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Summary: Idiopathic multicentric Castleman disease (iMCD) is a rare haematological disorder characterized by generalized lymphadenopathy with atypical histopathological features and systemic inflammation caused by a cytokine storm involving interleukin‐6 (IL‐6). Three clinical subtypes are recognized: thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly (iMCD‐TAFRO); idiopathic plasmacytic lymphadenopathy (iMCD‐IPL), involving thrombocytosis and hypergammaglobulinaemia; and iMCD‐not otherwise specified (iMCD‐NOS), which includes patients who do not meet criteria for the other subtypes. Disease pathogenesis is poorly understood, with potential involvement of infectious, clonal and/or autoimmune mechanisms. To better characterize iMCD clinicopathology and gain mechanistic insights into iMCD, we analysed complete blood counts, other clinical laboratory values and blood smear morphology among 63 iMCD patients grouped by clinical subtype. Patients with iMCD‐TAFRO had large platelets, clinical severity associated with lower platelet counts and transfusion‐resistant thrombocytopenia, similar to what is observed with immune‐mediated destruction of platelets in immune thrombocytopenic purpura. Conversely, elevated platelet counts in iMCD‐IPL were associated with elevated IL‐6 and declined following anti‐IL‐6 therapy. Our data suggest that autoimmune mechanisms contribute to the thrombocytopenia in at least a portion of iMCD‐TAFRO patients whereas IL‐6 drives thrombocytosis in iMCD‐IPL, and these mechanisms likely contribute to disease pathogenesis. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T‐cell (CAR‐T) therapy and bispecific T‐cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR‐T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo‐HCT). Thirty‐three MM patients with prior allo‐HCT received CAR‐T (n = 24) or BsAb (n = 9) therapy. CAR‐T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR‐T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR‐T and 78% of BsAb recipients, while immune effector cell‐associated neurotoxicity syndrome (ICANS) was observed in three CAR‐T patients. Infections of grade ≥3 were reported in 50% of CAR‐T and 44% of BsAb recipients. No exacerbation of graft‐versus‐host disease occurred except in one BsAb recipient. CAR‐T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo‐HCT. [ABSTRACT FROM AUTHOR]

Summary: Varnimcabtagene autoleucel (var‐cel) is an academic anti‐CD19 chimeric antigen receptor (CAR) product used for the treatment of non‐Hodgkin lymphoma (NHL) in the CART19‐BE‐01 trial. Here we report updated outcomes of patients with NHL treated with var‐cel. B‐cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty‐five patients with NHL were treated. Cytokine release syndrome (any grade) occurred in 84% of patients (4% grade ≥3) and neurotoxicity in 7% (2% grade ≥3). The objective response rate was 73% at Day +100, and the 3‐year duration of response was 56%. The 3‐year progression‐free and overall survival were 40% and 52% respectively. High lactate dehydrogenase was the only covariate with an impact on progression‐free survival. The 3‐year incidence of B‐cell recovery was lower in patients with NHL compared to ALL (25% vs. 60%). In conclusion, in patients with NHL, the toxicity of var‐cel was manageable, while B‐cell recovery was significantly prolonged compared to ALL. This trial was registered as NCT03144583. [ABSTRACT FROM AUTHOR]

Summary: The success of CD19 Chimeric antigen receptor (CAR) T‐cell therapy in large B‐cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off‐the‐shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the ʽstandard‐of‐care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020–2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression‐free survival (1‐year PFS 50% vs. 32%, p < 0.001) and overall survival (1‐year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high‐grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up‐to‐date clinical data when comparing CAR T against new treatment options for r/r LBCL. [ABSTRACT FROM AUTHOR]

Summary: CD19‐directed chimeric antigen receptor (CAR) T‐cell therapy is an important therapy for relapsed or refractory acute lymphoblastic leukaemia, but its use carries the risk of immune effector cell‐associated neurotoxicity syndrome (ICANS). In children, severe ICANS is almost universally reported in association with cytokine release syndrome and is reversible. We describe two cases of severe, intractable neurotoxicity following CAR T‐cell therapy in children with pre‐existing central nervous system (CNS) vulnerabilities. The cases were atypical in their delayed onset and independence from cytokine release syndrome and did not respond to standard therapies. [ABSTRACT FROM AUTHOR]

