Expert Conversations on CLL

Commonly Asked Patient Questions in CLL

Last Updated: Friday, November 18, 2022

Amber Koehler, PA-C, and Josie S. Montegaard, NP, discuss questions they frequently hear from patients with chronic lymphocytic leukemia (CLL). These include the role of CAR T-cell therapy, BTK inhibitors, and chemo-immunotherapy; when to treat versus monitor CLL; and what patients with CLL can do for their overall health.

Meet the faculty

Amber Koehler


Mayo Clinic Cancer Center

Amber Koehler, PA-C, is the Mayo Clinic enterprise lead CLL APP and an Assistant Professor of Medicine as well as the Outpatient APP Research/Education Lead in the Division of Hematology at Mayo Clinic Cancer Center in Rochester, Minnesota. She specializes in caring for patients with CLL and Richter transformation and is passionate about patient education as well as optimizing supportive care and quality of life in patients with CLL.

Josie Montegaard


Dana-Farber Cancer Institute

Josie S. Montegaard, NP, is a nurse practitioner in the CLL Center at Dana-Farber Cancer Institute, where she cares for a full panel of patients with CLL and Richter syndrome. She has participated in many investigator-led and registration CLL trials and holds a particular interest in the development of more defined length treatment options.

Josie Montegaard

Amber, let's take a few minutes to talk about the questions that patients ask most frequently. Is it your experience that the types of questions tend to come in waves based on common themes?

Amber Koehler

There are definitely certain questions that come up all the time in our CLL clinic. One question that patients often ask is whether they are a candidate for CAR T-cell therapy.

I think this question has stemmed, in part, from a recent article in Nature that highlighted “decade-long leukemia remissions” with CAR T-cell therapy.1 One of the earliest patients in the article with CLL who received CAR T-cell therapy has done really well and has been in remission for quite some time. It is important to note, however, that CAR T-cell is not yet approved for treatment of CLL—it's still in the clinical trial phase.

When CAR T-cell therapy works, it works quite well. We have seen durable responses in patients who get into a minimal residual disease–negative complete remission; however, CAR T-cell therapy may not be the miraculous cure that we were hoping it might be. Much of our current data come from the phase I TRANSCEND CLL O04 study,2 which was presented at both the American Society of Hematology (ASH) and American Society of Clinical Oncology Annual Meetings. These data show overall response rates ranging around 80%, with a 56% complete response rate. Some of the biggest adverse events that we see with CAR T-cell therapy, similar to what is seen in other disease states like large cell lymphoma, are cytokine release syndrome and neurotoxicity. One potential mitigation strategy in CLL is the concomitant use of ibrutinib, which seems to decrease the risk of cytokine release syndrome.

Researchers are currently investigating the many reasons CAR T cells aren't a home run in CLL. We know that there's something about the CLL microenvironment that makes the CAR T cells less effective. We also know that T cells in CLL are generally dysfunctional anyway. Although I think that CAR T-cell therapy does have a role in the relapsed setting, right now the only trials that we have available are in individuals whose disease has progressed on both BTK inhibition and venetoclax-based therapy. Again, it is important to understand that while there is a proportion of people with CLL who will do well for quite some time on CAR T-cell therapy, for the majority of patients if they do respond, it's unfortunately not quite as durable of a response as perhaps some of the initial data had shown. What's been your experience with CAR-T, Josie?

Josie Montegaard

I completely agree. We have had some patients on the clinical trials, and they have done well. But I have had a similar experience where right after the Nature article was published, a ton of untreated patients came into my office asking to be treated with CAR T-cell therapy. I think it really needs to be understood that while this is an exciting opportunity that patients with CLL may have, it can be a quite toxic and dangerous treatment. For this reason, it is not something that would ever be considered in the front-line setting in the near future, even if and when it's FDA approved for CLL.

