Targeted Therapies Reign in the Frontline Treatment of CLL

Jacqueline Claudia Barrientos, MD, MS

The chronic lymphocytic leukemia (CLL) paradigm has moved beyond chemotherapy into an era of targeted therapy. To appropriately navigate among the options available, prognostic markers, history of surgery or bleeding, adherence, and physical and financial toxicities must be considered, according to Jacqueline Claudia Barrientos, MD, MS.

“We are in a paradigm-changing time, a time when chemotherapy is [becoming] a thing of the past,” said Barrientos. “So many abstracts have shown amazing responses with targeted agents. Even though these novel targeted agents come with toxicities that need to be addressed, these are still manageable and better in terms of quality of life for a patient compared with the toxic chemoimmunotherapy regimens that we had before.”

In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Barrientos explained how she navigates among the options available in the frontline setting for patients with CLL and highlighted ongoing research efforts of interest. She is an associate professor at the Karches Center for Oncology Research, Feinstein Institutes for Medical Research, and an associate professor in the Division of Hematology and Medical Oncology, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.

OncLive®: What factors do you consider when choosing a frontline treatment strategy for your patients with CLL in practice? What is your selection process?

Barrientos: To choose what treatment to use for each patient, [I consider] several factors. For one, we check their prognostic markers. If the patient has 17p deletion del(17p), they need to be treated with a targeted agent or prioritized for clinical trial participation. If a patient has any issues with compliance, I may recommend a regimen such as obinutuzumab [Gazyva] with venetoclax [Venclexta], because it is a time-limited strategy that you can give for 1 year, [and you’ll see] excellent overall response rates and time in remission. It might be [the] better [choice] for them if you know they might have issues with [adhering to a regimen that needs to be given] over a long period of time.

If the patient has a recent history of major surgery, major bleed, or any prior spontaneous bleed [involving] the central nervous system, I will stay away from using a BTK inhibitor because I would be [concerned] about causing a relapse of that bleeding event. [I also determine] whether a patient is having issues with their heart, whether they have arrhythmia, and, [if so,] what type of arrhythmia they have. If it’s an atrial f ibrillation [that occurs rarely], I would feel comfortable managing a patient with a BTK inhibitor. However, if it’s a severe atrial fibrillation and you have the option of giving the patient a BCL-2 inhibitor, then I would probably do that because I know a BTK inhibitor may cause a relapse of the atrial fibrillation or make it uncontrolled.

Also, if a patient has any history of ventricular tachycardia or ventricle fibrillation, I will not use a BTK inhibitor because then I would be too concerned about a potential arrhythmogenic event that could lead to a bad outcome.

Are there certain patients to whom you would not give venetoclax?

For the majority of my patients, venetoclax, a BCL-2 inhibitor, is a very well-tolerated drug. The only issue is that the first 5 weeks of the dose ramp-up schema are very time intensive for the patient and for me. If the patient thinks that they might not hydrate well [or] do the laboratory evaluations in time because of some concerns [over] transportation, I don’t even consider [this option]; I admit them to the hospital and do the monitoring in real time.

How do financial and physical concerns affect your selection?

For the most part, you have 2 choices: You can choose a BCL-2 inhibitor or a BTK inhibitor. When you discuss this [choice] with patients, you have to also discuss the socioeconomic impact. If the co-pay is too [steep], it might be better for them to be on a fixed-duration regimen, as they might not be able to afford [treatment] over a period of several years with a BTK inhibitor. I do consider that, as well.

We also talk about the potential toxicities of treatment [with patients]. Some feel very strongly that they don’t want to be on a drug that potentially causes tumor lysis syndrome, because they have had family members or friends who have experienced it and they don’t want to risk it. We also talk about the fact that there’s no head-to-head comparison right now, so we can still choose which of these drugs may be a better approach.

What is your advice for your colleagues navigating the growing number of options?

Not knowing certain characteristics of a patients could [lead to] harm. At [the 2020] American Society of Hematology [ASH] Annual Meeting and Exposition, for example, one of my colleagues presented an abstract where we found that many physicians both in the community and academia are not testing for del[17p] or TP53 mutations, and patients [with these mutations] don’t respond well to chemotherapy. Because of that, they are receiving the wrong regimens, or they may not be given the best treatment. It’s very important to get that message out. Although [patients with] del[17p] and TP53 mutations respond to drugs like ibrutinib [Imbruvica] and venetoclax, we still need to test for [the mutations] because these are the patients who will relapse sooner. You should prioritize them for clinical trials or closely monitor them because, invariably, these patients have a higher risk of relapse. You need to know that before you start the first-line therapy.

What research is currently under way regarding targeted therapy?

We are now in the era of tailored treatment strategies. In the world of CLL, I tell my patients that targeted therapy is king—especially for frontline treatment strategies where we just use targeted agents or novel antibodies. [For instance,] an abstract presented at ASH [evaluated the] combination of umbralisib with ublituximab [TG-1101]. We eagerly awaited these data because [they represent] a new treatment strategy for our patients. At this moment in time, I think we have good options, but it’s always good to have [more]. The better the options, the better the outcomes for our patients.

Where should future efforts be focused?

Some say that we have more drugs than we have patients, but that’s not true. We really are trying to cure this disease, and having access to these novel agents allows us to offer our patients more options. When we [use] the right combination, we could potentially achieve as close to a cure as we can in these patients. [If we could] put them into remission for a long period of time after a time-limited treatment strategy, that would be great.