Liso-cel CAR-T ‘new potential treatment option’ for advanced chronic lymphocytic leukemia
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Key takeaways:
- Liso-cel induced an 18% complete response/CRi rate among adults with relapsed or refractory CLL or SLL.
- Median PFS had not yet been reached among patients who achieved complete response.
CHICAGO — Lisocabtagene maraleucel significantly improved complete remission rates among adults with relapsed or refractory chronic lymphocytic leukemia, results from the pivotal phase 2 TRANSCEND CLL 004 trial showed.
Investigators reported no disease progression or deaths among individuals who achieved a complete response (CR) to the chimeric antigen receptor T-cell therapy, according to a primary analysis of the study presented at ASCO Annual Meeting and published in The Lancet.
“A single administration of liso-cel demonstrated rapid, deep and durable responses in patients with relapsed or refractory CLL,” Tanya Siddiqi, MD, associate professor in the division of lymphoma at City of Hope National Medical Center and Healio | Cell Therapy Next Peer Perspective Board Member, said during a presentation. “These results support the use of liso-cel as a new potential treatment option for patients with relapsed or refractory CLL, especially after prior Bruton tyrosine kinase (BTK) inhibitor therapy.”
Background, methodology
There are no standard treatments for individuals with relapsed or refractory CLL or small lymphocytic leukemia (SLL) after disease progression, Siddiqi said.
“There is a high unmet need in patients with relapsed or refractory CLL or SLL after use of BTK inhibitors or venetoclax,” she said. “Real-world evidence indicates progressively worse outcomes as treatment options become exhausted, with low complete remission rates of less than 5% and short median overall survival.”
Lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb) — a CD19-directed chimeric antigen receptor T-cell therapy — is approved for treatment of adults with relapsed or refractory large B-cell lymphoma.
The multicenter TRANSCEND CLL 004 evaluated the efficacy and safety of the autologous cellular therapy for adults with relapsed or refractory CLL or SLL at the recommended phase 2 dose of 100×106 CAR T cells.
The study included 117 adults (median age, 65 years; range, 49-82; 68% men; 85% white patients) with relapsed disease who previously received a BTK inhibitor and were refractory to treatment with the BCL-2 inhibitor venetoclax (Venclexta; AbbVie, Genentech).
The full efficacy analysis population included 87 patients, with investigators evaluating a separate primary efficacy analysis subgroup of 49 patients with BTK inhibitor progression and venetoclax failure.
Study participants underwent preconditioning lymphodepletion followed by a single infusion of liso-cel.
CR rate — including complete remission with incomplete bone marrow recovery (CRi) —served as the study’s primary endpoint. Secondary endpoints included OS, PFS, duration of response and safety.
Key findings
Median follow-up was 21.1 months.
The study met its primary endpoint, showing a significant improvement in complete response rate with liso-cel compared with historical controls.
Investigators reported CR/CRi rates of 18% (95% CI, 11-28) for the full efficacy analysis population and 18% (95% CI, 9-32) for the subset of patients with BTK inhibitor progression/venetoclax failure.
Siddiqi described the result as “highly statistically significant” for the subgroup of patients previously treated with BTK inhibitors and venetoclax.
Median duration of response had not been reached among patients who achieved complete response; median response duration among patients who achieved any type of response to therapy was 35.3 months.
In the full study population, researchers reported median PFS of 18 months (95% CI, 9.4-30.1) and median OS of 43.2 months (95% CI, 26.9 to not reached).
In the primary efficacy analysis subset, researchers reported median PFS of 11.9 months (95% CI, 5.7-26.2) and median OS of 30.3 months (95% CI, 11.2 to not reached).
Five treatment-related deaths occurred during the study. Investigators considered four to be unrelated to liso-cel and attributed one death from macrophage activation syndrome-hemophagocytic lymphohistiocytosis related to the study drug.
Further safety analysis revealed neutropenia (61%), anemia (52%) and thrombocytopenia (41%) as the most frequent grade 3 or higher treatment-related adverse events.
Most study participants (85%) experienced cytokine release syndrome, with 9% having grade 3 symptoms. Investigators reported no grade 4 or grade 5 CRS.
Neurotoxicity occurred among 45% of study participants, including 18% with grade 3 symptoms and one patient with grade 4.
Clinical implications
The results showed a single infusion of liso-cel outperformed the historical control CR/CRi rate of less than 5% among individuals with relapsed or refractory CLL or SLL, Siddiqi said.
It did so along with a manageable safety profile that included low rates of grade 3 CRS or neurotoxicity, she added.
“Efficacy outcomes were similar in the full study population, demonstrating a broader clinical benefit of liso-cel,” Siddiqi said.
References:
- Siddiqi T, et al. Abstract 7501. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
- Siddiqi T, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)01052-8.
Perspective
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Lee Greenberger, PhD
CLL remains a difficult disease to eliminate, despite all the latest oral therapies and drug combinations.
And although CD19-directed CAR T-cell therapies have demonstrated the ability to cure some patients of their disease, often the disease stops responding to this type of treatment.
What’s exciting about the findings from TRANSCEND CLL 004 is that the use of the CAR-T liso-cel was associated with disease control and moderate to low rates of CRS and immune effector cell-associated neurotoxicity syndrome among a group of heavily pretreated patients with CLL and SLL.
There were, however, moderate- to high-level grade 3 infections seen in the study population. Moreover, prolonged cytopenia and hypogammaglobulinemia remain a concern in these individuals, particularly in those who may be susceptible to developing COVID-19 infections.
Long-term data need to be examined in the future to determine the durability of treatment responses, as well as overall survival.
It would also be helpful to see research that evaluates liso-cel in earlier lines of therapy or in patients who are at greater risk for treatment failure or having their disease progress to Richter’s transformation.
It is imperative that we continue to explore multiple options to cure CLL. As a result, The Leukemia & Lymphoma Society continues to fund new research investigating new CLL targets, BTK degraders, newer combination therapies and mechanisms that identify resistance to existing therapies.
Collapse
Siddiqi T, et al. Abstract 7501. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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