Chronic Lymphocytic Leukemia

Just talking about CLL, it is 1 of the most common leukemias in the adult population in the US, with roughly 24,000 cases diagnosed each year. That is the expectation this year as well. It is a mature B-cell malignancy. The vast majority of our patients come to our attention, incidentally, because they have a CVC done for some reason or undergo a scan for whatever reason. In order to have either lymphocytosis or lymphadenopathy, and additional workup is done that leads to this diagnosis.

I would estimate that roughly 5% to 10% of patients actually present with symptoms. Maybe they are fatigued, and they have anemia because of a high white count, or they have a lymph node that pops up and that leads to the diagnosis in this day and age.

Even with all the tools that are at our disposal, CLL really remains an incurable condition in that we can provide excellent treatment options, yet our goals of care really are to get the patient's overall survival similar to age and sex matched general population, because we really cannot say that we have been able to cure CLL quite yet, although that is really an ideal to reach eventually with newer treatment approaches etc.

This is something I talk to all my patients all the time. Just because something is not curable does not mean it is not treatable, and I generally will give the example of hypertension and diabetes. Unfortunately, none of these conditions are curative but you can give a lot of treatments that control these conditions and that is a similar concept in CLL.

[00:07:09]

CLL: Important Reminders

The median age of diagnosis is about 70 years. Roughly it is about 4 to 5 years on an average, where patients would actually wait before they need treatment. The median age at first CLL treatment is about 75.

Despite, again, all the advances that we have had in CLL, if a patient does not have any symptoms even if they have high risk features like a TP53 mutation or a del(17p) the recommendation remains no treatment unless patients actually have progression of disease that meets the criteria for therapy.

[00:07:46]

Indications for Therapy

Here are the indications of the criteria for initiation of CLL-directed therapy, which include disease-related symptoms. This is important because a lot of people will have fatigue or night sweats, etc., but they are not really from CLL. They are from sleep apnea or from hypothyroidism, etc. I think it is important to emphasize this to our patients because a lot of patients think, oh, I have fatigue and I am going to need CLL treatment, but they do not otherwise have any other symptoms or signs of CLL progression.

It is important to maintain that expectation and as you talk to patients about what symptoms would really drive the need for therapy.

End-organ function that is compromised is a newer addition. For example, if someone has spine involvement or kidney involvement or skin involvement, these are indications to treat. The traditional indications also include bulky lymphadenopathy or bulky splenomegaly or progressive or symptomatic, or if a patient has anemia or thrombocytopenia, the typical threshold for anemia is a hemoglobin of less than 11 or 10, and thrombocytopenia with a platelet count of less than 100. Those are indications to treat.

In addition, patients who may have steroid refractory autoimmune cytopenias also constitute an indication to treat CLL.

[00:09:06]

CLL in VHA System

Now, in the VA this is a unique group of patients. The incidence is relatively higher. It is not entirely clear why, but we believe it is secondary to demographics, meaning an older patient population that is seen there. Exposure to environmental toxins, particularly Agent Orange, and of course, higher comorbidities.

In a study that was published by the VA, patients who were diagnosed with CLL actually were much younger compared to the median at 63 years. Thankfully, although Agent Orange was associated with an increased risk of development of CLL, the therapeutic implication of exposure to Agent Orange does not matter. Patients responded equally well to whichever treatments they were administered, and their survival was similar to those patients who had CLL received the same treatment but did not have exposure to Agent Orange.

[00:09:59]

Prognostic Implications of IGHV Mutation Status in CLL

Now, we talk about what happens with an individual patient with CLL and of course, Rai stage is the cornerstone of how you would stage CLL. But that is a static thing, meaning you see the patient today and you can examine the patient, look for lymph nodes or look for anemia and thrombocytopenia and that will tell you what the stage of the disease is. But it is really the underlying biology of the disease that drives the clone.

One of the major reasons why someone has faster disease progression compared to not is the IGHV mutation status. This is a 1-time test that will establish the mutation status in CLL that I recommend that everyone get for all their patients, even at the time of initial diagnosis, because this is 1 of the most powerful indicators of how quickly the disease is likely to progress over time.

I think this is easily obtainable from the peripheral blood. Here in the classic paper from 1999 now, you can see that patients with mutated IGHV genes have a better prognosis compared to those with unmuted and IGHV genes.

[00:11:04]

Chromosomal Deletions/Duplications in CLL

The other major prognostic test is the CLL FISH profile, where the presence of deletion 17p in the steel curve on the bottom was associated with the worse survival compared to those with 13q in yellow that had the best outcome, and patients with 11q were closer to 17p deletion patients. And those in the purple in negative FISH or in green trisomy 12 had an intermediate prognosis.