Summary: In high‐risk myeloid malignancy, relapse is reduced using cord blood transplant (CBT) but remains the principal cause of treatment failure. We previously described T‐cell expansion in CBT recipients receiving granulocyte transfusions. We now report the safety and tolerability of such transfusions, T‐cell expansion data, immunophenotype, cytokine profiles and clinical response in children with post‐transplant relapsed acute leukaemia who received T‐replete, HLA‐mismatched CBT and pooled granulocytes within a phase I/II trial (ClinicalTrials.Gov NCT05425043). All patients received the transfusion schedule without significant clinical toxicity. Nine of ten patients treated had detectable measurable residual disease (MRD) pre‐transplant. Nine patients achieved haematological remission, and eight became MRD negative. There were five deaths: transplant complications (n = 2), disease (n = 3), including two late relapses. Five patients are alive and in remission with 12.7 months median follow up. Significant T‐cell expansion occurred in nine patients with a greater median lymphocyte count than a historical cohort between days 7–13 (median 1.73 × 109/L vs. 0.1 × 109/L; p < 0.0001). Expanded T‐cells were predominantly CD8+ and effector memory or TEMRA phenotype. They exhibited markers of activation and cytotoxicity with interferon‐gamma production. All patients developed grade 1–3 cytokine release syndrome (CRS) with elevated serum IL‐6 and interferon‐gamma. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T (CAR‐T) cell therapy is highly effective in inducing complete remission in haematological malignancies. Severe cytokine release syndrome (CRS) is the most significant and life‐threatening adverse effect of this therapy. This multi‐centre study was conducted at six hospitals in China. The training cohort included 87 patients with multiple myeloma (MM), an external validation cohort of 59 patients with MM and another external validation cohort of 68 patients with acute lymphoblastic leukaemia (ALL) or non‐Hodgkin lymphoma (NHL). The levels of 45 cytokines on days 1–2 after CAR‐T cell infusion and clinical characteristics of patients were used to develop the nomogram. A nomogram was developed, including CX3CL1, GZMB, IL4, IL6 and PDGFAA. Based on the training cohort, the nomogram had a bias‐corrected AUC of 0.876 (95% CI = 0.871–0.882) for predicting severe CRS. The AUC was stable in both external validation cohorts (MM, AUC = 0.907, 95% CI = 0.899–0.916; ALL/NHL, AUC = 0.908, 95% CI = 0.903–0.913). The calibration plots (apparent and bias‐corrected) overlapped with the ideal line in all cohorts. We developed a nomogram that can predict which patients are likely to develop severe CRS before they become critically ill, improving our understanding of CRS biology, and may guide future cytokine‐directed therapies. [ABSTRACT FROM AUTHOR]

Summary: The use of CD19 chimeric antigen receptor T‐cell (CAR‐T) therapy for relapsed/refractory solid organ transplantation (SOT)‐related post‐transplant lymphoproliferative disorder (PTLD) is not well studied. We conducted a multicentre, retrospective analysis of adults with relapsed/refractory SOT‐associated PTLD. Among 22 relapsed/refractory SOT‐PTLD patients, the pathology was monomorphic B cell. Prior SOTs included 14 kidney (64%), three liver (14%), two heart (9%), one intestinal (5%), one lung (5%), and one pancreas after kidney transplant (5%). The median time from SOT to PTLD diagnosis was 107 months. Pre‐CAR‐T bridging therapy was used in 55% of patients, and immunosuppression was stopped completely before CAR‐T infusion in 64%. Eighteen (82%) patients experienced cytokine release syndrome: one (5%) each grade (G) 3 and G4. The immune effector cell‐associated neurotoxicity syndrome was observed in 16 (73%) patients: six (27%) G3 and two (9%) G4. The overall response rate was 64% (55% complete response). Three patients (14%) experienced allograft rejection after CAR‐T. The two‐year progression‐free survival and overall survival rates were 35% and 58%, respectively. Additionally, the achievement of CR post‐CAR‐T was strongly associated with survival. Collectively, the safety and efficacy of CD19 CAR‐T therapy in relapsed/refractory SOT‐related PTLD appeared similar to pivotal CAR‐T data, including approximately one‐third of patients achieving sustained remission. [ABSTRACT FROM AUTHOR]

