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Simple Summary: Chimeric Antigen Receptor T-cell (CAR T) therapy has become the preferable therapeutic approach in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Detection of CAR Ts in peripheral blood smear (PBS) is challenging due to the low sensitivity of current morphological technologies. We provide herein a morphological analysis of CAR Ts during the production process and in consecutive PBS obtained from DLBCL patients undergoing CAR T therapy, employing a novel, highly sensitive microscopy platform. We found that activated morphology was attributed predominantly to transduced cells following engagement with target cells. The average number of day 5 CAR Ts, and their sustained presence, were significantly higher in patients obtaining complete response. Also, a high number of CAR Ts was associated with longer cytokine storm release syndrome. These data indicate that CAR T morphological surveillance in PB might serve as a simple, fast and inexpensive method to provide clinically relevant insights. Chimeric Antigen Receptor T-cell (CAR T) therapy has become the preferable treatment in relapsed/refractory diffuse large B-cell lymphomas (DLBCL) patients. Detection of CAR Ts in peripheral blood smear (PBS) is challenging due to insufficient data regarding their morphology and low sensitivity. The morphological evolution of CAR Ts along their production process, and in patients, was established by Full-Field Morphology (FFM), a novel digital microscopy approach that provides highly sensitive PBS analysis. At day 8 of production, 42.7 ± 10.8% of the CAR T transduced cells exhibited activated morphology compared with 9.3 ± 3.8% in untransduced cells. Moreover, engagement of transduced CAR Ts with target cells resulted in further morphological transformation into activated morphology (83 ± 5.6% of the cells). In patients, the average number of day 5 CAR Ts, and their sustained presence, were significantly higher in patients obtaining complete response. A high number of activated morphology CAR Ts at day 14 was associated with prolonged cytokine release storm. Overall, CAR Ts exhibited heterogeneous morphology, with the activated morphology attributed predominantly to transduced cells following engagement with target cells. Post-transfusion CAR T detection was associated with increased complete responses. FFM CAR T surveillance in PBS may serve as a simple inexpensive method to provide clinically relevant insights into this treatment modality. [ABSTRACT FROM AUTHOR]

Simple Summary: CAR T-cell therapy became standard of care for patients with relapsed or refractory large B-cell lymphoma. However, their administration can be accompanied by toxicities, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. It is important to identify patients at risk for these toxicities in order to start an early intervention in high-risk patients and guide outpatient CAR T-cell treatment. As a consequence, several easy-to-use risk scores including the EASIX and its derivatives were developed. However, in the available studies, disparities existed among the used endpoints and cutoff values, hampering the utility of these tools in practice. This study aims to validate these EASIX scores in a population-based cohort. This can be used to select the best predictive model and to further guide optimization of the proposed risk scores. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61–0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptor (CAR) T-cell therapies targeting CD19 have greatly improved the outcomes of many B-cell non-Hodgkin lymphomas, including relapsed/refractory large B-cell lymphoma (R/R LBCL). Nevertheless, a significant number of patients do not benefit. In this single-center retrospective study of patients with R/R LBCL, the outcomes of 66 patients are reported. We demonstrate that older and more frail patients are able to safely undergo CAR T-cell therapy but have significantly more infectious complications. We also demonstrate that ≥2 sites of extranodal involvement and ECOG at the time of CAR T-cell therapy are significant predictors of progression-free survival. Lastly, we demonstrate that the outcomes of patients who relapse after CAR T-cell therapy are poor. Chimeric antigen receptor T-cell (CAR T-cell) therapy has revolutionized the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We describe the real-world baseline characteristics, efficacy, safety, and post-relapse outcomes of adult patients with R/R LBCL who received CAR T-cell therapy at the University of California San Diego. A total of 66 patients with LBCL were treated with tisagenlecleucel or axicabtagene ciloleucel. The median age was 59.5, and 21% were over 70 years old. Additionally, 20% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance score of ≥2. Cytokine release syndrome incidence was 