benign histology. At 6-month follow-up, the patient remained clinically stable without chemotherapy, supporting the diagnosis of benign ectopic pancreas and suggesting the flow cytometric findings represented reactive “pseudo-monoclonality” secondary to inflammation. Conclusions: This case highlights mediastinal EP as a rare airway emergency and illustrates a major diagnostic pitfall: flow cytometric clonality and high proliferative fractions can occur in inflammatory settings and must not override benign architectural histology. When discordance persists and definitive tissue cannot be obtained, management should emphasize multidisciplinary review, deliberate specimen triage, and structured surveillance with predefined triggers for repeat higher-yield biopsy or surgical sampling and airway-stent reassessment. Full article

Burkitt lymphoma (BL) is an aggressive mature B-cell lymphoma that represents one of the most studied human malignancies. Initially described in equatorial Africa by the Irish surgeon Denis P. Burkitt, African (endemic) Burkitt lymphoma was the first human neoplasm shown to be associated with a virus, the Epstein–Barr virus (EBV), and also the first human neoplasm shown to harbor a recurrent chromosomal aberration, the t(8;14) (q24;q32) translocation that led to the identification of the central role of the MYC gene in tumorigenesis. In this review, we provide a brief historical introduction, followed by a presentation of important aspects of epidemiology, pathogenesis, and of diagnostic features including morphology, cytogenetics and molecular findings. We also provide a comprehensive overview of the findings convincingly demonstrating that subtyping of BL into EBV-positive and EBV-negative better describes the biological heterogeneity of this lymphoma entity than the historical subtyping into endemic, sporadic, and immunodeficiency-associated. As the distinction of BL from other B-cell lymphomas is important for providing optimal oncological care, we also discuss the differential diagnosis and how this lymphoma can be distinguished from other aggressive B-cell lymphomas. Full article

Bispecific antibodies represent a pivotal advancement in treating relapsed/refractory B-cell lymphomas, addressing unmet needs for patients with limited conventional options. This review examines CD20 × CD3 bispecific antibodies (BsAbs) like mosunetuzumab, epcoritamab, odronextamab, and glofitamab, which link malignant B-cells and T-cells, thus inducing targeted tumor lysis. These IgG-like molecules activate T-cells, triggering proliferation and cytotoxic molecule release, bypassing MHC presentation. These agents have received regulatory approval for the treatment of various B-cell lymphomas and exhibit substantial efficacy, with high overall and complete response rates in diffuse large B-cell lymphoma and follicular lymphoma. However, their use is associated with immune-related toxicities. Cytokine Release Syndrome, which is a systemic inflammatory response due to a cytokine surge, and Immune Effector Cell-Associated Neurotoxicity Syndrome, linked to endothelial activation and blood–brain barrier disruption, are critical concerns. This review details their mechanisms, grading, and management, including the use of tocilizumab and corticosteroids. Furthermore, BsAb therapy carries an elevated susceptibility to viral, bacterial, and opportunistic infections, often exacerbated by hypogammaglobulinemia. Expert recommendations for antimicrobial prophylaxis, including herpes and varicella zoster virus, pneumocystis, and immunoglobulin supplements are crucial for mitigating these risks. While BsAbs offer an “off-the-shelf” advantage, balancing their efficacy with comprehensive toxicity management is crucial for maximizing patient outcomes. Full article

Background: Follicular lymphoma (FL) is the second most common B-cell lymphoma in Western countries, typically presenting as an indolent disease with prolonged overall survival. Despite favorable initial responses to therapy, most patients experience relapse, and early progression is associated with poor outcomes. Methods: This guideline provides evidence-based recommendations from the Spanish GELTAMO group on the diagnosis, staging, treatment, and follow-up of FL. A systematic literature review was conducted, and recommendations were graded according to the GRADE system. Results: Histopathological diagnosis should be based on excisional biopsy. PET-CT is recommended for staging and response evaluation. For localized disease, involved-site radiotherapy (ISRT) remains the treatment of choice. In asymptomatic patients with advanced-stage disease and low tumor burden, a watch-and-wait approach is appropriate, although rituximab monotherapy is also acceptable. For advanced-stage disease with high tumor burden, immunochemotherapy with anti-CD20 antibodies (rituximab or obinutuzumab) combined with CHOP, CVP, or bendamustine is recommended, followed by maintenance therapy. Management of relapsed disease is tailored based on tumor burden, treatment history, and timing of relapse. Although novel immunotherapies (CAR-T therapy and bispecific antibodies) are emerging as promising options, autologous stem cell therapies may still be a valid option in young patients with early relapse who are sensitive to immunochemotherapy. Conclusions: FL is a heterogeneous disease requiring individualized management strategies. Recent advances in immunotherapy and molecular diagnostics are reshaping the therapeutic landscape. These updated GELTAMO recommendations aim to provide practical guidance for optimal FL management in clinical practice. Full article

