Patients who do develop resistance to a BTK [Bruton tyrosine kinase] inhibitor, or patients who develop intolerance to one of these novel therapeutics, is something to discuss. For patients who develop resistance to a BTK inhibitor, studies with ibrutinib as well as with acalabrutinib identify that about 80% of the time, these patients have resistance mutations in 

 itself or downstream PLC-gamma2. Because of the similar mechanism of action and binding of ibrutinib, acalabrutinib, and zanubrutinib, it wouldn’t make sense to switch from ibrutinib resistance to acalabrutinib.

There are now several next-generation noncovalent BTK inhibitors that have different mechanisms of binding to BTK and can get around those resistance mutations. A couple of these noncovalent BTK inhibitors are ARQ 531 and LOXO-305. We will hear more data at ASH [the American Society of Hematology annual meeting] about noncovalent BTK inhibitors and their role in CLL [chronic lymphocytic leukemia] and SLL [small lymphocytic leukemia]. One of those studies for LOXO-305, in which the abstract will be presented, will include almost 100 patients with CLL or SLL, the overwhelming majority of whom had previously been exposed to a BTK inhibitor. We will see what the safety and the efficacy look like in these patients who have been already exposed to a BTK inhibitor, especially for those who have been exposed and are resistant to prior BTK inhibitors, because these next generations of BTK inhibitors could overcome that either in monotherapy or in combination.

In terms of novel cellular therapies and the role of transplant for patients with CLL, one of the important points for transplant is that the patients have to be in a good response or certainly not with any kind of progressive disease to be able to benefit from that.

In the past couple of years, we’ve heard about CAR [chimeric antigen receptor] T-cell therapies for patients with CLL and SLL. At ASH we’ll hear about a cohort of patients who are receiving ibrutinib as they receive the CAR T with a product called liso-cel [lisocabtagene maraleucel]. It looks like the safety profile in terms of initial adverse effects is similar, and the hope is that it also helps in terms of responses in other CAR T-specific adverse effects, such as cytokine release syndrome or neurotoxicity.

Another thing in terms of unmet needs is for our patients with CLL or SLL who develop Richter transformation. This is usually defined as CLL that evolves into a more aggressive lymphoma, most commonly a diffuse large B-cell lymphoma. The outcomes for patients who develop Richter transformation, historically, are very poor. In the era of novel agents, patients who develop Richter transformation while receiving a novel agent, such as ibrutinib, acalabrutinib, and venetoclax, potentially have even more inferior outcomes. This is an important area to target for patients, and there are 2 ways. One is understanding what causes Richter to try to prevent it, and secondly, if it does happen, advocating for clinical trials that look at these patients and offer options.

In terms of trying to prevent it, we still need to look at who our highest-risk patients are and how do we change our approach to these patients. Do these patients require earlier intervention before the typical case? If patients have 

 aberrations or high-risk CLL IPI [International Prognostic Index] scores, how can we, in clinical trials, look at whether treating these patients earlier maybe prevents things down the road, such as resistance or Richter transformation, which is so difficult to treat once it occurs? There will be a SWOG Cancer Research Network-like cooperative group study looking at the role of early intervention in patients with high-risk CLL or SLL. So we should be looking to that and thinking how that can help our highest-risk patients potentially from the very start.

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Relapsed/Refractory CLL Treatment: Addressing Unmet Needs

In terms of what the remaining unmet needs are for patients with CLL [chronic lymphocytic leukemia] or SLL [small lymphocytic leukemia], now that there are several novel agents that have been approved and others are far along in development, there a couple of areas to discuss and also ongoing clinical trials to address some of these areas of unmet need.

One of the areas, in terms of unmet need for patients with CLL or SLL, is for patients to be able to receive a therapy that’s going to eliminate as much disease as possible up front with a novel therapy-based approach such that you can accomplish 2 things. If you can eliminate more disease up front, especially for young patients or patients with high-risk disease markers, it may prevent subsequent development of resistance or progression down the road. The other reason for trying to achieve a greater degree of depth of response in the frontline setting is that it potentially enables time-limited therapy, meaning patients don’t have to be on the novel agents for years where they could be at risk for development of intolerance or of resistance.

How we measure depth of response is certainly beyond going into full detail here, but often you’ll hear the terms undetectable minimal residual disease [MRD], or measurable residual disease, and how can that be used as a target in CLL or how we use the results of MRD to inform our therapy choices. There are a few clinical trials looking at combination, novel-novel inhibitor combination, to achieve undetectable MRD, or to look at the role of undetectable MRD in the treatment of patients with CLL. One of these is the CAPTIVATE clinical trial, which is a combination trial of ibrutinib plus venetoclax. Patients receive the ibrutinib for the first 3 cycles, and venetoclax is added in subsequently in combination. This study was designed so that patients, depending on their MRD status, at the end of that 1 year of combination, they’d then be randomized among their cohort. The cohort that met the undetectable MRD were randomized then to continue on ibrutinib or to receive a placebo. The patients still with detectable minimal residual disease would be randomized between ibrutinib or the combination to continue with ibrutinib and venetoclax.

The data that we have available published online with the ASH [American Society of Hematology annual meeting] abstracts will be reporting on the MRD cohort, that is the patients who were part of the cohort to randomize based on whether they met the undetectable MRD. As part of this trial, there is a cohort that wasn’t reported on yet that were time-limited therapies. Of the patients in the MRD cohort who reached undetectable MRD, at the initial date of reporting, there doesn’t seem to be a difference in the duration of response a year after for patients who had been randomized to get the placebo, so functionally stopped therapy versus continue on the ibrutinib.

This is interesting because, so far, it looks like that combination of ibrutinib then adding in and receiving ibrutinib plus venetoclax, has high undetectable MRD levels at the end of that 1 year. But also if patients do achieve that, they seem, at the follow-up we have available, to be able to continue functionally off therapy versus continuing on the ibrutinib. This will be an interesting study for just the MRD cohort and later to be able to look at the time-limited therapy cohort, all of the correlatives, and how MRD will be incorporated.

The trial, though it addresses the unmet need of trying to achieve deeper response and the role of that, the MRD testing outside of clinical trials is still not a standard of care for all patients with CLL. For some patients, it may not ultimately be the goal. Some patients can do well on BTK [Bruton tyrosine kinase] inhibitor monotherapy for many years. It’s an important reason to do clinical trials, but not that it’s standard of care that all patients with CLL should be getting the MRD testing, at least not by the data we have available so far.

Another thing in novel-novel therapy combinations to meet these unmet needs, is asking in the frontline setting: which is superior, for patients to do continuous therapy versus a novel-novel therapy combination and potentially achieve undetectable MRD and be able to stop therapy?

