Cellular Therapy in High-Risk Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter Syndrome

Barbanti, Maria Chiara; Appleby, Niamh; Kesavan, M.R.; Eyre, Toby A.

doi:10.3389/fonc.2022.888109

Cited by 6 publications

(5 citation statements)

References 89 publications

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“… 41 Anti-CD19 chimeric antigen receptor T-cell therapy has also been investigated in patients with DLBCL RT with early positive results. 42 , 43 , 44 , 45 However, these approaches need to be further studied to understand their optimum timing in the treatment schema, the need for subsequent allo-SCT and their effect on the underlying CLL compartment.…”

Section: Discussionmentioning

confidence: 99%

A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL

et al. 2023

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Richter transformation (RT) is a rare complication of CLL with dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized if combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of 24 cycles. Standard dose ibrutinib was initiated from cycle 2 onwards and continued daily until progression. A total of 24 patients with RT with a median age 64.5 years (range, 47-88) were enrolled. Ten patients (42%) had received prior treatment for RT and thirteen patients (54%) had received a prior BTKi. A total of 10 patients (42%) responded with a median duration of response of 15 months. The median overall survival was 13 months. Four of 24 (17%) patients had checkpoint inhibition-related immunological toxicities. In the CLL cohort, 10 patients were enrolled, of whom 3 patients converted from partial remission to complete remission; 1 patient had a grade 2 immunological toxicity. Combined nivolumab and ibrutinib is an active regimen for patients with DLBCL RT with an overall response rate of 42%. Given the limited treatment options for patients with RT, checkpoint inhibition provides a potential therapeutic option. This trial is registered at www.clinicaltrials.gov as NCT02420912.

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Section: Discussionmentioning

confidence: 99%

A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL

et al. 2023

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“…It is worth mentioning that HSCT as a consolidation therapy in RT has been available only to a selected group of younger, fit, and chemosensitive patients [31]. Only four of the 204 patients proceeded to allo-HSCT in one large single-institution publication of biopsy-proven RT, underlying the unmet need for effective induction therapies and the rarity of transplant-eligible RT patients [13].…”

Section: Aementioning

confidence: 99%

“…The limited efficacy obtained with conventional treatments for DLBCL-RT has prompted the investigation of novel therapies, including targeted inhibitors of Bruton's tyrosine kinase (BTKi) and BCL2. However, the outcomes of monotherapy treatment with novel agents have been reported in only small series and describe short PFS [31].…”

Section: Btki and Bcl Inhibitorsmentioning

confidence: 99%

Update on management of diffuse large B-cell lymphoma Richter's transformation

Sośnia,

Puła

2024

Acta Haematol Pol.

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Richter's transformation (RT) is defined as the development of an aggressive lymphoma in 2-10% of patients with chronic lymphocytic leukemia (CLL). Despite significant advances in the last decade, there is currently no established standard of care for RT, making its management a significant challenge. Questions regarding patients' treatment management in the era of novel agents and targeted therapies have yet to be answered. Nevertheless, several retrospective studies and clinical trials have emphasized the use of novel targeted agents to address this problem. In this review, we provide a summary of potential therapeutic options for RT.

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“…Other factors may contribute to CLL’s resistance to CAR-T therapy, such as high immune checkpoint protein expression, immune suppressive tumor microenvironment (TME), and high level of circulating inhibitory extracellular vesicles ( 100 ). The efficacy data of CD19-CAR T in RT remain scarce and conflicting ( 101 ). Some patients may even develop RT after CD19-CAR T, indicating the presence of intrinsic resistance mechanisms in RT to CD19-targeted therapy ( 102 ).…”

Section: B-cell Non-hodgkin Lymphomamentioning

confidence: 99%

Novel and multiple targets for chimeric antigen receptor-based therapies in lymphoma

Pang,

Ghosh

2024

Front. Oncol.

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Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 in B-cell non-Hodgkin lymphoma (NHL) validates the utility of CAR-based therapy for lymphomatous malignancies. Despite the success, treatment failure due to CD19 antigen loss, mutation, or down-regulation remains the main obstacle to cure. On-target, off-tumor effect of CD19-CAR T leads to side effects such as prolonged B-cell aplasia, limiting the application of therapy in indolent diseases such as chronic lymphocytic leukemia (CLL). Alternative CAR targets and multi-specific CAR are potential solutions to improving cellular therapy outcomes in B-NHL. For Hodgkin lymphoma and T-cell lymphoma, several cell surface antigens have been studied as CAR targets, some of which already showed promising results in clinical trials. Some antigens are expressed by different lymphomas and could be used for designing tumor-agnostic CAR. Here, we reviewed the antigens that have been studied for novel CAR-based therapies, as well as CARs designed to target two or more antigens in the treatment of lymphoma.

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Cellular Therapy in High-Risk Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter Syndrome

Cited by 6 publications

References 89 publications

A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL

A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL

Update on management of diffuse large B-cell lymphoma Richter's transformation

Novel and multiple targets for chimeric antigen receptor-based therapies in lymphoma

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