Serum lactate dehydrogenase (LDH) is a recognized prognostic biomarker in human lymphomas, yet its clinical significance in canine lymphoma remains insufficiently characterized. This study aimed to quantify serum LDH levels in healthy dogs and dogs with high-grade multicentric lymphoma (ML) (predominantly B-cell) and to investigate correlations between LDH levels and established clinical and laboratory prognostic indicators. Twenty-seven dogs were prospectively enrolled: healthy controls (G1, n = 7) and dogs with high-grade ML (G2, n = 20). Immunophenotyping was performed by immunohistochemistry (CD3/CD79a). LDH concentrations were measured at diagnosis (T0) and after six weeks of CHOP-based induction chemotherapy (T1). Statistical analyses included Kruskal–Wallis, Wilcoxon signed-rank, Pearson’s correlation, and mixed-effects models. Dogs with high-grade ML exhibited significantly elevated LDH levels compared to controls (median 545.5 U/L, range: 288.2–2816 U/L vs. 143 U/L, range: 66–272; p < 0.001). Dogs with thrombocytopenia had higher baseline LDH (median 746 U/L, range: 612–921; p = 0.006) and greater reductions following chemotherapy (median −1011.7 U/L, range: −159 to −2064; p = 0.004). LDH levels declined significantly after treatment (overall median reduction 50.7%; post-chemotherapy range: 60.4–752 U/L; n = 15; p = 0.013), with normalization achieved in 77.8% of dogs with complete response versus 16.7% with partial or progressive disease (p = 0.02). We confirmed that serum LDH is significantly elevated in dogs with high-grade ML and declines following effective chemotherapy, supporting its utility as a dynamic biomarker of tumor burden and treatment response. Thrombocytopenic dogs may represent a biologically distinct subset warranting further investigation. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) exhibits pronounced racial disparities in incidence and outcomes, yet the molecular basis remains poorly understood. Here, we examined racial differences in gene rearrangements (MYC, BCL2, BCL6), fusions (IGH::MYC, IGH::BCL2), and their interactions among White, Black, Asian, and Other-race groups in patients with DLBCL to uncover genetic drivers of disparities. Methods: We analyzed 919 DLBCL cases (2006–2023) from Johns Hopkins Hospital using fluorescence in situ hybridization to detect gene abnormalities. We used logistic regression and proportional odds models, adjusted for age and sex, to evaluate racial differences in five gene abnormalities and 10 gene–gene interaction pairs. Pearson’s Chi-squared and Goodman–Kruskal’s gamma tests assessed prevalence and interaction severity across racial groups. Results: MYC rearrangements and the MYC*IGH::MYC interaction were marginally more frequent in the White group than in Black and Other groups (p = 0.092, p = 0.098, respectively). IGH::BCL2 fusions were more prevalent in the Asian group than in the White group (p = 0.095), and the BCL2*IGH::BCL2 interaction was significantly higher in the Asian group (p = 0.049) than in the White group. Although high-grade B-cell lymphoma (HGBCL) prevalence showed no significant racial differences (p = 0.16), the Asian group exhibited a higher proportion of aggressive HGBCL with concurrent IGH::MYC and IGH::BCL2 fusions compared with the White group (p = 0.076). Age significantly influenced all gene abnormalities and interactions (p < 0.001–0.052), except for MYC rearrangements and specific pairs. Sex and sex–race interactions showed no significant effects. Conclusions: This study highlights molecular contributions to the racial differences in DLBCL disease. Further research collecting ancestry-specific biomarkers, treatment regimens, and clinical variables and outcomes is needed to advance personalized treatment strategies. Full article

Treatment paradigms for B-cell lymphomas have evolved significantly in the last decades. Nevertheless, the widespread clinical use of immunotherapy has demonstrated that it invariably leads to the development of resistance. This review outlines the underlying molecular mechanisms of resistance associated with emerging immunotherapeutic strategies, including Chimeric Antigen Receptor (CAR) T cell therapy and bispecific antibodies (BsAbs). In high-grade B-cell lymphomas, nearly 50% of patients progress following CAR T treatment due to host-related factors affecting CAR T cell proliferation and persistence, as well as tumor-intrinsic factors, such as loss of CD19 epitope expression, trogocytosis, and other genomic alterations (e.g., CD19 mutations, chromothripsis, APOBEC mutational activity, and deletions of RHOA). Additional genomic and epigenetic events, including mutations, alternative splicing of CD19, and aberrant promoter methylation, further contribute to resistance. BsAbs, representing an off-the-shelf T-cell-redirecting strategy, have recently shown promising single-agent efficacy with a manageable toxicity profile, predominantly characterized by T cell overactivation syndromes. Similarly to CAR T cell therapy, BsAb resistance arises through diverse mechanisms, such as antigen loss, T cell dysfunction (exhaustion and regulatory T cell activation), tumor-intrinsic alterations (e.g., TP53 mutations and MYC amplifications), and immunosuppressive influences from the tumor microenvironment. These findings underscore the complexity of immune evasion in B-cell lymphomas and highlight the ongoing need to optimize immunotherapeutic strategies and develop combination approaches to overcome resistance. Full article