 When determining first-line therapy in our patients with chronic lymphocytic leukemia [CLL], there are many things that are important to consider. Certainly the disease characteristics are important—knowing their cytogenetics or fluorescence in situ hybridization and what chromosomal abnormalities they have associated are very important. Do they have a 17p or a 

? What is their mutational status? Are they unmutated or mutated? That is very important to know because for those subgroups, many of us would move away from chemoimmunotherapy or chemoimmunotherapy alone. If they’re part of a clinical trial that has a novel agent plus some chemotherapy, that’s different because they’re getting a novel agent. Certainly, we would move away, so those are important.

Then you have to take into account a patient’s age and comorbidities. Age is becoming not as relevant as opposed to the era of chemoimmunotherapy. When we treated the older, frailer folks, we would move away from chemoimmunotherapy or dose reduce and things like that when we didn’t have all these novel agents, but now that we have these novel agents, that age is agnostic. Older patients can receive good therapy now for CLL, which is fantastic.

Comorbidities are still a problem, and that may help select what your decision-making is for folks. If they have cardiac issues, if they are on anticoagulation or antiplatelet agents, you may decide based on their comorbidities whether you are going to use a BTK [Bruton tyrosine kinase] inhibitor versus using a venetoclax-based regimen. If they have renal insufficiency, poor kidney function, and are at higher risk for tumor lysis, you’re going to choose a venetoclax-based regimen. Of course, patient preference is important to consider because there are strategies that are evolving. BTK as a monotherapy has been a continuous chronic therapy, so that’s 1 strategy and approach. With the venetoclax-based combinations, looking at more time-limited durations of therapy, something that’s shorter but obviously may have more issues up front when it comes to monitoring for tumor lysis and myelosuppression, such as neutropenia. You’re going to talk about those options with your patients. There are logistical issues. Is the patient able to come to the clinic more often or do they need hospitalization, depending on their comorbidities or tumor lysis risk factors, if you’re going to give a venetoclax-based regimen? All these need to be considered.

What is paramount for consideration from my standpoint is always disease characteristics, then patient comorbidities. Obviously we take that into consideration along with the patient’s preferences and other issues surrounding what might be best treatment options. You may choose to move away now that you have multiple options of therapy. You may then select things based on their comorbidities and decide to move away from 1 versus another based on those options and patient preferences. I think you have to consider all these factors now that we have multiple therapies for our CLL patients, which is fantastic. You have to consider all these options with your patient, and ultimately a longer conversation has to be had now that there are these options and there are many factors to consider.

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Selecting First-Line Therapy for CLL

 There has been a very rapid shift in therapies for CLL [chronic lymphocytic leukemia]. There have been many new approvals. BTK [Bruton tyrosine kinase] inhibitors, which now include ibrutinib as well as acalabrutinib, have been approved in front line and relapsed, plus or minus a CD20 monoclonal antibody. Zanubrutinib is not approved for CLL; that’s another BTK inhibitor that recently got approved for mantle cell lymphoma. Stay tuned; there are lots of data in CLL as well, so we’re awaiting the approval of zanubrutinib in CLL. Of course, recently we had the venetoclax BCL2 inhibitor in combination with obinutuzumab, and that’s also now approved in the front line. There are many options for our patients with chronic lymphocytic leukemia in the untreated patient setting. In frontline therapy, there different options to discuss with them.

In the relapsed setting, of course, there are more therapies, including PI3 kinase inhibitors, which are approved in the relapsed setting so patients have multiple options of therapies. In the relapsed setting, of course, part of that will be dependent upon therapies they might have gotten in the front line: Did they have any toxicities to those therapies? What are their disease characteristics now? There are different things we can talk about that play into how we choose now that we have multiple therapeutic options for our CLL patients.

The survival for CLL, given these novel agents, has dramatically improved, and that’s an important point for patients to take home. These novel agents have drastically improved the survival for patients with CLL. There are still some important things to consider when we look at patients for treatment and their prognostic markers, including their cytogenetics and fluorescence in situ hybridization, will help guide selecting the therapy. Also, there are differences in their prognosis based on some of their features, and the immunoglobulin heavy-chain variable region gene mutational status is also an important feature that we check on patients.

