Outcomes of first therapy after CD19-CAR-T treatment failure in large B-cell lymphoma

Tomas, Ana Alarcón; Fein, Joshua; Fried, Shalev; Flynn, Jessica; Devlin, Sean M.; Fingrut, Warren; Anagnostou, Theodora; Alperovich, Anna; Shah, Nishi; Fraint, Ellen; Lin, Richard J.; Scordo, Michael; Batlevi, Connie Lee; Besser, Michal J.; Dahi, Parastoo B.; Danylesko, Ivetta; Giralt, Sergío; Imber, Brandon S.; Jacoby, Elad; Kedmi, Meirav; Nagler, Arnon; Palomba, M. Lia; Roshal, Mikhail; Salles, Gilles; Sauter, Craig S.; Shem‐Tov, Noga; Shimoni, Avichai; Yahalom, Joachim; Yerushalmi, Ronit; Shah, Gunjan L.; Avigdor, Abraham; Perales, Miguel Angel; Shouval, Roni

doi:10.1038/s41375-022-01739-2

Cited by 40 publications

(39 citation statements)

References 45 publications

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“…In agreement with other studies, significant prognostic factors were CAR Tcell refractoriness and IPI at salvage. [9][10][11] In addition, not previously reported, salvage therapy following CAR Tcell failure was less efficient for patients with double-hit/ triple-hit (DH/TH) lymphomas and DLBCL other than PMBCL and tFCL. Six out of seven patients diagnosed with DH/TH lymphoma died, and one patient is alive but with a rapidly progressive disease.…”

Section: Discussionmentioning

confidence: 92%

“…Two retrospective studies reporting the outcome after CAR T cells failure showed an overall response rate of 14%–39% with a 1‐year OS of 25% 10,11 . These studies are fundamental as they demonstrated the ineffectiveness of standard chemotherapy in this setting.…”

Section: Discussionmentioning

confidence: 99%

“…Two retrospective studies reporting the outcome after CAR T cells failure showed an overall response rate of 14%-39% with a 1-year OS of 25%. 10,11 These studies are fundamental as they demonstrated the ineffectiveness of standard chemotherapy in this setting. Despite the short follow-up, both studies showed an OS advantage for patients treated with lenalidomide, given the potential effect on the expansion of CAR T cells.…”

Section: Discussionmentioning

confidence: 99%

“…7,8 Data regarding the clinical outcome after CAR T cells failure are limited. [9][10][11] Conventional treatment options for these patients include standard chemoimmunotherapy, allogeneic stem cell transplantation or lenalidomide. Recently, novel treatment approaches, including antibody-drug conjugates, 12,13 checkpoint inhibitors (CPIs) 14,15 and bispecific antibodies, [16][17][18][19] became available in the setting of clinical trials.…”

Section: Introductionmentioning

confidence: 99%

“…Data regarding the clinical outcome after CAR T cells failure are limited 9–11 . Conventional treatment options for these patients include standard chemoimmunotherapy, allogeneic stem cell transplantation or lenalidomide.…”

Section: Introductionmentioning

confidence: 99%

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Outcome after chimeric antigen receptor (CAR) T‐cell therapy failure in large B‐cell lymphomas

Dodero,

Bramanti,

Di Trani

et al. 2023

Br J Haematol

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SummaryThis 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.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Outcome after chimeric antigen receptor (CAR) T‐cell therapy failure in large B‐cell lymphomas

Dodero,

Bramanti,

Di Trani

et al. 2023

Br J Haematol

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C‐CAR066, a novel fully human anti‐CD20 CAR‐T therapy for relapsed or refractory large B‐cell lymphoma after failure of anti‐CD19 CAR‐T therapy: A phase I clinical study

