 A question that comes up all the time is a BTK [Bruton tyrosine kinase] inhibitor plus or minus a monoclonal antibody. We’ve seen mixed data that in some of the studies, adding rituximab to ibrutinib didn’t really look like it enhanced anything to ibrutinib monotherapy. We’ve had data looking at acalabrutinib and obinutuzumab, and that looked as though there may be more enhancement in that. Of course, there are no head-to-head data. but certainly I think 1 option is that many of us will use BTK monotherapy; however, I do think there might be some subtle times where using a CD20 monoclonal antibody could have advantages: If somebody has autoimmune cytopenias that are really prevalent initially upon starting therapy, and you want to calm that process down and add in the BTK. There are different ways where monoclonal antibodies are still very useful on our patients, but we don’t have conclusive data that adding a CD20 monoclonal antibody necessarily to a BTK inhibitor has improved survival or progression-free survival greater than just a BTK inhibitor alone. That’s something to consider.

When talking about comorbidities of our patients, like cardiac issues with our BTK inhibitors, obviously the second-generation BTK inhibitors such as acalabrutinib and zanubrutinib are being studied, and there are more when you’re thinking about anticoagulation and antiplatelet agents. Obviously, head-to-head data are still pending, meaning these studies are enrolled. One is closed to accrual, and that’s the ibrutinib versus acalabrutinib in high-risk, relapsed patients with CLL [chronic lymphocytic leukemia]. Data are still pending about second-generation BTK inhibitors decreasing frequency of adverse events, such as the cardiac issues, bleeding issues, and hypertension. We have lots of data on acalabrutinib, not head-to-head but suggesting that the adverse events may be less than ibrutinib. The head-to-head data are really what we’re all looking for, to really see if there’s decreased frequency.

If you’re considering a BTK inhibitor with your patient and you’re worried about some of these issues, many folks are prescribing the second-generation BTK inhibitors over ibrutinib. Again, I’m waiting for the head-to-head data to see because now you have more than 1 BTK inhibitor that you can choose for your patients.

When we’re talking about the venetoclax-obinutuzumab combination, it’s risk stratifying your patients to see if they have low, moderate, or high risk for tumor lysis and taking strategic measures to mitigate for tumor lysis syndrome. Certainly, if you have an older patient, maybe some borderline renal insufficiency and maybe moderate or high risk, hospitalization is something to consider because you really want to monitor for tumor lysis and protect those individuals because it’s very treatable.

Those individuals are going to require treatments to monitor for uric acid and electrolyte abnormalities more frequently than patients who are not getting a venetoclax-based combination. You’ve got to take that into consideration. The advantage of that is that there’s a time-limited duration of therapy for using venetoclax-obinutuzumab. Those discussions need to be held with your patients, and the comorbidities need to be taken into consideration.

In terms of chemoimmunotherapy in the frontline setting for patients, we still discuss the data that have come out from The University of Texas MD Anderson Cancer Center and others looking at that long-term tale of patients with the 13q deletion, who are mutated, with favorable disease characteristics, who may be in remission long term after chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. That’s still a discussion in that patient population. Many patients have clearly moved away from outright chemoimmunotherapy given the adverse-effect profile that we’ve seen with chemoimmunotherapy, but it’s still a discussion in that unique subgroup of patients who have favorable disease. I don’t necessarily throw that entirely out of the water, but most of my patients don’t choose to receive chemoimmunotherapy very frequently anymore given all these new agents that we have. We see less use of chemoimmunotherapy in our CLL patient population.

With regard to our high-risk patients as discussed previously, like the 17p, 

, complex karyotype, although unmutated—they’re higher risk than the mutated, but your choices are a little broader. When we talk about the 17p or 

 patients, the longest data we have are with BTK inhibitors. For up-front, untreated patients, I still favor a BTK, but there are very good data for venetoclax. The question many of us are still grappling with is because the venetoclax-based combinations are time-limited duration, in those high-risk patients such as the 17p or 

, such as venetoclax-obinutuzumab, the duration of therapy is 12 months, are we comfortable stopping at 12 months for those patients? That’s where we’re still looking for longer follow-up and longer data. I still preferentially will put my 17p/

 patients on a BTK inhibitor up front and continue for monotherapy. But it doesn’t mean that the venetoclax-obinutuzumab combination wouldn’t be adequate, because we obviously have very good data that that drug works very well in these high-risk patients. The stopping versus continuation of venetoclax, for example, is something that we don’t have enough follow-up on those high-risk individuals. Are you comfortable taking those patients off after the end of their time-limited duration, whether that’s in front line or if you’re doing this with venetoclax–rituximab in relapse à la the MURANO study? Are you stopping at 2 years of therapy? I tend to keep my patient on chronic therapy if they’re high risk in that sense, but the data are still pending.