We have all these other excellent oral agents and combination treatments that get people into deep remissions and are very tolerable. However, we already are seeing patients come out of the woodwork who are resistant to all of our current treatments and really don't have a great hope for a new durable treatment. So CAR T-cells might be useful in that scenario, but it just needs to be understood that it is a very toxic treatment. It's not a home run for everyone, but as you said, I definitely think it will have a place in the treatment of CLL.

Amber Koehler

I agree. Another question that both patients and practitioners are asking is what is the sequencing or the relationship between CAR T-cell therapy and transplant. When people hear the word “leukemia,” they may instantly think of bone marrow transplant. However, thanks to all of the new novel oral targeted agents as well as the advent of treatments like CAR T-cell therapy, the number of individuals with CLL who are appropriate to take to transplant has decreased significantly. For example, in the past 5 years that I've practiced specifically in CLL, I can only think of one individual who went to transplant. Has your experience been similar?

Josie Montegaard

It has been. I think as time goes on, we'll continue to see a decrease. This is another avenue where I think CAR T cells will be helpful—getting patients into a deep enough remission enough to go to transplant is challenging when patients are receiving later lines of treatment and have already become resistant to BTK inhibitors and venetoclax. I think CAR T cells will give those patients the opportunity hopefully to get into a remission so that then they could proceed with transplant. I don't know about you, but at my institution, we have a fair amount of young, 30- to 40-year-old patients who are starting on CLL treatment. I worry that these patients will not have any treatments left by the time they're 60.

Amber Koehler

Yes, I completely agree.

Josie Montegaard

Another question that patients commonly ask is what they should be doing for their overall health while being treated for CLL. Many of my patients, either before or while they're being treated for their CLL, decide to use us as their primary care doctors. When they ask this question, I tell them to go back to their actual primary care doctor because routine health maintenance is just as crucial in their long-term prognosis as the CLL treatment itself. As we know, the average age of people diagnosed with CLL is about 72, so often these patients may not actually die from their CLL. We want to keep them healthy in other ways, especially considering that patients with CLL are more at risk for secondary cancers and infections.

Staying up to date with health screenings can prevent both infections and cancers. We recommend that patients go once a year for dermatologic exams to look for atypical moles (or to go more frequently if their dermatologist recommends it). Most of my patients will have an atypical mole or non-melanoma skin cancer removed at some point in their life.

Additionally, I recommend that all my patients stay up to date with their colonoscopies, mammograms, and prostate-specific antigen screenings. As with the dermatologic exams, we usually tell patients that they don’t need to do these any more frequently than what's already recommended for the general cancer screening guidelines.

The best way to prevent infections is to stay up to date with available vaccinations. That includes annual flu shots as well as the pneumococcal vaccines. Traditionally, we have been recommending that patients receive pneumococcal 13-valent conjugate vaccine followed by pneumococcal vaccine polyvalent, which they then will repeat every 5 years. That being said, pneumococcal 20-valent conjugate vaccine is out on the market now, so our infectious disease team feels that this may at some point take the place of the pneumococcal vaccine polyvalent in general.

We also recommend that our patients get their shingles vaccine. The SHINGRIX vaccine is a non–live-virus vaccine, so it is safe for our patients to get. They should complete the two-dose series. Lastly, we recommend staying up to date with their tetanus vaccine and avoiding any other live-virus vaccine. Is that similar to what your counseling includes, Amber?

Amber Koehler

Yes, I would say that's right on par with what we would do. One thing I would add is when you look at the data on the quality of life for patients with CLL, particularly emotional distress, you find that not only do patients with CLL have decreased emotional quality of life compared to the general population, but it is also decreased compared with patients with other types of cancer.

I think a large piece of this stems from the fact that one of the questions on these surveys is “I worry my disease will get worse or will come back.” One of the hardest and most challenging aspects of CLL is that at this point it is incurable. We can get people into remissions, and we have fantastic novel oral targeted agents that work very well and in general are very well tolerated. However, they're not perfect. They're not the forever fix for everybody, especially for patients in their 30s to 40s who are already requiring treatment.