Li,

Liu,

Zhou

et al. 2024

American J Hematol

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Managing large B‐cell lymphoma (LBCL) that is refractory to or relapsed after chimeric antigen receptor (CAR)‐T therapy remains a significant challenge. Here we aimed to investigate the safety and efficacy of C‐CAR066, an autologous fully human anti‐CD20 specific CAR‐T, for relapsed/refractory LBCL after failure of anti‐CD19 CAR‐T therapy. This first‐in‐human, single‐arm, phase 1 study was conducted at two sites in China. Eligible patients had to be histologically confirmed with CD20‐positive LBCL and must have received prior anti‐CD19 CAR‐T therapy. Patients received a single intravenous infusion of C‐CAR066 at a target dose of 2.0 × 106 or 3.0 × 106 CAR‐T cells/kg. The primary endpoint was the incidence of adverse events (AEs). As of October 10, 2023, 14 patients had received C‐CAR066. The most common AEs of Grade 3 or higher were hematological toxicities. Cytokine release syndrome occurred in 12 (85.7%) patients, with only one was Grade 4 event. No patient experienced immune effector cell‐associated neurotoxicity syndrome events. The overall response rate was 92.9% with a complete response rate of 57.1%. With a median follow‐up of 27.7 months (range, 3.3–40.9), the median progression‐free survival and overall survival were 9.4 months (95% CI, 2.0 to NA) and 34.8 months (95% CI, 7.5 to NA), respectively. C‐CAR066 demonstrated a manageable safety profile and promising efficacy in patients in whom prior anti‐CD19 CAR‐T therapies had failed, providing a promising treatment option for those patients. This trial was registered with ClinicalTrials.gov, NCT04316624 and NCT04036019.

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Indicators describing the tumor lesion aggregation and dissemination and their impact on the prognosis of patients with diffuse large B cell lymphoma receiving chimeric antigen receptor T cell therapy

Dang,

Li,

Shen

et al. 2024

Cancer Medicine

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IntroductionChimeric antigen receptor (CAR) T cell therapy has markedly improved the prognosis of patients with diffuse large B‐cell lymphoma (DLBCL). The relative positioning of tumor lesions in lymphoma varies among patients, manifesting as either aggregation (clumped together) or dissemination (spread throughout the body). Prognostic significance of factors indicating the relative positioning of tumor lesions in CAR T cell therapy remains underexplored. For aggregation, prior research proposed the tumor volume surface ratio (TVSR), linking it to prognosis in chemotherapy. Regarding dissemination, indicators such as disease stage or extranodal involvement, commonly used in clinical practice, have not demonstrated prognostic significance in CAR T cell therapy. This study aims to analyze current indicators of tumor aggregation or dissemination and introduce a novel indicator to assess the prognostic value of tumor lesions' relative positioning in DLBCL patients undergoing CAR T cell therapy.MethodsThis retrospective study included 42 patients receiving CAR T cell therapy. Lesion image information was obtained from the last PET/CT scan prior to CAR T cell infusion, including total metabolic tumor volume, total tumor surface, diameter of lymphoma masses, and the sites of tumor lesions. We evaluated TVSR and bulky disease as descriptors of tumor aggregation. We refined existing indicators, stage III&IV and >1 site extranodal involvement, to distill a new indicator, termed ‘extra stage’, to better represent tumor dissemination. The study examined the prognostic significance of tumor aggregation and dissemination.ResultsOur findings indicate that TVSR, while prognostically valuable in chemotherapy, lacks practical prognostic value in CAR T cell therapy. Conversely, bulky disease emerged as an optimal prognostic indicator of tumor aggregation. Both bulky disease and extra stage were associated with poor prognosis and exhibiting synergistic prognostic impact in CAR T cell therapy.ConclusionsOverall, the relative positioning of tumor lesions significantly influences the prognosis of patients with DLBCL receiving CAR T cell therapy. The ideal scenario involves tumors with minimal dissemination and no aggregation.

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Outcomes of first therapy after CD19-CAR-T treatment failure in large B-cell lymphoma

Cited by 40 publications

References 45 publications

Outcome after chimeric antigen receptor (CAR) T‐cell therapy failure in large B‐cell lymphomas

Outcome after chimeric antigen receptor (CAR) T‐cell therapy failure in large B‐cell lymphomas

C‐CAR066, a novel fully human anti‐CD20 CAR‐T therapy for relapsed or refractory large B‐cell lymphoma after failure of anti‐CD19 CAR‐T therapy: A phase I clinical study

Indicators describing the tumor lesion aggregation and dissemination and their impact on the prognosis of patients with diffuse large B cell lymphoma receiving chimeric antigen receptor T cell therapy

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