Again, the CLL FISH profile is important to help us understand how a patient is likely to do over time. Despite the availability of many of our novel agents, there is inferior prognosis associated with deletion 17p still remains. I think it is important to therefore obtain CLL FISH profile on everyone who is about to begin CLL directed therapy.

In fact, similar data are also seen with the presence of TP53 mutation in the absence of deletion 17P. The only way you can find that TP53 mutation is by doing a next-generation sequencing study. About 5% patients will have a TP53 mutation in the absence of deletion 17p. It is necessary to do both tests: a CLL FISH that looks for del(17p) and an NGS test that looks for TP53 mutation.

Similarly on the right, you will see that these tests are also able to predict time for first CLL directed therapy.

[00:12:33]

Frontline Treatment for CLL

What are some of the updates in front-line therapy for CLL?

[00:12:36]

Case 1: Patient With Previously Untreated CLL

Here is a case that I would like to begin with. This is an 80-year-old male with a history of exposure to Agent Orange, who was first seen in 2018, had lymphocytosis, and much like many other patients, had early-stage disease and had a watch-and-wait strategy.

The cytogenetics were negative, IGHV genes were unmutated, and then the patient unfortunately developed progressive lymphocytosis up to 120,000 and then had symptoms of weight loss, night sweats, etc. Has a history of hypertension and chronic kidney disease. Performance status is 1. He lives about 45 minutes away from the infusion center and prefers not to drive there if he can avoid it.

[00:13:16]

Pretest 2

In your current practice, what would you consider to be the optimal therapy for this patient?

1. Would you give chemoimmunotherapy with either FCR or BR;
2. A first-generation BTK inhibitor like ibrutinib;
3. A second-generation BTK inhibitor like acalabrutinib or zanubrutinib;
4. Is venetoclax and obinutuzumab; or
5. Is venetoclax, acalabrutinib, and obinutuzumab.

I would like for you to please give me your response.

Speaker: The polling is open. Please vote. We will give everybody a few more seconds to submit the response. Here are your results.

Dr Parikh: Okay. Great. No one would choose chemotherapy. Ibrutinib is a choice. Mostly people chose a second-generation BTK inhibitor. Also, venetoclax, obinutuzumab and the triplet combination. We will talk about all of this in the upcoming slide.

I would really think that number 3 would be a preferred option, particularly because a patient says that he actually would not prefer to drive to the infusion therapy center. Both number 4 and 5 actually have obinutuzumab, which is an infusion, and so I think it would be reasonable to go with number 3 for that particular reason for this patient.

[00:14:58]

Key Biomarker Testing Prior to Treatment for CLL

Let us go with the data on what these treatment options are. Here are biomarker testing prior to treatment. We touched on all of these. The only thing I will add is that the CpG-stimulated karyotype is also now becoming an important prognostic marker. We typically try to obtain that either from peripheral blood or bone marrow biopsy prior to the start of therapy in CLL.

[00:15:20]

Guideline-Recommended First-line Therapy for CLL/SLL

Now, these are the most updated NCCN guidelines for the treatment of CLL. On the top here are patients who do not have del(17p) or a TP53 mutation and in the bottom are patients with del(17p) or TP53 mutation. You will note that for the most part, the preferred regimens and the other recommended regimens are essentially identical.

You could not go wrong choosing either of these treatment approaches for patients with or without del(17p). The only difference being that if a patient does have del(17p) in the CLL cells, then the duration of response is lower. That is the reason why you want to get the testing done beforehand. Otherwise the treatment options are essentially identical.

Then chemoimmunotherapy certainly remains an option. But I think with the availability of all of the novel agents, this has really fallen out of consideration and none of you chose that option to begin with. I am glad to see that.

[00:16:21]

First-line Management of CLL: Continuous Therapy With Covalent BTK Inhibitors

What about continuous covalent BTK inhibitors?

[00:16:23]

Phase III A041202: Ibrutinib ± R vs BR for Untreated CLL Older Patients - End of Chemoimmunotherapy Era in CLL

These are data from the ALLIANCE study that compared ibrutinib with or without rituximab against bendamustine-rituximab in older patients with CLL in the frontline setting. You can see in the progression-free survival curve, the 1 in green is with bendamustine and rituximab. That is clearly inferior compared to both the ibrutinib containing regimens in orange and teal. This suggested that ibrutinib was far better when it is given in a continuous fashion compared to chemotherapy in the front-line management of CLL.

Now, in this trial, crossover was allowed from bendamustine-rituximab to single-agent ibrutinib at the time of disease progression, and hence there was no difference In overall survival. However, the tolerability of ibrutinib was so much better that most people said this is the preferred treatment option compared to BR.

