Jennifer A. Woyach, MD, associate professor of hematology at The Ohio State University, spoke with CancerNetwork® about chronic lymphocytic leukemia (CLL) and the current frontline treatment options available for patients with this disease type at the 24th Annual International Congress on Hematologic Malignancies, held from February 27 to March 1, 2020 in Miami, Florida.

CancerNetwork®: What are the frontline options currently for the treatment of CLL?

Woyach: So, for CLL we have a number of frontline options. We have ibrutinib (Imbruvica), which can be used by itself, and usually is used by itself. We have acalabrutinib (Calquence) that can be used with or without obinutuzumab (Gazyva). And then we have venetoclax (Venclexta) plus obinutuzumab, in terms of our targeted agents. We also still do have chemoimmunotherapy options; FCR, which can be considered especially for those young, fit patients with IgHV-mutated disease. We also do have bendamustine rituximab (Bendeka) and chlorambucil (Leukeran)-obinutuzumab (Gazyva) still available, although there are not a lot of scenarios where you would use those.

What are the toxicity concerns with these agents?

So, with the BTK inhibitors, specifically with ibrutinib, we know a lot about long-term safety profiles. The toxicities that are of concern with ibrutinib are atrial arrythmias, which happen in about 10-15% of patients; much less likelihood of ventricular arrythmias, less than 1%; you can see hypertension up to 30%, grade 3 or higher, and that’s something that actually happens more commonly with the longer durations of therapy; and then you can see other side effects that are more common, but less dangerous, things like arthralgias, fatigue, upper respiratory infections.

With acalabrutinib, it seems like you probably do see some atrial arrythmias and hypertension, although it seems to be much less frequent than with ibrutinib. You tend to see less bruising with acalabrutinib than ibrutinib, but less arthralgias. You see headache with acalabrutinib which you don’t see with ibrutinib, although that is predominantly low-grade and goes away over time.

With venetoclax, you can see neutropenia, especially early on, and you can see risk of tumor lysis, especially with the first ramp ups. And then with chemoimmunotherapy, our primary considerations are cytopenias, both during therapy and prolonged after, and then with FCR specifically you have an almost 5% risk of therapy-related myelodysplastic syndrome or AML.

What are the novel approaches with CLL?

So, novel approaches that are standard of care would be either BTK inhibitors or Bcl-2 inhibitors. There’s a lot of interest right now in combining those 2, so there’s studies of ibrutinib or acalabrutinib with venetoclax with or without obinutuzumab. Right now, those should be done primarily in the context of a clinical trial, and I don’t use those approaches outside of a trial. But certainly, that’s something that looks to be very effective and we’ll continue to follow very closely for the future.

Could you discuss the ELEVATE-TN study?

ELEVATE-TN was the study that led to approval of acalabrutinib in the frontline setting in CLL, and in this study patients who were either over the age of 65 or who had multiple co-morbidities were included and they were randomized 1:1:1 to acalabrutinib given alone, acalabrutinib given in combination with obinutuzumab, or chlorambucil in combination with obinutuzumab.

The primary endpoint of the study was progression-free survival of the comparison between acalabrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab, and there was a secondary comparison of acalabrutinib alone versus chlorambucil plus obinutuzumab. So, the study read out around ASH in 2019 and showed an improved progression-free survival for acalabrutinib, both alone and in combination with obinutuzumab compared with chlorambucil plus obinutuzumab. Currently, there is not a difference in overall survival among those agents.

What were the toxicities observed with acalabrutinib?

Acalabrutinib does have some mild toxicities, it can cause some bruising. It has a less than 5% risk of atrial fibrillation at this point, though we’ll have to see what happens when patients are on for longer durations of treatment. Risk of hypertension appears to be less with acalabrutinib than with ibrutinib, and risk of major bleeding is very low with this agent as well. It actually is very well tolerated. There is a little bit more neutropenia and a little bit more risk of infection when the obinutuzumab is added to it.

What kind of challenges do we still need to overcome in the CLL space?

I think right now, one of the biggest challenges in CLL is trying to decide what is the best frontline therapy for each patient. There are a few randomized studies that I think will help us with that. One is a head to head comparison of ibrutinib and acalabrutinib, that it completed enrollment a few years ago and hopefully will read out sometime in the next few years. It actually is in relapsed high-risk CLL, but hopefully the efficacy differences, if any, between the two agents and the safety differences can be extrapolated to any setting.

We also, I think, are really interested in whether single agents given sequentially or in combination therapy is better, and to this point there are 2 NCTN studies, one led by ECOG, one led by the Alliance. The ECOG study is for patients under the age of 70, the Alliance study is for patients age 70 and older. Both are comparing ibrutinib plus obinutuzumab versus ibrutinib plus obinutuzumab venetoclax to see whether the addition of venetoclax is deepening the remission with ibrutinib based therapies and can allow for successful discontinuation of treatment.

So, what is sort of the main take home message from all of this?

Well, right now in CLL I think we’re in a very good time for frontline treatment, so there’s a lot of options. For most patients, we can very confidently say that there really isn’t a wrong option, and most patients will go on to have a long progression-free survival with any agent that we choose. I think one of the big challenges right now is going to be to make sure that we continue enrolling our patients on clinical trials so that we don’t become complacent with this approach right now and can really figure out what the best approach is for each patient.