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Abstract: T-cell engaging-therapies have transformed the treatment landscape of relapsed and refractory B-cell non-Hodgkin lymphomas by offering highly effective treatments for patients with historically limited therapeutic options. This review focuses on the advances in chimeric antigen receptor-modified T cells and bispecific antibodies, first providing an overview of each product type, followed by exploring the primary data for currently available products in large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. This review also highlights key logistical and sequencing considerations across diseases and product types that can affect clinical decision-making., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved in recent years. Targeted therapy with Bruton's tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors has emerged as an effective chemotherapy-free option for patients with previously untreated or relapsed/refractory CLL/SLL. Undetectable minimal residual disease after the end of treatment is emerging as an important predictor of progression-free and overall survival for patients treated with fixed-duration BCL-2 inhibitor-based treatment. These NCCN Guidelines Insights discuss the updates to the NCCN Guidelines for CLL/SLL specific to the use of chemotherapy-free treatment options for patients with treatment-naïve and relapsed/refractory disease.

Purpose of Review: This article reviews the current data and future directions of engineered T cell therapies in non-Hodgkin lymphomas., Recent Findings: Currently, four chimeric antigen receptor (CAR) T cell products are approved: axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, and brexucabtagene autoleucel. These products differ in construct, indication, manufacturing, clinical trial design, and toxicity profile, but all are autologous products targeting CD19. Encouraging early data is also emerging with the use of these products in additional subtypes of B cell lymphoma. Alternative engineered T cell products are also in development, including dual CD19/22 targeting CAR T cells, CD30-directed CAR T cells, allogeneic CAR T cells, and engineered natural killer (NK) cells. Preclinical data using novel CAR constructs such as cytokine-secreting CARs targeted gene delivery into the T cell receptor α constant (TRAC) locus, combination strategies, and third-generation CARs holds promise for additional novel approaches. CAR T cells have transformed the therapeutic landscape for patients with relapsed/refractory B cell lymphomas. Early data with novel engineered cellular products is encouraging and holds promise for future clinical use., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is a front-line treatment for patients with aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression and is antagonised by venetoclax. We aimed to assess the safety of venetoclax with dose-adjusted EPOCH-R as initial therapy in aggressive B-cell lymphoma., Methods: We conducted a single-arm, phase 1 study across seven treatment centres in the USA. Eligible patients were aged 18-80 years with histologically confirmed, previously untreated diffuse large B-cell lymphoma, transformed indolent non-Hodgkin lymphoma, high-grade B-cell lymphoma with double-hit or not otherwise specified, or primary mediastinal B-cell lymphoma, with Ann Arbor stage II-IV and Eastern Cooperative Oncology Group performance status of 0-2. Participants received six cycles of oral venetoclax 400 mg, 600 mg, or 800 mg once daily for 10 days per cycle with dose-adjusted EPOCH-R (one cycle every 3 weeks; baseline doses were intravenous rituximab 375 mg/m 2 on day 1, intravenous etoposide 50 mg/m 2 on days 1-4, oral prednisone 60 mg/m 2 twice daily on days 1-5, intravenous vincristine 0·4 mg/m 2 on days 1-4, intravenous cyclophosphamide 750 mg/m 2 on day 5, and intravenous doxorubicin 10 mg/m 2 on days 1-4). A subsequent cohort received venetoclax 600 mg once daily for 5 days per cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities, and the recommended phase 2 dose of venetoclax. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, NCT03036904, and enrolment is now closed., Findings: Between Feb 3, 2017, and June 4, 2019, 34 patients were assessed for eligibility, and 30 were enrolled and received venetoclax with dose-adjusted EPOCH-R. The median patient age was 64·0 years (IQR 51·6-69·4). The maximum tolerated dose was 800 mg for 10 days and the established recommended phase 2 dose was 600 mg for 5 days due to tolerability for treatment duration. One (3%) of 30 patients had a dose-limiting toxicity in cycle one (grade 4 thrombocytopenia with 800 mg dose). The most common grade 3-4 adverse events were cytopenias (28 [93%] of 30 patients); febrile neutropenia occurred in 19 (63%) patients. Grade 3-4 non-haematological adverse events included hypophosphataemia (n=10), hypokalaemia (n=7), and hyperglycaemia (n=5). Serious adverse events included infection (n=7) and gastrointestinal toxicities including abdominal pain (n=3), colonic perforation (n=1), and small intestinal obstruction (n=1). There was one treatment-related death (sepsis). Overall response rate was 96·7% (95% CI 82·8-99·9); 28 (93·3% [77·9-99·2]) of 30 patients had complete response and one (3·3% [0·1-17·2]) had a partial response., Interpretation: Venetoclax with dose-adjusted EPOCH-R showed an acceptable safety profile at the recommended phase 2 dose and had encouraging preliminary activity in this population at high risk of adverse outcomes, and is worthy of further study. The combination is being investigated in Alliance 051701 (NCT03984448)., Funding: Genentech., Competing Interests: Declaration of interests SCR has received research funding from Genentech Roche, Karyopharm, LAM Therapeutics, Regeneron; has consulted for AstraZeneca, Celgene, Dova, Juno, Karyopharm, Kite, Seattle Genetics; and has received payment for presentations from Bristol Myers Squibb (BMS) and Janssen. JSA has consulted for Abbvie, Allogene, AstraZeneca, BeiGene, Bluebird Bio, BMS, C4 Therapeutics, EMD Serono, Epizyme, Genenetech, Genmab, Incyte, Janssen, Karyopharm, Kite Pharma, Kymera, and Morphosys; and has received payment for presentations from BMS and Regeneron. NLB has participated on a data safety monitoring board or advisory board for Acerta, ADC Therapeutics, BTG, Roche Genentech, and Seattle Genetics. KM has consulted for ADC Therapeutics, Celgene, Pharmacyclics, Gilead, Genmab, and Karyopharm. YY serves as a statistical consultant to Abbvie, Amgen, BeyondSpring Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, BMS, MicuRx Pharmaceuticals, Servier, Starpax, and Vertex Pharmaceuticals. JW has consulted for ADC Therapeutics, AstraZeneca, BMS, Curis, Genentech, Iksuda, Kite, Morphosys, Novartis, and Umoja. JPL has consulted for Abbvie and Genentch Roche; and participated on a data safety monitoring board or advisory board for Genentech, unrelated to this study. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