The other notable finding from this study was the absence of an improvement in PFS with the addition of rituximab to ibrutinib. If you are going to choose ibrutinib, that alone is sufficient. You do not have to add an anti-CD20 antibody to ibrutinib because there was no apparent difference in PFS.

[00:17:32]

ELEVATE-TN: Frontline Acalabrutinib (Indefinite Therapy) ± Obinutuzumab vs CIT (Time Limited)

A separate study investigated a second-generation BTK inhibitor called acalabrutinib and compared that to chlorambucil and obinutuzumab and a third arm of acalabrutinib plus obinutuzumab. Similar to the prior study I was talking about, except in this older patient population, the comparator arm was chlorambucil and obinutuzumab, and instead of rituximab, the preferred CD20 antibody here was obinutuzumab. Again here, if a patient did have progression of disease on chlorambucil and obinutuzumab, crossover to single-agent acalabrutinib is allowed. This is previously untreated CLL patients, the ELEVATE-TN study. The primary endpoint was really a PFS comparison between acalabrutinib to chlorambucil and obinutuzumab.

[00:18:17]

ELEVATE-TN: PFS

As you can see at the most recent update of these data, patients in the orange curve who received chlorambucil and obinutuzumab had a far lower progression-free survival compared to both the acalabrutinib containing arms in blue on the top.

Now, interestingly, here, the addition of obinutuzumab to acalabrutinib had a significantly longer progression-free survival compared to acalabrutinib alone. At 6 years, there was about a 16% PFS difference. These data are intriguing and do suggest that the addition of obinutuzumab is better compared to single-agent acalabrutinib. However, the challenge is if you are going to choose a BTK inhibitor to be given continuously in a patient and not use venetoclax and obinutuzumab, which is the fixed duration therapy, you are trying to avoid the complications of the infusion, the fact that the patient has to come in every week for the first 3 weeks, and then every month for the next 5 months for an infusion.

A lot of people do not think that it is readily feasible to do the addition of obinutuzumab despite this impressive PFS difference. In my practice, if I am going to choose acalabrutinib, I will typically use it as a single agent. But I will try to think about adding obinutuzumab in a select group of patients. These include patients who have, let us say, autoimmune cytopenias where I am trying to get a faster response to the hemolytic anemia, or ITP, or if a patient has skin involvement or has glomerulonephritis or some other reason why I want a faster response. In that group of patients, I think it is reasonable to add the obinutuzumab.

Again, there was no overall survival difference between these arms again because of the crossover that was allowed.

[00:20:07]

ELEVATE-TN: Safety Analysis

Now, these are the safety data. This is no surprise because we have now begun to understand and appreciate the adverse events of special interest, which include atrial fibrillation, bleeding, hypertension in patients who receive a BTK inhibitor. You will see that the risk of atrial fibrillation was about 7% with acalabrutinib to 6% in the combination arm with acalabrutinib and obinutuzumab to about 0.6% of the chlorambucil and obinutuzumab. This is a real signal, and we need to counsel our patients about atrial fibrillation so that they can understand when they need to call if symptoms of AFib are beginning to appear.

Similarly increased risk of bleeding and hypertension. Now, these are present, and I will talk about this in a minute, are lower compared to ibrutinib which is a first-generation BTK inhibitor. But they are certainly not zero. We need to educate our patients to know about these side effects.

[00:21:07]

SEQUOIA: Frontline Zanubrutinib (Continuous) vs Bendamustine/Rituximab (Fixed Duration)

The third covalent BTK inhibitor that has recently gained FDA approval is zanubrutinib. These are data from the SEQUOIA study, where there were many cohorts in this frontline previously untreated patient population. But the specific cohort I am referring to here is cohort 1, where patients without del(17p) were randomized to either zanubrutinib 160 mg twice a day or bendamustine-rituximab.

[00:21:33]

SEQUOIA: PFS

Again, much like the other data that we have seen, treatment with zanubrutinib is associated with a longer progression-free survival compared to bendamustine and rituximab. Again, these data suggest that using a continuous BTK inhibitor is much better compared to any chemoimmunotherapy that you can use.

[00:21:52]

SEQUOIA: Safety

Similar data with safety for zanubrutinib as well. Here again you will see cardiac events and bleeding events, etc, being more common in the BTK inhibitor containing arm compared to bendamustine and rituximab.

Now, there are certain unique side effect profiles. For acalabrutinib, headache is a very common thing that happens in the first couple of weeks. It responds to Tylenol; it responds to caffeine. If a patient complains of that, these are effective measures. There are similar risks of hypertension with zanubrutinib. Again, that may be 1 unique differentiator of the toxicity profile between the 2 drugs.

