Just a few years ago, the standard frontline therapies for CLL were the combinations of fludarabine, cyclophosphamide, and rituximab (FCR) for young patients and bendamustine plus rituximab (BR) for older patients; however, as novel agents have been approved by the US Food and Drug Administration (particularly with ibrutinib, acalabrutinib, and venetoclax), the treatment paradigm has completely shifted away from chemoimmunotherapy.

The last few years have been defined, in large part, by ibrutinib as the standard of care for many patients with CLL. Even now, ibrutinib is still the most widely used frontline CLL treatment, although, over the last couple of years, some challenges associated with ibrutinib have become more apparent. Certainly, ibrutinib continues to look good overall in the recently published 7-year follow-up of RESONATE-2, but nearly a quarter of patients in that study discontinued treatment due to toxicities that included atrial fibrillation, hypertension, and arthralgias.

Challengers to ibrutinib in the frontline setting include venetoclax plus obinutuzumab and acalabrutinib. An advantage of venetoclax plus obinutuzumab is the time-limited treatment duration and the fact that it does not have the longer-term risks associated with chemotherapy, as it is a novel agent regimen. A challenge with this regimen is that it is intensive to get it started, particularly in the community setting, with obinutuzumab infusions and the venetoclax dose ramp-up, as well as the need for close monitoring for tumor lysis syndrome with venetoclax. You need to be able to get laboratory evaluations back in real time. But the beauty of the regimen is that you are finished at 1 year. Further, the recently presented 4-year follow-up of the CLL14 study reported a progression-free survival (PFS) rate of 74% at that time point. The other advantage of venetoclax is that many of our older frail patients with CLL have cardiovascular comorbidities, and venetoclax has no known cardiovascular or bleeding risks.

Another challenger to ibrutinib as the standard in the front line is acalabrutinib, which has really started to come of age. Four-year follow-up data from the ELEVATE-TN study, which was the registrational frontline study that led to the approval of acalabrutinib for CLL, were presented at the recent spring meetings. Data from the ELEVATE-RR head-to-head study of acalabrutinib vs ibrutinib in relapsed/refractory CLL provide reassurance that the PFS with these 2 drugs is equivalent, but there were significant advantages in terms of the safety profile of acalabrutinib, particularly regarding atrial fibrillation, hypertension, and arthralgias.

In my practice, I have generally moved toward using more acalabrutinib than ibrutinib because, if there is 1 agent in a class that is going to be comparably efficacious but better tolerated, I am probably going to recommend that agent for most patients. ELEVATE-RR further strengthens the evidence in this regard, and it likely will be impactful for the broader community to feel comfortable using more acalabrutinib in the frontline setting. However, that change will take time because there are many clinicians who have been prescribing ibrutinib for a few years now and feel comfortable with it.

We are clearly moving away from chemoimmunotherapy. Ibrutinib has been compared with every chemoimmunotherapy regimen in CLL, and, in some cases, there was a survival advantage with ibrutinib. In every single case, however, PFS was better with ibrutinib.

There are patients for whom chemoimmunotherapy should still be considered. We have multiple studies showing that FCR—but not BR—is associated with a plateau on the PFS curve. This is primarily seen in the population with an IGHV mutation, where approximately 50% to 60% of patients have durable PFS after about 20 years of follow-up. Because of this, I still think that FCR should be discussed with young and fit patients who have a mutated IGHV gene, where the potential for cure can be more important. Even though the targeted drugs are great, we do not currently have any drugs that we consider to be curative. For a patient in their 70s, we can potentially keep them alive long enough with novel agents so that CLL is not the cause of their mortality. That is not the case for a patient in their 50s, particularly with single agents used in succession.

Venetoclax plus obinutuzumab is likely the go-to regimen in most academic centers, while Bruton tyrosine kinase inhibitors are the go-to option in the community. The exception for academic centers is that Bruton tyrosine kinase inhibitors are used in patients with TP53 mutations or 17p deletion. Data from the CLL14 trial showed that those patients have a median PFS of almost 4 years. We also have frontline data with ibrutinib showing that the 4-year PFS in that population with P53 aberration is approximately 79%.

Venetoclax plus obinutuzumab is often too burdensome in the community setting, where there may not be point-of-care laboratory services, which are necessary for monitoring for tumor lysis syndrome. Per the prescribing information for venetoclax, you must order labs 4 to 8 hours after the first dose on days 1 and 8, no matter what the tumor lysis risk group is. Without point-of-care laboratory services, lab results are often delayed until the next day if they are ordered too late in the day.