CAR T-cells are autologous T-cells transduced with a chimeric antigen receptor which targets the modified T-cell against a specified cancer antigen. Anti-CD19 CAR T-cells currently represent transformational therapy for relapsed/refractory aggressive B-cell lymphomas where durable remissions can be induced in patients with previously incurable chemotherapy-refractory disease. Three anti-CD19 CAR T-cells are currently Food and Drug Administration and European Medicines Agency approved or in advanced-stage development: axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. Although all targeting CD19 on the surface of malignant (and healthy) B-cells, these products differ from one another in multiple ways including construct, manufacturing, dose, design of pivotal clinical trials, and toxicity profile. Efficacy and safety data for anti-CD19 CAR T-cell therapy in aggressive B-cell lymphomas will be reviewed, as well as novel CAR T-cell designs and strategies for overcoming treatment resistance., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aggressive B-cell lymphomas that are primary refractory to, or relapse after, frontline chemoimmunotherapy have a low cure rate with conventional therapies. Although high-dose chemotherapy remains the standard of care at first relapse for sufficiently young and fit patients, fewer than one-quarter of patients with relapsed/refractory disease are cured with this approach. Anti-CD19 chimeric antigen receptor (CAR) T cells have emerged as an effective therapy in patients with multiple relapsed/refractory disease, capable of inducing durable remissions in patients with chemotherapy-refractory disease. Three anti-CD19 CAR T cells for aggressive B-cell lymphoma (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene ciloleucel) are either U.S. Food and Drug Administration approved or in late-stage development. All three CAR T cells produce durable remissions in 33%-40% of treated patients. Differences among these products include the specific CAR constructs, costimulatory domains, manufacturing process, dose, and eligibility criteria for their pivotal trials. Notable toxicities include cytokine release syndrome and neurologic toxicities, which are usually treatable and reversible, as well as cytopenias and hypogammaglobulinemia. Incidences of cytokine release syndrome and neurotoxicity differ across CAR T-cell products, related in part to the type of costimulatory domain. Potential mechanisms of resistance include CAR T-cell exhaustion and immune evasion, CD19 antigen loss, and a lack of persistence. Rational combination strategies with CAR T cells are under evaluation, including immune checkpoint inhibitors, immunomodulators, and tyrosine kinase inhibitors. Novel cell products are also being developed and include CAR T cells that target multiple tumor antigens, cytokine-secreting CAR T cells, and gene-edited CAR T cells, among others.