There are 2 randomized studies, they’re somewhat complementary. They are ibrutinib plus obinutuzumab with or without the addition of venetoclax, and there are 2 cooperative group studies. The study for patients younger than age 70 is time-limited in the combination cohort. Patients are either randomized to ibrutinib/obinutuzumab or ibrutinib/obinutuzumab plus venetoclax. If they’re in that plus venetoclax arm, that is a time-limited therapy. Information is collected on patients being able to achieve undetectable measurable residual disease at the end of that combination, but decisions of continuing on therapy after that, it is a time-limited therapy.

The complementary study is the Alliance study for patients older than age 70, and it’s the same drugs and randomization, either ibrutinib plus obinutuzumab versus ibrutinib, obinutuzumab, plus venetoclax. In this setting, after the combination in that novel-novel combination arm, the achievement of undetectable MRD then determines patients’ subsequent therapy.

The unmet need here is, for different groups of patients, which is better, the continuous therapy versus novel-novel combinations? Though undetectable MRD might be higher with novel-novel, these studies will help to look at other complex things like, does it increase toxicity, does it increase toxicity in a certain group of patients? This will help address multiple questions that are ongoing. In terms of novel-novel, those first studies incorporated ibrutinib, as ibrutinib was the first BTK inhibitor approved in the front line. But there are also novel-novel combinations with or without anti-CD20 antibody with other BTK inhibitors, such as acalabrutinib as well as zanubrutinib. These are important to point out because all covalent BTK inhibitors are not the same. Without these trials, we won’t learn other important factors like intolerance or adverse effects when used in these combinations. We’ll look to these studies as well to see potentially the difference of the BTK inhibitors.

Frontline CLL Treatment: Addressing Unmet Needs

One question that sometimes still comes up is, what’s the role of cellular therapy for patients with CLL [chronic lymphocytic leukemia] or SLL [small lymphocytic leukemia]? Historically, allogeneic stem cell transplant has been difficult for patients with CLL or SLL because of both the short- and longer-term safety adverse effects for patients. With the relapsed and refractory setting, it is important to remember that allogeneic stem cell transplant best outcomes occur for patients who are already in a good response for whatever therapy. If a patient relapses, even in their second or third or subsequent relapse for their CLL or SLL, they’re not going to be able to move immediately to transplant if they have measurable or clinically progressive disease. The role of transplant there can’t overcome the progressive or significant disease burden. Patients are going to have to go on another therapy to get their disease control.

This has been shown from prior transplant studies showing that transplant can overcome some of the high-risk markers, such as if patients have deletion 17p, or are complex karyotype, but it can’t overcome patients who are not in a good response prior to going to transplant. Those are the historical data, and then more recently there have been published data in the era of the novel therapeutics showing the same thing for transplant. Even though it’s small numbers, a transplant can still benefit patients after novel therapy if they’re in a good response. However, this is not if they have a significant amount of disease and certainly not if they have progressive disease going into the transplant.

There may still be a role for patients who are truly refractory, not just intolerant to the novel agent, but become resistant to novel agents and you’re getting them into a response. We still talk to them about the role of transplant, but they have to be getting into a response before discussing it, not using the transplant for patients with significant remaining or certainly not with actively progressive disease.

Allogeneic stem cell transplantation is the only potentially curative approach for CLL. It’s certainly for highly selective individuals, with an appropriate donor, the patient should have a low comorbidity index, and be young and fit. Given the risks associated with allogeneic stem cell transplant, you can have up to 20% mortality in the first 12 months, depending on patient donor and patient status. Considering that most patients with CLL are older, it is something that is falling out of fashion, given the newer therapies we have available. There is this retrospective series of allogeneic stem cell transplantation in the novel agent era, and it doesn’t seem that previous use of novel agents is detrimental. By novel agents, I’m saying BCL2, PI3 kinase, or BTK [Bruton tyrosine kinase] inhibitors, are not detrimental to the therapeutic use of allogeneic transplant for patients. Because most of the patients are enduring a very long disease-controlled period with the newer agents, we’re not doing as many allogeneic stem cell transplantations, but it’s still a valid choice for the right patient with aggressive disease. Particularly for patients who have Richter transformation, allogeneic transplant makes a strong case for that.

I don’t use transplant often in CLL. This is a real success of the therapies that have been developed, that we often don’t need to consider a transplant. That being said, there are some patients for whom I think about transplant. The people we do think about transplant for are the ones who are fit, young, being under 75 years old, active without significant comorbidities, who have progressed on most of the available therapies. Especially, I consider it for people with 

 deletion or mutation, who fit that profile otherwise of being an appropriate medical candidate for that procedure.

Allogeneic Transplantation for CLL

In terms of the relapsed and refractory setting one question might be, what is the importance of the traditional prognostic markers in CLL [chronic lymphocytic leukemia] in the relapsed/refractory setting if you just said in that setting, you’re going to want to choose a novel agent over chemotherapy anyway? The reason we do those tests for those patients, such as repeating FISH [fluorescence in situ hybridization], repeating chromosomes, and repeating 

 mutation status, is to identify how high risk those patients are to respond to that novel agent and remain in response and not develop resistance.

There are several studies now identifying that in the relapsed/refractory setting, patients’ risk of developing resistance to BTK [Bruton tyrosine kinase] inhibitors such as ibrutinib, acalabrutinib, or to venetoclax is much higher if they carry the high-risk 

 aberrations. Knowing that ahead of time, you might still elect to start them on that novel agent, but it might change how you think of sequencing them down the road or being prepared for what happens after you get a response to that novel agent. We need to be thinking about that ahead of time; that’s for standard therapies that are available. The other reason to identify those patients is if they’re high risk for resistance before you start the novel agent, knowing that may lead us to have clinical trials for these patients and be able to offer clinical trials and improve long-term outcomes.

Cytogenetics is important at any line of therapy in CLL. What we’re looking at mostly in the second-line setting is if patients have complex cytogenetics, 17p deletion, 

 mutation—11q deletion, not as much anymore. It depends on what they’ve received before, but certainly, 17p, 

 disruptions, and cytogenetics will be the most important.

 mutation in the second-line setting matters less. You’re not going to give chemotherapy to this patient. Venetoclax and BTKi [BTK inhibitor] work in an IgG unmutated population. I would expect them to have been checked in the frontline setting. In terms of prognostication if they haven’t been checked, I check in the second-line setting so we know what we’re dealing with, but that doesn’t impact as much as therapy choices. We are looking for 17p deletion, 

 mutation, complex cytogenetics, what prior therapy they received, how long they were on that, and if they had a response or not. If patients do progress on a BTK inhibitor, I do test for the 

mutation that leads to resistance of medication so that we know what we’re dealing with and what was the mechanism of progression there.

I am more concerned with the patients who progressed on those medications who don’t carry a mutation. It’s the biology of the disease, you should go with a different dose. The patients are more concerned about not responding as well to venetoclax. Whereas patients who do develop a mutation that is secondary to selective...from the BTK inhibitor itself, then those are the patients I expect to have the standard response to venetoclax because the mechanism of resistance is specific to a BTKi, at that point.

