Novel Approaches Lead the Charge Away from Chemoimmunotherapy in CLL

Matthew S. Davids, MD, MMSc

With the rise of novel agents and several regulatory approvals, treatment for patients with chronic lymphocytic leukemia (CLL) continues to shift away from the use of chemoimmunotherapy, according to Matthew S. Davids, MD, MMSc, who added that, to date, chemoimmunotherapy is only used in a small number of young and fit patients.

“Over the past few years, a number of novel agents have been approved in CLL; however, ibrutinib (Imbruvica) seems to be most commonly used in the frontline setting,” said Davids. “Acalabrutinib (Calquence) is another BTK inhibitor that has been approved for use in the frontline setting. Those 2 agents are given continuously. However, we now have the combination of venetoclax (Venclexta) and obinutuzumab (Gazyva), which was designed to be a time-limited approach to replace chemoimmunotherapy.” 

In an interview with OncLive, Davids, director of clinical research in the Lymphoma Program and a medical oncologist at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School, discusses the shift away from chemoimmunotherapy in CLL and ongoing research in the space. 

OncLive: Despite the emergence of newer options, are there certain scenarios in which chemoimmunotherapy should still be used? 

Davids: I still discuss chemoimmunotherapy with younger, fit patients who have mutated IGHV and do not have any TP53 aberrations, meaning they don't have deletion 17p or a TP53 mutation. We know that these patients can often experience durable responses to the combination of fludarabine, cyclophosphamide and rituximab (FCR). Moreover, we now have follow-up data of 12 to 15 years in some patients who are still in remission after their original 6 months on FCR. That being said, we must counsel patients on the risks associated with this approach, including infections, prolonged cytopenias, as well as a late risk of myelodysplasia and even acute myeloid leukemia. 

When choosing among the modalities available, what factors do you consider?

As we think about which modality to select, I believe that comorbidities play an important role. When patients have significant cardiovascular disease, particularly if they're on anticoagulation for atrial fibrillation, BTK inhibitors may not be my first choice of therapy. Instead, I would consider a venetoclax-based regimen.

On the other hand, if a patient has poor renal function and is worried about tumor lysis risk, or if they're older and have difficulty getting back and forth to the medical center for frequent monitoring, I may favor a BTK inhibitor. These agents are straightforward and require less monitoring than venetoclax-based regimens.

Now that there are many combinations to choose from, what sequencing questions would you like to see addressed with future research?

As we consider frontline therapy, we now wonder whether we should start with continuous therapy [in the form of] single agents or combinations or whether we should be doing time-limited therapies followed by retreatment at the time of progression. 

Fortunately, some ongoing studies may be able to answer these questions in the future. A good example is the CLL17 study, which will be launching soon in Europe. In this study, investigators are going to examine continuous therapy with ibrutinib versus the combination of venetoclax and obinutuzumab as a time-limited therapy. Importantly, it also includes an arm combining ibrutinib with venetoclax as a time-limited therapy, which also needs to be explored.

What are some of the promising doublet and triplet regimens under exploration?

We're certainly excited about the data that we're seeing with doublet- and triplet-based therapies in the frontline setting. The CAPTIVATE trial is a good example of [promising research that involves] a doublet therapy comprised of ibrutinib and venetoclax. We do see some increase in toxicity when we use these agents together, compared with when they are used alone. However, we're seeing outstanding efficacy data [with this regimen]. By combining these 2 drugs early on, we may be able to achieve a time-limited approach with an all-oral regimen, which may be an advantage over venetoclax/obinutuzumab.

Triplet therapies are certainly very powerful. We've seen encouraging data from a group over at Ohio State University, as well as a group in Germany, that looked specifically at a regimen of ibrutinib, venetoclax, and obinutuzumab in patients with TP53 aberrations. In both cases, the triplet regimen was highly effective; however, again, we saw toxicity, with more infections and infusion reactions. We still don't know whether we need to add the CD20 antibody or whether the all-oral doublet will be enough. We hope to learn more about this in ongoing clinical trials. 

What are some of the doublet regimens under exploration for patients who progress on ibrutinib? 

Because BTK inhibitors are being used so widely in the frontline setting, we need to optimize the way that we're treating patients in the relapsed setting after they progress on ibrutinib. 

Combination approaches that include venetoclax, not just rituximab, are also of interest. A particularly promising combination is venetoclax with PI3K inhibitors. Additionally, we've done some early work on duvelisib (Copiktra) plus venetoclax and demonstrated promising results.

Other ongoing studies are evaluating the investigational PI3K inhibitor, umbralisib (TGR-1202), with venetoclax. I’m looking forward to hearing more data on patients who progressed on ibrutinib and are now being treated with these doublet therapies.

Where do you see CAR T-cell therapy fitting in to the CLL care continuum? For which patients will this approach be most beneficial?

CAR T-cell therapies have been more of a challenge to develop for CLL compared with [a disease like] diffuse-large B cell lymphoma. In patients with CLL, T cells are somewhat dysfunctional because the disease suppresses T-cell function. 

Although CAR T cells can be effective in some patients with CLL, including some who are refractory to other therapies, there's certainly room for improvement. I'm optimistic about some of the combination data that are emerging. For example, the addition of ibrutinib to CAR T-cell therapy may help the T-cell effector function to be more potent. 

I do believe that CAR T cells have a bright future in CLL. If [these products] receive approval, [this approach] will probably be [indicated for] a more heavily pretreated population where they have progressed following multiple novel agents or particularly those with TP53 aberrations. This is the role that allogeneic transplants [currently] play; however, I believe that CAR T-cell therapies could actually supplant [those procedures] for some patients.

I do hope that as CAR T-cell therapy becomes more effective in CLL, based on various combination approaches and an improved toxicity profile, it can be moved into earlier lines of therapy. I believe it will have an important role in the future of CLL treatment.