The optimal therapy for primary mediastinal B-cell lymphoma is a subject of ongoing debate, with no accepted standard of care. We performed a retrospective analysis of 63 patients in the modern era treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), with or without radiation. Median age was 37 years (range 20-82). Eighty percent had limited stage disease and 71% were bulky. By age-adjusted International Prognostic Index (IPI), 15% were low-risk, 52% low-intermediate, 27% high-intermediate and 6% high-risk. Some 77% of responding patients received consolidative radiotherapy. Overall and complete response rates were 79% and 71%. Primary induction failure occurred in 13 (21%) patients. Five-year PFS and OS were 68% and 79%, respectively. Adverse prognostic features included increased IPI, advanced stage, advanced age and multiple extranodal sites. These data demonstrate an unacceptably high rate of primary refractory disease on R-CHOP, particularly among patients with high-risk features. Novel treatment approaches are needed that reduce primary refractory disease and reliance on mediastinal radiation in young people.

A 77-year-old man was admitted to this hospital because of confusion and malaise after resection of a papillary urothelial cancer. He reported abdominal pain, facial and jaw pain, anorexia, lethargy, weakness, and night sweats; imaging revealed generalized lymphadenopathy.

B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements, also known as "double-hit" lymphomas (DHL), are rare neoplasms characterized by highly aggressive clinical behavior, complex karyotypes, and a spectrum of pathologic features overlapping with Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and B-lymphoblastic lymphoma/leukemia (B-LBL). The clinical and pathologic spectrum of this rare entity, including comparison to other high-grade B-cell neoplasms, has not been well defined. We conducted a retrospective analysis of clinical and pathologic features of 20 cases of DHL seen at our institution during a 5-year period. In addition, we carried out case-control comparisons of DHL with BL and International Prognostic Index (IPI)-matched DLBCL. The 11 men and 9 women had a median age of 63.5 years (range 32 to 91). Six patients had a history of grade 1 to 2 follicular lymphoma; review of the prior biopsy specimens in 2 of 5 cases revealed blastoid morphology. Eighteen patients had Ann Arbor stage 3 or 4 disease and all had elevated serum lactate dehydrogenase (LDH) levels at presentation. Extranodal disease was present in 17/20 (85%), bone marrow involvement in 10/17 (59%) and central nervous system (CNS) disease in 5/11 (45%). Nineteen patients were treated with combination chemotherapy, of whom 18 received rituximab and 14 received CNS-directed therapy. Fourteen patients (70%) died within 8 months of diagnosis. Median overall survival in the DHL group (4.5 mo) was inferior to both BL (P=0.002) and IPI-matched DLBCL (P=0.04) control patients. Twelve DHL cases (60%) were classified as B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, 7 cases (35%) as DLBCL, not otherwise specified, and 1 case as B-LBL. Distinguishing features from BL included expression of Bcl2 (P<0.0001), Mum1/IRF4 (P=0.006), Ki-67 <95% (P<0.0001), and absence of EBV-EBER (P=0.006). DHL commonly contained the t(8;22) rather than the t(8;14) seen in most BL controls (P=0.001), and exhibited a higher number of chromosomal aberrations (P=0.0009). DHL is a high-grade B-cell neoplasm with a poor prognosis, resistance to multiagent chemotherapy, and clinical and pathologic features distinct from other high-grade B-cell neoplasms. Familiarity with the morphologic and immunophenotypic spectrum of DHL is important in directing testing to detect concurrent IGH-BCL2 and MYC rearrangements when a karyotype is unavailable. The aggressive clinical behavior and combination of genetic abnormalities seen in these cases may warrant categorization as a separate entity in future classifications and call for novel therapeutic approaches.