The reason we consider these factors important is because selection of therapies is really based on some of these markers. If somebody has a 17p or a 

 mutation, you’re going to go to a novel agent, and that is very important. Thankfully the survival of those individuals has dramatically improved as well compared with the era of chemoimmunotherapy. We all would agree that for patients with a 17p or a 

 abnormality, these are patients who should receive a novel agent. Our longest data happens to be with BTK inhibitors in this subgroup, but certainly there are data for venetoclax-based combinations as well in this poor prognostic group of patients. That’s an important factor to know about prior to treating your patient because you would select, and let’s say chemoimmunotherapy or chemoimmunotherapy alone is not an option here—meaning you’re on a clinical trial that combines chemoimmunotherapy plus a novel agent. That would be fine, but it has to be a novel agent for patients with that feature.

Also, when we look at unmutated patients, certainly we’re going to move away from chemoimmunotherapy for unmutated folks as well. Again, checking the mutational status is important and knowing that because then you might decide to say we’re not doing chemoimmunotherapy. Remember, some of our patients who may otherwise seemingly have what we think is a good prognostic marker, like a 13q deletion, if they are unmutated, we would not give them chemoimmunotherapy. We would put those folks to a novel agent or a novel agent plus. Prognostic markers are still very important to obtain in our patients.

Remember, patients can change their chromosomal abnormalities if they have had therapy already in the front line. You’re going to want to check them again prior to their next subsequent therapy. If they now acquire a 17p or a 

mutation, that would be important to note. Prognostic markers are important, and we need to utilize them to learn more, particularly knowing that the patients have done so much better and their survival has improved dramatically and are akin to better players. That’s important. Getting these data is important, but they also help us select therapies for our patients given the multiple therapies we now have for our CLL patients.

Advances in Frontline Therapy for CLL

 Something that has changed over the past 4 months is the COVID-19 [coronavirus disease-2019] experience—dealing with COVID-19 in our medical centers, our institutions, and in our patient population. I think Dr Shadman and Dr Allan probably have more experience than Dr Burke and myself in terms of treating patients who are COVID-19 positive, being in Seattle and in New York City, respectively. 

I would like to hear a little bit from each of you in terms of how you are managing patients in the watch and waits, particularly thinking about COVID-19. Do you do different things for patients with CLL [chronic lymphocytic leukemia] in the COVID-19 era that you didn't do previously? What has been your experience with COVID-19 in the last several months?

 This is a very dynamic situation. The prevalence of COVID-19 is changing. When we were in the peak of the pandemic, we made decisions consistent with what had been published by different expert groups. In general, for patients who are in the watch and wait period, most of the time, conversations about starting treatment are not overnight conversations. We usually have weeks or months before we start a patient on treatment. With that, a lot of patients who need treatment can wait, and the treatment could be delayed for weeks or months.

For example, if the patient has a low blood count, such as thrombocytopenia, but not at a high-risk level, we would be able to monitor that patient closely. We utilize local labs for these patients, for patients who come from areas that are far from our center. We use telehealth platforms and telemedicine to talk to them and review their lab results. This has been our practice in the past few months. As things are changing and as we passed the peak, we are starting to slowly go back to our normal practice.

There are patients who need treatment, and I think it is important to emphasize the fact that it is always important to make sure that we can offer treatment to patients who need it. Unfortunately, we have had a few patients who were not referred in a timely manner or decided to wait until the end of the pandemic. As a result, we had a more complicated situation in terms of starting treatment. For patients on treatment, especially those on novel agents, if they have a stable disease and there were no adverse effects, we try to minimize their visits by utilizing telemedicine and local labs when possible. Most of the time, if they receive intravenous therapy, for example, using monoclonal antibodies in combination with some of the novel agents, most of the time those treatments can be skipped or delayed, and we've been doing that.

