Authored by Ann Liu, PhD
Medically reviewed by Dr. Brian Koffman
The introduction of targeted therapies revolutionized the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). While chemoimmunotherapy was common a decade ago, now patients are much more likely to be treated with Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, or BCL2 inhibitors such as venetoclax. These treatments produce much better outcomes for patients than chemoimmunotherapy, but they are not curative, and patients can develop resistance to them over time. In this video, Dr. Meghan Thompson from Memorial Sloan Kettering Cancer Center discusses some of the up-and-coming novel agents being tested in clinical trials that may be helpful for patients who have developed resistance to all the BTK inhibitors and BCL2 inhibitors. Most of these therapies are considered experimental at this time, and they are being tested in numerous ongoing clinical trials.
BTK Degraders
This class of drugs destroys the BTK protein rather than inhibiting it. BTK degraders bind to BTK and tag it for degradation by the proteasome. The proteasome acts as the cell’s garbage disposal, taking in unwanted cellular garbage and destroying it by chopping it into tiny pieces. BTK degraders work on both mutated and unmutated BTK. There are several ongoing clinical trials testing different drugs in this class, including NX-5948, BGB-16673, ABBV-101, and NX-2127.
Bispecific Antibodies
Bispecific antibodies are immunotherapy that works by binding to a cancer cell and a T cell simultaneously and bringing them together in close proximity. Bispecific antibodies for B cell cancers usually bind to CD20 on the B cell and CD3 on the T cell. An example of this type of bispecific antibody is epcoritamab. Dr. Brian Koffman has been documenting his experiences as a participant in an epcoritamab clinical trial on his blog.
MALT1 Inhibitors
MALT1 inhibitors target a protein in the B cell receptor (BCR) pathway, which is critical for B cell proliferation. MALT1 is downstream of BTK and PLCG2. So, if a patient has developed resistance mutations in BTK or PLCG2, a drug that blocks a protein further down the BCR pathways, such as MALT1, could be an alternative way of inhibiting the BCR pathway. There is currently an ongoing clinical trial of MALT1 inhibitor ABBV-525.
Dual Covalent / Noncovalent BTK Inhibitors
This class of drugs can bind to BTK both covalently (like ibrutinib) and noncovalently (like pirtobrutinib). We previously covered the phase 1 clinical trial results of LP-168 in relapsed / refractory B cell cancers.
CAR-T Therapy
CAR-T therapy is an immunotherapy that engineers a patient’s immune system to recognize and fight cancer cells. Because of its limited efficacy, it has long been considered experimental for patients with CLL, but in March 2024, the FDA approved Liso-cel as the first and only CAR-T therapy for CLL / SLL. It is specifically indicated for patients who have previously been treated with a BTK inhibitor and a BCL2 inhibitor.
While CLL treatments and patient outcomes have greatly improved, there is still an unmet need for curative therapies. Testing new therapies with novel mechanisms of action is an important part of trying to meet the needs of patients with CLL and Richter’s transformation.
Links and Resources:
Watch the interview with Dr. Meghan Thompson here:
