Patients with high-risk CLL are in the specific group that can progress on our currently available therapies, but this occurs in the minority of patients when appropriate targeted therapies are used. High-risk patients are the individuals for whom, in the context of a clinical trial, you may consider upfront combination therapies. We really need to focus on developing newer therapies and newer combinations because the patients with aberrant TP53 have a high predisposition to progression and, ultimately, death from CLL or associated complications. 

In defining high-risk, I do not necessarily distinguish between the presence of 17p deletion (del[17p]) at just 1 allele or this together with a TP53 on the other allele in the sense that both groups of patients progress on therapy in the front and second lines. One unclear area is when just a TP53 mutation exists without del(17p) because the literature is somewhat vague. In most treatment studies, there are insufficient numbers of such patients to draw conclusions about their outcomes. For those with TP53 aberrancy, we know from the phase 3 CLL14 trial that the group taking the 12-month treatment with venetoclax plus obinutuzumab does not do as well. You would direct these patients toward a second-generation BTK inhibitor (ie, acalabrutinib or zanubrutinib). You could consider acalabrutinib plus obinutuzumab, which is the approach that is taken for most of these patients in my setting, because the phase 3 ELEVATE-TN study showed that treatment had a trend toward improved progression-free survival (PFS) vs acalabrutinib alone. 

Several studies are looking into intermittent therapy and/or periods of treatment discontinuation and are observing patients when they are off therapy. That is a reasonable thing to do, but perhaps not for this high-risk group (ie, if and when the disease comes back, you start therapy again). There is an ongoing study at The University of Texas MD Anderson Cancer Center (NCT04505254) that is testing intermittent acalabrutinib therapy in combination with obinutuzumab in treatment-naive patients. Similar studies involving discontinuation are ongoing at other sites.

Finally, in the high-risk category, some rare genetic features may be associated with progression and/or nonresponse to BTK inhibitor therapy that have been linked to Richter transformation. The significance of these findings is not entirely clear, but Miller et al have shown that near-tetraploidy and complex karyotype may be associated with more aggressive disease, progression, and the development of Richter transformation. 

For patients with TP53 aberrancy, most of us in the field prefer BTK inhibitor therapy over venetoclax plus obinutuzumab. Ibrutinib has been a standard option for the treatment of high-risk and relapsed/refractory CLL; however, ibrutinib is associated with cardiovascular and other adverse effects, which may be attributed to off-target kinase inhibition. Acalabrutinib and zanubrutinib are more selective for BTK inhibition, exhibit less off-target kinase activity than ibrutinib, and have a more favorable cardiovascular risk profile.

One of the problems with the study of high-risk CLL in the front line has been limited data. Patients with high-risk mutations usually represent a single-digit percentage of study participants, unless the trial is designed to actively enrich for such patients. In terms of the frontline treatment of high-risk CLL, the ELEVATE-TN trial provided a direct comparison between acalabrutinib alone and/or in combination with obinutuzumab in treatment-naive individuals. Acalabrutinib with or without obinutuzumab significantly improved PFS compared with chemoimmunotherapy using obinutuzumab plus chlorambucil. For all patients, the PFS with acalabrutinib and obinutuzumab was better than the PFS with acalabrutinib alone. However, when you look at the PFS curves of the high-risk patients, namely those with del(17p) or TP53 mutations, there is no difference between the 2 acalabrutinib curves, which is disappointing. That is, it is disappointing to conclude that the addition of the antibody provided no added benefit in the high-risk patients. We need longer-term data. Outcomes in CLL trials could look one way at 2 years and then look very different at 4 years.

Patients with high-risk CLL in the frontline setting can be described as those having TP53-aberrant disease; the role of complex karyotype in defining high-risk status in the absence of TP53 aberrancy is still unclear. So, for patients with del(17p) or TP53 disruption, the current approach in the front line is continuous BTK inhibitor therapy. Regarding the potential benefit of adding obinutuzumab, I am not completely sure that a benefit might not emerge with longer follow-up. I think that there are a number of datasets out there that hint at the concept that there could be a benefit to deeper remission in this patient population. Hopefully, we will get more data on that over time.

As Dr Byrd alluded to, there is some research that is evaluating time-limited regimens for these patients. In the German CLL2-GIVe trial, obinutuzumab, ibrutinib, and venetoclax therapy was tested in previously untreated patients with del(17p) and/or TP53 mutation. Most participants stopped therapy at 15 months, and the 3-year PFS was still 80%. 

Here at our institution, we conducted a phase 2 triple-drug study using acalabrutinib instead of ibrutinib (ie, acalabrutinib, venetoclax, and obinutuzumab [AVO]) in treatment-naive patients with and without TP53 aberration. After 16 months of treatment, we found that the rates of undetectable minimal residual disease in the bone marrow (BM-uMRD) were actually comparable between the group with TP53 aberrancy (83% BM-uMRD) and all patients (86% BM-uMRD). In this study, patients with BM-uMRD may elect to discontinue therapy and undergo MRD monitoring every 3 months with the option to re-treat at early MRD recurrence. This is the way to do it; if we are going to pursue time-limited combination therapy for patients with high-risk CLL, I favor an investigative approach of treating to uMRD, monitoring closely thereafter, and perhaps considering retreatment early. Although this approach is currently limited to clinical trials, it is a promising way to improve outcomes for these patients.