Pharmacy Practice in Focus: Oncology
This CAR T-cell therapy has revolutionized the management of high-risk and relapsed or refractory disease.
Treatment of non-Hodgkin lymphoma (NHL) has historically been centered around the administration of chemotherapy. In the relapse setting, autologous stem cell transplantation (ASCT) is a mainstay of treatment. However, with the introduction of cellular therapies such as bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy, the treatment landscape for NHL has changed. Given that more than 120 types of NHL exist, with a wide variance in morphologic, immunophenotypic, genetic, and clinical features, it is often difficult to find a single cellular product with efficacy across subtypes. Lisocabtagene maraleucel (lisocel, Breyanzi; Juno Therapeutics, Inc) has begun to bridge this gap, as this product has revolutionized the management of high-risk and relapsed/refractory (R/R) NHL, gaining FDA approvals in large B-cell lymphoma (LBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In this therapeutic spotlight, we will review the new indications for liso-cel and how this CAR T-cell therapy varies in its efficacy and toxicity profile.
Although all FDA-approved CAR T-cell products target CD19, slight variances in the binding domain led to differences in the efficacy and toxicity profiles. Liso-cel comes as a 1:1 ratio of CD8 and CD4 CAR T cells. Despite lacking the CD8 hinge and transmembrane region seen in other products, liso-cel utilizes an immunoglobulin G4 hinge region and CD28 transmembrane domain, which play a role in the CAR T-cell activation and proliferation.
The original approval in R/R LBCL came as a result of data from the TRANSCEND NHL 001 study (NCT02631044) in 2021.1,2 In efforts to expand the scope of CAR T-cell use, investigators compared liso-cel with ASCT in the early R/R setting (less than 12 months post completion of first-line chemotherapy) in the TRANSFORM trial (NCT03575351).3 The trial’s primary end point was event-free survival, and liso-cel demonstrated significant improvement among patients at 10.1 months (95% CI, 6.1-not reached) vs 2.3 months (2.2-4.3) among those in the ASCT arm.2 Notably, patients who are at a high risk of early relapse following frontline chemotherapy are often considered to have chemorefractory disease and do not respond as well to transplant as those who have durable responses from first-line chemotherapy. Despite this trend, the TRANSFORM data proved that liso-cel could provide benefit to patients with LBCL who experienced relapse less than 12 months following the completion of first-line treatment.1-3
Indolent NHLs have historically been difficult to treat despite being much more prevalent. A prime example is CLL/SLL, as new cases occur at a rate of 4.5 per 100,000 men and women per year. Studies have shown that new targeted therapies including Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL2) inhibitors have demonstrated significant efficacy. However, patients with R/R CLL/SLL who experience progression after receiving BTK and BCL2 inhibitors often have few treatment options and poorer outcomes. Real-world evidence has demonstrated that as these treatment options are exhausted, CLL no longer behaves as an indolent or chronic disease, indicating an unmet need. In March 2024, liso-cel received the first CAR T-cell therapy approval for the treatment of adult patients with R/R CLL/SLL who have received at least 2 lines of therapy, including a BTK inhibitor and a BCL2 inhibitor, following data from the TRANSCEND CLL 004 study (NCT03331198).4
TRANSCEND CLL 004 is a phase 1/2 open-label multicenter study that enrolled 139 patients, 117 of whom received liso-cel infusion at 2 different dose levels. The primary end point was complete response or remission, and the rate was 18% at a median follow-up of just under 20 months. These responses were also durable, with a median duration of response (DOR) of 35.3 months overall; this was not reached prior to data publication in those who achieved a complete response. Because a single infusion of liso-cel was shown to induce a complete response or remission in patients with R/R CLL or SLL while maintaining a manageable adverse effect profile, liso-cel received its indication for this subset of patients.4
Soon after its approval in CLL/SLL, liso-cel gained one of its most recent indications in another indolent lymphoma. In May 2024, the FDA approved the agent for adults with R/R FL who have also received 2 or more lines of prior therapy. This approval was supported by the results of the multicenter, open-label phase 2 TRANSCEND FL study (NCT04245839). CAR T therapy is an option for R/R FL after 2 or more lines of prior systemic therapy; previously, there was no consensus on the optimal timing in the disease course, as no data existed on the second-line treatment of patients with high-risk features. Investigators evaluated liso-cel in TRANSCEND FL in the second-line setting for patients who had disease progression within 24 months after treatment with an anti-CD20 antibody and alkylator less than 6 months following diagnosis. In the second line, the FL ORR was 96%, and all responders achieved a complete response. The DOR rate was 77.1% at 18 months. Following the response rates and DOR seen in this study, liso-cel gained this indication under an accelerated approval.5
For patients with MCL, consolidative ASCT is often administered in the first-line setting. Without ASCT, patients are left with few options for treatment. However, newer combination therapies are moving salvage treatment options to the front-line.
In a small cohort in the TRANSCEND NHL 001 trial, investigators assessed liso-cel for patients with R/R MCL, the results of which supported FDA approval for this indication in May 2024. This study included 104 patients (88 of whom received the CAR T-cell infusion) with R/R MCL. These patients were required to have disease that was refractory to at least 2 prior lines of therapy, including but not limited to BTK inhibitors, alkylating agents, and CD20-targeted agents. The median DOR was 15.7 months (95% CI, 6.2 to 24.0), and PFS was 15.3 months (95% CI, 6.6 to 24.9), making liso-cel the first commercial CAR T-cell product to show benefit in MCL. It is important to note that 23% of patients were TP53 positive, 31% had blastoid morphology, and only 30% had received prior ASCT, indicating that patients included in this cohort are likely those with less aggressive disease who respond well to other treatment options.6
Although the avoidance of traditional chemotherapy toxicities presents advantages, the use of cellular therapies such as CAR T cell introduces novel complications, such as cytokine release syndrome (CRS) and neurotoxic events (NEs), that can be challenging to manage. Understanding these toxicities’ frequency, onset, and duration is essential in early and appropriate management (Table1-6). Compared with other CAR T-cell therapies, liso-cel generally presents with a later onset of CRS and NEs. In clinical practice, this facilitates the ability to discharge patients for outpatient monitoring much earlier on, as the expected onset of toxicity occurs between 5 and 8 days following cell infusion. Liso-cel cellular toxicities also present with a shorter duration and decreased frequency of grade 3 or higher toxicities, making this product a potential option for patients who may not tolerate intensive treatment in the R/R setting. Despite the rates of CRS and NEs seen in these trials, monitoring is recommended for at least 7 days following infusion, and this therapy is available only through a restricted Risk Evaluation and Mitigation Strategy program.
Eve Hughes, PharmD, is a PGY-2 oncology pharmacy resident at Roswell Park Comprehensive Cancer Center in Buffalo, New York.
Jordan Scott, PharmD, is a clinical pharmacy specialist at Roswell Park Comprehensive Cancer Center in Buffalo, New York.
Overall, liso-cel is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of a broad range of R/R B-cell malignancies, including LBCL, CLL/SLL, FL, and MCL. The efficacy is supported by clinical trial data showing high response rates and durable remissions in these historically difficult-to-treat disease states. The expanded indications of CAR T therapy have transformed the treatment landscape of R/R B-cell malignancies, providing a novel therapy for patients who have exhausted multiple lines of traditional subsequent therapies. Despite expanded access to these treatments, it remains vital to provide appropriate toxicity monitoring and management based on expected frequency and onset. Future research and clinical trials will be crucial as CAR T-cell therapies continue to be optimized, addressing further unmet needs for patients with lymphoma.
