Q: In view of the potential advantages of newer time-limited therapies in patients with CLL, are there any uncertainties or concerns regarding the use of such regimens?

Patients like the idea of getting a course of therapy and being in remission and stopping treatment. This is because they have the hope that they may have a very long duration of remission or that they may even be cured, and then they are back to living their lives and feeling normal again. When you are on chronic therapy, you are likely to accumulate side effects and you are constantly reminded of your disease. Furthermore, the idea that we are not going to select for adverse clones with novel agents is not proven. We know that we select for adverse clones with chemoimmunotherapy (CIT), and I think that venetoclax is likely to have the same effect, although perhaps not as strongly because it has more activity against high-risk clones. With ibrutinib, the clonal selection pattern is somewhat different because the selection is for the resistance mutations specifically associated with ibrutinib. There is some suggestion that these ibrutinib resistance mutations may change the biology of the disease, but this is still very poorly understood and is under active investigation. Nevertheless, a rationale for using combination therapy over sequential single-agent therapy is that 2 drugs with different mechanisms of action are less likely to select for these resistant clones. Yet, we only have approximately 1 to 2 years of follow-up data with our frontline novel agent combination regimens. We do not yet have any progression-free survival data, just response and MRD negativity data. That is not enough to go on in terms of understanding these regimens and mechanisms of resistance. Additionally, further investigation at this stage is challenging because most of the patients with CLL on these excellent combinations become MRD negative, so there is essentially no disease left to study. Thus, we have to wait.

Outside of the context of clinical research, there are essentially 2 options for time-limited therapy in the frontline setting. One is FCR, which is increasingly relegated to a smaller patient population. In my mind, FCR can be considered for patients under 65 years of age who are IGHV mutated and TP53 intact. The standard regimen is 6 cycles, but some individuals may be considered for an abbreviated course, based on MRD status in the bone marrow. Another time-limited option for young, fit patients with CLL would be a 12-month regimen of venetoclax plus obinutuzumab (ie, the approach used in the CLL14 trial). Ironically, the CLL14 study included mainly older patients with comorbidities rather than young, fit patients. I think that it is fairly universal that younger individuals are interested in finite treatment approaches, and, so, a time-limited approach is considered important to these patients. Bruton tyrosine kinase inhibitor ± anti-CD20–based therapy is still a continuous therapy strategy at this point in time. 

There is controversy surrounding whether a time-limited approach is relevant for patients with persistent disease, particularly based on their MRD status, at the end of therapy. There is also debate involving MRD, including questions regarding the best methodology to use in its assessment (eg, which compartment to use) and the significance of MRD when assessed various ways. A third controversy in this area is whether it is appropriate to discontinue a novel agent–based therapy in the setting of having a molecular or genetic poor risk feature that is predictive of a poor outcome and in situations with limited options for these patients should they relapse. If you look at the long-term follow-up data for CIT, many of these types of controversies largely disappeared when treatment was limited to those patients who were the best candidates for CIT in the first place.

There are potentially huge financial benefits of time-limited therapies, particularly for older patients with CLL on Medicare who may not qualify for co-pay–reducing patient access programs. There is also an obvious psychological benefit of time-limited treatments because you are not reminded every day that you have cancer. Another potential benefit is that, theoretically, you would not be driving the development of resistant clones with continuous therapy, which could translate to a longer life span. This is still conjecture at this point, but constant exposure to a drug could be driving resistance. There is interest in exploring alternative, time-limited dosing schedules and combination therapies to help prevent resistance. Currently, how to combine these therapies for optimal effects is unknown. We are looking into ways to maintain the disease’s sensitivity to small molecules, potentially extending the time that a particular novel agent can be used by several years. However, this has yet to be demonstrated. As relates to currently available novel agent combinations, venetoclax plus obinutuzumab for 1 year might be an effective time-limited treatment, but we do not have enough follow-up data to know the average time to progression.