Search

Summary: CD7‐targeted chimeric antigen receptor T‐cell (CAR‐T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T‐cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T‐ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo‐HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T‐ALL/LBL who underwent allo‐HSCT after achieving CR with autologous CD7 CAR‐T therapy. These were compared with 124 consecutive T‐ALL/LBL patients who received allo‐HSCT in CR following chemotherapy. The study revealed that both the CAR‐T and chemotherapy cohorts exhibited comparable 2‐year overall survival (OS) (61.9% [95% CI, 44.1–78.1] vs. 67.6% [95% CI, 57.5–76.9], p = 0.210), leukaemia‐free survival (LFS) (62.3% [95% CI, 44.6–78.4] vs. 62.0% [95% CI, 51.8–71.7], p = 0.548), non‐relapse mortality (NRM) rates (32.0% [95% CI, 19.0–54.0] vs. 25.3% [95% CI, 17.9–35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0–26.0] vs. 15.8% [95% CI, 9.8–25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR‐T group achieved high 2‐year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR‐T therapy followed by allo‐HSCT is not only effective and safe for r/r T‐ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM. [ABSTRACT FROM AUTHOR]

Summary: Several products containing chimeric antigen receptor T cells targeting CD19 (CART19) have been approved for the treatment of patients with relapsed/refractory non‐Hodgkin's lymphoma (NHL) and acute lymphoblastic leukaemia (ALL). Despite very impressive response rates, a significant percentage of patients experience disease relapse and die of progressive disease. A major cause of CART19 failure is loss or downregulation of CD19 expression in tumour cells, which has prompted a myriad of novel strategies aimed at targeting more than one antigen (e.g. CD19 and CD20 or CD22). Dual targeting can the accomplished through co‐administration of two separate products, co‐transduction with two different vectors, bicistronic cassettes or tandem receptors. In this manuscript, we review the pros and cons of each strategy and the clinical results obtained so far. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T‐cell (CAR‐T) therapy targeting B‐cell maturation antigen (BCMA) has shown profound efficacy and manageable toxicity in patients with relapsed/refractory multiple myeloma (RRMM). However, determining the best course of treatment for post‐CAR‐T therapy relapse remains a significant challenge. We conducted a retrospective analysis of patients from the phase I LEGEND‐2 study (NCT03090659) enrolled at the Xi'an site, analysing the first salvage line of therapy and outcomes in patients with RRMM who progressed after receiving LCAR‐B38M CAR‐T therapy. Of 45 eligible patients, 34 (76%) had progressive disease (PD). Overall response rate (ORR) to salvage treatment was 50.0%. Median progression‐free survival (PFS) after starting salvage treatment was 16.3 months. Median PFS of patients receiving proteasome inhibitor (PI)‐based combination therapy was longer (28.2 months) than that of patients receiving a second BCMA CAR‐T (including LCAR‐B38M; 3.9 months, p = 0.0022) or chemotherapy (1.67 months, p = 0.0001). All patients with extramedullary disease at baseline (n = 11) progressed after CAR‐T therapy; ORR to salvage therapy was 25.0% and median PFS was 9.7 months. In conclusion, salvage therapy in patients with PD after receiving LCAR‐B38M CAR‐T cells produced moderate efficacy, with better outcomes for PI‐based salvage regimens. [ABSTRACT FROM AUTHOR]

This article discusses a case of fulminant cerebral edema (FCE) following CAR T-cell therapy, a treatment for certain types of cancer. FCE is a rare but severe complication that can lead to brain death within 24 hours. The patient in this case was successfully treated with prompt neurointensive support and immunosuppressive anti-cytokine therapy. The article emphasizes the importance of managing intracranial pressure (ICP) to prevent brain damage and highlights the need for aggressive neurointensive measures in addition to immunosuppressive therapy. The underlying pathophysiology of FCE is not fully understood, but the disruption of the blood-brain barrier and cytokine-mediated inflammation are believed to play a role. The article concludes that FCE is a potentially reversible complication and that early intervention is crucial for a positive outcome. [Extracted from the article]

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: Autologous patient‐derived adoptive T‐cell therapies have revolutionized the management of relapsed multiple myeloma (MM). However, the current manufacturing and quality control processes result in lengthy vein‐to‐vein time, making bridging therapy necessary for most patients. Yet the decision and choice of optimal bridging therapy are complex in the heavily pretreated relapsed MM patient. In this perspective piece, the authors provide their approach and considerations while selecting an optimal bridging regimen before autologous chimeric antigen receptor T‐cell therapy. [ABSTRACT FROM AUTHOR]