88%; immune effector cell-associated neurotoxicity syndrome incidence was 56%. All-grade infection occurred in 48% of patients and in 79% of patients > 70 years old. Complete response (CR) was achieved in 53% and partial response in 14%. Median progression-free survival (PFS) was 10.3 months; median overall survival (OS) was 28.4 months. Patients who relapsed post-CAR T-cell therapy had poor outcomes, with a median OS2 of 4.8 months. Upon multivariate analysis, both ECOG (HR 2.65, 95% CI: 1.30–5.41; p = 0.007) and ≥2 sites of extranodal involvement (HR 2.22, 95% CI: 1.15–4.31; p = 0.018) were significant predictors of PFS. Twenty-six patients were R/R to CAR T-cell therapy; six patients were in remission at the time of data cut off, one of whom received allogeneic transplant. Overall, older patients can safely undergo CAR T-cell therapy, despite the increased risk of all-grade infection. In our cohort, ECOG performance score and ≥2 sites of extranodal disease are significant predictors of PFS. [ABSTRACT FROM AUTHOR]

Simple Summary: 20–40% of patients with Burkitt lymphoma (BL) have relapsing or refractory (r/r) disease, and standard treatment for such patients is poorly established. An unexplored treatment option is the bispecific T-cell engager blinatumomab, as used for the treatment of r/r and minimal residual disease (MRD) positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL). So far, data on the use of blinatumomab in r/r BL are limited. In this retrospective multi-center case series, we investigated blinatumomab treatment in nine patients with r/r BL after 1–3 previous therapy lines. Data on safety and efficacy were collected. No high-grade (≥grade 3) adverse effects (AEs) occurred, and use of blinatumomab was found to be safe. The best response to blinatumomab and survival data varied considerably among patients, but with five from nine patients responding, blinatumomab seems to have activity in patients with r/r BL. Our data suggest that blinatumomab could be further explored in r/r BL. In patients with relapsed/refractory Burkitt lymphoma (r/r BL), overall survival (OS) is poor, and effective therapies and evidence for the best therapy are lacking. The monoclonal antibody blinatumomab may represent a novel option. However, only limited data on the use of blinatumomab in r/r BL are so far available. This multi-center, retrospective case series investigated nine patients with r/r BL treated with blinatumomab. The safety of blinatumomab was assessed with respect to frequency and severity of adverse effects (AEs) infections, cytokine release syndrome (CRS) and neurotoxicity. Progression-free survival (PFS), OS and overall response rate (ORR) were analyzed to assess efficacy. No AEs > grade 2 occurred, and AEs were generally treatable and fully reversible. The best response to blinatumomab was complete remission in 3/9 patients and partial remission in 2/9, whilst 4/9 presented with progressive disease. Median PFS and OS were 2 and 6 months, respectively, ranging from 5 days to 32 months and 11 days to 32 months, respectively. Blinatumomab treatment was a successful bridging treatment to stem cell transplantation in 3/9 patients. The response to blinatumomab varied widely, and only one patient survived longer term, but activity in patients with r/r BL was evident in some patients, with its use being safe, warranting its prospective investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: B-cell lymphomas are the most commonly occurring blood cancer and the second leading cause of cancer-related death among blood cancers. Chemotherapy and stem cell transplantation have long served as the standard therapies for relapsed or refractory aggressive B-cell lymphomas with very poor survival, historically. Recently, the development of multiple chimeric antigen receptor T-cell (CAR-T) products has translated into dramatically improved outcomes and survival for patients with relapsed or refractory B-cell lymphoma. Meanwhile, basic, translational and clinical development within the field has progressed rapidly. The aim of this review is to summarize the current state of the art of CAR-T therapies for B-cell lymphomas within this rapidly evolving field, focusing on current United States Food and Drug Administration (US FDA)-approved products and a selection of promising areas of future clinical development. Non-Hodgkin Lymphoma accounts for >460,000 cases and >240,000 deaths globally and >77,000 cases and >20,000 deaths in the U.S. annually, with ~85% of cases being B-cell malignancies. Until recently, patients with relapsed/refractory B-cell lymphoma following standard chemotherapy in combination with anti-CD20 monoclonal antibodies and autologous stem cell transplantation experienced a median overall survival (OS) of <6 months. However, with the approval of four different CD-19 CAR-T therapies between 2017 and 