Liso-cel Shows Continued Durability in Long-Term Follow-Up Data of r/r CLL/SLL

Tanya Siddiqi, MD

The efficacy and safety of lisocabtagene maraleucel (liso-cel; Breyanzi; Bristol Myers Squibb) in patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) has shown long-term durability and consistency with established data, according to 23.5-month follow-up data from TRANSCEND CLL 004 study (NCT03331198) presented at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, in San Diego, California.¹

The autologous, CD19-directed, 4-1BB CAR T cell product was assessed in individuals with CLL/SLL who reported lack of success with treatment on Bruton tyrosine kinase inhibitors (BTKis) and venetoclax (meaning these patients reported either intolerance to the medicines or disease progression despite their administration)—a group with no established standard of care and poor outcomes, according to study investigator Tanya Siddiqi, MD, and colleagues.

Patients were assessed at 2 dose levels: 50 × 106 cells (dose level 1) and 100 × 106 cells (dose level 2). All told, the safety dataset included 118 patients who were leukapheresed and received liso-cel (dose-level 1, n = 9; dose level 2, n = 88), and another 54 (dose-level 1, n = 4; dose level 2, n = 50) were in the primary efficacy analysis set.

In the efficacy data set, the complete response (CR) CR with incomplete marrow recovery (CRi) rate was 20% (95% CI, 10.0-33.7) for those on dose level 2, with an overall response rate (ORR) of 44% (95% CI, 30.0-58.7). A single patient with a best overall response of partial response/remission at primary analysis had deepened to CR/CRi by the 18-month mark without additional treatment. Of the 9 total patients who had a best overall response of CR/CRi at the primary analysis point, 8 reported ongoing CR/Cri, and the 1 completed the study with the last assessment as CR/CRi.

Undetectable minimal residual disease (uMRD) rates in blood and marrow were 64% (95% CI, 49.2–77.1) and 60% (95% CI, 45.2–73.6), respectively. The median duration of response reported was 35.3 months (95% CI, 12.4–not reached [NR]). The median duration of CR/CRi was NR, the median progression-free survival (PFS) was 11.9 months (95% CI, 5.7–26.2), and the median overall survival (OS) was 30.3 months (95% CI, 15.0–NR).

“With longer follow-up, liso-cel continued to demonstrate durable CR/CRi, high uMRD rates, and a manageable safety profile in patients with heavily pretreated, high-risk r/r CLL/SLL. The safety results from longer follow-up were similar to those reported in the primary analysis with no new safety signals and were consistent across age groups,” Siddiqi, an associate professor in the department of hematology/hematopoietic cell transplantation and director of the CLL program at City of Hope, and colleagues wrote.

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Siddiqi et al noted that among the full dose level 2 population, the efficacy outcomes were similar, with 10 of 16 patients who had a best overall response of CR/CRi at primary analysis reporting ongoing CR/CRi.

In the safety dataset, the rates of any-grade and grade 3 or higher treatment-emergent adverse events (AEs) were similar across age groups. Any-grade cytokine release syndrome (CRS) was reported among 85% of patients (grade 3, 8%; no grade, 80%) and the rate of neurological events (NEs) was 45% (grade 3, 18%; grade 4, 1%; grade 5, 0%). Of those with CRS or Nes, 69% received tocilizumab and/or corticosteroids as treatment. The median time to onset and then resolution of AEs was 4 days (range, 1-18) and 6 days (range, 2-37) for CRS, and 7 days (range, 1-21) and 7 days (range, 1-83) for NEs, respectively.

Instances of prolonged cytopenia (defined as grade ≥3 at 30 days post–liso-cel-infusion), infections of grade 3 or higher, hypogammaglobulinemia, tumor lysis syndrome, second primary malignancy, and macrophage activation syndrome occurred in 54%, 18%, 15%, 11%, 9%, and 3% of patients, respectively. All together, 33% (n = 45) of the 137 leukapheresed patients died after liso-cel infusion (disease progression, 20% [n = 27]; AE, 4% [n = 6]; other reasons, 9% [n = 12])

In that safety set, the median age was 65 years (range, 49-82), with 83% of patients having high-risk cytogenetics (del[17p], 42%; TP53 mutation, 47%; unmuted immunoglobulin heavy-chain variable gene, 47%; ≥ 3 chromosomal aberrations, 61%), and a median line of prior therapy of 5 (range, 2-14). All patients had prior BTKi treatment.

In June 2023, the FDA approved Bristol Myers Squibb’s supplemental biologics license application for liso-cel as second-line therapy for patients with large B-cell lymphoma (LBCL),² after it was originally approved in February 2021 for adults with relapsed or refractory diffuse LBCL who have not responded to at least 2 other treatments. That decision was based on data from the pivotal phase 3 TRANSFORM (NCT03575351) trial.³

Similar data to what was presented at ASH 2023 were presented at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois, by Siddiqi. Those data also showed durable CRs among 49 patients with r/r CLL and SLL treated in the phase 1/2 TRANSCEND CLL 004 clinical trial.⁴

“For people living with relapsed or refractory CLL or SLL after treatment with BTKi and BCL2i-based regimens, there is no standard of care treatment,” Siddiqi said in a statement at the time.⁵ “Achieving deep and lasting remission in this situation is challenging as most patients experience disease progression despite continuous treatment. The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T-cell-based treatment approach delivered as a 1-time infusion into clinical practice for a complex and historically incurable disease.”

Click here to read more coverage of the ASH 2023 meeting.

REFERENCES
1. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene Maraleucel (liso-cel) in R/R CLL/SLL: 24-Month Median Follow-up of TRANSCEND CLL 004. Presented at: 2023 ASH Annual Meeting & Exposition, December 9-12; San Diego, California. Abstract 330
2. U.S. FDA Approves Bristol Myers Squibb’s CAR T Cell Therapy Breyanzi® for Relapsed or Refractory Large B-cell Lymphoma After One Prior Therapy. News release. Bristol Myers Squibb. June 24, 2022. Accessed December 11, 2023. https://news.bms.com/news/details/2022/U.S.-FDA-Approves-Bristol-Myers-Squibbs-CAR-T-Cell-Therapy-Breyanzifor-Relapsed-or-Refractory-Large-B-cell-Lymphoma-After-One-Prior-Therapy/default.aspx
3. FDA Approves New Treatment For Adults With Relapsed Or Refractory Large-B-Cell Lymphoma. News release. FDA. February 5, 2021. Accessed December 11, 2023. https://www.prnewswire.com/news-releases/fda-approves-new-treatment-for-adults-with-relapsed-or-refractory-large-b-cell-lymphoma-301223275.html
4. Siddiqi T, Maloney DG, Kenderian S, et al. Lisocabtagene maraleucel (liso-cel) in R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Primary analysis of TRANSCEND CLL 004. Presented at: the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois. Abstract #7501
5. Bristol Myers Squibb’s Breyanzi (lisocabtagene maraleucel) is first and only CAR T to deliver deep and durable efficacy in pivotal multicenter trial in relapsed or refractory chronic lymphocytic leukemia, based on data presented at ASCO 2023. News release. Bristol Myers Squibb. May 25, 2023. Accessed December 11, 2023. https://news.bms.com/news/corporate-financial/2023/Bristol-Myers-Squibbs-Breyanzi-lisocabtagene-maraleucel-is-First-and-Only-CAR-T-to-Deliver-Deep-and-Durable-Efficacy-in-Pivotal-Multicenter-Trial-in-Relapsed-or-Refractory-Chronic-Lymphocytic-Leukemia-Based-on-Data-Presented-at-ASCO-2023/default.aspx