Investigational therapies superior to standard-of-care in double-exposed CLL

Patients with chronic lymphocytic leukaemia (CLL) with prior exposure to both a covalent Bruton’s tyrosine kinase (BTK) inhibitor and venetoclax demonstrated better responses to non-covalent BTK inhibitors, allogeneic stem cell transplantation (SCT), or CAR T-cell therapy than to PI3K inhibitors or chemo+/-immunotherapy (CIT). These results cast doubt on the use of PI3K inhibitors or CIT in double-exposed patients with CLL [1].

A subset of patients with CLL treated with both a covalent BTK inhibitor and venetoclax will still develop progressive disease. Dr Meghan Thompson (Memorial Sloan Cancer Center, NY, USA) explained that data is limited regarding therapy efficacy in these double-exposed patients. Therefore, practice patterns vary.

The current international, retrospective, multicentre study compared the efficacy of in USA available approved options (i.e. CIT or PI3K inhibitors) with investigational options (i.e. non-covalent BTK inhibitors, CAR T-cell therapy, or allogeneic SCT) in double-exposed patients with CLL (n=125). The primary endpoint was the investigator-assessed overall response rate.

The overall response rate was 85.7%, 76.5%, and 75.0% in patients treated with CAR T-cell therapy (n=7), allogeneic SCT (n=17), or non-covalent BTK inhibitors (n=43), respectively. In contrast, patients who received PI3K inhibitors (n=24) or CIT (n=23) achieved response rates of 40.9% and 31.8%, respectively. In addition, the median progression-free survival (PFS) was 3 months and 5 months in patients treated with CIT or PI3K inhibitors, whereas patients treated with allogeneic SCT achieved a median PFS of 11 months. The subset of patients that received non-covalent BTK inhibitors had not yet reached median PFS (see Table).

Table: Therapy responses [1]

AlloSCT, allogeneic stem cell transplantation; CAR T, chimeric antigen receptor T-cell therapy; CIT, chemo+/-immunotherapy; ncBTKi, non-covalent Bruton’s tyrosine kinase inhibitor; ORR, overall response rate; PI3Ki, PI3K inhibitor.

The results showed that CIT or PI3K inhibitors yield poor outcomes compared with non-covalent BTK inhibitors, allogeneic SCT, or CAR T-cell therapy. Dr Thompson argued that the results suggest that the use of CIT and PI3K inhibitors is questionable in double-exposed patients with CLL and that treatment with allogeneic SCT or non-covalent BTK inhibitors should be considered in these patients. The administration of CAR T-cell therapy in this population should be further explored, according to Dr Thompson.

1. Thompson MC, et al. Addressing a New Challenge in Chronic Lymphocytic Leukemia: Outcomes of Therapies after Exposure to Both a Covalent Bruton’s Tyrosine Kinase Inhibitor and Venetoclax. Abstract 2628, ASH 2021 Annual Meeting, 11–14 December.

 

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Posted on 4 February 202215 February 2024