Summary: Mantle cell lymphoma (MCL) is a B‐cell non‐Hodgkin lymphoma characterised by a heterogeneous clinical course. Patients can often receive sequential treatments, yet these typically yield diminishing periods of disease control, raising questions about optimal therapy sequencing. Novel agents, such as chimeric antigen receptor T‐cell therapies and bispecific antibodies, show promise in relapsed MCL, but are often reserved for later treatment lines, which may underserve patients with aggressive disease phenotypes who die early in the treatment journey. To assess the problem of patient attrition from lymphoma‐related death limiting sequential treatment, we performed a multicentre retrospective cohort analysis of 389 patients treated at Australian and UK centres over a 10‐year period. Deaths from MCL increased after each treatment line, with 7%, 23% and 26% of patients dying from uncontrolled MCL after first, second and third lines respectively. Patients with older age at diagnosis and early relapse after induction therapy were at particular risk of death after second‐line treatment. This limitation of sequential treatment by lymphoma‐related death provides support for the trial of novel therapies in earlier treatment lines, particularly in high‐risk patient populations. [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]

Chimeric antigen receptor T‐cell (CAR‐T) therapy for the treatment of multiple myeloma (MM) has fundamentally changed the relapsed and refractory therapeutic landscape, but the disease remains incurable. Two CAR‐T products, idecabtagene vicleucel (ide‐cel; Abecma) and ciltacabtagene autoleucel (cilta‐cel, Carvykti), have been FDA‐ and EMA‐approved for the treatment of relapsed/refractory MM (RRMM); both target B‐cell maturation antigen (BCMA), a surface glycoprotein highly expressed on MM cells. Despite deep and durable responses following CAR‐T therapy, most patients will need subsequent treatment, and the optimal next‐line therapy is presently unclear. Commentary on: Liu et al. Outcomes in patients with multiple myeloma receiving salvage treatment after BCMA‐specific CAR‐T therapy: A retrospective analysis of LEGEND‐2. Br J Haematol 2024;204:1780‐1789. [ABSTRACT FROM AUTHOR]

Summary: This study retrospectively evaluated the outcome of salvage therapy in 51 patients who failed axicabtagene ciloleucel or tisagenlecleucel for relapsed/refractory large B‐cell lymphomas. Of these patients, 22 (43%) were enrolled in clinical trials (glofitamab or loncastuximab tesirine + ibrutinib), whereas 29 received standard therapies (lenalidomide [Len], checkpoint inhibitors [CPIs], ibrutinib [I], chemoimmunotherapy and radiotherapy) or supportive care. Overall, 26 of 39 (67%) treated patients received a treatment based on immunotherapy (glofitamab, CPI, Len) that was mainly represented by bispecific antibody (n = 18). In this subgroup, plasma samples were collected and analysed for circulating tumour DNA (ctDNA) using cancer‐personalized profiling by deep sequencing (CAPP‐seq). The study found that patients with high ctDNA had poor outcomes. At a median follow‐up of 11.7 months, the estimated 12‐month overall survival (OS) was 35%. Factors adversely affecting the prognosis in the multivariable model were the absence of response to CAR T‐cell therapy (HR: 3.08; p = 0.0109) and a diagnosis other than PMBCL and t‐FL (HR: 4.54; p = 0.0069). The outcome of patients failing CAR T cells is poor and requires further investigation. [ABSTRACT FROM AUTHOR]

In their paper, the authors present their experience with the use of chimeric antigen receptor T cells targeting CD7 as a bridge to allogeneic haematopoietic cell transplantation in patients with relapsed/refractory T‐cell acute lymphoblastic leukaemia/lymphoblastic lymphoma. Commentary on: Cao et al. A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T‐cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T‐cell therapy. Br J Haematol 2024;204:2351‐2364. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplant remains an option for patients with myeloma. Given the unfortunate inevitability of the majority of patients, relapsing salvage therapy options are needed. Although there is a potential concern for subsequent T‐cell redirection therapy in these patients, Hammons et al. provide a retrospective look at patients treated this way with no new significant adverse safety or efficacy signal. Commentary on: Hammons et al. Chimeric antigen receptor and bispecific T‐cell engager therapies in multiple myeloma patients with prior allogeneic transplantation. Br J Haematol 2024;204:887‐891. [ABSTRACT FROM AUTHOR]