Expert Discusses Unanswered Questions in CLL Treatment Paradigm

Jacqueline Claudia Barrientos, MD

Jacqueline Claudia Barrientos, MD

Venetoclax (Venclexta) was recently approved by the FDA as a monotherapy and in combination with rituximab for the treatment of patients with chronic lymphocytic leukemia (CLL), with or without 17p deletion, following at least 1 prior therapy.

Both chemo-immunotherapeutic treatment regimens and targeted agents are being used in the treatment landscape of CLL. Other treatment options for this patient population include the BTK inhibitors acalabrutinib (Calquence) and ibrutinib (Imbruvica), and idelalisib (Zydelig), a PI3K inhibitor.

Experts still do not have a lot of data available on what treatment options are superior for patients with CLL, but the recent approval of venetoclax provides another option for these patients. Data from ongoing trials is expected soon, says Jacqueline D. Barrientos, MD, MS.

In an interview withTargeted Oncology, Barrientos, an associate professor at The Feinstein Institute for Medical Research at Northwell Health, discussed the current treatment landscape for CLL. She also highlighted some of the biggest challenges for physicians and gave her insight on how to move forward in the field.

TARGETED ONCOLOGY:What do you think are the best practices right now for an physician treating patients with CLL?

Barrientos: The most important thing is to recognize a CLL patient has a very varied clinical course. There are some patients that probably never had a need for therapy, but they might at some point need therapy.

There are certain markers that can really tell the patient how they will do over the next couple of years, and so for that matter, we're discussing how important it is to check the immunoglobulin heavy-chain status of the patient. That doesn't change over time, so you only need to test it once. Whether you are mutated or unmutated, you prefer to be mutated, because those patients have more of a benign clinical course. Also, you need to test for fluorescence in-situ hybridization (FISH) analysis, particularly for 17p deletion orTP53mutation. The reason for that is because we know that chemo-immunotherapeutic regimens don't really work well. Even if a patient has symptoms, we have to wait for that data before we start therapy because a patient that gets FCR [a regimen of fludarabine, cyclophosphamide, and rituximab] or BR [bendamustine plus rituximab] will not respond for a long period of time, so these patients should be treated with ibrutinib or another targeted agent, such as venetoclax or idelalisib, that are currently available.

That is the main focus: how to advice our patients. It's very anxiety-provoking once you have the diagnosis of CLL, and so it is important to recognize there are ways to help our patients understand their disease a little bit more.

TARGETED ONCOLOGY:What are the challenges you see in this treatment landscape?

The field is evolving really fast, and as of right now, we don't have a good understanding of the sequencing. Whether we start with chemotherapy and then move on to a TKI or if we have a TKI, what selection would be best for the patient after a TKI failure or intolerance? It depends on a lot.

A patient that stops taking ibrutinib due to an intolerance is a different patient than a true refractory patient that stops responding to the drug because they develop aBTKmutation or some other sort of mutation that rendered them no longer responsive. That is a big challenge. We still don't have an answer for that.

We also still don't have an answer on whether chemotherapy is better than targeted agents or targeted agents are better than chemotherapy. We're currently waiting for major phase III trials that are ongoing. The data has been acquired, but we are still waiting for the data to mature. Once these data are out, we will know for a fact how to advise our patients best, whether chemo-immunotherapy regimens are better than targeted agents or not.

There are 2 major ongoing trials. One is in fit, young patients with FCR against ibrutinib in combination with rituximab. The other trial is [in patients] older than 65, and it is BR against ibrutinib in combination with rituximab. We are all very excited about these novel agents because there's a chance that we can probably give the patients a good response, but at the same time we need to compare. These are currently therapies that we take indefinitely, for a long period of time. Whereas, in chemotherapy approaches, they are only upon a limited course. We are still trying to debate what is best in light of all these new agents at our disposition.

TARGETED ONCOLOGY:What are some of the advances you are excited about in CLL?

We are all very excited with the most recent FDA approval of venetoclax, a BCL-2 inhibitor, in combination with rituximab for all patients with CLL. We so much needed this new compound because it has proven to be efficacious after ibrutinib failure or idelalisib failure. Now, it's another option for our patients. Let's say if you had a patient with a recent surgery that was major, or atrial fibrillation. It would be very hard for you to manage that patient with ibrutinib because it could make the bleeding worse or the arrhythmia worse. Having venetoclax at your disposal really allows you to have more options of care.