Earlier clinical trials evaluating chemoimmunotherapy in the frontline setting often included relatively young patients, and this can sometimes limit the generalizability of the findings given that the median age of CLL diagnosis is around 72 years. One of the advancements in CLL clinical research in the last few years has been that the frontline trials have focused more on older patients and on those with comorbidities. This includes the ELEVATE-TN trial, which evaluated acalabrutinib with or without obinutuzumab vs obinutuzumab plus chlorambucil, and the CLL14 trial, which evaluated fixed-duration treatment with venetoclax plus obinutuzumab in elderly patients and in those with comorbidities. These are data sets that we can use to help guide a large number of our patients with CLL to make treatment decisions.

An important consideration is how well the drugs will be tolerated. For example, we would probably steer patients with cardiovascular comorbidities toward venetoclax plus obinutuzumab rather than Bruton tyrosine kinase (BTK) inhibitors because of the cardiovascular side effects associated with BTK inhibitors. On the other hand, we would avoid venetoclax-based regimens in those with significant renal dysfunction in whom we would be worried about tumor lysis syndrome risk and/or in patients who do not want to come into the clinic for infusional therapy. Such patients could do very well with BTK inhibitor monotherapy. For patients with 17p deletion (del[17p]) or mutated TP53, my preference and priority is BTK inhibitor–based therapy because I think that these individuals require continuous therapy and a maintenance-type strategy. For patients with del(17p) or mutated TP53 who progress on BTK inhibitors, I would typically treat with continuous BCL-2 inhibitor therapy (ie, venetoclax) in the second line. Nevertheless, while patients with del(17p) or mutated TP53 do appear to do better with BTK inhibitors, I think that we need to see more data for the venetoclax and obinutuzumab combination in this group; I was actually somewhat impressed that patients with these abnormalities in the CLL14 trial had not reached a median progression-free survival (PFS) after 3 years, which was 2 years off therapy.

It is important to note that being older and having significant comorbidities are not absolute contraindications to any of the small molecules. Thus, with respect to these patients, it is important to remember that the small molecules generally have much better tolerability than chemotherapy. The adverse effect we worry about the most with BTK inhibitors, especially with ibrutinib, is atrial fibrillation. Atrial fibrillation can be overt, but I have also encountered a number of patients who are asymptomatic when they come into the clinic but are found to have atrial fibrillation when their vitals are taken. This adverse effect is important because there are significant consequences of atrial fibrillation, the most important of which is the potential for stroke. Additionally, depending on their CHA₂DS-VAS_C scores, many of these patients may require anticoagulation. And, although I have certainly given anticoagulation to patients on BTK inhibitors, one does it with a bit of trepidation because we know that these individuals have more bleeding episodes due to the platelet dysfunction that we see with these agents. 

Given these issues, the presence of cardiac disease, particularly a history of atrial fibrillation, is probably the biggest relative contraindication to using a BTK inhibitor. For patients with del(17p) and TP53 mutations, I would agree that BTK inhibitors are likely going to be preferred, irrespective of comorbidities, based on recent data. Updated results from the CLL14 study suggest that patients with del(17p) or P53 mutation may have a shorter PFS with venetoclax/obinutuzumab compared with patients without these aberrations. In contrast, a recent analysis presented at the 62nd American Society of Hematology Annual Meeting and Exposition included combined long-term efficacy data for 89 patients with TP53 aberrations pooled from 4 different frontline clinical trials of ibrutinib. The 4-year PFS was 79% and overall survival was 88%. That is, first-line BTK inhibitor therapy appeared to partially overcome the poor prognosis in this high-risk population, so I think that this is going to be the way to go. 

I would agree that targeted therapies are likely the best option, particularly for our older patients and for those with comorbidities. We use very little chemoimmunotherapy these days in the frontline and relapsed settings. The issue of fixed-duration therapy vs continuous therapy is another important part of the conversation when we select a first-line regimen. We have good data for venetoclax plus obinutuzumab and for ibrutinib in the frontline setting, with both regimens giving very long PFS and extremely good disease control. The novel agent–based combinations, in a fixed duration, are appealing to me and to others, and this seems to be the direction that we are going in based on the newer clinical trials. Some of these new investigational strategies are focused more on minimal residual disease–free status as an outcome of treatment. While that is not a standard of care yet, I am optimistic that, at some point in the near future, this will become a part of the conversation. This will allow patients to get off treatment. We also look forward to data regarding the effects of new treatment regimens on immunity constitution, which can influence the risk for second cancers and infections.