I do molecular testing at every subsequent line of therapy in addition to at the time of the patients’ first therapy. 

 mutations, in particular, are known to be high-risk markers. For a young patient who is very fit, I consider referring them to an allogenic stem cell transplant, not at the beginning of their therapy, but once they have been progressed on and been failed by a number of novel agents. These patients should meet with a transplant doctor to discuss the risk/benefits of that procedure. I do think it’s important to check that test again with subsequent lines of therapy for patients who aren’t already known to have the mutations because those can be acquired with time and with years of therapy. We know those patients do not have long-lasting responses to any of our existing therapies, and so they may benefit from transplantation, provided they are an appropriate medical candidate.

Relapsed/Refractory CLL: Repeat Molecular Testing

Because CLL [chronic lymphocytic leukemia] is not a curable disease, patients will eventually relapse. The question is what do we do once that happens? This would be defined by what patients received in the first-line or second-line setting. In general terms, we try to change the mechanism of action of the drug we’re giving in the relapsed setting because theoretically, they were either resistant or progressed to whatever they received in the frontline setting. When the patients do present with relapse, we need to remember that it’s not because they have relapsed disease that they need treatment. The criteria for treatment in the second, third, and fourth line are the same as the frontline setting. Patients may relapse, or never achieve full remission with the frontline therapy and stayed away for many years.

At the time the criteria are met for treatment to be reinitiated, then we need to remember to retest those patients for some cytogenetic abnormalities. We don’t need to retest for 

, that doesn’t change, whether it’s mutated or unmutated, because it’s the cell of origin. But certainly, we need to recheck for 17p deletion, 

 mutation because relapsed populations are more enriched for those abnormalities. They are dynamic and can change over time. You can have clonal progression. It’s important to know that.

It’s important to evaluate patients for the risk of high-grade Richter transformation and ensure that hasn’t happened. If their lymph nodes are larger than you would expect, if you have a PET [positron emission tomography] scan that has very hypermetabolic areas, consider a biopsy on those sites, ensuring that the patient doesn’t present with a high-grade transformation, which is not the most common scenario, but we need to exclude that anyway.

The next question after testing this, is what did the patient receive before? Has the patient received a previous BTK [Bruton tyrosine kinase] inhibitor, which is more frequent since it’s been on the market for a longer period? If yes, then next we’re going to try a venetoclax-based regimen, if they haven’t received that before. In the second line, if the patient had a BTK inhibitor [BTKi] first, I use venetoclax with a monoclonal antibody. Even though the MURANO trial used rituximab, I use obinutuzumab in the second-line setting based on the fact that it is a higher carrier of undetectable MRD [minimal residual disease].

I’m trying to use a fixed-duration treatment for those patients, and trying to achieve an undetectable MRD state would be ideal. In the second line, remembering we use venetoclax for 2 years rather than 1 year. If the patients do have 17p deletion or 

 mutation at that time, I will discuss it with the patients at the time of completion of therapy, when they’re approaching those 2 years, if it would be worthwhile for them to continue venetoclax beyond that time. Remembering that the initial trial with venetoclax for the population with 17p deletion was of continuous therapy, it was not a fixed-duration therapy. There are data to continue with the treatment, particularly remembering that 17p deletion was a predicator of progression in the MURANO relapsed trial. But if the patients don’t have this high-risk abnormality, I stop at 2 years.

If the patients have not received a BTK inhibitor prior, then we ask what they received prior. We have a number of patients who received chemoimmunotherapy before, and then we have the same discussion as in the frontline setting. Who will be better off having a BTK inhibitor versus a venetoclax-based regimen? If the patient had 17p deletion or 

 mutation, I usually go for a BTK inhibitor continuously. If not, then I can use venetoclax/obinutuzumab for 2 years.

We know, based on retrospective data that were presented at ASH [the American Society of Hematology annual meeting] in 2019, that you can salvage venetoclax-exposed patients who’ve progressed in third line or further but are BTKi naïve. You can use a BTKi at that point, and salvage to the tune of about an 80% response rate. The flip side is also true. If you used a BTK inhibitor for patients who have progressed, we can also salvage them with a venetoclax-based regimen. There’s going to be discussion about who should have fixed-duration vs nonfixed duration therapy, adverse effects, logistics, it goes back to the same discussion at in the frontline setting.

Patients who did receive a venetoclax-based regimen, stopped, and progressed, can receive venetoclax, you can rechallenge them. There are data showing that for those patients who did have an initial response, these are patients who have refractory disease or never responded or progressed while on venetoclax therapy. But for those who received it for a year and then started having progression a year or two later, it is reasonable to treat those patients again with venetoclax.

At that point, I would use venetoclax continuously. I wouldn’t stop it because the disease has already shown its face, progressing after discontinuation. But it’s certainly a reasonable approach, and then if they don’t have a response to the venetoclax, a BTKi will be used.

Very rarely, I use chemotherapy in a relapsed setting. We still have PI3 kinase inhibitors available if patients progress on venetoclax and a BTK inhibitor. Idelalisib and duvelisib have been approved, and there are others coming up soon. I prefer duvelisib because it is better tolerated. But then those are the patients we evaluate for clinical trials, CAR [chimeric antigen receptor] T-cell therapy trials, or even allogeneic stem cell transplantation if they have progressed through all the novel agents.

The biggest factor when thinking about sequencing of therapies in CLL is what did the patient get for the first line. There are plenty of patients who have been in remission for a while, they received chemoimmunotherapy 5 years ago as their frontline therapy. BTKi and venetoclax regimens are both very reasonable. We individualize that discussion with the patient to see which is more preferable to them based on toxicity profile and length of therapy. For patients who get a BTK inhibitor in the front line, I usually am going toward venetoclax-based regimens in first relapse. There are some patients for whom doing the tumor lysis monitoring is not feasible due to transportation issues or personal preference, and in those patients PI3 kinase inhibitors are reasonable. They are somewhat limited as far as their toxicity profile, but for the patient who prefers an oral-only regimen, that’s an option. I always discuss clinical trial options with my patients as well.

There was an initial concern about using venetoclax prior to BTKi because there weren’t a lot of data on whether the BTK inhibitors would work as well following venetoclax. I don’t have reservations with that, now we have a bit more data and the BTK inhibitors appear to work quite well following venetoclax. So I don’t have reservations in changing the sequence of therapy for patients who want to give a shot at a time-limited regimen and do the venetoclax before the BTK.