That sense of loss of control can be very challenging for patients. Focusing on supportive care can give patients back that sense of agency or locus of control. There's a little bit of phase II data on green tea, or EGCG, supplementation in pretty high doses—2,000 mg twice a day.3 They did find some evidence that green tea supplementation at that high of a dose could potentially mitigate the progression of CLL. However, if a patient chooses to do that, we need to monitor for GI toxicity and watch their liver function tests to evaluate for hepatotoxicity. Really, these data are not particularly robust, but if a patient asks what they can do and really just needs something to hold on to, I will offer that and walk them through those data.

Josie, as you alluded to, our patients are at such an increased risk of not only getting infections but also of developing more severe infections, so getting the vaccines is very important. Unfortunately, as we know, the vaccines are less effective in patients with CLL than in the general population. This is likely related to some of that B-cell dysfunction, the treatments that they're on, and T-cell dysfunction. Intravenous immunoglobulin (IVIG) is something that we'll use in our individuals who are hypogammaglobulinemic, specifically if their immunoglobulin G (IgG) is low. The typical criteria we use to warrant institution of IVIG Infusions would be an IgG level of less than 400 with three or more infections requiring hospitalization or antibiotics over the past 6 months. IVIG is an infusion that does take several hours. Usually, it is given about once a month to start, and sometimes it can be spaced it out to every 6, 8, or 12 weeks. It does sometimes get a little tricky in terms of billing and insurance, particularly if you practice at a larger center that gives a lot of IVIG – insurance companies like Medicare can be very strict about needing specific trough levels (usually an IgG level less than 600), and this must be monitored quarterly. Unfortunately, IVIG replacement is often an indefinite treatment—it doesn’t fix the issue, which is lack of production.

Josie Montegaard

Sometimes with the IVIG, if we are struggling with a patient's insurance or just a patient who doesn't want to commit to monthly infusions indefinitely, we'll regularly check their IgG level and continue them on monthly IVIG through cold and flu season in the winter months. Then, if their IgG level is holding in the normal range in the spring, we'll give them a holiday through the summer. We’ll then repeat the IgG level again that fall to confirm if they need to be restarted at that time That can be an option to give patients a little bit of a break from the infusion. Some patients are able to stop for a period of time, and although their IgG usually inevitably drops, their infection rate does not always resume the way that it was. Sometimes we can get away with just watching their low IgG level but not resuming the infusions unless they start having frequent or life-threatening infections again.

Amber Koehler

I agree completely. Is there any IgG level that you would say regardless of infection status, you need to replete with IVIG?

Josie Montegaard

Typically, no. Some of that has to do with the question of why give something if the patient isn't having obvious negative effects from it. A lot of our patients are naturally hypogammaglobulinemic but aren't having frequent infections. Additionally, our insurance companies have been quite strict with their IVIG approval. Even if we wanted to give it for solely a low level of IgG, insurance will want to see the infection documentation. So sometimes our hands are tied regardless.

Amber Koehler

One of the most common questions I get asked by patients is whether or not they need treatment. Sometimes, it can be really tough for a patient with a new diagnosis of CLL to grasp that we’re going to monitor their disease rather than treat it. I think that’s because leukemia has a connotation of people getting diagnosed and then dying within a short timeframe. Patients may think about people who they've known who have had to be in the hospital, had IV chemotherapy, lost their hair, had significant side effects, etc.—things that are typically seen more with the acute leukemias.