Videos

Frontline Treatment Options in CLL

 Indications for starting treatment haven’t changed recently, so we’re still using those indications that we used for many years, which are aggressive anemia, progressive thrombocytopenia, or disease-related symptoms that we want to go away and that are impacting the patients' quality of life. John Burke, maybe you can help us understand how you think about prognostic factors and how they're useful in terms of selecting first-line therapy. What are the things that you're thinking about when you're assessing the patient and deciding on first-line therapy, in terms of the prognostic factors?

: I think for the prognostic factors—some of them we’ve already discussed—I go through the CLL-IPI [chronic lymphocytic leukemia International Prognostic Index], of which one of the factors is age. The older the patient, that's an adverse factor. The more advanced the stage, the farther along the disease is. I look at 

 mutational status, which seems to be the most important as a prognostic factor with chemotherapy. I look for 17pdeletion and other chromosomal abnormalities on the FISH [fluorescence in situ hybridization] panel, and then on the next-generation sequencing panel, I look at the 

Those are things I look at. There is this formal CLL-IPI score that one can calculate. I confess I don't often actually do the math, but I look at those factors when I'm thinking through the patient and his or her prognosis.

: In terms of thinking about options for first-line therapy, we've had chemoimmunotherapy for many years now. We have BTK [Bruton tyrosine kinase] inhibitor-based therapy. We have BCL2 inhibitor-based therapy. Help me understand a little bit about how you select which treatments you're going to use, because we know and we’ve known for many years that agents work best in the front-line setting. Therefore, the response rates with a BTK inhibitor are going to be higher and the progression-free survival is going to be longer for a BTK inhibitor, for example, when used in the front-line setting compared to the relapsed setting.

Selection and choice of first-line therapy is an important decision to make for patients. We have options, and we have a lot of data to support what our decisions are. We have differing opinions in terms of how to prioritize and how to select front-line therapy. John Burke, we'll start with you, and maybe you could just highlight what are the factors that help you select for a BTK inhibitor versus a BCL2 inhibitor versus chemoimmunotherapy.

: I would say for most patients, the choice comes down to a BTK inhibitor versus BCL2 inhibitor, venetoclax-obinutuzumab combination. The exception where it becomes even more complicated, I would say, is the younger, fit patient who has favorable risk factors, that is, mutated 

 and lack of any adverse factors on FISH and lack of a 17p deletion and 

I think the reason is that that group of patients seems to have a particularly good outcome with FCR [fludarabine, cyclophosphamide, rituximab] and chemotherapy. As you and your group have shown, potential for significant percentage of those patients treated with FCR to continue to be disease free well beyond 10 years now, so that's a group that seems to get particular benefit from the FCR regimen. In that group, I think the FCR regimen or something similar to that still comes into play as an option.

For most everyone else, the choice in my mind is probably going to be a BTK inhibitor versus venetoclax-obinutuzumab. How do you choose between those? Honestly, it doesn't have as much to do for me with the disease, the biology, the gene mutation, etc. A lot of it comes down to other factors related to the patient and the patient's preferences. For example, venetoclax-obinutuzumab is a 1-year, fixed-duration therapy. That's a big difference from indefinite therapy with a BTK inhibitor. That factor of the different duration of therapy comes into play in that discussion. Other factors like the presence of underlying cardiac disease, atrial fibrillation, or use of an anticoagulation therapy really is going to knock BTK inhibitors a little bit to the side because of their toxicity profile. That's going to help make the decision. For the patient who doesn't have the obvious contraindication, it comes down for me to patient preference. As Dr Shadman said, it's really a long conversation over a period of many visits, often weeks or months, and sorting out what works for the individual patient. So, that's how I approach it.

: So it is highly individualized, and it sounds like you engage the patient quite a bit in the decision.