Therapeutic Sequencing in Relapsed/Refractory CLL

Helping to care for patients during COVID-19 [coronavirus disease 2019] has caused us to go back and look at our practices, evolve, and change them very quickly. We had to think about how that might have an impact on how we see patients, in person or telemedicine, how we conduct clinical trials, in guidance with national guidelines and institutional guidelines. When we have multiple therapeutic options, the pandemic has also affected which we choose for patients considering their risk in the short and long term. Notably, in the short term we consider how extra visits, infusions, or certain risk factors and exposures affect the patient who is high risk for COVID-19.

This has changed a lot since March here at Duke Cancer Institute and across the country. Like many institutions, there have been a lot of steps trying to protect patients as much as possible but also allow them access for the situations where we do need to see patients. We’ve seen patients who have come in for treatment where we identify that their exam or in-person testing is needed, but then we also identify patients who could have local labs and do telemedicine visits to prevent the travel as well as potential exposure within the institutions. Over the summer when things changed across the country and cases were going down, we tried to get some of the patients back in that had been telemedicine. As cases go up again, we’re shifting the patients to telemedicine where possible and safe for the patient.

This takes into account how long the patient has had their disease, what kind of therapy they’re on, etc. In terms of what type of therapy in CLL [chronic lymphocytic leukemia], because many of the novel therapies are oral, that has helped in many cases. However, if you’re talking about 2 treatment choices for that given patient in the short and long term, what is known about them is fairly equivalent. It has caused us to shift more toward trying to offer therapies that wouldn’t require as many visits, treatment room time, or added risk factors.

Since the pandemic started, it shifted how many patients were on telemedicine and how many come into the office. Between April and July, 35% to 40% of my patients were on telemedicine. Since August, the number dropped to about 10% to 15%. As we’re seeing a spike in the cases again, we’re transitioning more back to telemedicine. The majority of patients need to follow up with telemedicine, with a physical exam here and there. We can intermingle a bit. There are a number of our patients who need to be seen because of physical exam abnormalities or alterations that need to be discussed and addressed in person.

At the beginning of the pandemic, we were doing almost all telemedicine. There were a lot of unknowns at the time. Many of us hoped that the pandemic would have subsided. As time went on, the amount of telemedicine has declined. In my practice I started with almost all patients doing telemedicine, to limit exposure. About 6 to 8 months in, there were a lot of patients who wanted to come in person. There are things you can assess in person that you can’t over the telephone, such as a physical exam. Also, the doctor-patient relationship is different in person in the same room as opposed to over a video or phone. We have been deferring to patient preference, but we have made ourselves available. Some patients still feel safer doing videoconferencing, and some prefer to come in person. About a third of my patients are still doing telemedicine, and the other two-thirds come in person at this point in the pandemic.

We’re going to continue seeing some proportion of patients via telemedicine as long as COVID-19 is active. Some patients are extremely cautious, and I applaud them for that. There isn’t a completely right or wrong answer. UNC [University of North Carolina School of Medicine] has adopted safety protocols so it’s safer to come in person, but it’s never without risk.

CLL Patient Management During COVID-19 and Telehealth

In light of the pandemic, we have had a trend of doing more BTK [Bruton tyrosine kinase] inhibitors. The benefit of doing BTK inhibitors, which are oral-only options, is that there are fewer clinic visits and therefore less risk for potential exposures. That being said, we still initiate patients on venetoclax-based treatment approaches. If there are preferences for a time-limited regimen, it can be done safely. Now that we are many months into the pandemic, most institutions have adopted safety protocols such as universal masking and screening for COVID-19 [coronavirus disease 2019] symptoms. These make the visits safer than at the beginning, before we had these standard procedures established.

Outpatient initiation of venetoclax-obinutuzumab is feasible for many patients. There is a subset that will need inpatient administration, at least in this day and age, based on having a very bulky lymph node that doesn’t shrink enough in that 3-week OB [obinutuzumab] lead-in. Also, some patients have an abnormal kidney function that need close inpatient monitoring. It’s feasible, but it’s not always possible in every single patient based on those factors that can come into play.

The current role for chemoimmunotherapy has become slim with the adoption of all these novel treatment regimens that, in most cases, have superior efficacy. However, there is a select patient population in which chemoimmunotherapy can be considered, and that patient population, specifically young and fit patients, who have mutated immunoglobulin heavy chain mutation status. The reason that that FCR [fludarabine, cyclophosphamide, rituximab] as the main chemoimmunotherapy option is still reasonable, is that there have been long term follow-ups of the early studies that show over half of patients with that profile mutated 

 who get FCR [fludarabine, cyclophosphamide, rituximab] are still in remission. That is a great benefit to be able to be in remission 10 or 15 years out.

It also is with great cost, and FCR [fludarabine, cyclophosphamide, rituximab] is an extremely toxic regimen. When we have that discussion with patients who fit that profile, very few want to proceed with FCR [fludarabine, cyclophosphamide, rituximab] because of these long-term risks. The 1 that is most worrisome for patients is a risk of a secondary myeloid neoplasm, which occurs in 2% to 8% of patients getting FCR [fludarabine, cyclophosphamide, rituximab]; that’s a life-changing and often fatal complication. There is this benefit in that slim population of young, fit, mutated 

The optimal therapy for a patient with high-risk biologic markers depends on what the high-risk marker is. Let’s discuss an unmutated immunoglobulin because those patients can respond well to both BTK inhibitor up front and venetoclax-obinutuzumab. Those are both acceptable options for a patient who has unmutated 

Let’s contrast with the other very high-risk marker, which is the 17p deletion or 

 mutation. There is some concern in the CLL [chronic lymphocytic leukemia] community that time-limited therapy may not offer as great of a benefit as up front BTK in that subset. Those 2 have not been compared head-to-head, but when you look at the cross-trial comparison, looking at the 

-mutated or -deleted patients from CLL14, there is a 70% PFS [progression-free survival] at the 2-year mark. In contrast, when you look at the long term follow-up of BTK inhibitors, specifically of ibrutinib in patients with 17p and 

 deletion, it seems that their PFS is longer. There are motivated patients with 17p and 

 that’s acceptable to do venetoclax-obinutuzumab depending on what their goals are. If their goal is to have time off therapy, it can be considered. Discuss with them that based on somewhat limited data and nonrandomized data, the most likely longest PFS benefit that they would get is from a BTK inhibitor up front. It’s at the expense of potential toxicity and the need for indefinite therapy until progression.

CLL Treatment Approaches During COVID-19

In the frontline setting, the question of whether to choose a BTK [Bruton tyrosine kinase] inhibitor–based therapy or a venetoclax-based therapy becomes 1 of the longest and most challenging questions and counseling sessions for patients. We have these options available for patients, but as of today there’s no 1 clinical trial that randomizes and has long follow-up showing clear superiority of a BTK-based therapy vs a venetoclax-based therapy. Much of the data we take extrapolates from other frontline trials that have shown beneficial PFS [progression-free survival] of the monotherapy or combination with anti-CD20 of either BTK inhibitors vs chemotherapy or venetoclax-based regimens vs chemotherapy.

