Axicabtagene ciloleucel

A second chimeric antigen receptor (CAR) therapy has gained FDA approval, this time for the treatment of aggressive large B-cell lymphoma in adults.

Axicabtagene ciloleucel is indicated for adults with relapsed/refractory large B-cell lymphoma after at least 2 lines of therapy.

Axicabtagene is a option for patients with relapsed or refractory follicular lymphoma in the third line setting or beyond and is an approved treatment for an indolent lymphoma.

An autologous, anti–CD 19 chimeric antigen receptor T-cell therapy.
Has been approved for the treatment of large cell lymphomas, high-grade lymphomas, primary mediastinal B-cell lymphoma, transformed follicular lymphoma and follicular lymphoma.

The CAR consists of of an anti-CD19 single chain variable fragment plus the costimulatory signaling domains C28 and CD3 zeta: activating downstream signaling cascade that lead to T cell activation, proliferation, acquisition of effective functions, and secretions of inflammatory cytokines and chemokines eventually leading to apoptosis and necrosis  of CD19 expressed target cells.

Targets CD19 and uses CD28 costimulatory domain.

The antigen CD is expressed along wide range of B-cell cancers it has restricted expression in healthy tissues.

Indications include: diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma and diffuse large B-cell lymphoma arising from follicular lymphoma.

T-cells are extracted from the patient and genetically reengineered with CAR molecules that help T cells attack cancer cells, after being reinfused to the patient.

The engineered T cells engage with a T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory molecules, resulting in cell death.

Average time from harvesting to reinfusion is 17 days.

Chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta) approved for the treatment of de novo and transformed diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, and high grade B-cell lymphoma in adults who have failed or relapsed after two or more prior treatments.

ZUMA-1, the multicenter clinical trial that led to the approval of axicabtagene ciloleucel, included over 100 adult patients with refractory or relapsed large B-cell lymphoma, with an overall response rate of 82%, and 58% achieved a complete remission.

Can lead to long-term on-going remissions in patients with high-risk poor-prognosis, refractory large-cell lymphoma.

In the above study 56% of patients were alive at 15 months.

ZUMA-1 suggests that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma,

Only patients with complete response have durable remissions.

Most patients develop develop hypogammglobulinemia, and B-cell aplasia.

Axicabtagene ciloleucel, is marketed as Yescarta is approved for use in adults with large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL).

Patients must have failed at least two other treatments before axicabtagene ciloleucel can be tried.

ZUMA-1, a multicenter clinical trial of 101 adults with refractory or relapsed large B-cell lymphoma.

72% of patients responded, including 51% who achieved complete remission.

CAR-T therapy can cause severe, life-threatening side effects, most notably cytokine release syndrome (CRS) and neurologic toxicities.

Approval CAR T-Cell Therapy for Adults With Aggressive Lymphomas

The CAR T-cell therapy is approved in patients who have failed or relapsed after two or more prior treatments.

Thirteen percent of patients in ZUMA-1 experienced grade 3 or higher cytokine release syndrome and 31% of patients experienced neurologic toxicities.

The most common grade 3 or higher adverse events include: CRS, encephalopathy, febrile neutropenia, fever, hypotension, hypoxia, and infections.

Serious AEs occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias and serious infections.

Fatal cases of CRS and neurologic toxicity have occurred.

Approved with a risk evaluation and mitigation strategy (REMS) due to the risk of CRS and neurologic toxicities.

Axicabtagene ciloleucel approved for the treatment of adult patients with relapsed/refractory indolent follicular lymphoma after 2 or more lines of systemic therapy.

Axicabtagene-cel compared to standard therapy in patients with a relapsed or refractory large B cell lymphoma: The 24 month event free survival was 41% and 16%, respectively; the response rate was 83% compared to 50% in the standard care group. with complete responses of 65% in 32%, respectively.

Phase 2 ZUMA-5 trial in which the CAR T-cell product elicited a response in 94% of patients with relapsed/refractory follicular lymphoma; this included 60% of patients who achieved a complete remission (CR). 


Notably, 74% of patients had a continued remission at 18 months. 


Among all patients with follicular lymphoma, the median duration of response (DOR) was not yet reached at a median follow-up of 14.5 months.


Once a follicular lymphoma patient’s disease relapses, the duration of response shortens with each round of therapy: for patients with follicular lymphoma in the third line of therapy, the 5-year survival rate is only 20%,



91% of relapsed patients in the ZUMA-5 study responded to a single infusion of axicabtagene ciloleucel, including an estimated 74% of patients in a continued remission at 18 months.



Grade 3 or higher cytokine release syndrome (CRS) was reported in 8% of patients, while grade 3 or higher neurologic toxicities were reported in 21%. 



The median time to onset of  cytokine release syndrome  and neurological effects was 4 days and 6 days, respectively. 



The most frequently reported toxicities:  grade 3 or higher in severity were febrile neutropenia, encephalopathy, and infections with unspecified pathogens.

The list price for a single treatment of axicabtagene ciloleucel is $373,000.

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