Selecting Frontline Therapy for CLL

 Let's hear a little bit from Dr Allan in terms of what his experience has been in regard to COVID-19 [coronavirus disease of 2019], if it's been any different, and if he has any helpful suggestions or recommendations for us.

: Absolutely. So, obviously, this is an evolving time that we live in now. I think we have to prepare and expect that COVID-19 is here to stay; it's not going anywhere anytime soon. Essentially, we have to prepare for that expectation for our patients. In my experience, obviously this is a devastating disease. This is something that we do not want our patients to get. We do know there is emerging data that chemotherapy patients, cancer patients on therapy in general are at a higher risk for poor outcomes.

We know that our patient population, being older in general, has already one of the major risk factors for severe complications from the disease. We really have to do our best to protect them, and 1 way is encouraging social distancing, the mask, the hand hygiene, and really reiterate that. We know from health care workers that if you practice these very basic things, you can decrease your infection rate. I think that's important to get across to our patients as well as to our physicians. I think that's more recognized in our system.

With our patients with CLL [chronic lymphocytic leukemia], I have found when we are in this exponential phase, this is not a time when you want to be initiating treatment on a patient, for all the factors that Dr Shadman had spoken to about—minimizing interaction, the immunosuppressive effects of some of these treatments. Essentially if you have a watch and wait patient, you want to push them toward telemedicine, minimize labs, and schedule local labs where patients can avoid public transportation.

Obviously, if you have a very sick patient and they need to initiate treatment, you do have to make some decisions, but I think we are fortunate to have many options. BTK [Bruton tyrosine kinase] inhibitors are a great option for patients that need to get out of trouble. You can start a drug, sometimes you can have it delivered, and it has low toxicities. Then, you can do video visits with them, see how they're feeling, and get local labs at 2 weeks or a month later. That's a great way to get somebody out of trouble who needs treatment in that situation. There’s a VenG [venetoclax + obinutuzumab]-based approach when you need to ramp up, and there's obinutuzumab, an anti-CD20 monoclonal antibody, and frequent hospitalizations, so it's probably not ideal.

So, I think it's region specific. What I found now where New York has gone back to normal. We have low infection rates. We have low daily admission rates. I think in New York State, we only had about 30 total hospital admissions in the last day or so. If you look at our curve, we are maybe in total a couple hundred new coronavirus diagnoses a day. At this point, we are in a window of opportunity that at least in New York, we can go back to our previous thinking and reasoning for specific patients.

At this point in time, if there is a good patient that is eligible for a VenG-based approach, I'm not so scared to do that, though I think it's going to be region specific. If you're in a state or city where you're seeing increases like we are seeing in some of our states currently, where you’re increasing and even in an exponential phase, we don't know when that's going to bottom out. I can say that we are at high risk for having serious issues in some of those places where you don't want to be initiating treatment. It's all region specific. It's patient specific. If you can wait until you're on the downswing and the situation is better controlled, it's best to do that. Obviously, if you are in a situation where you need treatment and you are in a place where there are increased cases of this disease, discuss with your doctor, and maybe a BTK inhibitor approach is probably a little bit easier and more likely indicated.

We don't have any evidence right now that patients with anti-CD20 therapy or specific treatments have worse outcomes or more severe outcomes. I can tell you from just personal experience, I've had patients get sick that have had anti-CD20. They have gotten over it and took a little time to clear, but then they finally have developed antibodies and have cleared the disease. This is while being on a BTK inhibitor plus an anti-CD20. The anti-CD20 for several months prior and was done. They had severe complications, but they had other risk factors—hypertension, renal insufficiency, and some of these things that we get concerned about. I’ve had patients in their 70s who are on a BTK inhibitor but are relatively healthy, get the disease, and have very mild, minimal symptoms. I’ve had other patients on watch and wait have very mild, minimal symptoms. I've had people on watch and wait get hospitalized but not ventilated. I've also had many patients with CLL just properly doing infection control, social distancing, not even get the disease.

I want to reiterate to patients and other physicians out there that just because the patient with CLL is going to get sick does not mean he or she is going to have horrible outcomes, though they are at risk for those things. I think that over time, we're going to start to understand what types of treatments may put patients at risk.

