Lower Tumor Burden Increases Liso-cel Response Likelihood in R/R CLL/SLL

Overall, investigators noted that factors potentially correlating with an elevated risk of neurological toxicity included inflammatory markers, bulky disease, and lower estimated creatine clearance rates.

Factors associated with a lower disease burden, such as absence of bulky disease, conferred a higher probability of response to lisocabtagene maraleucel (liso-cel; Breyanzi) among those with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to exploratory analysis findings from the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198) presented at the 2024 European Hematology Association (EHA) Congress.

The overall response rate (ORR) was 54.5% (95% CI, 32.2%-75.6%) among patients with a maximum of 3 prior lines of therapy (n = 22) compared with 44.6% (95% CI, 32.3%-57.5%) in those who received more than 3 prior lines (n = 65; odds ratio [OR], 1.49; 95% CI, 0.56-3.93).

The ORR for patients without bulky disease (n = 38) was 63.2% (95% CI, 46.0%-78.2%) vs 31.7% (95% CI, 18.1%-48.1%) in those with bulky disease (n = 41; OR, 3.69; 95% CI, 1.46-9.37). Additionally, the mean sum of the product of perpendicular diameters (SPD) was 24.1 cm2 (95% CI, 19.8-29.2) in those with a response (n = 37) compared with 52.7 cm2 (95% CI, 41.7-66.6) among patients without a response (n = 42). The mean lactate dehydrogenase (LDH) level prior to lymphodepletion chemotherapy was 226.2 U/L (95% CI, 200.6-255.0) in patients with a response (n = 40) vs 298.9 U/L (95% CI, 259.0-344.9) in those without a response.

A complete response (CR) occurred in 29.7% (95% CI, 15.9%-47.0%) of patients with Rai stage 0 to II disease (n = 37) compared with 11.4% (95% CI, 3.8%-24.6%) of those with stage III to IV disease (n = 44; OR, 3.30; 95% CI, 1.03-10.61). The mean SPD was 21.5 U/L (95% CI, 15.6-29.7) in patients with a CR (n = 14) vs 40.9 U/L (95% CI, 34.1-49.1) in those without (n = 65). Additionally, the mean β-2 microglobulin level was 3.4 U/L (95% CI, 2.8-4.2) in patients who had a CR (n = 14) vs 5.4 U/L (95% CI, 4.5-6.5) in those without (n = 61).

In the open-label, multicenter phase 1/2 TRANSCEND CLL 004 trial, patients underwent leukapheresis followed by lymphodepletion with fludarabine at 30 mg/m² plus cyclophosphamide at 300 mg/m² for 3 days. Investigators then administered liso-cel at 2 to 7 days following lymphodepletion chemotherapy. The recommended phase 2 dose was 100 x 10⁶ CAR-positive T cells.

With a primary analysis data cutoff date of September 29, 2022, the primary end point of CR or CR with incomplete hematologic recovery rate was 18% (95% CI, 11%-28%) across the full evaluable population (n = 87). Primary analysis data relating to secondary end points included an ORR of 47% (95% CI, 36%-58%), median duration of response (DOR) of 35.3 months (95% CI, 19.8-not reached [NR]), a median progression-free survival (PFS) of 18.0 months (95% CI, 9.4-30.1), and median overall survival (OS) of 43.2 months (95% CI, 26.9-NR).

In this post hoc analysis of the TRANSCEND CLL 004 trial, investigators used a univariable evaluation to determine the demographic features, disease characteristics, and biomarker lab tests that impacted responses and safety outcomes following treatment with liso-cel. End points of interest in this analysis included the ORR, CR rate, any-grade safety, and grade 3 or higher safety.

Patients 18 years and older with relapsed/refractory CLL or SLL who had progressed on or were ineligible for treatment with Bruton tyrosine kinase (BTK) inhibitors were able to enroll on the trial. Other requirements for study entry included having an ECOG performance status of 0 or 1; adequate bone marrow, organ, and cardiac function; and no Richter transformation nor active central nervous system involvement.

The median patient age was 65 years (IQR, 59-69), and the median number of prior lines of systemic therapy was 5 (IQR, 4-7). Most patients had prior treatment with BTK inhibitors plus venetoclax (Venclexta; 79%) as well as Rai stage III or IV disease (51%). Common risk factors included unmutated IGHV (47%), 17p deletions (39%), TP53 mutations (41%), and complex karyotype disease (60%).

The ORR was 41.5% vs 63.2% in patients with (n = 41) and without (n = 19) unmutated IGHV (OR, 0.41; 95% CI, 0.13-1.27), and the CR rates in each respective arm were 22.0% vs 21.1% (OR, 1.05; 95% CI, 0.28-3.98). Additionally, the ORR was 47.1% for those with 17p deletions (n = 34) vs 45.1% in those without (n = 51; OR, 1.08; 95% CI, 0.45-2.58), and the CR rates were 26.5% vs 13.7%, respectively (OR, 2.26; 95% CI, 0.75-6.82). The ORR was 41.7% in patients with TP53-mutated disease (n = 36) vs 50.0% for those without (n = 50; OR, 0.71; 95% CI, 0.30-1.69); the CR rates were 22.2% vs 16.0%, respectively (OR, 1.50; 95% CI, 0.50-4.46).

Data showed an ORR of 44.0% in patients with both 17p deletions and TP53-mutated disease (n = 25) vs 46.7% in those without (n = 60; OR, 0.90; 95% CI, 0.35-2.30), and the respective CR rates were 28.0% and 15.0% (OR, 2.20; 95% CI, 0.72-6.78). The ORR in patients with a complex karyotype (n = 52) was 44.2% vs 52.9% in those without (n = 34; OR, 0.70; 95% CI, 0.30-1.68), and the CR rates were 19.2% vs 17.6%, respectively (OR, 1.11; 95% CI, 0.36-3.40).

Any-grade cytokine release syndrome (CRS) and neurological events, respectively, occurred in 85% and 46% of patients across the overall population. Grade 3 CRS affected 8% of patients; investigators highlighted no grade 4 or 5 instances of CRS. Grade 3 neurological events occurred in 18% of patients, and 1% had grade 4 toxicity.

The incidence of any-grade neurological events was 53.3% (95% CI, 26.6%-78.7%) in patients with an estimated creatine clearance rate of less than 60 mL per minute (n = 15) vs 43.7% (95% CI, 31.9%-56.0%) in those with a clearance of at least 60 mL per minute (n = 71; OR, 1.47; 95% CI, 0.48-4.51). Additionally, the rate of grade 3 or higher neurological toxicity was 46.7% (95% CI, 21.3%-73.4%) vs 14.1% (95% CI, 7.0%-24.4%) in each respective group. Overall, investigators noted that factors potentially correlating with an elevated risk of neurological toxicity included inflammatory markers, bulky disease, and lower estimated creatine clearance rates.

Reference

Wierda WG, Maloney DG, Kenderian SS, et al. Characteristics associated with response to lisocabtagene maraleucel in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: exploratory analyses from TRANSCEND CLL 044. Presented at the 2024 European Hematology Association (EHA) Hybrid Congress; June 13-16, 2024; Madrid, Spain. Abstract S158.