Most patients with CLL do not need therapy when they are first diagnosed. They typically have relatively early-stage disease and are largely asymptomatic. We just observe these patients, usually once every 6 months. For those with very stable disease, more frequent surveillance is not typically necessary.

In terms of considering the appropriate time for progression to therapy, I focus primarily on the patient's mutational status with respect to IGHV and TP53. We do a much more detailed prognostic workup that includes a karyotype and a large panel of somatic mutations, all of which combined gives us a good profile of the patient’s disease so that we can make informed decisions regarding treatment. I tend to use these assays a bit more than I use the existing prognostic models, which I find to be good on a population basis but not necessarily for individual patients.

Approximately 25% to 30% of patients with newly diagnosed CLL may never need treatment; however, a steady increase in a patient's white blood cell (WBC) count may be an indication that they will probably eventually require treatment. I do not initiate treatment based solely on the WBC count or the rate that it increases, as these factors can be variable (eg, the count can go up quickly for a short period and then slow down or level off). Usually, I monitor the patient's WBC count to see if the rate of increase is changing very rapidly. Cytopenias are the main reason I start treating most patients with CLL. Lymph nodes can also be a problem, but generally not to the same degree as cytopenias.

Symptoms are a bit more difficult to measure. Most people are fatigued, and there are often many reasons for the fatigue. Treating someone just for fatigue in the absence of a significant disease burden can be challenging because the treatments themselves can cause fatigue. So, I try not to start treatment on the basis of fatigue, although sometimes this does happen if I am able to rule out all other causes of the fatigue. 

TP53 mutational status is the most important factor that affects our approach to initial treatment. Some patients with higher-risk, TP53-aberrant disease need immediate treatment, while others may not need treatment for years. When treatment is needed, I tend to favor continuous BTK inhibition over venetoclax and obinutuzumab as initial therapy, although venetoclax and obinutuzumab might actually rival BTK inhibitors in terms of total duration of benefit, assuming that it can be repeated a second time. I consider ibrutinib to have an unfavorable risk-benefit profile, now that we have second-generation BTK inhibitor options that are safer from a cardiac standpoint. If the patient has a very strong preference for time-limited therapy, we may consider venetoclax plus obinutuzumab if they have relatively low-risk TP53-aberrant disease, which I define as having 1 allele affected rather than 2, a normal karyotype, mutated IGHV, or the absence of other somatic mutations. 

Very few people are currently recommending ibrutinib in the frontline CLL setting. In fact, I have not written a prescription for ibrutinib for CLL, outside of a trial, in more than 1 year. When selecting a BTK inhibitor, I think that most people are moving to second-generation BTK inhibitors for first-line therapy. We have learned a lot about long-term BTK inhibitor exposure from the long-term follow-up from some of the earliest studies. Ibrutinib is a well-studied BTK inhibitor with the longest follow-up evidence. Acalabrutinib and zanubrutinib have better toxicity profiles than ibrutinib due to minimal off-target effects, but their long-term data are limited. 

For asymptomatic patients, I would only offer treatment within a clinical trial. When patients get to the point of needing treatment, the 2 factors that shape my therapy choices the most are the patient’s age and tumor genetics, especially TP53 and IGHV mutations or 1 of the unusual mutations that correspond with poor response to a specific treatment. 

As a low-risk example, for a young, IGHV-mutated, TP53-unmutated patient, you have a discussion to lay out the benefits of chemoimmunotherapy, such as curative FCR (fludarabine, cyclophosphamide, and rituximab), vs the long-term risks of FCR, including the development of therapy-related myeloid neoplasia. As a high-risk example, the phase 3 CLL14 study showed that patients with TP53 aberrations do not do as well with venetoclax plus obinutuzumab. I direct these patients toward either of the second-generation BTK inhibitors zanubrutinib or acalabrutinib. 

In a patient with newly diagnosed CLL, one of the first things to determine is whether the patient needs therapy or is a good candidate to watch and wait. In general, approximately 70% to 75% of patients with CLL are diagnosed with early-stage disease, and the diagnosis is frequently made incidentally. If the patient is completely asymptomatic and without significant cytopenias, we follow the watch-and-wait approach. The following question then arises: Is there any reason to do a prognostic factor analysis at this point? In the early, asymptomatic CLL setting, one could argue, “Why do the testing if you are not going to use the results, since the patient is not being treated?” There is no absolutely correct answer here, but I find the prognostic testing results to be very helpful when it comes to monitoring the patient.

The CLL International Prognostic Index (CLL-IPI) scoring system is probably the best tool that we have for giving a patient some estimation of when they are going to need treatment. The key prognostic factors in the CLL-IPI are the fluorescence in situ hybridization (FISH) analysis and the mutation status. For example, if I do FISH testing on 2 newly diagnosed patients and 1 patient has a 17p deletion (del[17p]) and the other patient has a 13q deletion (del[13q]), the frequency with which I will be following these patients will be different. I am going to see a patient with high-risk del(17p) disease more frequently than a patient with low-risk del(13q) disease. 

Another reason to obtain prognostic testing up front is to educate the patient about what to expect moving forward. For instance, I can tell a patient with del(13q) and mutated IGHV that they will probably not need therapy for years. If the patient is 80 years old, I might tell them that, based on this profile, they may never need treatment. Now, I would not say this to a 60-year-old patient, but I might say it to an 80-year-old patient if they have very good prognostic factors according to the CLL-IPI.