Targeted therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules (“molecular targets”) that are involved in the growth, progression, and spread of cancer. Identifying potential molecular targets requires an understanding of the underlying biology of the cancer. In chronic lymphocytic leukemia (CLL), scientists have been able to study cells from patients with CLL and compare them to normal B cells. In doing so, they have been able to identify major drivers of the disease such as the B-cell receptor (BCR) signaling pathway. Blocking Bruton’s tyrosine kinase (BTK) blocks the BCR pathway that is critical for the proliferation and survival of CLL cells.
Our increased understanding of the biology of CLL has led to the development of numerous new targeted therapies. This includes BTK inhibitors such as ibrutinib which have revolutionized the treatment of CLL. The hope is that by targeting the specific molecular drivers of CLL, we will be able to achieve deeper remissions and better outcomes for patients.
At the annual meeting of the American Society of Hematology (ASH) 2020, our own Dr. Brian Koffman interviewed Dr. Thomas Kipps, Professor of Medicine at the UC San Diego Moores Cancer Center. They discussed the role of targeted therapies such as ibrutinib for the treatment of CLL with high-risk genomic features.
Takeaways:
- In CLL, certain genetic mutations have been identified which may affect patient outcomes, but they are rare at the time of diagnosis (5-10% of patients). See our Test Before Treat handout for more information on some of these mutations.
- These mutations are not necessarily the drivers of CLL, but they do influence the nature of the disease and how it behaves.
- Some mutations are known to affect how well patients respond to chemoimmunotherapy (i.e., patients with the TP53 mutation do not respond well to chemoimmunotherapy).
- Because these mutations are rare, researchers must look at many patients to study them.
- So far, no mutations have been identified in treatment naïve patients that confer resistance to targeted therapies. However, these mutations are sometimes acquired during or after treatment, reducing the effectiveness of the targeted therapy.
- A recent integrated analysis across two phase 3 studies found that first-line ibrutinib treatment was effective irrespective of cytogenetic and mutational risk features, including those with unmutated IGHV, NOTCH1 mutation, and del(17p)/TP53 mutation/BIRC3 mutation.
- Patients with del(11q) have traditionally had worse outcomes on chemoimmunotherapy, but they actually have better outcomes on ibrutinib.
- Targeted therapies such as ibrutinib can be well-tolerated and very effective in subgroups of patients with different genetic mutations.
Conclusions:
Research on the basic biology of CLL has led to targeted therapies, which have revolutionized the treatment of CLL. With all the new drugs being developed for CLL, comparative efficacy trials are needed to determine if there is a significant improvement in patient outcomes or safety or both. However, running these types of trials is also challenging due to the number of patients needed and the length of follow up to determine any differences in outcomes. Additionally, large numbers of patients are needed to study effects in subgroups with rare genetic mutations. As always, there is more research to be done so that we can help patients achieve better outcomes.
Please enjoy this interview with Dr. Kipps from the virtual ASH meeting which was held December 2020.
You can read the actual abstract here: Outcomes of First-Line Ibrutinib in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL / SLL) and High-Risk Genomic Features with up to 6.5 Years Follow-up: Integrated Analysis of Two Phase 3 Studies (RESONATE-2 and iLLUMINATE)
Take care of yourself first.
Ann Liu, PhD