Summary: Large B‐cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi‐cel) or tisagenlecleucel (tisa‐cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa‐cel versus axi‐cel (52% vs. 48%) compared to 20% versus 80% in ASCT‐fit patients; p < 0.0001. The drop‐out rate from approval to infusion was significantly higher in the ASCT‐unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression‐free and overall survival were similar in both cohorts. CAR T was well‐tolerated in ASCT‐unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real‐world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant. [ABSTRACT FROM AUTHOR]

Summary: Cytokine release syndrome (CRS) and consumptive coagulopathy can complicate the treatment with chimeric antigen receptor T (CAR‐T) cells. The modified version of the Endothelial Activation and Stress Index (mEASIX), a score derived from haematopoietic stem cell transplantation, combines platelets, C‐reactive protein (CRP), and lactate dehydrogenase (LDH) and has been correlated with CRS and endothelial biomarkers. In 38 consecutive patients with aggressive lymphoproliferative disease we measured a coagulative laboratory panel at baseline and early after infusion of anti‐CD19 CAR‐T. The panel was investigated also in the presence of CRS graded 2 or higher, or immune effector cell‐associated neurotoxicity syndrome (ICANS). Moreover, we examined the relationship between mEASIX, coagulation biomarkers, and toxicities of CAR‐T cells. During CRS grade 2 or higher, we found increased prothrombin time (PT) and activated partial thromboplastin time (aPTT), fibrinogen, D‐dimer, factor VIII (FVIII), and von Willebrand factor (vWF) antigen levels, and decreased platelet count and antithrombin levels. The occurrence of immune effector cell‐associated neurotoxicity syndrome was associated with higher PT values, D‐dimer, FVIII, and vWF levels, and decreased fibrinogen levels and platelet count. A higher mEASIX score correlated with increased aPTT values, fibrinogen, D‐dimer, FVIII and vWF levels, and decreased antithrombin levels. Baseline mEASIX was predictive for consumptive coagulopathy and CRS graded 2 or higher, and for progression‐free survival and overall survival. [ABSTRACT FROM AUTHOR]

Summary: Numerous studies have shown peculiar morphological anomalies in COVID‐19 patients' smears. We searched all the peer‐reviewed scientific publications that explicitly reference the cytomorphological alterations on peripheral blood smears of patients with COVID‐19. We extracted data from sixty‐five publications (case reports, patient group studies, reviews, and erythrocyte morphology studies). The results show that frequent alterations concern the morphology of lymphocytes (large lymphocytes with weakly basophilic cytoplasm, plasmacytoid lymphocytes, large granular lymphocytes). Neutrophils display abnormal nuclei and cytoplasm in a distinctive cytomorphological picture. Besides a left shift in maturation, granulations can be increased (toxic type) or decreased with areas of basophilia. Nuclei are often hyposegmented (pseudo‐Pelger‐Huёt anomaly). Apoptotic or pycnotic cells are not uncommon. Monocytes typically have a large cytoplasm loaded with heterogeneous and coalescing vacuoles. Platelets show large and giant shapes. The presence of erythrocyte fragments and schistocytes is especially evident in the forms of COVID‐19 that are associated with thrombotic microangiopathies. Such atypia of blood cells reflects the generalized activation in severe COVID‐19, which has been demonstrated with immunophenotypic, molecular, genetic, and functional methods. Neutrophils, in particular, are involved in the pathophysiology of hyperinflammation with cytokine storm, which characterizes the most unfavorable evolution. [ABSTRACT FROM AUTHOR]