In reality, I think what we've shown time and time again from just patients with COVID-19 that age, hypertension, kidney disease, diabetes, obesity, pulmonary disease are the things what really come together in a perfect storm, this inflammatory basal state that the patient has that tips over. Patients are dying from this inflammatory overwhelming condition that occurs with the virus that we haven't seen before and are still trying to grapple with and understand.

So, complicated answer to a tough question, but I think what the important take-home is: Watch your region. Watch the state you're in, and if you are in one of these places where it's not well controlled and it’s in an exponential, taking-off phase, you have to be careful and really think about your approach. If you’re in an area that is past that point, like we are in New York, I'm starting to tell my patients that it's safer to reengage with society. I'm now starting to think that my previous reasoning, if I thought that patient would benefit from a VenG-based approach pre-COVID-19, I'm comfortable doing this. I feel like there's a window of opportunity, though that could change in 3 months if we start to see a second wave. You just have to pay attention to your caseload and where the virus is specific to your region.

 I would agree. My thought has been that our patients are in tune to social distancing already, even before COVID-19, and they have good hand hygiene, which may have reduced the risk. But we haven't here seen that a diagnosis of CLL puts patients at an increased risk more so than any other factor that we already know about. Has that been your experience, John?

 Our patients are immunosuppressed at baseline, and when we see our numbers and look at some of our data—I know there'll be data emerging with larger cohorts coming out, I'm sure, by the ASH [American Society of Hematology] annual meeting and others in the near future—we do see more serious complications in this patient population than what we would for all patients. But I think, again, that also represents our patient population. They're typically older. They have underlying CLL. So, some of that is based in those risk factors inherently. I do think that they are at greater risk for complications, so with that said, it's not everybody. It's not the majority, and most patients can be OK. A minority don't have major problems. There is a middle ground that they get hospitalized but they're not on the ventilator and all these types of things. There's also that other quarter to maybe a third or whatever it is that we see in our own practice and in our own ICUs [intensive care units] that have had very serious complications. Some have survived. Others have passed away. But it is something that I agree that our patients are at higher risk for severe complications.

COVID-19 and CLL Treatment Initiation

 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.

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.

Initial Work-up for Chronic Lymphocytic Leukemia

Mazyar Shadman, MD, MPH, assistant member, Clinical Research Division, Fred Hutchinson Cancer Research Center, assistant professor, Medical Oncology Division, University of Washington School of Medicine, and attending physician, Hematologic Malignancies, Seattle Cancer Care Alliance, discusses the efficacy of venetoclax (Venclexta) in chronic lymphocytic leukemia (CLL).

The BCL-2 inhibitor is being tested in many hematologic malignancies. In multiple myeloma, the FDA placed a hold on all clinical trials examining the agent due to toxicity concerns. Although the hold on venetoclax has been lifted for certain trials, there is still no indication for it in the disease. The drug has also shown a lot of activity in mantle cell lymphoma (MCL) as a single agent and in combination, says Shadman.

In CLL, some high-risk patients have genetic abnormalities that make the CLL cells resistant to the normal death mechanisms in the cancer cells. Because venetoclax works by inducing apoptosis related to BCL-2—a protein that's highly expressed in CLL&mdash;high responses have been observed irrespective of risk status. The same principle applies to lymphoid malignancies, adds Shadman, specifically MCL. Venetoclax currently has an indication in CLL as well as acute myeloid leukemia, but its use may be expanded to other diseases pending further investigation.

Dr. Shadman on the Efficacy of Venetoclax in CLL

Mazyar Shadman, MD, MPH, assistant member, Clinical Research Division, Fred Hutchinson Cancer Research Center, assistant professor, Medical Oncology Division, University of Washington School of Medicine, and attending physician, Hematologic Malignancies, Seattle Cancer Care Alliance, discusses the phase III CLL14 trial in chronic lymphocytic leukemia (CLL).

At the 2019 ASCO Annual Meeting, the results of the German CLL14 trial were presented. In the trial, treatment-naïve patients were randomized to receive the combination of venetoclax (Venclexta) and obinutuzumab versus chlorambucil and obinutuzumab. The combination with venetoclax resulted in a significant improvement in progression-free survival versus the combination of chlorambucil and obinutuzumab. These data have since become the most important data in CLL since the 2018 ASH Annual Meeting, says Shadman.

