Liso-Cel Elicits Consistent Responses in R/R CLL/SLL, Irrespective of High-Risk Features

Lisocabtagene maraleucel (liso-cel; Breyanzi) produced consistent responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), regardless of high-risk disease features, according to data from a post hoc analysis of the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198) presented at the 2024 SOHO Annual Meeting.

Among patients with unmutated IGHV (n = 41) and those without (n = 19), the objective response rate (ORR) with liso-cel was 41.5% vs 63.2%, respectively (odds ratio [OR], 0.41; 95% CI, 0.13-1.27), and the complete response (CR) rates were 22.0% vs 21.1% (OR, 1.05; 95% CI, 0.28-3.98). For patients with 17p deletions (n = 34) and those without (n = 51), the ORR was 47.1% vs 45.1% (OR, 1.08; 95% CI, 0.45-2.58), and the respective CR rates were 26.5% vs 13.7% (OR, 2.26; 95% CI, 0.75-6.82). Additionally, for patients with TP53-mutated disease (n = 36) and those without (n = 50), data showed an ORR of 41.7% vs 50.0% (OR, 0.71; 95% CI, 0.30-1.69) and CR rates of 22.2% vs 16.0% (OR, 1.50; 95% CI, 0.50-4.46).

The ORR for patients with 17p deletions plus TP53 mutations (n = 25) and those without (n = 60) was 44.0% vs 46.7%, respectively (OR, 0.90; 95% CI, 0.35-2.30). The CR rates in each group were 28.0% vs 15.0% (OR, 2.20; 95% CI, 0.72-6.78). For patients with complex karyotype (n = 52) and those without (n = 34), the ORR was 44.2% vs 52.9% (OR, 0.70; 95% CI, 0.30-1.68), and the CR rates were 19.2% vs 17.6% (OR, 1.11; 95% CI, 0.36-3.40). Patient age did not appear to influence the likelihood of a response.

The median number of prior lines of therapy was 4 (IQR, 3-6) for patients with a response (n = 41) compared with 6 (IQR, 4-8) among those without a response (n = 46). Investigators reported that the ORR was 54.5% (95% CI, 32.2%-75.6%) among patients with a maximum of 3 prior lines of treatment (n = 22) and 44.6% (95% CI, 32.3%-57.5%) in those with more than 3 prior lines (n = 65; OR, 1.49; 95% CI, 0.56-3.93).

Study treatment yielded an ORR of 63.2% (95% CI, 46.0%-78.2%) for patients without bulky disease (n = 38) compared with 31.7% (95% CI, 18.1%-48.1%) in those with bulky disease (n = 41; OR, 3.69; 95% CI, 1.46-9.37). The mean sum of the product of perpendicular diameters (SPD) was 21.5 U/L (95% CI, 15.6-29.7) in patients with a CR (n = 14) compared with 40.9 U/L (95% CI, 34.1-49.1) in those who did not achieve a CR (n = 65). Additionally, patients who achieved a CR (n = 14) had a mean β-2 microglobulin level of 3.4 U/L (95% CI, 2.8-4.2) vs 5.4 U/L (95% CI, 4.5-6.5) in those without a CR (n = 61).

“One of the more important features of these data and analysis is that patients did respond, including those who had high-risk features [such as] unmutated [IGHV], 17p deletion, TP53 mutations, and complex karyotype. Better outcomes in terms of achieving response were seen in patients who had a lower bulk of disease,” William G. Wierda, MD, PhD, said in the presentation. “Overall, I believe that these data support an expectation and anticipation that better outcomes would be seen with this strategy in looking at a less refractory population of patients who are earlier in the course of their disease and/or looking at strategies to debulk the disease prior to [treatment with] liso-cel.”

Wierda is from the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center.

In the open-label, multicenter TRANSCEND CLL 004 study, patients underwent lymphodepletion with fludarabine at 30 mg/m² plus cyclophosphamide at 300 mg/m² for 3 days prior to treatment with liso-cel at a recommended phase 2 dose of 100 x 10⁶ CAR-positive T cells.

For this post hoc analysis, investigators assessed how pretreatment variables such as demographic features, disease characteristics, and biomarker lab tests correlated with response and safety outcomes following treatment. Efficacy end points included the ORR and CR rates. Safety end points included any grade and grade 3 or higher cytokine release syndrome (CRS) or neurological events.

Patients 18 years and older with relapsed/refractory CLL or SLL and disease progression on or ineligibility for prior Bruton tyrosine kinase inhibitors were able to enroll on the trial. Other requirements for study entry included having an ECOG performance status of 0 or 1 and adequate bone marrow, organ, and cardiac function.

Of 87 patients in the full efficacy-evaluable population, the median age was 65 years (IQR, 59-69), and the median number of prior lines of therapy was 5 (IQR, 4-7). Additionally, most patients had Rai stage III or IV disease at screening (51%). In terms of risk factors, patients presented with unmutated IGHV (47%), 17p deletions (39%), TP53-mutated disease (41%), and complex karyotype (60%).

Any-grade neurological events affected 46% of patients, and 20% had events that were grade 3 or higher. Of note, the mean SPD was 49.1 cm2 (95% CI, 40.7-59.2) in patients with any neurological event (n = 38) and 27.7 cm2 (95% CI, 21.6-35.7) in those without any neurological events (n = 41). Additionally, the mean C-reactive protein level was 16.6 mg/L (95% CI, 9.6-28.5) in patients with neurological toxicity (n = 38) compared with 5.1 mg/L (95% CI, 3.5-7.5) in those without (n = 47).

Any-grade neurological events occurred in 53.3% (95% CI, 26.6%-78.7%) of patients with an estimated creatine clearance (CrCl) rate of less than 60 mL per minute (n = 15) compared with 43.7% (95% CI, 31.9%-56.0%) in those with an estimated CrCl rate of 60 mL per minute or higher (n = 71; OR, 1.47; 95% CI, 0.48-4.51). Additionally, grade 3 or higher neurological toxicity was reported in 46.7% (95% CI, 21.3%-73.4%) and 14.1% (95% CI, 7.0%-24.4%) in each respective group (OR, 5.34; 95% CI, 1.58-18.00).

Overall, Wierda noted that inflammatory markers, bulky disease, and lower estimated CrCl rates may increase the risk of neurological toxicity following treatment with liso-cel.

Reference

Wierda WG, Maloney DG, Kenderian SS, et al. Characteristics associated with response to lisocabtagene maraleucel (liso-cel) in patients with R/R CLL/SLL: exploratory analyses from the phase 1/2 TRANSCEND CLL 004 study. Presented at the 2024 Society of Hematologic Oncology Annual Meeting (SOHO); September 4-7, 2024; Houston, Texas. Abstract CLL-184.