When you extrapolate for the superiority of the novel agents, and when talking to patients about BTK inhibitor vs venetoclax in the frontline setting, there are a couple of things to take into account. Tell them that it’s going to be a long conversation because in many cases there’s not 1 clear right answer. There is not a trial showing head-to-head superiority. Then use a number of patient-specific factors and disease-specific factors. In some cases, it may cause us to lean more toward BTK inhibitor–based therapy or venetoclax-based therapy.

When talking about patient-based therapy, look at their comorbidities. If patients have medications or cardiac comorbidities, they might be on anticoagulation or have AFib [atrial fibrillation] or at high risk for cardiovascular events. If you’re going to add a BTK inhibitor to that, it’s not completely contraindicated, but you might raise their bleeding risk or interaction. If they have those baseline factors, they can be at a higher risk for atrial fibrillation—at least from the studies—from ibrutinib. It’s not a complete contraindication, but this is an example of a patient-specific factor that might lead you away from BTK inhibitors.

In terms of things that can be concerning when considering venetoclax-based therapy, look at the adverse effects of venetoclax and the tumor lysis risk. If patients have bulky disease or have reduced renal function, that’s not a complete contraindication, but patients have to know the higher risk. That might require in-patient monitoring to be able to complete that therapy. Neither of which is a complete contraindication, but they are examples of how to look at patient-specific factors and counsel patients on those risks.

For disease-specific factors, CLL is heterogeneous in the markers and how patients present. Is it a lot of bulky nodal disease? Is it a marrow-based disease? How is their disease presenting? The other factor is checking up front for 

 aberration. That can be found either by deletion 17p when you do FISH [fluorescence in situ hybridization] testing or by looking for 

 mutations. The reason we check for that, as of right now, is just having a couple of years’ longer follow-up data with continuous therapy with BTK inhibitors, namely published data with ibrutinib. Often for patients with 

 aberrations, if they don’t have any patient-specific factors making us lean 1 agent vs the other, often we will consideration BTK inhibitor therapy for those high-risk patients.

What this highlights is that without clear answers and options for improvement, if we have clinical trials, then that’s what we favor in the frontline setting.

Frontline CLL: Treatment Algorithms

Minimal residual disease [MRD] in CLL [chronic lymphocytic leukemia] is a complicated and controversial question. CLL is not, in general terms, a curable disease. The holy grail is to allow patients to enjoy the longest possible time without the disease being active and causing symptoms, without the need for any treatment for the longest period of time. Since chemoimmunotherapy has been used, particularly FCR [fludarabine, cyclophosphamide, rituximab], the question of anywhere near minimal residual disease undetectability is never negative because there’s a threshold of detection of the tests.

MRD undetectability is a predictor of PFS [progression-free survival]; patients who have a deeper response seemed to enjoy a longer progression-free survival. This was shown initially in the CLL-8 trial of FC [fludarabine, cyclophosphamide]vs FCR [fludarabine, cyclophosphamide, rituximab]. In the University of Texas MD Anderson Cancer Center data set, patients who had MRD undetectability and were 

 mutated, over that long PFS there were some differences compared with patients who had detectable minimal residual disease.

There are some caveats to this because the way to test minimal residual disease is in the blood or in the bone marrow. You can eliminate the component of CLL in the bone marrow but not necessarily eliminate it in the molecular compartment. You can have a partial remission with an MRD undetectability. Based on some data from a couple of different trials, we know that there is a difference in patients who show FCR [fludarabine, cyclophosphamide, rituximab] with undetectable MRD. It is a strong predictor, but we have put everything into perspective and put all the data together to understand what’s going on.

In the MURANO data, which was venetoclax-rituximab vs bendamustine-rituximab, undetectable MRD was the main predictor of recurrence of disease, after discontinuation of therapy. Venetoclax in that trial was given for 2 years. For patients who did achieve undetectable MRD, it was done by real-time qPCR [quantitative polymerase chain reaction]. The lowest threshold of detectability was 10-4, 1 in 10,000 cells. For patients who had undetectable MRD at the median follow-up of about 10 months, 97.6% of them were progression-free. Patients who had what they call low-MRD positive, between 10-4 and 10-2, 87% were progression-free at 10 months postdiscontinuation of venetoclax. Patients who had high MRD up to true positivity of MRD, which was more than 10-2. Only 21% of patients were progression-free after 10 months postdiscontinuation; 78.6% of the patients did progress after discontinuation of treatment.

This showed that achieving an undetectable MRD status with that particular agent was important because the goal was to discontinue the therapy. Should the patients who have positive MRD at the end of the treatment continue on therapy or not? We don’t know the answer. They relapse a little quicker than the ones who are MRD undetectable. It does not seem that increasing length of treatment, particularly with a venetoclax-based regimen, increases the depth of MRD for these patients. If patients don’t achieve an MRD-undetectable state during the first 10 to 12 months, that’s not going to convert afterward. Transitioning to the frontline setting, looking at the patients who received venetoclax plus obinutuzumab, we know that obinutuzumab is a decent driver of MRD undetectability based on the results of the CLL11 trial. The levels of undetectable MRD were much higher in the obinutuzumab-chlorambucil arm than in the rituximab-chlorambucil arm.

In the CLL14 trial of venetoclax plus obinutuzumab vs obinutuzumab and chlorambucil, after 18 months they address the MRD state. Close to half the patients in the VenG arm [venetoclax, obinutuzumab] had undetectable MRD; it was 47.2%, and the level of detectability was 10-4; 13% had low MRD, between 10-4 and 10-2; 71.9% had high MRD, above 10-2. The real number we’re looking for is undetectable, less than 10-4. That’s 47.2% in the VenG [venetoclax, obinutuzumab] arm, whereas in the chlorambucil-obinutuzumab arm it was 7.4% undetectable MRD. In this trial after discontinuation of therapy, it seemed that patients who had undetectable MRD at the time of fixed duration enjoyed a longer progression-free survival.

That question comes into play with newer therapeutic approaches. We know that the use of BTK [Bruton tyrosine kinase] inhibitors as monotherapy doesn’t drive MRD undetectability as much. The levels of undetectable MRD, particularly with the monotherapy with BTK inhibitors, are lower. These patients are on therapy continuously, so is it important to achieve that for those patients? We don’t know for sure. But by combining novel agents—BCL3 inhibitors with the BTK inhibitor and anti-CD20 monoclonal antibody—with the intent of stopping therapy after a fixed duration of time, achieving undetectable MRD is of high importance. It may be the guide of therapy for those patients.