There are no head to head comparison studies of acalabrutinib to zanubrutinib for us to tell which one is better, but for the most part, both appear to be very effective and are less toxic compared to the first-generation BTK inhibitor ibrutinib, which is really why both of these have really become the agents of choice when you choose continuous BTK inhibitor based therapy in CLL.

[00:22:58]

Common and Important BTK Inhibitor Toxicities in CLL

Here are some of the common toxicities. We talked about all of these. On the left, there are some other toxicities including arthralgias, myalgias, diarrhea, fatigue. A lot of these may be nuisance side effects. You can lower the dose, hold the treatment for some time, and things get better and you can put the drug back on. Then there are other toxicities like nail changes that respond to biotin, nausea, rash, etc. Again, you can hold the drug and then you can restart with the same dose or a slightly lower dose if it occurs again.

[00:23:38]

Monitoring and Managing BTKi-Related AEs in Practice

For the most part, these BTKi related adverse events for atrial fibrillation, hypertension, really, we try our best to coordinate care with our colleagues in cardio oncology who are really the experts in helping us manage AFib and hypertension. We routinely will get a 12-lead EKG to try and help predict who is going to likely get AFib or hypertension, or if someone has AFib at baseline, then you monitor them a little bit more closely, and you can make dose adjustments if they are on concomitant anticoagulation, particularly if they are on antiplatelet therapy as well, there is a higher risk of bleeding.

Then there are many other ways by which you can manage some of the common toxicities. Some of these are written over here. There are prospective data that actually suggest that switching from ibrutinib to either acalabrutinib or zanubrutinib, you can mitigate many of these side effects or reduce the incidence, or sometimes even stop the BTKi completely if a patient has received the treatment for at least a year or 2 years, preferably, because then they have achieved a good partial remission.

If these side effects are too difficult for the patients to handle, they do not necessarily have to continue with treatment for the long term.

[00:24:59]

ELEVATE-TN: PFS in Patients With del(17p) and/or Mutated TP53

Then what about deletion 17p or TP53 mutation? I just have data from 1 trial. Here you will note that those patients who have deletion 17p actually have an inferior PFS compared to those who do not. In the solid blue line, you will see with del(17p) in the doublet of A plus O arm. That PFS is much lower compared to those patients who received A plus O but did not have del(17p) in this dotted line up here suggesting that if you do have del(17p), your PFS is lower.

Now, interestingly, there was no difference in the PFS for patients who received A plus O vs A alone in those who had del(17p), suggesting that the addition of antibody was not terribly effective. Again, the standard of care in a patient who does have del(17p) in the front-line setting is continuous second-generation BTK inhibitor with either acalabrutinib or zanubrutinib.

[00:25:57]

SEQUOIA (Cohort 2): PFS in Patients With del(17p)

These are data from zanubrutinib from cohort 2 of the SEQUOIA study. Now, I will just remind everyone that if you practiced many years ago, when FCR was the only treatment option available for us, even in patients with del(17p), the median PFS in the frontline setting with FCR in patients with del(17p) was about 18 months.

Now, here you see that at 5 years, the median PFS is not reached, and it is about 72%. These are remarkable data, and they really show how the field has evolved and changed. Our patients are so much better off having many of these agents available to treat them or treat their disease.

[00:26:39]

GAIA/CLL13: Time-Limited First-line Venetoclax + Anti-CD20 mAb ± Ibrutinib for CLL

We talked about continuous therapy. What about fixed duration therapy?

Here are some data talking about venetoclax. In CLL, when you use venetoclax, typically, in the frontline setting, we will talk about venetoclax being used in a fixed duration setting for 1 year. Here are data from the CLL13 trial that look at ibrutinib plus venetoclax plus obinutuzumab. That is the triplet regimen combined compared to venetoclax and obinutuzumab compared to venetoclax and rituximab compared to chemoimmunotherapy.

This is a large phase III study led by the German CLL study group where the primary endpoint was MRD undetectable status across all of these 4 arms.

[00:27:28]

GAIA/CLL13: uMRD in PB at 15 Mo

Not surprisingly, you will note that the highest MRD undetectable status was noted with the triplet arm of I plus V plus O compared to V plus R which was at 57% and 52% with the chemoimmunotherapy arm. The V plus O regimen was also very effective with an undetectable MRD rate of 86%.

These are the first data that actually compared the MRD undetectable status of V plus R, rituximab compared to V plus obinutuzumab. Because of these data now typically we would consider the use of obinutuzumab for any CLL patient. Because that antibody certainly seems to be much more potent in inducing a response and getting a longer PFS, as we will see in the following slide.

