Blinatumomab can induce a complete haematological remission in patients in 46.6% with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) resulting in a survival benefit when compared with chemotherapy. Only bone marrow blast counts before therapy have shown a weak prediction of response. Here we investigated the role of regulatory T cells (Tregs), measured by CD4/CD25/FOXP3 expression, in predicting the outcome of immunotherapy with the CD19-directed bispecific T-cell engager construct blinatumomab. Blinatumomab responders (n=22) had an average of 4.82% Tregs (confidence interval (CI): 1.79-8.34%) in the peripheral blood, whereas non-responders (n=20) demonstrated 10.25% Tregs (CI: 3.36-65.9%). All other tested markers showed either no prediction value or an inferior prediction level including blast BM counts and the classical enzyme marker lactate dehydrogenase. With a cutoff of 8.525%, Treg enumeration can identify 100% of all blinatumomab responders and exclude 70% of the non-responders. The effect is facilitated by blinatumomab-activated Tregs, leading to interleukin-10 production, resulting in suppression of T-cell proliferation and reduced CD8-mediated lysis of ALL cells. Proliferation of patients' T cells can be restored by upfront removal of Tregs. Thus, enumeration of Treg identifies r/r ALL patients with a high response rate to blinatumomab. Therapeutic removal of Tregs may convert blinatumomab non-responders to responders.

Tafasitamab, an anti-CD19 immunotherapy, is used with lenalidomide for patients with autologous stem cell transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma based on the results of the phase II L-MIND study (NCT02399085). We report the final 5-year analysis of this study. Eighty patients ≥18 years who had received one to three prior systemic therapies, and had Eastern Cooperative Oncology Group performance status 0-2 received up to 12 cycles of co-administered tafasitamab and lenalidomide, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. The primary endpoint was the best objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, and safety. Exploratory analyses evaluated efficacy endpoints by prior lines of therapy. At data cutoff on November 14, 2022, the objective response rate was 57.5%, with a complete response rate of 41.3% (n=33), which was consistent with prior analyses. With a median follow-up of 44.0 months, the median duration of response was not reached. The median progression-free survival was 11.6 months (95% confidence interval [95% CI]: 5.7-45.7) with a median follow-up of 45.6 months. The median overall survival was 33.5 months (95% CI: 18.3-not reached) with a median follow-up of 65.6 months. Patients who had received one prior line of therapy (n=40) showed a higher objective response rate (67.5%; 52.5% complete responses) compared to patients who had received two or more prior lines of therapy (n=40; 47.5%; 30% complete responses), but the median duration of response was not reached in either subgroup. Other exploratory analyses revealed consistent long-term efficacy results across subgroups. Adverse events were consistent with those described in previous reports, were manageable, and their frequency decreased during tafasitamab monotherapy, with no new safety concerns. This final 5-year analysis of L-MIND demonstrates that the immunotherapy combination of tafasitamab and lenalidomide is well tolerated and has long-term clinical benefit with durable responses.

With the introduction of anti‐CD19 chimeric antigen receptor (CAR) T‐cell (CAR T) therapies, bispecific CD3/CD20 antibodies and anti‐CD19 antibodies, immunotherapy continues to transform the treatment of diffuse large B‐cell lymphoma (DLBCL). A number of novel immunotherapeutic strategies are under investigation to build upon current clinical benefit and offer further options to those patients who cannot tolerate conventional intensive therapies due to their age and/or state of health. Alongside immunotherapies that leverage the adaptive immune response, natural killer (NK) cell and myeloid cell‐engaging therapies can utilize the innate immune system. Monoclonal antibodies engineered for greater recognition by the patient's immune system can enhance antitumor cytotoxic mechanisms mediated by NK cells and macrophages. In addition, CAR technology is extending into NK cells and macrophages and investigational immune checkpoint inhibitors targeting macrophage/myeloid cell checkpoints via the CD47/SIRPα axis are in development. Regimens that engage both innate and adaptive immune responses may help to overcome resistance to current immunotherapies. Furthermore, combinations of immunotherapy and oncogenic pathway inhibitors to reprogram the immunosuppressive tumor microenvironment of DLBCL may also potentiate antitumor responses. As immunotherapy treatment options continue to expand, both in the first‐line setting and further lines of therapy, understanding how to harness these immunotherapies and the potential for combination approaches will be important for the development of future DLBCL treatment approaches.

CD19 is an important target for novel anti-lymphoma treatments as it is broadly and homogenously expressed across many B-cell malignancies [1,2]. Approximately 30–50% of patients with diffuse large...

Background Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative modality in the treatment of patients with cancer. However, it is increasingly evident that this therapeutic approach is not without its challenges. The unique nature of CAR-T cells as living drugs introduces a distinct set of side effects. As the application of CAR-T cell therapy expands to treat a broader range of diseases, it becomes increasingly important to devise effective strategies for handling the associated toxicities. Challenges in treating patients with CAR-T cells include addressing complications such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and cytopenias. This comprehensive review seeks to systematically identify, categorize and elucidate all previously described neurological and psychological side effects associated with CAR-T cell therapy, shedding light on the pertinent laboratory findings that underscore these phenomena. Methods PubMed, Springer Link, and ScienceDirect were systematically searched for empirical studies on adult patients with cancer receiving CAR-T cell therapy for hemato-oncological malignancies. Quality assessment was conducted using Version 2 of the Cochrane risk-of-bias tool (RoB 2) for randomized trials and adherence to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist for observational studies. The synthesis of findings was conducted via a narrative approach, consolidating the diverse array of data into a coherent framework. Results From an initial pool of 2,276 citations, 546 studies met the inclusion criteria, exhibiting a rich tapestry of heterogeneity in terms of study characteristics and patient samples. The incidence of neuropsychological symptoms varied notably across different CAR-T cell products and hematological malignancies. Among the most frequently reported neuropsychological symptoms were aphasia, attention deficits, impaired consciousness, and disorientation, alongside a constellation of other symptoms including confusion, cognitive impairment, memory loss, writing difficulties, fatigue, headache, agitation, tremor, seizures, and psychomotor retardation. Early intervention strategies, including corticosteroids and tocilizumab, have shown the potential to reduce the intensity of neuropsychological symptoms and prevent their progression to critical complications. Conclusion These insights underscore the imperative of extending neuropsychological assessments beyond the conventional Immune Effector Cell-Associated Encephalopathy score framework.

Patients who relapse or are refractory after first-line therapy for diffuse large B-cell lymphoma (DLBCL) frequently have poor prognoses, especially when they are not candidates for autologous stem cell transplant (ASCT). Tafasitamab is a humanized monoclonal anti-CD19 antibody that has recently been approved by the FDA in combination with lenalidomide for the treatment of relapsed/refractory (R/R) DLBCL in patients who are not eligible for ASCT. Tafasitamab has an Fc region which has been modified to have an increased affinity for Fcγ receptors, to potentiate antibody-dependent cellular cytotoxicity and antibody-dependent cell-mediated phagocytosis. Here, we review the development, mode of action and clinical data for tafasitamab in combination with lenalidomide in R/R DLBCL, and discuss the various ways in which this novel antibody could be utilized in the treatment sequence to improve clinical outcomes for patients with DLBCL.