Really, the strategy is to minimize the patients’ exposure to the health facilities and help them practice the physical distancing that we are advising them to do.

Impact of COVID-19 on Management of CLL

 titled “Evolving Therapies in Chronic Lymphocytic Leukemia.” I am Dr William Wierda, from The University of Texas MD Anderson Cancer Center in Houston, Texas.

Joining me today for this discussion are my colleagues Dr John Allan, assistant professor from Weill Cornell Medical Center in New York City; Dr John Burke, associate chair at US Oncology Hematology Research Program at the Rocky Mountain Cancer Centers in Denver, Colorado; and Mazyar Shadman, associate professor from the University of Washington Fred Hutchinson Cancer Research Center in Seattle, Washington.

Today we're going to discuss a number of topics pertaining to first-line therapy for CLL [chronic lymphocytic leukemia] as well as second line and therapies for relapsed/refractory CLL. We’ll discuss the latest research in the field, including updates from the ASCO [American Society of Clinical Oncology] 2020 Virtual Meeting, and the impact of recent clinical trials on making treatment decisions for your patients. Let’s get started on our first topic. We’ll start from the beginning, and that is initial diagnosis and initial work-up for our patients. We’ve seen a revolution in therapies, and we’ll get into that, but let’s start from the beginning and talk a little about the initial work-up and what we’re doing initially for patients in the watch and wait time. We’ll start with you, Dr Shadman. In terms of initial work-up, what's your standard work-up for patients, including the prognostic factor profiling, and how do you use this information?

 After making a diagnosis for a patient with CLL, usually what happens between a physician and a patient is we talk about some of the prognostic markers that are relevant for CLL and mainly we use them to decide on the best treatment option. Having that information at the time of diagnosis does not necessarily change the plan. In some patients, who may be high risk for the disease, we may decide to have a closer follow-up. Usually, based on the conversations, some of the patients decide to have access to the information at the time of diagnosis, and others decide to have it only when there is a need for treatment.

With the novel agents that we have access to these days, there is a lot of research going on to utilize those drugs earlier in the course, maybe soon after diagnosis. Because of that, having the prognostic information is becoming more relevant even earlier, and maybe even at the time of treatment. For example, from the chemoimmunotherapy era, we know that early intervention, starting treatment doesn't really benefit the patient in terms of helping them live longer, which is the ultimate goal, especially in that space. In the past few years, we have been studying our novel agents in high-risk patients at the time of diagnosis, and unless we have the prognostic markers in hand, we would not be able to offer those trials to the patient. In my practice, I have started having a more serious conversation about the importance of having those markers in patients who are defined as high risk. We may be able to offer them some treatments that are designed for high-risk patients earlier in the course of disease and before they meet the standard criteria for treatment.

: We always start with the FISH [fluorescence in situ hybridization] and karyotype. That’s the most important prognostic and predictive panel to have for a patient with CLL. We have a molecular panel because having information regarding the 

 mutation specifically, and then a CLL-specific panel, is part of our work-up. If we offer chemoimmunotherapy to the patient, then we will need the information regarding the 

 [immunoglobulin heavy locus] mutational status.

In short, I would say the chromosome analysis, the molecular panel, and 

 mutational status are the standard basic panel that we would need for somebody to define their risk.

: It sounds like those are important when you're thinking about treatment. Do you routinely get them at initial diagnosis when you're in the watch and wait phase?

: Because we now have studies that are targeting high-risk patients at the time of diagnosis or within the first year from the time of diagnosis, we need to know which patients are high risk, so we have those conversations. If patients are interested in potentially participating in those studies, then we perform the tests at the time of diagnosis. But absolutely, if they don't have that information and when it is time for treatment, we would definitely need to perform those tests.

: That hasn't really changed that much, I think, over the past several years.

John Allan, MD, Weill Cornell Medicine

Articles

Selecting First-Line Therapy for CLL

Advances in Frontline Therapy for CLL

Impact of COVID-19 on Management of CLL

Initial Work-up for Chronic Lymphocytic Leukemia