There are more data coming. Things are going to be updated at ASH [American Society of Hematology Annual Meeting], particularly in MRD undetectability for CLL. We understand the importance of checking for MRD, particularly for predicting the patients who may progress after discontinuation of therapy. Taking into consideration other disease states with the hematology malignancies—CML [chronic myelogenous leukemia] and ALL [acute lymphoblastic leukemia]—we’re looking for an MRD-undetectable state, and that does make the difference in survival. We’re certain that this will translate and speak to a significance in CLL as well.

Minimal Residual Disease in CLL

Fixed-duration therapy is attractive for several reasons. It’s desirable from a patient standpoint to not have to be on therapy indefinitely, and there are cost benefits given that you don’t have to pay that monthly co-payment every month. You pay it for only 12 months, for example. As an added benefit, should you have any toxicity from the regimen, there is a defined end point, and many of the agents that are given indefinitely can have toxicities that can persist over time. A fixed-duration regimen can give a patient a reprieve from many toxicities that may occur while on therapy. It also helps with well-being. Taking chemotherapy every day reminds one of the fact that they have cancer, so it can also restore a degree of normalcy to the patient’s life to have a break.

Resistance mutations are known to develop. In earlier trials of venetoclax, about half of patients if not more developed resistance to the drug usually at 2 to 3 years. Subsequent studies have shown that the main mechanism of resistance is acquired mutations in BCL2. What we know is that these mutations occur with prolonged exposure, and it’s feasible that limiting the exposure to these drugs may limit the development of these resistance mutations. This needs to be further studied by longer-term follow-up of these fixed-duration regimens.

The venetoclax-obinutuzumab regimen certainly is beneficial when compared with the chlorambucil-obinutuzumab regimen with respect to progression-free survival [PFS]. The difference between the ways that the regimen performs is the most notable for patients with unmutated 

. They have a very high advantage with respect to progression-free survival when comparing how they do with chlorambucil-obinutuzumab regimen. Other high-risk markers still perform well with the regimen, but it does appear that patients with 

 mutations or deletions may not have the same level of benefit as patients without those mutations. They still respond, but the degree of patients that attain that MRD [minimal residual disease] negative is lower than the overall population.

Venetoclax-obinutuzumab is different from the predecessor regimen that was used in the relapsed/refractory setting from the MURANO study of venetoclax-rituximab. The old way of doing venetoclax was you would ramp up and then add the CD20 afterward. Venetoclax-obinutuzumab in contrast has a 3-week lead-in of obinutuzumab, which is important to know. The 1 problem with this is that you can see obinutuzumab-infusion reactions, but the benefit outweighs that risk. Debulking can occur in those first 3 weeks, and patients who would otherwise have been at a higher risk for tumor lysis syndrome can actually have their risk downgraded because of that 3-week lead-in prior to the venetoclax subsequently starting.

Venetoclax-obinutuzumab is initiated most successfully and safely when it’s done with an experienced provider and team. At my own institution, we have a multidisciplinary team of myself, an excellent oncology-dedicated pharmacist, a nurse practitioner, and a nurse. This helps with patient safety to have an experienced team. It is important that there are good instructions on the manufacturer’s web page on how to initiate this drug safely. The key is stratifying the patient from the tumor lysis risk standpoint. The main tenants of that are knowing what their largest lymph node diameter is, which is from cross-sectional imaging and knowing what their absolute lymphocyte count is. You also need to know their renal function because even a patient of medium risk for tumor lysis, who has suboptimal kidney function, may be a patient who would be better served by initiating venetoclax in the hospital setting.

A decent portion of patients can get this—the venetoclax-initiated outpatient—after having their tumor lysis risk downgraded from the obinutuzumab. But you need to look at the numbers on the day of the venetoclax start to help determine that. Often the white blood cell count can come down with just that brief lead-in, which would then lead to a downgrading of the tumor lysis risk and potential outpatient initiation. The patient initially may have need inpatient had you started with the venetoclax by itself.

Frontline CLL Treatment With Fixed-Duration Regimens

In terms of BCL2 inhibitors, venetoclax is the approved agent at the moment. In the initial trials with venetoclax as a monotherapy for patients with a relapsed disease with 17p deletion and 

 mutation. Even as a monotherapy, BCL2 had significant activity there. The idea behind the use of venetoclax is to reinstate the ability of the CLL [chronic lymphocytic leukemia] cells to regrow apoptosis. BCL2 is an antiapoptoticmolecule, and by inhibiting that we allow the release of pro-apoptotic back into the cytosol of the cells. The efficacy signal seen in the phase 2 trials, the first venetoclax was combined with an anti-CD20 monoclonal antibody. In that case, the rituximab in the MURANO trial for relapse set disease compared with BR [bendamustine, rituximab], and it showed an improved PFS [progression-free survival] and overall survival in patients in that trial.

As the development of the drug was brought to the frontline setting the decision was made to combine it with obinutuzumab; another anti-CD20 molecule antibody. Obinutuzumab has been shown to improve in this trial to be superior to rituximab in CLL, particularly the CLL11 trial. Not only in terms of response but prolonged PFS and much higher rates of minimal residual disease negativity in those patients. The mechanism of action doesn’t cross. It is an antibody-dependent cell site of toxicity-driven monoclonal antibody. It also leads to some complement-dependent cytotoxicity and direct cell death. Rituximab does not drive that mechanism of action. It’s an interesting compound to combine with venetoclax, particularly in the frontline setting.

At the time that the frontline trial was designed, CLL14, the benchmark for comparison was chlorambucil and obinutuzumab, which was the benchmark developed from CLL11. Using the obinutuzumab in both arms certainly made sense. So, patients with untreated CLL were randomized to receive either chlorambucil for 12 months and obinutuzumab for 6 months vs obinutuzumab for 6 months and venetoclax for 12 months. The duration of therapy was the same, which is important because it gave a better benchmark for comparison, in terms of how long the disease was supposedly suppressed by a treatment. There were 432 enrolled patients through a randomized 1:1 and this included patients with high-risk disease 

-mutated disease. This year there was an update with the 39.6 months of follow-up presented at ASCO [American Society of Clinical Oncology annual meeting]. This study was first presented a year ago and then presented again this year with a longer follow-up. Progression-free survival was superior for venetoclax-obinutuzumab when compared with chlorambucil-obinutuzumab. That superiority was sustained in the updated data set. The median PFS for venetoclax-obinutuzumab was not reached, and the PFS for chlorambucil-obinutuzumab was 35.6 months with a very interesting hazard ratio of .31—a very statistically significant 

It’s estimated progression-free survival at 3 years in the venetoclax-obinutuzumab arm was 81.9% and the chlorambucil-obinutuzumab arm was 49.5%. This benefit was sustained across all subset group analyses, including high-risk disease, which was the question at the beginning. This improvement was also seen in the 

-mutated subset of patients. A previous study, iLLUMINATE, which used obinutuzumab with ibrutinib, compared with the same arm, chlorambucil vs obinutuzumab, didn’t show a superiority in the 

-mutated or lower-risk population. This was an interesting finding of the study, cementing the position of venetoclax-obinutuzumab as a solid choice for patients in the frontline setting. This includes patients with high-risk disease. However, for patients with high-risk disease, even though the PFS was superior when compared with chlorambucil-obinutuzumab, upon discontinuation, these were patients who would start seeing the progression happening a little sooner. It is still up for questioning whether the exploration treatment is appropriate for patients with high-risk disease. But taking the other side, for other patients, it is certainly a very good choice.

