Recent Developments and Emerging Therapies in Chronic Lymphocytic Leukemia

Ian Flinn, MD, chief scientific officer for Tennessee Oncology and OneOncology, speaks with the Journal of Clinical Pathways about recent developments in chronic lymphocytic leukemia treatment, emerging therapies that show promise, and how Tennessee Oncology’s new research center will improve access to clinical trials for more patients. 

Transcript: 

Ian Flinn, MD:  I'm Ian Flinn. I'm the chief scientific officer of Tennessee Oncology and OneOncology in Nashville, Tennessee.

Can you discuss some of the recent advancements in chronic lymphocytic leukemia (CLL) treatment, and how these developments have influenced your approach to managing patients with CLL?

Dr Flinn: So there's been a significant trend away from chemo-immunotherapy in the last few years towards more targeted therapy. And there's basically two families of treatments. One is a BTK inhibitor-based approach, and another is a BCL2 inhibitor-based approach and the only BCL2 inhibitor these days is venetoclax. I think this has really revolutionized our care for patients with CLL. The way you choose one therapy for a patient versus another is based on several factors. One is based on purely logistics and patient's choice. For instance, the BTK inhibitors are much easier to give. They do not require a patient to come into the clinic very often. But they are also given continuously. And so this is a problem for many patients, because they like to get off therapy rather than being on a drug forever. 

The other, using a venetoclax-based approach, is more logistically difficult. For instance, the patient has to come into the clinic twice a week for 5 weeks to do a ramp up the dose to prevent tumor lysis syndrome. On the other hand, it's tremendously appealing, because generally it's a time-limited therapy. In the front line therapy we generally give it in combination with obinutuzumab for one year, and patients only, you know, therefore, can come off the drug after that. And so it's incredibly appealing for many. And so different patients will choose different approaches. We can also look at it from a different, slightly different approach. There's some treat … Some patients have some certain genetic factors that make me want to use a BTK inhibitor versus venetoclax, and so, for instance, at high-risk abnormality such as the 17p deletion, I generally often give a patient a BTK inhibitor.

Are there any promising emerging therapies or ongoing clinical trials in the field of CLL that you find particularly intriguing or that you believe may have a significant impact on future treatment approaches? 

Dr Flinn: There are a number of different approaches that are being investigated for patients with CLL. They involve sort of 2 different groups of approaches. One is using drugs that we already have, FDA approved, in combination and trying to find a better way of giving them, a more efficacious way. And then there are a number of new drugs that are also being investigated.

So let's talk about the combination studies right now. Now we have BTK inhibitors, we have venetoclax, we have anti-cd20 monoclonal antibodies, but no one really knows which is the best 2- or 3-drug regimen to use. So there are certainly a number of different trials going on to investigate that. But not only which 2 or 3 drug regimen is best, but how long we should be giving these therapies for.

For instance, some patients with high-risk cytogenetics might require more therapy than those patients who have good-risk disease. And so we're using measurements of undetectable minimal residual disease to figure out whether the patient can come off therapy or not. And so that's a tremendously promising area getting patients into very deep remissions and getting them off treatment rather than having them to be continuously treated.

The whole other area therapy that's being investigated is new treatments. The one area that I'm particularly excited about is using BTK degraders. So in the past we have have blocked BTK through inhibitors, both through covalently bound inhibitors and the most and the most recently one that was just approved a week or 2 ago, pirtobrutinib, which is a non-covalently bound inhibitor. But there's another whole approach, which is trying to degrade BTK, and this is … there are many, many different drugs that are being investigated through phase 1 and now into phase 2 trials. So I think that's an exciting area of research.

Can you expand on the concept of BTK degraders, and what the benefits are of this therapy over BTK inhibitors? 

Dr Flinn: Right: the BTK degraders’ attractiveness might be that they are have a better safety profile, but also that they overcome resistance patterns that we see with the inhibitors. So sometimes patients, whether on a covalent inhibitor or non-covalent inhibitor, develop mutations that prevent the drug from bonding and having its effect. For instance, with a covalent-bound inhibitors, the most common one is the cysteine 481 mutation that prevents drugs, the first generation, covalent inhibitors, such as ibrutinib, acalabrutinib, zanubrutinib, from working. If you're actually just degrading the BTK, then there's no problem with some of these mutations.

You were recently appointed CSO for Tennessee Oncology’s new research center. What led to the creation of the center, and what impact do you anticipate the new facility will have on providing care to more patients and improving outcomes?

Dr Flinn: Tennessee Oncology recently underwent a reorganization of its research program. This research program was founded many years ago by Tony Greco and John Tainsworth, with the principle of bringing research to the community. The notion was that most patients were not seen in large academic centers. Most patients in oncology are seen by in the community practice. And therefore, the goal here was to bring trials to the patients to increase their access and improve their level of care. So this recent reorganization has allowed us to go back to our roots and to improve patients’ access in the community that has sort of slipped away over years as trials got more complicated, and as trials became more phase 1 oriented, and they became … the trend was to centralize again. We think that it's really important to bring the trials back out to the community and allow more and more patients to participate.

Can you speak briefly about your role as chief scientific officer for OneOncology?

Dr Flinn: In my role as chief scientific officer for OneOncology, we aim to improve access to clinical trials or community practice across the country. There are many, many different centers that are part of OneOncology. Many have a very active clinical search portfolio, but our goal here is to improve that even more and to increase access for patients throughout our sites.