Expert Highlights Potential of Targeted Therapies in Combinations for CLL

Danielle Ternyila

The treatment paradigm of chronic lymphocytic leukemia continues to advance, with many ongoing clinical trials investigating combinations seeking to build upon the success seen with Bruton’s tyrosine kinase inhibitors. Such potential combination therapies for CLL include venetoclax (Venclexta) with either ibrutinib (Imbruvica) or acalabrutinib (Calquence).

John C. Byrd, MD

The treatment paradigm of chronic lymphocytic leukemia (CLL) continues to advance, with many ongoing clinical trials investigating combinations seeking to build upon the success seen with Bruton’s tyrosine kinase (BTK) inhibitors. Such potential combination therapies for CLL include venetoclax (Venclexta) with either ibrutinib (Imbruvica) or acalabrutinib (Calquence).

The goal with these combinations is to improve upon the responses seen with single-agent BTK inhibitor therapy so that a patient may ultimately be able to stop taking therapy, without compromising on toxicity, explained John C. Byrd, MD. However, he noted, this approach will not work for all patient populations.

In an interview withTargeted Therapies in Oncologyduring the 22nd Annual International Congress on Hematologic Malignancies hosted by Physicians’ Education Resource, Byrd, the D. Warren Brown Chair of Leukemia Research at The Ohio State University Comprehensive Cancer Center, discussed novel combinations on the horizon and the patient populations these regimens would benefit, as well as the biggest challenges that still exist in the field of CLL.

TARGETED ONCOLOGY:Can you provide an overview of your presentation?

Byrd:My talk focused on both novel combinations and new therapies that are coming forward. Particularly, these novel combinations are exciting because with targeted therapies, many by themselves don’t induce minimal residual disease and allow patients to stop therapy. Currently, we’re exploring a number of these, particularly the BTK inhibitors, ibrutinib or acalabrutinib, combined with venetoclax and other agents to induce a complete response in patients, and then to afford them the opportunity to go off therapy.

TARGETED ONCOLOGY:How do you go about choosing which combination to give a patient?

Byrd:Both of the BTK inhibitors in combination therapy are in trials. Right now, we are looking at both of them. Our own preference at Ohio State is moving toward more selective BTK inhibitors when we’re not looking for the immune modulation that ibrutinib requires. By giving a more selective agent with other therapies, you tend to see fewer adverse effects. That’s the experience we have had with acalabrutinib thus far. With its approval for mantle cell lymphoma, while it is an off-label use, particularly in the setting of relapsed disease, it falls within National Comprehensive Cancer Network guideline criteria. When we have access to it, that’s what we have been using.

TARGETED ONCOLOGY:Do you envision the field moving toward triplet regimens?

Byrd:I think for younger patients, where there is a desire to stay off therapy for an extended period of time, we are going to be doing trials, and the field will move to [triplet regimens]. However, others, particularly elderly patients who don’t want the headache of intravenous therapies or the increased risk of adverse effects that likely come with combination therapies, the ability to go on ibrutinib or acalabrutinib will afford them the opportunity to be in remission, likely for the rest of their life, and they will go with that option.

I suspect that if we look forward 10 to 15 years, there will be a permutation of the CLL community where patients with CLL receive single oral therapy often and don’t do combination therapy. We will have subsets of patients who do that, and subsets of patients who don’t. We will be giving chemoimmunotherapy probably to a very small population.

TARGETED ONCOLOGY:Are there any ongoing trials you are particularly excited about?

Byrd:I am very excited to see where these triplet combinations are going to go. Several randomized phase III studies are starting now in England and Germany, and will be starting in the United States. I’m also excited to see if using targeted therapy early for patients who have high risk can subvert the clonal evolution, and then patients developing high-risk CLL wouldn’t have to receive the aggressive therapy.

I’m also quite excited to see how targeted therapies that modulate the immune system are going to affect the complications in CLL over time. We are already seeing that when patients go on BTK inhibitors, they don’t develop autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura. It’s going to be interesting over time with the randomized studies if we see if secondary cancers and other immune-suppressive cancers occur in patients with CLL.

An area that we need help in and are working hard on right now is Richter’s transformation. When patients get that, we don’t have good therapies, so understanding that and bringing forth new drugs for that indication are going to be very important.

TARGETED ONCOLOGY:What are some of the other challenges that we are facing today in the field?

Byrd:Two challenging areas we have are BTK inhibitor—resistant CLL or venetoclax-resistant CLL, and with both of those, the drugs are cross-reactive. We have other small molecules that are coming and are likely to be active in that setting. Those patients eventually have to go on to transplant or chimeric antigen receptor T cells. For Richter’s transformation that occurs in the kinase era or the targeted therapy era, we don’t understand the biology of that yet. That’s the challenge, understanding the biology and why it happens, then getting to the molecular underpinning of what’s causing it, and either trying to prevent it or using the vulnerability that caused the transformation [and targeting it] with a drug. This is ongoing work we are excited about. We are working to continue to create models and such to ultimately bring new therapies forward.

TARGETED ONCOLOGY:What is the key takeaway from your presentation?

Byrd:We are at an exciting place in CLL. There’s a small subset of patients with CLL [to whom we will] continue to give chemoimmunotherapy, such as theIGHV-mutated group. Looking forward for the other groups of patients, there is great hope that they can go on to either a BTK inhibitor—based therapy or venetoclax, perhaps with rituximab, and have a long remission. A good number of patients will be able to stay on that therapy and live with their CLL as long as they would have lived without their disease.