Alexey Danilov, MD, PhD, City of Hope, Los Angeles, California, discusses exciting developments in the chronic lymphocytic leukemia (CLL) clinical research landscape, highlighting updates in Bruton's tyrosine kinase (BTK) and BCL-2 inhibitors, as well as BTK degraders.

“I think the future of therapy in CLL is bright with all these advances coming along and I'm looking forward to more updated data at the upcoming American Society of Hematology (ASH) meeting,” concluded Dr Danilov.

Transcript:

My name is Alexey Danilov. I'm a professor in the department of hematology and director of the lymphoma center at the City of Hope in Los Angeles.

We will talk briefly about some of the recent development in the CLL clinical research landscape and some novel targets that have been investigated. We now have a particular subset of CLL emerging as an unmet medical need: CLL which has become refractory to both BTK and BCL-2 inhibitors. While this population is still reasonably rare, the frequency of it will increase as more and more patients are getting exposed to both drugs, which were only approved in the past decade.

In this space there is a new approval for [the] non-covalent BTK inhibitor pirtobrutinib. Unfortunately, it doesn't fully solve the problem as progression-free survival with this agent is a median of 16 months, so we really need new therapies there. We know there is also an approval for chimeric antigen receptor (CAR) T-cells, however many patients are not very good candidates for CAR T-cell [therapy] due to age and comorbidities and it is a toxic treatment.

There are some exciting developments in this space, and I would like to first mention BTK degraders. These [] don't simply inhibit the kinase function, but lead to kinase degradation through the ubiquitin-proteasome pathway (UPP). There are several compounds which are currently being developed by Abbvie, ABBV-101. There is a Biogen compound and there are 2 Nurix compounds, NX-2127 and NX-5948.

In fact, we presented a follow-up on a phase 1 study of NX-5948, at the European Hematology Association (EHA) annual meeting in Madrid, and in double refractory patient population, meaning, patients who progressed on BTK inhibitors and venetoclax and some also progressed on pirtobrutinib. [The] overall response rate was 70% and responses were ongoing and durable, and the safety of the compound was very high, [with] very few grade 3 toxicities. So BTK degradation is an exciting target.

Another exciting target is leveraging the immune system and here we have bispecific antibodies. Of course, several CD20-targeting bispecific antibodies have been approved in therapy of lymphoid malignancies. That includes glofitamab, epcoritamab, [and] mosunetuzumab. Odronextamab is another antibody in development, but none have been approved in CLL so far.

Nevertheless, initial dataset on epcoritamab, a CD3-CD20 targeting dual body has been disclosed. In [the] double refractory patient population, it's been associated with [an] overall response rate upwards of 70%, frequent complete responses, and very good safety as well. There is a risk of cytokine release syndrome (CRS) with this agent, just like we expect with bispecific antibodies [and] T-cell engagers. There hasn't been much neurotoxicity and other rare complications for bispecific antibodies and the risk of infection as this can be a therapy which may induce some temporary low count in B-cell numbers. But now, it's a highly effective therapy and it's also effective in patients with complex genomic abnormalities.

I think the future of therapy in CLL is bright with all these advances coming along and I'm looking forward to more updated data at the upcoming American Society of Hematology (ASH) meeting.