2021, approximately 60–80% of patients receiving CAR-T therapy now achieve an objective response with >3 years median OS. Here, we review the current state of the art of CD19 CAR-T therapies for B-cell lymphomas, focusing on current updates in US FDA-approved products, along with their associated efficacy and toxicities. Lastly, we highlight a selection of promising clinical developments in the field, including various novel strategies to increase CAR-T therapy efficacy while mitigating toxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptor T (CAR-T) cells have become clinical practice for the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphoma. The aim of this retrospective study was to assess infection complications after lymphodepletion and CAR-T cell therapy. Infections were commonly detected, but manageable in most cases. Fast and appropriate identification as well as treatment were critical, especially in this very vulnerable patient group. Effective strategies to prevent infections as well as adequate medical management also include standardized prophylaxis and additional supportive therapy. Chimeric antigen receptor T (CAR-T) cell therapy has proven to be very effective in patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). However, infections—related either due to lymphodepletion or the CAR-T cell therapy itself—can result in severe and potentially life-threatening complications, while side effects such as cytokine release syndrome (CRS) might complicate differential diagnosis. Sixty-seven dosings of CAR-T cells in sixty adult patients with NHL (85%) and ALL (15%) receiving CAR-T cell therapy were assessed for infectious complications. Almost two-thirds of patients (61%) developed fever following lymphodepletion and CAR-T cell dosing. Microbiological or radiological findings were observed in 25% of all cases (bacterial 12%, viral 5%, fungal 8%). Inpatient infections were associated with more lines of therapy and more severe CRS. However, overall serious complications were rare after CAR-T therapy, with one patient dying of infection. Pathogen detection after inpatient stay was infrequent and mostly occurred in the first 90 days after dosing. Infections in CAR-T cell treated patents are common. Fast and suitable identification and treatment are crucial in these heavily pretreated and immunocompromised patients. In most cases infectious complications are manageable. Nonetheless, standardized anti-infective prophylaxis and supportive therapy are mandatory to reduce morbidity and mortality in CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: CAR-T therapy is a breakthrough treatment in our fight against cancer. It was recently approved for the treatment of advanced diffuse large B-cell lymphoma and acute lymphoblastic leukaemia after the failure of previous multiple therapies. The positive results achieved in the registration studies for those patients were remarkable. Unfortunately, this was not the end of this chapter. Disease relapses occur in the range of 30–60% of patients treated with CAR-T therapy. Cytokine release syndrome represents a major side effect for treatment with CAR-T therapy. Notwithstanding, the high positive results triggered the start of a huge research activity of CAR-T therapy in other haematologic malignancies such as acute myelogenous leukaemia, Hodgkin's disease, chronic lymphocytic leukaemia, and multiple myeloma. The research is also trying to overcome the hurdles stated above. These activities represent a new chapter in the management of haematologic malignancies with CAR-T therapy. Chimeric antigen receptor-T (CAR-T) therapy targeting CD19 has revolutionised the treatment of advanced acute lymphoblastic leukaemia (ALL) and diffuse large B-cell lymphoma (DLBCL). The ability to specifically target the cancer cells has shown high positive results as reported in the registration studies. The success of CAR-T therapy in the first two indications led to the initiation of a large number of studies testing CAR-T therapy in different haematologic tumours such as acute myelogenous leukaemia (AML), Hodgkin's disease (HD), chronic lymphocytic leukaemia (CLL), multiple myeloma (MM), as well as different solid tumours. Unfortunately, relapses occurred in patients treated with CAR-T therapy, calling for the development of effective subsequent therapies. Likewise, this novel mechanism of action was also accompanied by a different toxicity profile, such as cytokine release syndrome (CRS). Patients' access to the treatment is still limited by its cost. Notwithstanding, this did not prohibit further development of this new therapy to treat other malignancies. This research activity of CAR-T therapy moves it from being used as an end-stage treatment for ALL and DLBCL to a new therapeutic option for a wide range of patients with different haematologic and solid tumours. [ABSTRACT FROM AUTHOR]