It’s important to recognize that we have the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria,4 which very specifically outlines when patients need treatment, and there are reasons for that. For example, the absolute value of the white blood cell count is far less important than how quickly it’s changing and what those white blood cells are doing. Are they causing bulky lymphadenopathy or massive splenomegaly? Are they crowding out the healthy space in the bone marrow resulting in anemia or thrombocytopenia? Another consideration with cytopenias in CLL is that patients have an increased risk of autoimmune complications, so it is important to evaluate for that. I also see anemia due to the more common things like iron or B12 deficiency. Finally, significant B symptoms, such as drenching night sweats, unintentional weight loss, fevers unexplained by an infection for 2 weeks or more, and severe fatigue due to disease progression, would all necessitate treatment. Fatigue alone as indication for treatment can be a little tricky. It’s important to rule out and address other potential contributing factors such as undiagnosed sleep apnea, thyroid abnormalities, stress, depression, obesity, and insomnia, to name a few. I have found that CLL-related fatigue is really a different level of fatigue than the run-of-the-mill daily fatigue that many people experience.

Those are the things I think about. There's also the soft call of lymphocyte doubling time of 6 months or less. But again, the more concrete iwCLL criteria for treatment would be those cytopenias, large symptomatic lymph nodes or splenomegaly, and B symptoms.4 Josie, do you want to talk about why we have the iwCLL criteria, and how we've looked at it in the past with some of the early intervention data?

Josie Montegaard

We follow the iwCLL criteria because there have been a number of studies that have looked at early intervention for CLL, and the overall survival did not change between patients who had early interventions versus patients who waited. However, the patient-reported toxicities and quality of life was different. Patients who were on treatment obviously reported more side effects than patients who continued to live their life off treatment. That's really important for our patients with CLL to understand because I think during the observation period many of our patients have anxiety that by delaying their treatment, it will affect overall prognosis and actually cause them to feel worse than if they just started treatment and got their CLL into a nice remission. However, it’s clear from these studies that overall survival was not impacted by delaying treatment and that treatments themselves do not come without side effects.

In our practice, we go through treatment options over a number of visits so that patients are prepared. However, I think that because of this, a lot of patients tend to think that someday they're going to come into the clinic feeling great, but I'm going to tell them that their labs look terrible and that we should have started treatment yesterday. I always tell patients that if they feel well, it's very unlikely I'm going to tell them any different when we review their blood work or do their exam.

The other thing that I like to counsel my patients on, especially with regard to the B symptoms, is that patients rarely are going to have drastic, severe B symptoms without other indications for needing CLL treatment.

As you said, fatigue is a big beast that many people even without CLL face. There is a common misconception that fatigue alone is a reason to treat CLL. I agree with you, Amber, in that CLL-related fatigue that warrants treatment is very obvious when it happens. It is quite debilitating and often actually is related to the patient developing a more significant anemia due to CLL infiltration in the bone marrow or, again, other signs that CLL treatment is warranted.

If someone is reporting many symptoms that don't align with their CLL, it's very important to work them up or refer them back to their primary care physician for a workup to understand why they're feeling that way. We don't want to discount patients’ feelings, but again, we don't want to expose them to unnecessary side effects early on. As we discussed earlier, we have a few great treatment options for CLL, but once a patient starts them, there are only so many options we have if their disease progresses on them. I always say we kick the can down the road as long as we can before beginning treatment.

Amber Koehler

Absolutely. It’s very common that individuals with fatigue, or even their other care providers, are quick to blame the fatigue on the CLL – even in a Rai stage 0 CLL with normal hemoglobin and platelet count, no adenopathy on exam, and no other B symptoms. One of the phrases that I have found helpful is to explain to patients that although the CLL may not be helping their fatigue, I would not expect it to be driving their fatigue, based on their low disease burden.

Josie, do you want to tell us about pirtobrutinib (formally known as LOXO-305)?

Josie Montegaard

One very exciting development in the field of CLL is progressing the role of BTK inhibitors. We know that BTK inhibitors are durable treatment options for patients. Over the years, we've developed newer generations of those medications that are better tolerated. However, what do we do once a patient’s disease stops responding to the treatment, or the patient develops a side effect that they just really cannot live with? Some of these patients have already received venetoclax and had disease progression on it, so that's not an option for them anymore. Or maybe there's another reason they cannot go onto venetoclax. We were hitting a wall with treatment options in these cases up until recently, when studies began looking at pirtobrutinib, a third-generation BTK inhibitor.

