In the first line, the main opportunity for tailoring therapy occurs in patients with TP53-aberrant CLL, which is treated with continuous Bruton tyrosine kinase (BTK) inhibitor therapy. TP53 is a relatively common mutation in that it is found in approximately 10% to 15% of those with CLL in the frontline setting. Other mutations, both common and rare, may provide useful information but do not determine therapy in the first line. 

In the second and third lines, there is often a place for using genetics to tailor therapy. If a patient with CLL has been treated with a covalent BTK inhibitor and starts progressing, it is important to identify any BTK mutations. This is particularly true now that the noncovalent BTK inhibitor pirtobrutinib has been approved by the US Food and Drug Administration in relapsed or refractory mantle cell lymphoma and is being studied in other B-cell malignancies. Patients with relapsed or refractory CLL and BTK mutations may have access to noncovalent BTK inhibitors or other investigational agents (eg, BTK degraders) in clinical trials. 

The most common BTK mutation is C481S, which is seen in approximately 50% to 75% of patients who progress on a covalent BTK inhibitor. Other mutations, such as the gatekeeper mutation T474I and rare mutations within the kinase domain, may also be present. Alternatively, one could have a mutation in PLCG2. Sometimes, a patient might not have a mutation in BTK or PLCG2 at all, but instead there might have been some clonal evolution, along with the development of a KRAS or a BRAF mutation, for instance. If the patient has neither BTK nor PLCG2 mutations, alternative strategies may be appropriate. In this situation, I might consider either venetoclax or the enrollment in a clinical trial, perhaps one exploring a novel approach such as a BTK degrader.

However, for patients with BTK inhibitor resistance and an identified mutation in the BTK gene, this generally tells us that the CLL cells are most likely still dependent on BTK. Treatment with a noncovalent BTK inhibitor makes sense in such individuals. In contrast, in the presence of a PLCG2 mutation, the leukemic cells have essentially developed a mechanism to bypass BTK, and it is not as clear that there would be any benefit from treatment with a noncovalent BTK inhibitor. This is a situation in which you might consider venetoclax. 

Another scenario in which genetics can be very helpful is the case of progression after venetoclax plus obinutuzumab or after venetoclax plus rituximab, as in the phase 3 MURANO trial. If the patient has a Bcl-2 mutation, even at a low variant allele frequency, you would not consider retreatment with venetoclax. Instead, you would consider a covalent BTK inhibitor such as acalabrutinib or zanubrutinib. 

One final point regarding genetics and tailored therapy relates to the case in which you are considering giving venetoclax, but you also have other options (eg, clinical trial participation). And let us say that the patient has low blood counts, and a bone marrow biopsy reveals no evidence of myelodysplastic syndrome, but the sequencing panel reveals clonal hematopoiesis. In this scenario, I would be much more reserved about giving venetoclax, which is myelosuppressive. We also know that venetoclax is associated with BAF mutations that can trigger myeloid neoplasia. Patients with clonal hematopoiesis have a high risk of developing treatment-related myeloid neoplasia, even before starting treatment with venetoclax. So, in this case, a clinical trial would be a more attractive option.