Anti-BCL2/CD20 Combination Therapy for Frontline CLL

There are very few patients for whom I would add an anti-CD20 agent to the BTK [Bruton tyrosine kinase] inhibitor if it’s a BTK-based treatment. The reason is based on the results of several clinical trials. In the context of venetoclax, I often add a CD20 inhibitor because the pivotal trials demonstrating a superiority of venetoclax-based regimen were paired with a CD20 agent. We don’t have randomized comparisons of venetoclax by itself to venetoclax with the CD20. Typically, I add a CD20 to venetoclax-based regimens, but I do not do so with BTK-based regimens. The exception to that is if there is a separate indication for an anti-CD20 agent, which primarily would be a patient with CLL [chronic lymphocytic leukemia] and an active autoimmune hemolysis or autoimmune cytopenia that would have a separate indication for the anti-CD20.

E1912 was a pivotal trial that demonstrated the superiority of an ibrutinib-containing regimen to the prior gold standard therapy of FCR: fludarabine, cyclophosphamide, and rituximab. The standard arm was compared with the investigational arm, which is ibrutinib plus rituximab, because at the time of the study design it was not clear whether rituximab had an added benefit to ibrutinib.

The study was a 2:1 randomization and the ibrutinib-rituximab arm demonstrated superiority both from a progression-free survival [PFS] and an overall survival [OS] standpoint. However, 2 other studies did compare ibrutinib-rituximab with ibrutinib by itself, which is my main reasoning for not adding rituximab to the majority of patients. The first trial that demonstrated no added benefit from a PFS or OS standpoint with the addition of rituximab to ibrutinib was the Alliance trial published by Jennifer Woyach, et al, in 2018. That was a 3-arm study, and both ibrutinib-containing regimens—the ibrutinib monotherapy and the ibrutinib-rituximab regimens—were superior to bendamustine-rituximab in older adults with CLL. However, there is no difference in the patients who received ibrutinib by itself vs the patients receiving ibrutinib with rituximab.

A randomized phase 2 trial published by Jan Burger, et al, in 

, 2019 was mostly relapsed-refractory CLL patients, though there were some up-front CLL patients who had the same findings. It demonstrated no added benefit either from a PFS or OS standpoint when adding rituximab to ibrutinib.

ELEVATE-TN is a recent phase 3 trial that compared 3 different regimens: acalabrutinib monotherapy, acalabrutinib with obinutuzumab, and a previously accepted standard-of-care regimen chlorambucil with obinutuzumab. This study demonstrated the superiority of the acalabrutinib-containing regimens compared with the prior standard of care, chlorambucil with obinutuzumab.

There was a post-talk analysis to this study that seems to suggest a potential benefit of adding obinutuzumab to acalabrutinib, but the added benefit is modest at best. At this time I do not add obinutuzumab to my patients getting acalabrutinib because the benefit is pretty modest, and it does add toxicity. The main toxicities that seem to be exaggerated in the acalabrutinib-obinutuzumab–treated patients, compared with the acalabrutinib-only–treated patients, were an increased risk of infusion-related reactions and an increased risk for infections. It’s not clear that the benefit of adding that drug is worth the potential cost, both financially and with respect to toxicity.

Anti-CD20/BTKi Therapy for Frontline CLL

BTK inhibitors change the paradigm of treatment for CLL [chronic lymphocytic leukemia]. Ibrutinib was approved in 2014 for CLL and actively changed the way we see the disease and how to treat the disease. Before that, the only options were chemoimmunotherapy and chemotherapy with an anti-CD21 antibody.

Since then, we had a second-generation BTK [Bruton tyrosine kinase] inhibitor approved for CLL as well, acalabrutinib. There are others on the way that should be approved in the next year or 2. Because ibrutinib was the first 1 to come to market, in terms of the novel agents, there is a broader uptake in the community. There’s a larger wealth of experience with this medication and certainly longer follow-up when compared with these other products that are now available in the market.

We have learned a lot of things by evaluating how patients tolerate the treatment and what kind of potential risks are associated with it. Not always what you see in the clinical trials, a more select population of patients, is necessarily what we see in the real-world evidence once we start using these drugs in clinical practice. Certainly, it was different for ibrutinib, which opened our eyes to several things.

BTK inhibitors, as a general class, do carry an increased risk of bruising and bleeding because of the interaction they have. It is not a contraindication if patients are using other antiplatelet medications for cardiac issues or if they are on anticoagulation. Certainly those patients need to be followed more closely because there is an increased risk of bleeding. Additionally, it can cause arthralgias as well because it can cause diarrhea. Ibrutinib particularly has a higher risk of atrial fibrillation and cardiac arrhythmias. Acalabrutinib has a higher risk of headaches, which are highly responsive to caffeine, for instance. But each of these medications has its own set of adverse effects and viscosity profile.

When choosing this treatment, we need to be mindful of what other diseases the patients have. What is their lifestyle? How may it impact your lifestyle? How old are they? We know that older patients, particularly older than 65, have a higher risk of intolerability with ibrutinib. This has been shown in a number of retrospective studies. Particularly the cardiac toxicity, including hypertension, is more prominent in older patients when compared with younger patients.

A patient who is 70 or 75 years old and may have hypertension at baseline, will raise certain concerns about using a BTK inhibitor for a longer period of time because that may worsen those baseline conditions. It also may increase their polypharmacy because they’re already on a multitude of medications. We don’t want to end up giving more medications and then have 2 other medications to treat hypertension or atrial fibrillation.

Not to say that all these are going to develop; that’s not the case. But we need to monitor that closely and we need to be aware of the risks associated with it. Besides that, older patients tend to not have the extent of commercial coverage, in terms of their medical insurance for medications, as younger patients in general. We need to take that into consideration as well because the out-of-pocket cost may be for a long period of time and may make the choice of a certain therapy impossible because a number of patients wouldn’t be able to afford it.

Acalabrutinib was recently approved based on the ELEVATE-TN trial that was published earlier this year. It is a second-generation BTK inhibitor. One of the main goals in developing the drug was to have a “cleaner drug” that was more specific to the BTK enzyme and had less off-target enzyme inhibition. We’ve hypothesized a number of the adverse effects seen on ibrutinib are secondary to the multitude of off-target enzymes that acalabrutinib inhibits.