Pirtobrutinib is considered a non-covalent BTK inhibitor. First- and second-generation BTK inhibitors are considered covalent BTK inhibitors. The non-covalent BTK inhibitors have a mechanism where they can bind to BTK and still prevent cell proliferation in CLL cells, when covalent BTK inhibitors cannot, say due to a developed BTK resistance mutation, which we are able to test for. Currently, PLCG2 and BTK C481 mutations can be readily tested for. When patients develop these mutations, their disease can no longer respond to ibrutinib, acalabrutinib, or zanubrutinib. However, because pirtobrutinib can bind to BTK in a slightly different way, it is still effective for those patients. It also is, again, a more selective BTK inhibitor, so it tends to be very well tolerated. I would say that it is on par with the second-generation BTK inhibitors, if not better tolerated, in my experience.

I've had some patients who did not tolerate prior BTK inhibitors go on pirtobrutinib on clinical trials, and they did better on it. It opens a new door, not only for patients who have developed BTK resistance genes, but also for those who have been intolerant to prior BTK inhibitors. It's a really exciting development and another opportunity for our patients who are getting to that point where our best durable options are not available to them anymore.

Amber Koehler

I agree completely, Josie. I think about patients who have seen some of the earlier BTK inhibitors and had progression with or without these resistance mutations, as well as those patients who have had progression through venetoclax. There are some studies showing that re-treatment with venetoclax can have some efficacy, but again, it's not necessarily a home run. There are lots of factors there. So once a patient has progression through the BTK and BCL2 inhibitors that are currently approved in CLL, it's a little trickier. Certainly there are the PI3 kinase inhibitors, but they have several side effects that can come with them, including black box warnings for severe diarrhea and colitis without very durable remissions, averaging around 7 to 8 months. So, I see pirtobrutinib as a fantastic opportunity for that really unmet need in the treatment of CLL.

The other thing I tell patients about these newer BTK inhibitors—whether it's acalabrutinib versus ibrutinib or pirtobrutinib versus acalabrutinib—is that I think about the first-generation drugs like buckshot. They spread out a little bit; you hit your target, but you also hit a couple other things that maybe you weren't intending to hit. Third-generation drugs such as L0X0-305 act more like snipers in terms of being much more specific about the different kinases that they act on. Because they’re so specific about what target they’re hitting, they’re going to have fewer off-target side effects. So I agree—I think it's a very exciting development.

In my practice, we often have the opportunity to meet with patients who come to us for a second opinion on management of their CLL. A question that often comes up is, “What is the role of chemo-immunotherapy in CLL, given today's treatment landscape?” We've talked about so many of these new novel oral targeted agents, so let’s take a moment to discuss the more traditional treatments for CLL, such as fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine plus rituximab (BR).

In 2018, data from the ECOG E1912 trial5 as well as the Alliance A041202 trial were presented at the ASH Annual Meeting, and both trials were subsequently published in the New England Journal of Medicine.6 Both of those trials looked at traditional chemo-immunotherapy compared to novel targeted therapies, specifically ibrutinib-based therapies. The E1912 trial looked at individuals who were aged 70 or younger without significant comorbidities. These patients were randomly selected to receive either FCR or ibrutinib plus rituximab. Individuals treated with frontline ibrutinib plus rituximab had improved progression-free survival (PFS) and overall survival compared with patients who received FCR.

The Alliance trial patient population was a bit different. These patients were older and had more comorbidities. The trial also had three arms: individuals were randomly selected to receive bendamustine plus rituximab, ibrutinib monotherapy, or ibrutinib plus rituximab. At the last data cutoff, there was a PFS benefit for ibrutinib-based therapy with no statistically significant difference between the arms of ibrutinib monotherapy and ibrutinib plus rituximab. However, to date there has not been a demonstrated overall survival benefit in the ibrutinib arms in the Alliance trial compared to the more traditional approach of bendamustine plus rituximab.