Summary: Haemophagocytic lymphohistiocytosis‐like toxicity following chimeric antigen receptor T cells (CAR‐HLH) is being increasingly recognized, while published data are limited and criteria for recognition are elusive. We describe three patients who developed CAR‐HLH after infusion of brexucabtagene autoleucel (n = 2) or axicabtagene ciloleucel (n = 1). All three patients presented following cytokine release syndrome, with fever, recurrent or worsening cytopenias, hyperferritinaemia, elevated soluble interleukin (IL)‐2 receptor, hypofibrinogenaemia, hypertriglyceridaemia, elevated liver transaminases, and decreasing C‐reactive protein and IL‐6. Clinical improvement following treatment with anakinra (n = 2) and ruxolitinib (n = 1) was observed. Our report offers an opportunity for prompt recognition and initiation of potentially life‐saving treatment for CAR‐HLH. [ABSTRACT FROM AUTHOR]

Summary: Outcomes remain poor for patients with relapsed/refractory B‐cell non‐Hodgkin lymphoma (R/R B‐NHL). While chimeric antigen receptor (CAR) T‐cell therapy has revolutionised treatment, a significant proportion of patients relapse or fail to respond. Odronextamab is a CD20 × CD3 bispecific antibody that has demonstrated durable responses and a manageable safety profile in patients with R/R B‐NHL in a first‐in‐human trial (NCT02290951). Here, we document two patients with diffuse large B‐cell lymphoma refractory to CART‐cell therapy. Both achieved complete responses that remain ongoing for ≥2 years following odronextamab. Neither patient experienced Grade ≥3 cytokine release syndrome or Grade ≥3 neurological adverse events during treatment. [ABSTRACT FROM AUTHOR]

Summary: CD19 CAR‐T have emerged as a new standard treatment for relapsed/refractory (r/r) large B‐cell lymphoma (LBCL). CAR‐T real‐world (RW) outcomes published to date suggest significant variability across countries. We provide results of a large national cohort of patients intended to be treated with CAR‐T in the UK. Consecutive patients with r/r LBCL approved for CAR‐T by the National CAR‐T Clinical Panel between December 2018 and November 2020 across all UK CAR‐T centres were included. 404/432 patients were approved [292 axicabtagene ciloleucel (axi‐cel), 112 tisagenlecleucel (tisa‐cel)], 300 (74%) received the cells. 110/300 (38.3%) patients achieved complete remission (CR) at 6 months (m). The overall response rate was 77% (52% CR) for axi‐cel, 57% (44% CR) for tisa‐cel. The 12‐month progression‐free survival was 41.8% (axi‐cel) and 27.4% (tisa‐cel). Median overall survival for the intention‐to‐treat population was 10.5 m, 16.2 m for infused patients. The incidence of grade ≥3 cytokine release syndrome and neurotoxicity were 7.6%/19.6% for axi‐cel and 7.9%/3.9% for tisa‐cel. This prospective RW population of CAR‐T eligible patients offers important insights into the clinical benefit of CD19 CAR‐T in LBCL in daily practice. Our results confirm long‐term efficacy in patients receiving treatment similar to the pivotal trials, but highlight the significance of early CAR‐T failure. [ABSTRACT FROM AUTHOR]

Decreased serum phosphate levels are a useful biomarker to predict occurrence and severity of cytokine release syndrome in chimeric antigen receptor T-cell therapy Key sentences CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy is an innovative treatment[1] for patients with diffuse large B-cell lymphoma (DLBCL). Keywords: chimeric antigen receptor T cell (CAR-T); cytokine release syndrome (CRS); hypophosphataemia; predictive marker EN chimeric antigen receptor T cell (CAR-T) cytokine release syndrome (CRS) hypophosphataemia predictive marker e1 e3 3 12/22/22 20230101 NES 230101 Decreased serum iP can be a predictive marker for subsequent severe CRS. [Extracted from the article]

Summary: Patients with acute myeloid leukaemia (AML) have a five‐year survival rate of 28·7%. Natural killer (NK)‐cell have anti‐leukaemic activity. Here, we report on a series of 13 patients with high‐risk R/R AML, treated with repeated infusions of double‐bright (CD56bright/CD16bright) expanded NK cells at an academic centre in Brazil. NK cells from HLA‐haploidentical donors were expanded using K562 feeder cells, modified to express membrane‐bound interleukin‐21. Patients received FLAG, after which cryopreserved NK cells were thawed and infused thrice weekly for six infusions in three dose cohorts (106–107 cells/kg/infusion). Primary objectives were safety and feasibility. Secondary endpoints included overall response (OR) and complete response (CR) rates at 28–30 days after the first infusion. Patients received a median of five prior lines of therapy, seven with intermediate or adverse cytogenetics, three with concurrent central nervous system (CNS) leukaemia, and one with concurrent CNS mycetoma. No dose‐limiting toxicities, infusion‐related fever, or cytokine release syndrome were observed. An OR of 78·6% and CR of 50·0% were observed, including responses in three patients with CNS disease and clearance of a CNS mycetoma. Multiple infusions of expanded, cryopreserved NK cells were safely administered after intensive chemotherapy in high‐risk patients with R/R AML and demonstrated encouraging outcomes. [ABSTRACT FROM AUTHOR]

Summary: In the relapsed/refractory setting for treatment of large B‐cell lymphoma (LBCL), chimeric antigen receptor T‐cell (CAR‐T) therapy has emerged as an effective treatment modality. Patients often have aggressive disease that requires prompt treatment in the form of bridging therapy (BT) for disease stabilisation while CAR‐T cells are manufactured. Patients (n = 75) undergoing CAR‐T therapy infusion for LBCL at our institution were identified. A total of 52 (69·3%) received BT and 23 (30·7%) received no BT (NBT). BT modalities included systemic BT (SBT) in 28 patients, radiation BT (RBT) in 14, and high‐dose steroid BT (HDS) in 10. There was no difference in incidence of cytokine release syndrome or immune effector cell‐associated neurotoxicity syndrome between BT and NBT (P = 0·18 and P = 0·53 respectively). Prolonged cytopenias at Day 180 were more common in BT than NBT (50% vs. 13·3%, P = 0·04). The SBT and RBT subgroups had more cytopenias at Day 180 compared to the HDS and NBT subgroups (58·3% and 57·1% vs. 20% and 13·3% respectively, P = 0·04). Disease response at last follow‐up, progression‐free survival and overall survival were similar between BT, NBT, and BT subgroups. In summary, BT can be safely considered in patients undergoing CAR‐T therapy. However, those undergoing BT with SBT or RBT are at higher risk of prolonged cytopenias after CAR‐T therapy. [ABSTRACT FROM AUTHOR]

Summary: Axicabtagene ciloleucel (axi‐cel) is an autologous anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed or refractory large B‐cell lymphoma (R/R LBCL). To reduce axi‐cel–related toxicity, several exploratory safety management cohorts were added to ZUMA‐1 (NCT02348216), the pivotal phase 1/2 study of axi‐cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti‐CD19 CAR T cells/kg after conditioning chemotherapy. Forty‐one patients received axi‐cel. Incidences of any‐grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone‐equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA‐1 cohorts. With a median follow‐up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi‐cel. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T-cell (CAR-T) therapies such as axicabtagene ciloleucel (axi-cel), and brexucabtagene autoleucel (brexu-cel) are approved by the United States Federal Drug Administration for relapsed or refractory large B-cell lymphoma (LBCL), follicular lymphoma and mantle cell lymphoma (MCL).1-5 Given the risk of significant toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), the registrational trials for axi-cel and brexu-cel required hospitalisation for close monitoring. Patients received lymphodepleting chemotherapy and CAR-T infusion in the outpatient clinic and were subsequently monitored with twice daily in-person visits and one overnight remote visit via telemedicine through day 14 post-infusion. Safety and feasibility of outpatient chimeric antigen receptor (CAR) T-cell therapy: experience from a tertiary care center. [Extracted from the article]

Summary: Chimeric antigen receptor T‐cell (CAR T‐cell) therapy is associated with significant toxicities secondary to immune activation, including a rare but increasingly recognised severe toxicity resembling haemophagocytic lymphohistiocytosis (carHLH). We report the development of carHLH in 14·8% of paediatric patients and young adults treated with CD19‐specific CAR T‐cell therapy with carHLH, occurring most commonly in those with high disease burden. The diagnosis and treatment of carHLH required a high index of suspicion and included multidrug immunomodulation with variable response to therapies. Compared to patients without carHLH, patients with carHLH had both reduced response to CAR T‐cell therapy (P‐value = 0·018) and overall survival (P‐value = < 0·0001). [ABSTRACT FROM AUTHOR]