[00:28:19]

GAIA/CLL13: PFS at 3 Yr

Here this compares the PFS of venetoclax plus rituximab in green to venetoclax and obinutuzumab in orange. You can see it is much better with the addition of obinutuzumab to venetoclax.

[00:28:32]

GAIA/CLL13: PFS at 3 Yr

In contrast, the addition of ibrutinib plus venetoclax and obinutuzumab in the steel color was not any better compared to V plus O, although now at PFS at 4 years at the most recent meeting, we did see that there was a slight separation of curves, suggesting that the triplet is better than the doublet of V plus O, although I think we need to be a little bit cautious before applying that routinely to our patient population.

Regardless, it appears that any obinutuzumab containing regimen with venetoclax certainly is far better compared to rituximab plus venetoclax in the frontline setting for CLL.

[00:29:10]

GAIA/CLL13: Safety

Safety data were pretty consistent with what we would expect. There were lots of infections, unfortunately, in this group of patients, and you will note that the risk of infections with chemotherapy was about 20% compared to about 22% with the triplet regimen. I know at least 1 person in the group chose the triplet regimen of acalabrutinib, venetoclax, and obinutuzumab. In the question that I had posed, you have to be a little bit careful in an 80-year-old patient with the use of this triplet regimen. These data predate COVID. There was a high incidence of infection.

Unfortunately, in an 80-year-old patient, infections can really become problematic, particularly because of obviously their age, comorbidities, but also treatment-related infections can actually push them over the edge. I would be careful using a triplet regimen in an older patient population.

[00:30:04]

Management of Venetoclax-Associated Toxicities

We all are aware of the venetoclax-associated toxicities. There is a risk of tumor lysis syndrome. This is really based on the knowledge and what we saw with the initial studies where patients really developed rapid CLL cells, lysis and kidney failure. There is now this very nice risk assessment profile that is set up. All patients actually should undergo a CT scan before starting treatment to accurately classify the risk of TLS into low, intermediate and high because this is really based on the lymph node size.

Then depending on how you do debulking strategies, there are risk mitigation strategies with allopurinol, rasburicase, etc. In general, I try to power through the venetoclax as best as I can by giving you elasto growth factor support. Because if the neutropenia is because of treatment, but the patient also has significant bone marrow infiltration by CLL, giving venetoclax and continuing with the dose escalation is the only way you can actually clear the bone marrow. The patient will need G-CFS support along the way. That is really the best way of pushing through the treatment.

Of course if a patient does have significant neutropenia and gets admitted to the hospital or has febrile neutropenia, certainly that time you should hold the drug and go back to treating the patient's infection and then reintroducing the dose escalation schema.

[00:31:34]

Obinutuzumab vs Rituximab in CLL

We talked about this. This is obinutuzumab vs rituximab. We really would encourage the use of obinutuzumab in the frontline setting simply because in randomized phase III studies, increased undetectable MRD rates and PFS with the use of obinutuzumab. Of course, that comes with some cost, and this is really the infusion reactions that happen. Really, use lots of premeditation, liberal use of corticosteroids before the start of infusion while the patient is receiving infusion.

It is split in 2 days. The first time is 100 mg, and then the next day is 900 mg. But the 100-mg dose is really where you get into trouble. Many times, we would just extend the infusion from 4 hours to 6 hours, etc. and go very slowly and tell the patient that we expect that there will be a side effect of infusion reaction, but we know how to deal with it.

[00:32:30]

What is the Optimal Frontline Treatment Approach

I talk to you about continuous BTK inhibitor-based therapy with ibrutinib, zanubrutinib, and acalabrutinib. We talked about fixed duration therapy with venetoclax and obinutuzumab. What is really the frontline treatment approach?

[00:32:42]

Factors Considered by Experts When Choosing Between Covalent BTK Inhibitors and Venetoclax + Obinutuzumab

I mean there is no one size that fits all. Thankfully, all of these are acceptable options. But then you choose treatments based on what the patient's comfort level is with proceeding with a certain treatment type. For example, this patient did not want to come to the infusion therapy center, so obinutuzumab infusions are going to be hard sell in that patient. A continuous BTK inhibitor might be just fine.

If a patient is on dual antiplatelet therapy because they had a stent in the heart placed, they have AFib, etc. In that patient population, a BTK inhibitor is going to be a difficult thing to do. I think depending on the patient's comorbidities, toxicity profile, etc., I think that is really where you really have to make a decision.

[00:33:25]

Which Therapy Is the Best Initial Therapy in CLL?

