Treatment Options for Chronic Lymphocytic Leukemia Beyond Chemotherapy

In this interview, the Journal of Clinical Pathways spoke with Matthew Cortese, MD, Roswell Park Cancer Institute about recent updates in the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of chronic lymphocytic leukemia (CLL), ongoing clinical trials in this space, and how clinical pathways are developed and used at Roswell Park.

Please introduce yourself by stating your name, title, organization, and relevant professional experience.

I'm Matthew Cortese. I'm a CLL and lymphoma physician and assistant professor of oncology at Roswell Park Cancer Institute, also known as the Roswell Park Comprehensive Cancer Center, in Buffalo, New York.

I've been in practice for 3 years after training at the Cleveland Clinic, where I was mentored by some wonderful staff, including Ryan Hill, MD, PhD and Robert Dean, MD. I am the principal investigator (PI) on some active clinical trials at Roswell Park. I’m also leading translational research efforts, using big data and looking at outcomes research in the new era of targeted therapies and new molecular testing.

It's an honor and a privilege to see patients, practice medicine, write clinical trials, and lead  groundbreaking research into the future.

What are some of the latest updates in the NCCN guidelines for the treatment of CLL?

As a first-year attending, I was very proud to be part of the NCCN. One of the biggest changes that we've had in our recent updates to our CLL guidelines is the deprioritization of chemotherapy, including for patients with intact 17P and without mutations in TP53, which was the historical breakdown to determine chemo eligibility.

Chemotherapy has declined in use in favor of targeted therapies. Typically our second generation covalent Bruton’s tyrosine kinase (BTK) inhibitors, acalibrutinib with or without anti-CD20 therapy with obinutuzumab, zanubrutinib, and venetoclax-based therapies are typicall front-line treatments and usually second-line treatments for CLL and small lymphocytic lymphoma.

There have also been some notable additions to the guidelines with the recent US Food and Drug Administration (FDA) approval of pirtobrutinib, which is considered a noncovalent or reversible BTK inhibitor and has a favorable safety profile. It can also work in cases where mutations have shown resistance to prior generations of BTK inhibitors and works for several years for heavily pretreated patients who have had BCL2 inhibition with venetoclax and received covalent BTK inhibitors as prior lines of therapy.

The other notable addition in the relapse refractory setting is the addition of CAR T-cell therapy.  After about 12 years of research in trying to apply CAR T-cell therapy technology to CLL, a CD-19-directed autologous CAR T-cell platform called lisocabtagene maraleucel  (also known as Breyanzi), has been approved. The overall response rate for the therapy is about 40% and complete response at about 20%. It’s not a true home run, but it's the best we've seen so far with also a fairly reasonable safety profile. This is also now in the NCCN guidelines.

We're also rewriting our guidelines for richer transformations and update how we look at other mutations besides TP53 and IGHV mutation status in prognostic and predictive algorithms. But that's all preliminary work so far.

Are there any promising ongoing clinical trials in the field of CLL at Roswell Park, or elsewhere, that you believe may have a significant impact on future treatment?

There are ongoing clinical trials here at Roswell Park and across the country. CAR T-cell therapy is approved but there is a need to make these better for patients with CLL, particularly those with bulky disease or high-risk features and those with transformations.

We have two ongoing CAR T-cell studies here at Rosswell Park. I'm the PI for a trial with a company called Synthekine. This is an orthogonal interleukin-2 (IL-2), autologous CD-19-directed CAR T-cell therapy that uses a novel mechanism to boost CAR T-cells along with a kind of tight-beam communication that uses IL-2 that's modified on the CAR T-cells and a modified version of that cytokine, which is given exogenously by injection or infusion.

Another interesting study here at Roswell Park— led by Renier Brentjens, MD, PhD, deputy director— is armored IL-2 CAR T-cell therapy, which can be given with or without lymphodepleting chemotherapy. This is an exciting CAR T-cell product and the first-in-human study is now open.

So, those are two exciting CAR T-cell studies with many others ongoing throughout the country. In trying to advance the CLL field, CAR T-cell therapy is a hot area of research because it can overcome some nasty molecular resistance features and also has the opportunity to potentially cure some patients.

Notably, a couple years ago, some patients were still in remission after being 10 years out from receiving CAR T-cell therapy. Even though the experience with CAR T and CLL has been challenging, we've been advancing at an accelerating pace, and we expect new CART cell therapies to be better in the future.

We also have other small molecules with treatment for CLL. There is a promising BTK degrader study with a company called Beigene that is looking at a way to overcome some certain resistance mutations to BTK inhibitors, specifically kinase dead mutations, which no longer phosphorylate their downstream targets, but they have another function called scaffolding. This basically takes the whole BTK kinase and throws it away by proteasomal degradation. These are an exciting class of drugs that are still in fairly early phases of research—our study is a phase 2—but look promising and similar to BTK inhibitors otherwise.

We're also looking at other targeted therapies, such as MALT-1, cereblon, and other small molecule agents that are in our pipeline for opening. These may also have activity in CLL, and I'm excited about them as well.

And lastly, I want to mention there are ongoing studies outside of Roswell Park for other mechanisms of action, including new BCL2 inhibitors, next generation ones after venetoclax that have a faster ramp up period or less side effects.

There are also trials looking at new combination treatments. We also had accrued to the MAJIC study, which is looking at new combinations of covalent BTK inhibitors such as acalibutinib with venetoclax and not just our monothelial antibodies.

We are trying to make treatment more convenient, more flexible, and better. My passion is also to look for options for those patients who progress on standard therapies and need more to keep them going, and I'm optimistic about the promising research we're doing here and throughout the country.

How are clinical pathways developed and used at your cancer center?

We have a full clinical pathways guideline committee. This is a centralized process, which we roll out to our affiliate sites called the RPCN affiliate network.

Andrea Darrall—one of our rockstar advanced practice practitioners—leads this here at Roswell Park and is doing a fantastic job. And we're always working to adapt these pathways to reflect the standard of care, which changes very quickly, especially as we have new and promising trial results.

We have academic oversight for these pathways, which are multi-institutional on a web-based platform that works with our clinical care to map and mirror our notes and our decision-making to centralize this information and then use it for quality control. We use them quite a lot.

What are the advantages to implementing pathways at an oncology practice?

One of the advantages to implementing pathways is standardizing treatment, which can be good if you have good guidelines and good pathways that are contemporaneous, not out of date and missing new things that are potentially less toxic and better efficacy-wise.

Good guidelines and good pathways can greatly improve and standardize patient care so that patients uniformly get the best treatment. And you're limiting or reducing or even eliminating practices that are out of date or not appropriate, based on high-quality evidence. Clinical pathways are a way to improve the quality of care and standardize our practice throughout a large network and around the country.