Summary: ZUMA‐1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi‐cel), an autologous CD19‐directed chimaeric antigen receptor (CAR)‐T cell therapy, in refractory large B‐cell lymphoma. To reduce treatment‐related toxicity, several exploratory safety management cohorts were added to ZUMA‐1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end‐points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days −5 through −3), 2 × 106 CAR‐T cells/kg (day 0) and once‐daily oral dexamethasone [10 mg, day 0 (before axi‐cel) through day 2]. Forty patients received axi‐cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty‐eight per cent of patients did not experience CRS or NEs within 72 h of axi‐cel. With a median follow‐up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor (CAR) T cells are a rapidly emerging form of cancer treatment, and have resulted in remarkable responses in refractory lymphoid malignancies. However, their widespread clinical use is limited by toxicity related to cytokine release syndrome and neurotoxicity, the logistic complexity of their manufacturing, cost and time‐to‐treatment for autologous CAR‐T cells, and the risk of graft‐versus‐host disease (GvHD) associated with allogeneic CAR‐T cells. Natural killer (NK) cells have emerged as a promising source of cells for CAR‐based therapies due to their ready availability and safety profile. NK cells are part of the innate immune system, providing the first line of defence against pathogens and cancer cells. They produce cytokines and mediate cytotoxicity without the need for prior sensitisation and have the ability to interact with, and activate other immune cells. NK cells for immunotherapy can be generated from multiple sources, such as expanded autologous or allogeneic peripheral blood, umbilical cord blood, haematopoietic stem cells, induced pluripotent stem cells, as well as cell lines. Genetic engineering of NK cells to express a CAR has shown impressive preclinical results and is currently being explored in multiple clinical trials. In the present review, we discuss both the preclinical and clinical trial progress made in the field of CAR NK‐cell therapy, and the strategies to overcome the challenges encountered. [ABSTRACT FROM AUTHOR]

Summary: We studied the efficacy and safety of humanized CAR‐T therapy following intensive chemotherapy for refractory/relapsed (R/R) acute lymphoblastic leukaemia (B‐ALL). Twenty‐three patients with R/R B‐ALL were pretreated with intensive chemotherapy (fludarabine combined with medium‐dose cytarabine) 12 days before CAR‐T therapy. Adverse events (AEs), curative effects, infection indicators and cytokine release syndrome (CRS) were monitored. Each of the 23 patients received a dose of 1·0 × 106 cells/kg CAR‐T cell infusion on day 0. After 14 days, 19 patients (82·61%) achieved complete response (CR) or CR with incomplete count recovery. No survival benefit was achieved with consolidative haematopoietic stem‐cell transplantation (HSCT), with a median follow‐up of 14·0 months (range, 1·5–21·0 months). The notable AEs were grade 1–2 CRS in 18 patients, while the other five patients were grade 3 CRS. No patients died of CRS. Only one patient died of respiratory failure due to cytomegalovirus infection 24 days after infusion. The proportion of leukaemic cells in bone marrow on infusion day and the peaks of IL‐6, TNF‐α and IL‐8 levels were correlated with CRS levels. A lower disease burden was achieved by intensive lymphodepleting chemotherapy, and the subsequent CAR‐T therapy had a high response and manageable toxicity. Trial registration: The patients were enrolled in a clinical trial of ChiCTR‐ONN‐16009862, and ChiCTR1800019622. [ABSTRACT FROM AUTHOR]

