An emerging challenge in chronic lymphocytic leukemia (CLL) treatment is managing patients who progress after treatment with covalent Bruton tyrosine kinase (BTK) inhibitors and venetoclax. These patients represent a growing unmet need, requiring novel therapeutic strategies. Recent data presented at medical conferences highlight several promising approaches, including CAR T-cell therapy, BTK degraders, and bispecific antibodies.
CAR T-cell Therapy with Lisocabtagene Ciloleucel
The phase 1/2 TRANSCEND CLL 004 trial (NCT03331198) investigated lisocabtagene ciloleucel (liso-cel; Breyanzi) in patients with relapsed/refractory CLL who had limited treatment options. Patients were enrolled if they were ineligible for a BTK inhibitor, had high-risk disease after two prior therapies, or standard-risk disease after three prior therapies. The study met its primary endpoint, demonstrating a complete response/complete hematologic recovery (CR/CRi) rate of 19.3% (95% CI, 11.7%-29.1%) in the full population. Notably, 18.4% of patients achieved CR/CRi after progressing on both a BTK inhibitor and venetoclax. This data supported the FDA approval of liso-cel in March 2024 for CLL patients who have received two or more prior lines of therapy.
BTK Degraders: BGB-16673 and NX-5948
To address the continued progression seen after multiple lines of therapy, researchers are developing novel agents like BTK degraders. The phase 1/2 CaDAnCE-101 trial (NCT05006716) evaluated BGB-16673 in patients with relapsed/refractory B-cell malignancies, including 49 patients with CLL/small lymphocytic lymphoma (SLL). With a median follow-up of 4.6 months, 82% of patients remained on treatment. The median number of prior therapies was 4, and a significant proportion of patients had high-risk features, including unmutated IGHV (82%), del(17p) or TP53 mutations (60%), and complex karyotype (47%).
Results showed an overall response rate (ORR) of 72% (n = 31/43) among response-evaluable CLL/SLL patients, with a disease control rate of 88%. The median time to first response was 2.8 months (range, 2.6-6.2). The most common grade 3 or higher adverse events included neutropenia/neutrophil count decrease (20%) and pneumonia (12%). Importantly, ORRs were similar in patients who had previously received covalent BTK plus BCL2 inhibitors (70%), had del(17p) or TP53 mutations (68%), or complex karyotype (67%). Responses were also observed in patients with C481S, T474I, and/or L528S BTK mutations, as well as PLCG2 mutations.
Another BTK degrader, NX-5948, is being investigated in the phase 1a/b NX-5948-301 trial (NCT05131022). This study enrolled up to 66 patients with CLL/SLL, with 31 continuing on step-up dosing of NX-5984. Preliminary results showed an objective response rate of 69.2% (95% CI, 48.2%-85.7%), with no complete responses (CRs) but a 69.2% partial response (PR) rate. Stable disease was observed in 23.1% of patients, and 7.7% had progressive disease. The median duration of treatment was 2.8 months. The study also demonstrated robust degradation of both wild-type and mutant BTK. Common grade 3 or higher adverse events included neutropenia (15.2%) and thrombocytopenia (8.9%).
Bispecific Antibodies: Epcoritamab-bysp
Bispecific antibodies represent another promising avenue for CLL treatment. The phase 1b/2 EPCOR CLL-1 trial (NCT04623541) is evaluating epcoritamab-bysp (Epkinly) in relapsed/refractory CLL patients. The expansion cohort enrolled 23 patients, 70% of whom had IGHV-unmutated CLL and 65% with TP53 aberrations. The median number of prior lines of therapy was 4 (range, 2-10), with 65% having received 4 or more lines. All patients had previously received a small molecule inhibitor and a BTK inhibitor, and 83% had received a BCL2 inhibitor.
In the efficacy-evaluable group (n = 21), the ORR was 62%, with 33% achieving CRs and 29% achieving PRs. Responses occurred early and appeared durable. Treatment-emergent adverse events were generally low-grade, with cytokine release syndrome (73.9%), peripheral edema (17.4%), and constipation (17.4%) being the most common grade 2 events.
These emerging therapies offer hope for patients with relapsed/refractory CLL, particularly those who have exhausted standard treatment options. Further research and clinical trials are needed to fully understand their long-term efficacy and safety profiles.