The head-to-head trial between acalabrutinib and ibrutinib has no readout yet. It is the relapse setting for high-risk disease. The trial is not in the frontline setting, but that will give us more information comparing head to head the adverse-effect profile of these drugs. We don’t expect a significant difference in efficacy between those medications because their mechanisms of action are the same. They bind to the same cysteine residue and the BTK molecule with very similar affinity. However, a difference to therapy is important because the BTK enzyme recycles and regenerates on a very constant basis, by removing the inhibition it gives leeway to resistance progression of disease. Having a therapy that patients will veer more to is very important.

In my clinical experience, acalabrutinib should be better tolerated than ibrutinib. It’s a different adverse- effect profile. I’ve seen less intense arthralgia initially—which is an issue with ibrutinib—and less development of cardiac arrhythmias, atrial fibrillation, and high-grade hypertension in these patients. It is important to note that the follow-ups with these patients are shorter than with ibrutinib. Although most adverse effects did decrease over time, similar adverse effects, particularly hypertension with ibrutinib, increased over time. My particular clinical preference has been, in terms of BTK inhibitor usage, to use acalabrutinib over ibrutinib. In my experience, patients do tolerate that better. The only time I use ibrutinib instead of acalabrutinib is for patients who are on proton pump inhibitors [PPIs]. That’s a contraindication to use with acalabrutinib because that impairs the absorption of the drug. Patients who have peptic ulcer disease, who cannot transition from a PPI to an anti-H2, for instance, should not receive acalabrutinib. If I’m using a BTK inhibitor, those patients will use ibrutinib. But much of it is a personal preference. This has been my clinical practice, not to say that ibrutinib is not a great drug; it is. We just have some issues with tolerability.

BTK Monotherapy for Frontline CLL

 Fortunately, we have many options to treat CLL [chronic lymphocytic leukemia] today, still including chemoimmunotherapy for a subset of patients who are highly selected. We have continuous therapy with Bruton tyrosine inhibitors [BTK]—the approved ones are ibrutinib and acalabrutinib—with or without the use of an anti-CD20 antibody.

Certainly, all these therapies have pros and cons. One of the issues we discuss quite a bit is, who would be an ideal candidate for continuous therapy? There are a number of issues associated with continuous therapy. One issue is prolonged exposure to treatment and prolonged exposure to potential adverse effects and risks. Of course, cost associated with the therapy is also an issue, particularly for patients who don’t have commercial insurance coverage.

Based on the data seen in multiple frontline trials, it seems that, for most patients, therapy is appropriate, particularly for those patients with 

 mutations. Those patients, certainly, can enjoy a long-term progression-free survival and treatment-free survival without the need for continuous therapy.

However, it seems that for patients with high-risk cytogenetics, particularly with a 17p deletion or 

 mutation, this therapy may not be the best answer. We don’t have a head-to-head comparison trial to evaluate that, but by looking at the curves of trials that include a discontinuation of therapy at a certain period of time, it seems that those patients with high-risk disease started to progress earlier than we would expect, especially compared with their non-high-risk counterparts.

It is my opinion that for the very high-risk patients, continuous therapy would be more appropriate, given the data that we have at the moment. Of course, this may change as we have more data moving forward, but it seems that those patients may enjoy a longer control of disease by having the disease continuously suppressed by a therapy.

Not all patients require treatment upon diagnosis, and some don’t require treatment for many years. Some don’t require treatment at all. But once treatment is indicated, we discuss options. Starting with 

 mutations, we look at cytogenetic risk, as well as performance status, comorbidities, if the patient is fit, what the patient will be able to tolerate, what are the patient’s goals are, and so on.

But all things being equal, we’ll look at the cytogenetic risk—an 

 mutation is the first determining factor. Certainly, for patients who have a disease that’s unmutated in the IGHV molecule, which is higher risk—this is about 65% of patients who do require treatment in the first-line setting—chemoimmunotherapy is, truthfully, not indicated for those patients. FCR[fludarabine, cyclophosphamide, rituximab]and BR [bendamustine, rituximab]don’t have that much of a role anymore in this particular population.

Then we discuss novel therapies, which in the frontline setting include venetoclax and obinutuzumab, acalabrutinib, or ibrutinib with or without anti-CD20 therapies. Of course, there are pros and cons to each approach.

The biggest advantage of venetoclax and obinutuzumab is that they are given in a fixed duration. It’s about a year worth of therapy. Logistically, it is a bit more complex than using 1 of the BTK inhibitors. It requires an infusion of an antibody. There are 4 infusions of an antibody in the first month. Once you start the venetoclax-BR [bendamustine, rituximab] therapy, there is a weekly ramp-up over 4 weeks that requires a number of doctor visits and several laboratory check-ups. Sometimes these need to occur 2 days in a row. Some patients require hospitalization, particularly patients who are high-risk for tumor lysis syndrome. This is a very potent medication, in terms of killing the CLL cells.

Using a tyrosine kinase inhibitor does not require such frequent lab check-ups, and certainly, there are fewer doctor visits. This type of treatment does not require hospitalization. It does not require an infusion. You don’t have the ramp-up, so logistically it’s much easier. However, you need to take that continuously until disease progression or intolerability.

We discuss the particular adverse-effect profile of each treatment with the patient. As of right now, we don’t have a head-to-head comparison of those agents to understand which option will be better and which will be worse. It seems like all of them work very well.

After discussing all these factors, including patient-specific characteristics, then we decide the preferred approach for that patient.

Shared decision-making is a huge component of care for a patient with CLL. I don’t think there is aright answer to what is the best treatment. We have a lot of treatments that work pretty well; they are just very different. Some are oral only. Some are oral plus IV [intravenous]. They have different adverse-effect profiles. Depending on a patient’s comorbidities and tolerance of certain toxicities, really coming together as a team to make the best decision is the best approach when selecting a frontline therapy.

There are key considerations that I take into account when selecting a therapy for any given patient. In addition to their preference for therapy, there are biological factors that are very important. I consider genetic risk of any given patient, which is determined both by cytogenetic testing via FISH [fluorescence in situ hybridization] and karyotype testing, to look for high-risk genetic abnormalities such as 17p, complex karyotype, 11q deletions, TP mutations, and also the status of the 

gene, whether it is mutated or unmutated. Depending on the presence or absence of high-risk markers, that can make us lean in the direction of 1therapy more than another.

In addition to these biological factors, patient preference plays a role as well. Some patients are very open to doing a more intensive treatment, provided that they have the benefit of being able to stop therapy. However, other patients prefer oral-only options. It depends not only on their biological risk factors, but of course what their preferences are.

Lastly, all these therapeutic regimens have different adverse-effect profiles. For example, one therapeutic regimen may be a better fit for a patient who has cardiovascular disease than a patient who has renal disease, to avoid toxicities that may make them have trouble with the therapy going forward.

Alan P. Skarbnik, MD, Novant Health Cancer Institute

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