Keywords: COVID-19; haemophagocytic syndrome; bone marrow morph EN COVID-19 haemophagocytic syndrome bone marrow morph 686 688 3 08/18/21 20210815 NES 210815 We read with interest the correspondence by Wood I et al i . relating to the limited utility of the HScore in identifying possible cases of secondary haemophagocytic lymphohistiocytosis (sHLH) that may contribute to the excess mortality seen in COVID-19.1 A subset of patients is at risk of developing a markedly dysregulated immune response associated with a "cytokine storm" that strongly resembles the pathological and clinical features of sHLH.2 HLH is a rare immune-mediated hyperinflammatory syndrome characterised by fever, hepatosplenomegaly, cytopenias and several biochemical features. Panels (A) and (B) demonstrate evidence of haemophagocytosis on bone marrow aspirate. gl Discussion This case supports the notion that a distinct inflammatory syndrome accompanies COVID-19 that may be secondary HLH. Limited utility of the HScore in detecting secondary haemophagocytic lymphohistiocytosis in COVID-19. [Extracted from the article]

Primary mediastinal large B-cell lymphoma in paediatric and adolescent patients: emerging questions in the era of immunotherapy Keywords: paediatric; refractory; mediastinal; B-Cell lymphoma EN paediatric refractory mediastinal B-Cell lymphoma e114 e117 4 07/20/20 20200715 NES 200715 Relapsed/refractory primary mediastinal large B-cell lymphoma (PMLBCL) is rare among paediatric patients and is associated with a dismal prognosis. None of these patients had prior CAR T-cell therapy or checkpoint inhibitors.13 Remission consolidation post-CAR T-cell therapy with allogeneic HCT in patients with PMLBCL remains an active debate. [Extracted from the article]

Two CD19 chimeric antigen receptor (CAR) T cell therapies are now approved by the US Food and Drug Administration for the treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and histological variants: axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) (Neelapu I et al i , [6]; Schuster I et al i , [9]). Clinically, it remains unclear as to when the HLH features of CRS are significant enough to consider treatment with therapies used for non-CAR T-associated HLH, such as etoposide or methotrexate (Neelapu I et al i , [8]). Our case series suggests that the timing of onset of CAR T-associated HLH may differ between patients, with concern when delayed or recurrent HLH symptoms occur with a rising ferritin level, which is when HLH-directed therapies should be considered. [Extracted from the article]

This 17-year-old male initially presented to the Accident and Emergency department with a 3-week history of tender, cervical lymphadenopathy, parotid gland enlargement and fevers. There was also an enlarged left intraparotid lymph node measuring 1.1 cm. The left parotid gland demonstrated a heterogeneous, pseudonodular echo pattern, suggestive of coexistent parotid inflammation. Imaging is often non-specific with computed tomography findings often showing multiple affected lymph nodes with homogeneity and perinodal infiltration.3 The aetiology of KFD is a subject of debate. [Extracted from the article]

Summary: Chimeric antigen receptor‐modified (CAR)‐T cells have demonstrated impressive results in the treatment of haematological malignancies. However, cytokine release syndrome (CRS) and neurotoxicity are common toxicities which are potentially life‐threatening in severe cases. Risk factors for CRS and neurotoxicity identified so far include disease burden, lymphodepletion intensity and CAR‐T cell dose administered. Risk‐adapted dosing, with lower CAR‐T cell doses administered to B‐cell acute lymphoblastic leukaemia patients with high marrow blast counts, has been successful at decreasing severe CRS rates in this population. Intervention with therapies, such as tocilizumab and corticosteroids, have been effective at ameliorating toxicity, enabling CAR‐T cells to be administered safely to many patients without significantly compromising efficacy. Deeper understanding of the pathophysiology of underlying CRS and neurotoxicity will enable the development of novel approaches to reduce toxicity and improve outcomes. [ABSTRACT FROM AUTHOR]

Treatment of relapsed/refractory B-precursor acute lymphoblastic leukaemia (R/R B-ALL) in children remains a challenge, with only 30-50% of patients being salvaged by intensive chemotherapy and allogeneic haematopoietic stem cell transplantation (HSCT),1 with a dismal survival for those who relapse after HSCT.2 Results of immunotherapy with blinatumomab or autologous/allogeneic chimeric antigen receptor (CAR)-T cells hold out a promise of better outcomes3-6 and are now moving to the front-line of treatment protocols for selected high-risk patients (AALL1721/CASSIOPEIA, NCT03876769). The panel database included 230 patients with B-ALL, and for 138 patients (60%) the referring centre sought advice on curative treatment. The panel recommended antibody therapy for 47 patients (34%): blinatumomab for 34 patients, inotuzumab for eight, either blinatumomab or inotuzumab for five. [Extracted from the article]