In that setting, it is very comforting to see that regardless of what treatment option you choose, the PFS outcomes are pretty comparable for the vast majority of the drugs. Now, of course, the PFS is not as good in a fixed duration setting such as CLL 14, where venetoclax and obinutuzumab was given, if you compare that with continuous BTK inhibitor–based treatment.

However, you can always retreat patients with venetoclax containing regimen if they have disease progression after fixed duration therapy, which obviously is not true if a patient is receiving single-agent continuous BTK inhibitor–based therapy. If you get continuous BTK based therapy, you are not able to give them that same agent when they do have progression or disease.

I am just looking at the question here that says, how do you talk to patients about trade-offs between fixed duration therapy and continuous therapy? I think the way I tell them is that there is a pill that you have to take continuously every day. You have to remember to take that on a daily basis and it can be associated with nuisance side effects, the risk of bleeding, the risk of atrial fibrillation, rash, hypertension, etc. That comes with financial toxicity as well.

On the other hand, fixed duration therapy, yes, there is a higher upfront effort required because if you do venetoclax and obinutuzumab, which is the only frontline treatment option available so far in the US, you need to be seen or come to the clinic at least once a week for the first 9 weeks as you go through the ramp up. Then you are done with the treatment in a year.

Yes. There is an initial upfront investment of time and effort, but you are done in a year and then you do not have to then take a pill every day for the rest of the next several years. The median PFS as you can see are 6 years with the use of venetoclax and obinutuzumab, whereas it is about 75% at 5 years with the use of any continuous BTK inhibitor-based treatment.

In general, I prefer the fixed radiation therapy, and I try to steer my patients towards that, because I truly think that that works very well, gives us the flexibility of using the same drugs down the road, should a patient have progression of disease or even switch to a BTK inhibitor down the road, if necessary.

But then there are unique situations, like if a patient does not want to come into the infusion therapy center, or if a patient has TP53 mutation. There as you saw, the continuous BTK inhibitor-based therapy was really the preferred treatment option because there was a longer PFS associated with it.

My bias would be to think about doing fixed duration therapy. But there would always be instances where a patient cannot do that in which case I think it is perfectly fine to do continuous BTK inhibitor. In fact, the PFS is better there. That is how I tried to navigate this. But again, you could choose either or, I do not think you would go wrong.

[00:36:42]

AMPLIFY: First-line Fixed-Duration Acalabrutinib + Venetoclax ± Obinutuzumab vs CIT in CLL

Again, another question here is, do you prefer zanubrutinib or acalabrutinib in patients with cardiac issues on anticoagulation? I generally prefer zanubrutinib in that instance. The reason I do that I would say that is because zanubrutinib is available in 80-mg pills. The dose is 160 mg twice a day. I generally prefer reducing the dose of the BTK inhibitor by 50% if someone is on apixaban or Lovenox or something like that.

Doing 80 mg twice a day with zanubrutinib is possible. With acalabrutinib, you do not have 50 mg pills, so you can only do 100 mg once a day. That does not scientifically sound correct. In general, I prefer using zanubrutinib in that group of patients where I do have to dose reduce them if there is concomitant anticoagulation going on.

The more recent study was the AMPLIFY study, which looked at acalabrutinib plus venetoclax compared to the triplet, acalabrutinib, venetoclax, and obinutuzumab, or to FCR and BR.

[00:37:47]

AMPLIFY: PFS per IRC

These data showed that the triplet regimen of AVO was associated with a superior progression-free survival compared to acalabrutinib and venetoclax compared to FCR or BR. It is likely that either or both of these regimens will gain FDA approval.

Now, I do not show you the overall survival curves here, but in the overall survival curves, AV was better compared to AVO. When you see in any phase III trial where a PFS rate is better with a regimen, but overall survival is worse, it means that there was increased toxicity noted with that regimen and which in fact was the case with AVO as well. There were more infection related deaths in AVO.

What this means is that if AV does become an approved option, in fact, both of these are now on the NCCN guidelines. A plus V will likely become an all-oral fixed duration therapy where AV is given for 14 cycles. That is an option available to you for your patients where instead of using obinutuzumab as the agent to debulk prior to starting venetoclax, you would actually use acalabrutinib for 2 months prior to starting venetoclax.

This is an attractive treatment option for patients. It works very well. I think obviously these are early data with a median follow up of about 4 years. This is early in the CLL world. I think longer follow-up will be very instructive and we all eagerly await to see the next set of data cut off.

[00:39:17]

AMPLIFY: AEs of Clinical Interest

Again, much like every other BTK inhibitor-based treatment, there were more cardiac events noted, more bleeding events noted with A plus V or A plus VO compared to the chemoimmunotherapy arms.

