Breyanzi® (lisocabtagene maraleucel) was approved by the US FDA to treat Large B-cell Lymphoma and its sybtypes in adult patients who have received one prior therapy. Photo: Bristol Myers Squibb.
Breyanzi® is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy developed by Bristol-Myers Squibb. Credit: Bristol-Myers Squibb.
Large B-cell Lymphoma (LBCL) accounts for one out of every three Non-Hodgkin’s Lymphoma (NHL) cases worldwide. Credit: Design_Cells/

Breyanzi is a CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma (LBCL), after first-line treatment.

Developed by US-based pharmaceutical company Bristol Myers Squibb, the personalised therapy holds the broadest patient eligibility for second-line LBCL, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL3B).

Breyanzi is a gene-modified autologous therapy. In the US, a single dose of Breyanzi contains 90 to 110 x 10⁶ CAR-positive viable T cells for LBCL after one line of therapy, and 50 to 110 × 10⁶ CAR-positive viable T cells for LBCL after two or more lines of therapy. It is administered to the patients through a single transfusion intravenously.

In May 2023, positive top-line results from two studies, namely TRANSCEND FL, evaluating Breyanzi in patients with relapsed or refractory follicular lymphoma (FL); and TRANSCEND NHL 001, evaluating Breyanzi in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, including mantle cell lymphoma (MCL) were announced. With these results, Breyanzi has demonstrated clinically meaningful benefits across the broadest array of B-cell malignancies of any CD19-directed CAR T cell therapy, underscoring the company’s leadership in advancing innovative therapies for many types of haematological malignancies.

Regulatory approvals for Breyanzi

The US Food and Drug Administration (FDA) provided the initial approval of Breyanzi for the treatment of adult patients with r/r LBCL following two or more lines of systemic therapy in February 2021, based on data from the TRANSCEND NHL 001 clinical trial.

In March 2021, Japan’s Ministry of Health, Labour and Welfare (MHLW) approved the drug for the treatment of patients with r/r LBCL and r/r FL.

The European Commission (EC) approved Breyanzi for the treatment of adult patients with r/r DLBCL, PMBCL, and FL3B after two or more lines of systemic therapy in April 2022.

Breyanzi entered the second-line setting for the treatment of r/r LBCL in the US in June 2022, based on results from the Phase III TRANSFORM and Phase Ⅱ PILOT clinical trials. The therapy was approved for the second-line treatment of r/r LBCL in Japan in December 2022. In May 2023, the EC approved Breyanzi for the treatment of adult patients with r/r DLBCL, HGBCL, PMBCL and FL3B for second-line treatment.

Large B-cell lymphoma causes and symptoms

LBCL is a type of non-Hodgkin lymphoma (NHL), a cancer that originates in the lymphatic system.

LBCL is a fast-growing cancer that affects B-cells, a type of white blood cell that helps fight infections. There are several subtypes of LBCL based on their genetic and molecular characteristics, with diffuse large B-cell lymphoma (DLCBL) being the most common form of NHL. Other common subtypes include PMBCL and HGBCL.

Some of the symptoms of LBCL include painless swelling in one or more lymph nodes, fever, night sweats, unintentional weight loss, persistent fatigue, loss of appetite, a sensation of bloating caused by an enlarged spleen, enlargement of the liver, itchy skin, and rashes.

The exact cause of LBCL is not known. Some of its risk factors may include HIV, Epstein-Barr virus, family history of NHL or Hodgkin lymphoma (HL), obesity, and chemical exposure.

LBCL is typically diagnosed through a biopsy of an enlarged lymph node or other affected tissue.

Breyanzi’s mechanism of action

Breyanzi is a CAR T cell therapy that specifically targets CD19 expressed on the cell surface of tumour and normal B cells. The CAR contains an FMC63 monoclonal antibody-derived single chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB costimulatory domain, and CD3 zeta activation domain.

CD3 zeta signalling is important for initiating activation and antitumor activity while 4-1BB (CD137) signalling promotes the expansion and persistence of the drug.

The CAR binds to CD19 and triggers the activation and proliferation of CAR T cells, leading to the release of pro-inflammatory cytokines and the cytotoxic death of cancer cells.

Clinical trials on Breyanzi

The TRANSCEND NHL 001 clinical trial was an open-label, multicentre, multicohort, Phase I study, to determine the safety, antitumor activity and pharmacokinetics of Breyanzi in adults with r/r DLBCL, HGL, PMBCL, FL3B and MCL.

During the trial, 268 participants with r/r LBCL received Breyanzi. It was the largest pivotal trial in third-line plus R/R LBCL that included patients with a broad range of histologies and high-risk diseases. In the trial, Breyanzi was administered in the inpatient and outpatient settings.

In the study, 192 patients were treated with Breyanzi and evaluated for efficacy. Of them, 73% achieved a response, including 54% who had minimal or no detectable lymphoma remaining following treatment and 19% who achieved a partial response.

The median duration of response was 16.7 months in all responders, and for patients who achieved a complete response (CR), median duration of response was not reached; for patients with a best response of partial response (PR), a median duration of response was 1.4 months. Of 104 patients treated with Breyanzi who achieved a best overall response of CR, 65% had remission lasting at least six months and 62% had remission lasting at least nine months.

Another notable trial is the Phase III TRANSFORM clinical trial, which was a global, randomised, open-label, multi-centre study, which evaluated Breyanzi against the standard-of-care (SOC) regimens, including high-dose chemotherapy (HDCT) and hematopoietic stem cell transplant (HSCT), in adults with r/r LBCL after first-line chemotherapy.

A total of 184 patients were randomised in a 1:1 ratio to receive either a single infusion of Breyanzi or SOC. The primary endpoint of the study was event-free survival (EFS), while progression-free survival in patients was also evaluated in the study.

The patients treated with Breyanzi achieved a median EFS of 10.1 months compared to 2.3 months in patients in the SOC arm.

Approximately 66% of patients receiving Breyanzi achieved a CR compared to 39% of patients in the SOC arm. Additionally, Breyanzi more than doubled the progression-free survival (PFS) in patients compared to SOC. The safety profile of the drug was also well established in the study.

Phase II trials of Breyanzi

The single-arm, open-label, multi-centre Phase Ⅱ PILOT clinical study evaluated the efficacy of Breyanzi as a second-line treatment in transplant-ineligible patients with r/r LBCL. The PILOT study enrolled a broad patient population based on age, performance status and/or organ function and comorbidities, and regardless of time to relapse following first-line treatment.

Breyanzi showed deep and durable responses, with an overall response rate of 80%, the study’s primary endpoint, and a CR rate of 54%, with median time to CR of one month (range: 0.8 to 6.9 months). Median duration of response was 11.2 months, with the median duration of response not reached for those patients who achieved a CR.

The most common adverse events observed in patients during the clinical trials were cytokine release syndrome (CRS), fever, fatigue, musculoskeletal pain, and nausea.

Breyanzi is also being investigated for the treatment of adults with r/r chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) in a multi-centre, Phase I/II, open-label, single-arm clinical trial named TRANSCEND CLL 004.

In January 2023, top-line results from this study were announced, showing the study met the primary endpoint of complete response rate compared to historical control in the prespecified subset of patients with R/R CLL that was refractory to a BTK inhibitor and pre-treated with a BCL-2 inhibitor.