The study served as the basis for the FDA approval of venetoclax in the frontline setting. The study was designed to include patients with comorbidities and patients who did not have perfect kidney function. However, the combination is approved for use in all patients with CLL. Although the study was designed for a specific subpopulation, every patient is likely to see a benefit from it, Shadman concludes.

Dr. Shadman on the CLL14 Trial in CLL

Mazyar Shadman, MD, MPH, assistant member, Clinical Research Division, Fred Hutchinson Cancer Research Center, assistant professor, Medical Oncology Division, Department of Medicine, University of Washington School of Medicine, and attending physician, Seattle Cancer Care Alliance, discusses fixed durations of treatment in chronic lymphocytic leukemia (CLL).

Last year, many patients would likely opt for a chemoimmunotherapy regimen as opposed to an oral drug like ibrutinib (Imbruvica) because it is a fixed duration of treatment, says Shadman. After approximately 6 months, patients could enjoy their remission off treatment, which could last for years.

Now, patients have the added option of considering a nonchemotherapy drug that gives them the opportunity of potentially having a fixed duration of treatment. However, this is not a guarantee because studies, such as CLL14 or MURANO, were designed to give venetoclax (Venclexta) in combination with a CD20-targeted antibody for 1 and 2 years, respectively. It is not yet known what happens after these patients stop treatment. In the phase III MURANO study, there are short-term data to suggest that patients who achieve a deep remission may be relapse-free for a long time.

Just the fact that the field can have conversations regarding the potential of getting patients to a treatment-free and disease-free timepoint is promising in and of itself, says Shadman. Not only is time-limited treatment important for a patient, but it is also significant for physicians and the health system. This opportunity was never possible with BTK inhibitors or PI3K inhibitors, as these drugs are not designed to induce deep remissions that could translate to long-term remissions. Venetoclax may change that, adds Shadman, although longer follow-up data are needed.

Dr. Shadman on Fixed Durations of Treatment in CLL

Mazyar Shadman, MD, MPH, assistant member, Fred Hutchinson Cancer Research Center, assistant professor, Medical Oncology Division, Department of Medicine, University of Washington, and attending physician, Seattle Cancer Care Alliance, discusses challenges with CAR T-cell therapy.

As with any other therapy, safety is always a priority, says Shadman; it does not matter if the therapy is effective if it is not safe. However, progress has been made in ensuring that the CAR T-cell products that are brought to market have manageable toxicities. Physicians are learning more about how to manage associated toxicities and how to decrease a patient’s risk of these toxicities, namely cytokine release syndrome and neurotoxicity.

From a practical standpoint, it is becoming a crowded space to bring new CAR T-cell products or combinations to, says Shadman. Having an FDA-approved CAR T-cell therapy is great, but it also makes it more challenging to bring a more effective product to market, he explains. It is a good problem to have, but it will slow down enrollment on clinical trials and research in terms of sequencing strategies because patients will be less likely to progress. Despite this, Shadman is confident that investigators will be able to overcome such challenges with the volume of research that is being done.

Dr. Shadman on Challenges With CAR T-Cell Therapy

Mazyar Shadman, MD, MPH, assistant member, Fred Hutchinson Cancer Research Center, discusses the future of venetoclax (Venclexta) in the treatment of chronic lymphocytic leukemia (CLL).

Venetoclax is a novel BCL-2 inhibitor that has demonstrated excellent efficacy in CLL, explains Shadman. When it comes to B-cell receptor inhibitors, physicians rarely see complete responses with minimal residual disease (MRD) negativity, notes Shadman. Though this may not be an issue for a patient who is receiving ongoing treatment, many patients express that they would like to discontinue treatment.

Treatment discontinuation is only possible if patients are able to achieve a deep response, explains Shadman. What is unique about venetoclax is the fact that it can provide very deep responses. Many patients tend to have a good response in terms of lymph node size reduction, and there are also those who demonstrate MRD in the bone marrow or in the blood. With longer follow up, venetoclax may allow more patients to discontinue treatment, notes Shadman.

Ongoing studies are combining venetoclax with the B-cell receptor inhibitors, namely ibrutinib (Imbruvica) and next-generation drugs, with the intention of eradicating disease in the bone marrow and inducing lymph node response. With the combination, physicians are hoping to induce a better and deeper response that may segue into more patients being able to discontinue treatment, concludes Shadman.

Mazyar Shadman, MD, MPH, Fred Hutchinson Cancer Research Center

Articles