[00:39:30]

SEQUOIA Cohort D: First-line Zanubrutinib + Venetoclax in CLL

Similar data have also been published with first-line zanubrutinib and venetoclax regimen. At this time, this is neither on the NCCN guidelines nor has it been approved by the FDA. But again, these are very promising data that show that you can administer fixed duration therapy with a different type of a BTK inhibitor called zanubrutinib with venetoclax.

[00:39:54]

Revisiting Case 1: Patient With Previously Untreated CLL

Just revisiting this case, 80-year-old, initially lymphocytes, watch-and-wait, normal cytogenetics, unmutated IGHV, now has progressive disease. Has hypertension, chronic kidney disease. Lives 45 minutes away and now needs treatment.

[00:40:10]

Posttest 2

What would you choose?

1. Chemoimmunotherapy;
2. Ibrutinib;
3. Acalabrutinib or zanubrutinib;
4. Venetoclax plus obinutuzumab; or
5. The triplet of V-A-O.

Speaker: The polling is open. Please vote. I will give everybody just a few more seconds. Here are your results.

Dr Parikh: Okay. Most everyone chose a second-generation BTK inhibitor, which is great. I think V plus O is not the bad option at all. It would work very well, except if the patient does not prefer to drive to the infusion therapy center, you may not be able to do it. But I think this is great.

[00:41:16]

Case 2: Patient With Relapsed CLL After BTK Inhibitors and Venetoclax-Based Therapy

Let us now talk about relapse/refractory CLL. Let us start with the question. I have a few minutes. I would like to see how much we can get through for the relapsed/refractory portion of things.

This is a 64-year-old male diagnosed with stage IV CLL many years ago, has hypertension, but has unmuted IGHV genes deletion 11q by FISH. No TP53 mutation. Was initially treated with ibrutinib and rituximab and then venetoclax and obinutuzumab, and actually continued with venetoclax and now returned to see you earlier this year and has progressive disease with lymphadenopathy. White count is increased. Hemoglobin is low. Repeat CLL FISH shows no changes. NGS profile now shows a new TP53 mutation. There is clonal evolution, and then there is worsening lymphadenopathy and splenomegaly.

[00:42:07]

Posttest 3

The question is in this patient who has received ibrutinib initially as first-line therapy, has received a second-line therapy and is now having disease progression on venetoclax. What would you treat this patient with? Would you:

1. Continue venetoclax;
2. Switch to acalabrutinib;
3. Switch to pirtobrutinib; or
4. Switch to zanubrutinib; or
5. Switch to a PI3 kinase inhibitor and a CD20 antibody.

Speaker: The polling is open. Sorry about that, Dr Parikh. I opened that a little bit early on you. Give everybody a few more seconds. Here are your results.

Dr Parikh: I think this is important to talk through. The correct answer is really C or 3, which is switch to pirtobrutinib. I will tell you why.

This patient has had disease progression on ibrutinib. Ibrutinib is a covalent BTK inhibitor. Acalabrutinib and zanubrutinib are also covalent BTK inhibitors. Technically, it would be unlikely for the patient to have a response to either of these 2 agents. You obviously would not continue venetoclax in a patient who is having disease progression on venetoclax.

Switching to PI3 kinase inhibitor is fair, but I think those treatments in CLL are associated with increased toxicity. Pirtobrutinib in contrast is a non-covalent BTK inhibitor, and the binding site of pirtobrutinib on the BTK molecule is different compared to any of the covalent BTK inhibitors. It has now been approved by the FDA in the management of patients that have had prior disease progression on both the BTK inhibitor and a BCL-2 inhibitor, much like this patient.

[00:44:14]

Guideline-Recommended Second-line Therapy for CLL/SLL

That is also on the NCCN guidelines. Now, they mentioned second-line therapy, but you have to remember what are the 2 or 3 prior lines of therapy or 1 prior line of therapy the patient has had. In this case, because the patient has received ibrutinib we would not expect acalabrutinib or zanubrutinib to work. That is why in the preferred regimens, the top 2 options would not be correct.

In addition, venetoclax and obinutuzumab, the patient already on the venetoclax. That does not make sense. Therefore pirtobrutinib is really the correct option in this patient.

Now, you could also choose a combination of venetoclax and ibrutinib. But generally speaking that would not yield a lot of PFS benefit compared to pirtobrutinib, which is really where this question was driving towards.

[00:45:01]

Relapsed CLL: Prior CIT Only (Naive to All Novel Agents)

There is still a population of patients in our clinic where we see them after they had received FCR or BR 5 or 10 years ago and have never received any novel agents. All the data that we talked about in the frontline setting are applicable over here, and there are lots of studies that show that acalabrutinib or zanubrutinib given continuously really work very well and both of these agents in head-to-head comparison studies have shown that they are better tolerated compared to ibrutinib.

