TRANSCEND CLL Trial: Liso-cel Plus Ibrutinib Provides ‘Promising New Therapeutic Strategy’

Lisocabtagene maraleucel (liso-cel) plus ibrutinib demonstrates substantial efficacy, deep remissions, and manageable safety in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to primary results from the TRANSCEND CLL 004 trial presented at the 66^th American Society of Hematology Annual Meeting & Exposition in San Diego, California.

For the study, 56 adult patients started or continued ibrutinib at 420 mg daily through leukapheresis and for up to 90 days following liso‑cel infusion. Patients received liso-cel at 50 × 10⁶ CAR⁺ T cells (DL1, n=5) or 100 × 10⁶ CAR⁺ T cells (DL2, n=51).

Fifty-five (98%) patients had high-risk cytogenetics, such as del(17p), TP53 mutation, and unmutated IGHV. Patients had a median of five prior therapies, such as Bruton tyrosine kinase inhibitor and venetoclax.

The primary endpoint was the rate of complete response or complete response with incomplete count recovery (CRi) at DL2. Secondary endpoints included safety, overall response rate (ORR), duration of response (DOR), duration of CR/CRi (DOCR), time to response, time to CR/CRi, progression-free survival (PFS), overall survival (OS), and the rate of undetectable measurable residual disease (MRD) in the blood.

At the data cutoff of January 12, 2024, 28 (50%) patients discontinued the study, 11 (20%) completed the study, 17 (30%) were ongoing, and five of 28 (18%) eligible patients enrolled in a separate long-term follow-up study. The median follow-up was 24.8 months for both the primary study and the long-term follow-up.

At DL2, the ORR was 86% (95% CI; 73.7–94.3), the median time to first response was one month (0.9–6.0), and the median DOR was 41.4 months (95% CI; 23.3–not reached). The CR/CRi rate was 45% (95% CI; 31.1–59.7), the median time to first CR/CRi was 3.1 months (0.9–12.1), and the median DOCR was not reached (95% CI; 26.6–NR) The median PFS was 31.4 months (95% CI, 20.1–not reached), and the median OS was not reached (95% CI, 27.5–not reached).

As for safety, 48 (86%) patients experienced grade 3 or higher treatment-related adverse events (AEs), most commonly neutropenia (52%) and anemia (41%). Forty-five (80%) patients had cytokine release syndrome (CRS) of any grade, 23 (41%) had neurological events (NE) of any grade, eight (14%) had infections of grade 3 or higher, and five (9%) had second primary malignancies. Twenty-five (45%) patients had prolonged cytopenias (grade 3 or more at D30), but most recovered to grade 2 or less by D90. Sixteen patients died after infusion: six due to progressive disease, six unknown, three due to COVID-19, and one due to septic or cardiogenic shock.

“Though comparisons should be made with caution and there were differences in disease characteristics between cohorts, liso-cel [plus ibrutinib] showed a numerically higher ORR/CR rate and lower [grade] ≥ 3 CRS/NE rates [versus] liso-cel monotherapy, supporting the combination as a promising new therapeutic strategy for pts with [relapsed or refractory] CLL/SLL,” the researchers concluded.

Reference

Wierda WG, Dorritie K, Gauthier J, et al. “Lisocabtagene maraleucel (liso-cel) combined with ibrutinib (ibr) for patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): primary results from the open-label, phase 1/2 Transcend CLL 004 study.” Abstract #887. Presented at the 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, California.