When I consider the role of chemo-immunotherapy, there are a few things that I think about. We’ve got two large head-to-head frontline trials that are demonstrating improved outcomes with novel oral targeted agents. I also think about the risk down the road of things like myelodysplastic syndrome, and how the fludarabine in FCR can flare some of those autoimmune cytopenias that we can see in CLL.

There is an argument based on the data from the E1912 trial that if individuals have low-risk CLL (specifically, mutated IGHV genes) they could be given an abbreviated course of FCR on a measurable residual disease–driven basis (they could be given maybe three cycles of FCR to get into a remission, and then just be observed from there). One of the main arguments at the time was that ibrutinib-based therapy was indefinite, and some people don't want to be on a pill for the rest of the foreseeable future. That argument doesn't work as well anymore because we now have time-limited therapy options with venetoclax-based regimens that can result in durable remissions.

One other really important consideration in the conversation surrounding the role of chemoimmunotherapy in CLL is that we've known for years that chemo-immunotherapy is not appropriate for individuals who have high-risk features such as TP53 mutation or deletion 17P by FISH. So when you're getting ready to start somebody with CLL on treatment, especially if chemotherapy is being brought into the conversation—either by colleagues, the patient, or whomever—getting those genetic markers is critical to ensure that they're receiving appropriate treatment. What would you say, Josie?

Josie Montegaard

I completely agree. We see quite a few patients who received chemo-immunotherapy prior to coming to us, or their local oncologist has recommended it, and they are coming for a second opinion. As a whole, we really are not using chemo-immunotherapy for the exact reasons that you have already spoken about, between the toxicity and the fact that most patients do not fall into that favorable risk category where chemo-immunotherapy would even be appropriate from an efficacy standpoint—those patients with del(13q)s and IGHV mutations. I think when we do have that sort of unicorn patient walk through our door, it is a young person with those prognostic markers. We always will tell them of the option of chemotherapy, but with the caveats that there are the substantial side effects that could occur during treatment or may arise down the road, such as the risk of myelodysplastic syndrome.

So it doesn't come without heavy counseling. Many times, these patients who have been recommended chemo-immunotherapy have not had a prognostic workup done. That's really the problem that plagues us—we don't even know if these patients would be appropriate candidates, yet they are being recommended this toxic treatment. So I would argue that the takeaway is that it's a very specific circumstance where it's appropriate, but the full molecular and genetic profiling of the patient's CLL needs to be done first and foremost at diagnosis before any treatment is recommended.

Amber Koehler

Absolutely. I can think of one patient who's gotten chemo-immunotherapy in our clinic since 2018. And that was three cycles of FCR. It was a young individual who had very low-risk disease, and it was prior to the approval of venetoclax-based regimens in the frontline setting.

One important factor that we haven’t discussed yet is cost. One of the arguments that I've heard from colleagues who practice in smaller settings is that chemo-immunotherapy is covered by insurance, and you don't have to navigate the use of specialty pharmacies, insurance company mandates, etc. So just to speak a little bit to our process, I can tell you that out of the hundreds of individuals that I've treated with novel oral targeted agents—either BTK inhibitors or venetoclax—there are very few for whom it ended up being cost prohibitive in the end. We send the prescription to our specialty pharmacy, and have this incredible team that works with patients, insurance companies, and patient assistance organizations to get individuals the medication they need, whether it is from us or from another specialty pharmacy. I feel very fortunate to have this resource. What does this process look like at your institution, Josie?

Josie Montegaard

It's very similar. I would completely agree that we’ve only had a handful of patients who had a high copay yet were over the income limit for copay assistance through one of these programs. We're very lucky in that we have a department that checks all of the available resources. I don't have to do it myself, but when I have dipped my toes in to help out, I have found that the PAN Foundation7 and the Leukemia & Lymphoma Society8 make it quite simple to apply and help get your patients access to funding and grants. They're trying to stop that from being a barrier even for smaller practices that don't have someone whose primary role is to look into that.


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