FDA Approves Breyanzi for Relapsed/Refractory CLL/SLL

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Breyanzi has been approved by the FDA for some previously treated patients with CLL or SLL — marking the first CAR-T cell therapy approved for this patient population.

The Food and Drug Administration (FDA) has approved Breyanzi (lisocabtagene maraleucel) for the treatment of adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) following prior treatment at least two prior lines of therapy, including with a Bruton tyrosine kinase inhibitor (BTKi) and B-cell lymphoma 2 inhibitor (BCL2i), Breyanzi’s manufacturer Bristol Myers Squibb has announced.

The manufacturer Bristol Myers Squibb announced in November that the FDA had granted priority review to the company’s supplemental biologics license application for the treatment based on the results from the primary analysis of the phase 1/2 TRANSCEND CLL 004 study.

Twenty percent of patients treated with Breyanzi experienced a complete response (no evidence of disease), and among those patients a median duration response was not reached as of data cutoff, meaning more than half of those patients were still experiencing a complete response. The study’s objective response rate (patients whose disease responded partially or completely to treatment) was 45%, with a median duration of response of 35.3 months.

Patients who experienced a complete response had a minimal residual disease negativity (absence of detectable malignant cells) of 100% in the blood and 92.3% in the bone marrow, according to Bristol Myers Squibb.

Bristol Myers Squibb noted that Breyanzi is the first CAR-T cell therapy approved for this patient population.

“CLL and SLL are currently considered incurable diseases with few treatment options in the relapsed setting that can confer complete responses, something that has historically been associated with improved long-term outcomes,” said Dr. Tanya Siddiqi, lead investigator and associate professor, Division of Lymphoma, City of Hope National Medical Center, in the announcement. “The FDA approval of [Breyanzi] in relapsed or refractory CLL and SLL after treatment with prior BTKi and BCL2i is a remarkable breakthrough, shifting the treatment paradigm from continuous therapy with sequential regimens to overcome drug resistance, to a one-time personalized T-cell based approach that has the potential to offer patients complete and lasting remission.”

While treatments approved for CLL in the past several years — including oral agents such as BTK inhibitors, Venclexta (venetoclax), as well as the combination of these agents with or without anti-CD20 antibodies — have increased progression-free survival times (the amount of time a patient lives without their disease spreading or worsening) and reduced toxicities associated with chemotherapy or first-generation BTK inhibitors, they were not curative, as Lee Greenberger, chief scientific officer of the Leukemia and Lymphoma Society, explained.

“Therefore, patients typically need to stay on therapy for many years or indefinitely and as long as the toxicity is acceptable. Beyond this, there are patient populations, such as those with p53 mutations, that underperform compared to the general CLL population and need better therapies,” Greenberger said to CURE®. “It is therefore highly relevant that, after receiving [Breyanzi] therapy, 18% of [patients with CLL] who have failed BTK inhibitor and [Venclexta] therapy obtained a complete response or incomplete marrow recovery (CRi). The median PFS was 18 months, and the median OS was 43 months. Therefore, [Breyanzi] therapy represents a life-extending option for [patients with CLL] that have failed conventional therapy and typically contain high-risk molecular markers.”

In the 89 patients treated with Breyanzi, most occurrences of cytokine release syndrome (CRS) and neurologic events (NE) were low grade, with any grade CRS occurring in 83% of patients and grade 3 occurring in 9% of patients, with n grade 4 or 5 CRS events reported. Any grade NEs were reported in 46% of patients, with grade 3 NEs reported in 20% of patients and one case of a grade 4 NE, according to the announcement.

Previous Findings

Study results previously published in The Lancet showed that in the trial’s 117 participants, among the 49 patients whose results who were analyzed in the primary efficacy analysis, nine experienced complete response or remission, a finding researchers determined to be “statistically significant.”

A single infusion of Breyanzi, researchers noted, “was shown to induce complete response or remission … in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and [Venclexta] failure. The safety profile was manageable.”

CRS is the large, rapid release of cytokines into the blood from immune cells affected by the immunotherapy, with symptoms including fever, nausea, headache, rash, rapid heartbeat, low blood pressure and trouble breathing, according to the National Cancer Institute.

“Among 51 deaths on the study, 43 occurred after [Breyanzi] infusion, of which five were due to treatment-emergent adverse events (within 90 days of [Breyanzi] infusion),” researchers reported in The Lancet, further noting that one death was related to Breyanzi, of macrophage activation syndrome-haemophagocytic lymphohistiocytosis — described in the Journal of Hematology as “two overlapping, potentially fatal syndromes classified by disorganization and malfunction of the immune system that results in wide spread inflammation and end-organ damage.

The FDA had previously approved Breyanzi in 2021 and in 2022 for the treatment of adults with certain subtypes of large B-cell lymphoma who either relapsed after or did not respond to two prior lines of systemic treatment.

However, unmet needs persist, as Greenberger explained.

“While we have seen incredible progress in the treatment of CLL, patients can expect to remain on treatment for the disease once it has passed the ‘watch-and-wait’ stage,” he said. “The hope is that combination therapy will provide long-lasting disease control with manageable side effects for the remainder of the patient’s life. Moreover, a new combination therapy is being explored where one or more of the components of therapy can be discontinued, thereby avoiding potential toxicities, as well as reducing costs. CD19 CAR-T therapy such as [Breyanzi] fills a gap in care although this still is not likely to cure most patients. Access to CAR-T therapies, as well as the high cost of the therapy remains an issue with many patients.”

Meanwhile, Greenberger explained, the work continues for organizations such as LLS, which has worked to identify and develop treatment options for decades.

“We continue to fund new work to understand why some [patients with CLL] do not respond to these therapies, as well support work to advance the most potent, safe and accessible combination therapies for [patients with CLL],” he said. “Eventually, we expect that someday cures can be achieved for many [patients with CLL] and [that they] can live a therapy-free life after treatment.”

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