Keywords: myeloma; COVID-19; cytokine release syndrome; interleukin-6; tocilizumab EN myeloma COVID-19 cytokine release syndrome interleukin-6 tocilizumab e9 e11 3 07/01/20 20200701 NES 200701 Coronavirus disease 2019 (COVID-19) presents with a broad clinical spectrum, varying from asymptomatic infection to severe pneumonitis, leading to acute respiratory distress syndrome and death.[1] Accumulating evidence suggests that in severe COVID-19, an acute hyperinflammatory syndrome characterised by fever, hypoxia and increased serum inflammatory markers, occurring 5-10 days from the first symptoms, is the major driver of morbidity and death.[2] Hyperinflammation is not specific to COVID-19. We report treatment with tocilizumab in two patients with myeloma with confirmed COVID-19, who developed CRS-like syndrome and respiratory failure. GLO:1XW/01jul20:bjh16787-fig-0001.jpg PHOTO (COLOR): 1 A. Clinical observations in patient 1 during cytokine release syndrome-like syndrome and treatment with tocilizumab (TCZ) B. C-reactive protein (CRP) and serum ferritin levels steadily decline after TCZ infusion. [Extracted from the article]

The article reports on the case of a ten-year-old boy who developed serious cytokine release syndrome (CRS), a complication of chimeric antigen receptor (CAR)-modified T cell (CAR-T) therapy in a phase-one clinical trial. The patient, who was diagnosed with B-cell acute lymphoblastic leukaemia eight years ago, suffered from central nervous system (CNS) symptoms and coagulopathy. The importance of timely diagnosis and the right approach to the management of CNS problems is emphasized.

Idecabtagene vicleucel (ide-cel, Abecma, Bristol Myers Squibb [BMS], New York, NY, USA), is the first FDA-approved cell-based gene therapy for multiple myeloma, the first chimaeric antigen receptor (CAR) T cell therapy directed at B-cell maturation antigen (BCMA), and a drug with an astonishing price tag.1 BMS and Bluebird Bio, marketing in unison, have listed the CAR T-cell therapy at a price of $419 500 per treatment.2 Approval was based in part on the KarMMa study (NCT03361748), a phase 2 trial that found a 73% response rate and a median progression-free survival of 8-8 months based on a modified intention-to-treat analysis.3 This recent approval serves as an opportunity to assess ide-cel's clinical implications and explore whether this price tag is sustainable for a therapy that does not appear to cure even a fraction of patients. Since this treatment is likely non-curative, physicians may anticipate an eventual relapse and justify maintenance therapy with active but expensive agents such lenalidomide, carfilzomib, bortezomib, or daratumumab. The treatment-free interval and theoretical accompanying QoL gain anticipated for patients responding to ide-cel per the KarMMa study protocol would then vanish, with patients unable to escape the burden of therapy-related toxicities (both medical and financial). [Extracted from the article]

Patients with severe COVID-19 do have a hyperinflammatory process, but it should not necessarily be regarded as sHLH - therefore the HLH 2004/HScore systems should not be used to determine treatment in this setting. Limited utility of the HScore in detecting secondary haemophagocytic lymphohistiocytosis in COVID-19: response Keywords: immunosuppressive therapy; COVID-19; hyperinflammatory syndrome EN immunosuppressive therapy COVID-19 hyperinflammatory syndrome 688 689 2 08/18/21 20210815 NES 210815 We initially responded1 to the prior recommendations in the I Lancet i on screening with the HScore to guide immunosuppressive therapy in COVID-19 patients.2 We identified that this is likely to be inappropriate due to the differences in the COVID-19-related hyperinflammatory syndrome I versus i other alternate causes of secondary haemophagocytic lymphohistiocytosis (sHLH).1 In this letter, Sangha I et al i . acknowledge that the HScore is not well suited to guide immunosuppressive therapy in COVID-19 patients. [Extracted from the article]