Purpose: CD52 is a GPI-linked glycoprotein expressed by B cells, T cells, monocytes, and macrophages. The humanized monoclonal antibody alemtuzumab (CAMPATH-1H) is specific for CD52 and is Food and Drug Administration - approved for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL). The utility of CAMPATH in the treatment of other hematologic neoplasms has been explored; however, a comprehensive survey of CD52 expression among a broad spectrum of WHO-defined tumor types has not been completed., Experimental Design: We evaluated 294 hematologic neoplasms for the presence of CD52 using standard immunohistochemical techniques on paraffin-embedded biopsy specimens fixed with formalin, B-Plus, Zenker's acetic acid, or B5-formalin., Results: The vast majority of low-grade B cell lymphoproliferative disorders (CLL/small lymphocytic leukemia, follicular lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, and mucosa-associated lymphoid tissue lymphomas) express CD52. In addition, we found that the majority of precursor B cell acute lymphoblastic leukemia/lymphomas express this antigen. In contrast, there is surprising heterogeneity in CD52 expression among more aggressive B cell lymphomas, with 25% of cases of diffuse large B cell lymphoma and Burkitt lymphoma demonstrating no detectable CD52. In addition, the majority of neoplasms of the T cell lineage are negative for the antigen, including most cases of precursor T cell acute lymphoblastic leukemia/lymphoma, anaplastic large cell lymphoma, and peripheral T cell lymphoma, not otherwise specified. Finally, the vast majority of cases of acute myeloid leukemia, Hodgkin lymphoma, and multiple myeloma are negative for CD52 expression., Conclusion: In contrast with CLL, the variable expression of CD52 among other hematologic malignancies suggests that target validation on a case-by-case basis will likely be necessary to guide the rational analysis of CAMPATH therapy.

T-cell/histiocyte-rich B-cell lymphoma (T/HRBCL) is an uncommon morphologic variant of diffuse large B-cell lymphoma (DLBCL). Pathologically, it is distinguished by <10% malignant B cells amid a majority population of reactive T lymphocytes and histiocytes. Diagnosis of this entity is occasionally difficult, as it may appear similar to other lymphoid diseases, such as nodular lymphocyte-predominant Hodgkin's lymphoma and classic Hodgkin's lymphoma. Accurate diagnosis therefore rests with careful immunohistochemical analysis of the tumor cells and the inflammatory microenvironment. Clinically, T/HRBCL occurs in younger patients, predominantly affects men, and involves the liver, spleen, and bone marrow with greater frequency than traditional DLBCL. Despite the unique clinical features and robust host inflammatory response, T/HRBCL follows a natural history similar to those of other DLBCLs and responds similarly to therapy. Recent gene expression analysis demonstrates that a productive relationship with the host immune response may extend beyond this small DLBCL variant to include as many as one third of all DLBCLs. At present, T/HRBCL should be treated similarly to other stage-matched DLBCLs, though future therapies will likely be targeted at the relationship of the tumor cells with their inflammatory microenvironment.