In my practice, if I am going to choose a single-agent BTK inhibitor in a continuous fashion in the first relapse after chemoimmunotherapy, I am happy to choose either of these 2 to be given continuously.

On the other hand, venetoclax and rituximab given for 2 years, you give rituximab for 6 cycles and venetoclax for 2 years, and this is pirtobrutinib MURANO regimen would actually be another option for treatment in a patient that has never received a novel agent in the past.

Now, because we just discussed that obinutuzumab is better compared to rituximab, we can easily switch the rituximab out to obinutuzumab. It is now on the NCCN guidelines, and therefore it is easy to obtain insurance approval. This is again fixed duration therapy.

You could use venetoclax continuously as a monotherapy in patients with del(17p) because that is on label. This is in patients who have never received any novel agents.

[00:46:27]

Approach to Relapsed CLL

But how about a patient that has received a novel agent? Here is an algorithm that I try to follow. If a patient has received a prior covalent BTK inhibitor like ibrutinib, zanubrutinib, or acalabrutinib and has not received a BCL-2 inhibitor, then the first question to ask is why was the BTK inhibitor discontinued? If it was for toxicity, you could consider an alternative covalent BTK inhibitor. Example switch from ibrutinib to zanubrutinib or acalabrutinib.

Or if those toxicities are really problematic like a faber, bleeding, etc, you can directly switch over to venetoclax and obinutuzumab. On the other hand, if the reason for the discontinuation of BTK inhibitor was progression of disease, then you obviously have to choose a different treatment class, which is venetoclax. Then at this point, the patient should be evaluated for either CAR T therapy or a transplant, depending on the patient's age, availability of donor, etc., because then the patient has had disease progression on both the best agents that we have.

On the right is the treatment algorithm, where a patient has previously received venetoclax. Someone got venetoclax plus obinutuzumab CLL14 as a first-line therapy. They have never received BTK inhibitor. Again, if they had venetoclax discontinued for toxicity, you got to go to a covalent BTK inhibitor. If they had disease progression on venetoclax, go to a covalent BTK inhibitor.

But increasingly, we see patients who have progression of disease after they finished 1 year of V plus O. In that case, you go to how long the duration of responses has been. If it has been long, and long is variably defined, 24, 36 months, you can retreat with venetoclax and obinutuzumab.

On the other hand, if it is a short-lived duration of response, you can go to a covalent BTK inhibitor. The patient that we talked about was really over here, which would be double refractory CLL. We will go over some of those data.

[00:48:19]

Mechanisms of Disease Resistance to Ibrutinib

The mechanisms of disease resistance to ibrutinib or any covalent BTK inhibitor are where you start seeing mutations in the BTK gene PLC gamma 2 gene or both of these. This is really where switching from ibrutinib, which is a covalent BTK inhibitor, to another covalent BTK inhibitor, would not make sense.

You would see some of these mutations up to a year prior to actual clinical progression of disease. If you start seeing a patient who is on, let us say ibrutinib and has evidence of lymphocytosis, and you check for 1 of these mutations and you find a BTK mutation, simply the presence of a mutation should not make you switch treatment.

We have had patients who have remained on ibrutinib, or any of the covalent BTK inhibitors for up to a year, a year and a half after having mild lymphocytosis detected prior to actual clinical disease progression that would necessitate treatment change.

You want to maximize the amount of time that you can get on a BTK inhibitor and that is really the rationale for waiting before switching.

[00:49:22]

Efficacy of Venetoclax-Based Regimens After BTKi Failure

Now, these are data that show the efficacy of the venetoclax-based regimens after BTKi stops working. You can see that the prospective study there is only 1 with 91 patients where about  half of them had ibrutinib discontinued because of progression of disease and the median progression-free survival was not that great, it was about 20 to 22 months, suggesting that once you have disease progression on ibrutinib, venetoclax is not expected to work for a very long period of time. Two years and then you are starting to think about alternative treatment strategies, suggesting that this is a high-risk group of patients.

On the right, again, these are retrospective analyses from 2 different institutions, again showing similar median PFS. That is not very good at about 14 months or even 20 months. Again, once you have a patient that has had disease progression on ibrutinib and you are going to give venetoclax, start thinking about what next you are going to offer this patient and that is where we will talk about pirtobrutinib in a minute.

[00:50:20]

Efficacy of Therapies After Venetoclax

You can always retreat with venetoclax. For the sake of time, I am not going to go through this slide. But again remember that you can give venetoclax again after fixed duration therapy.

[00:50:29]

A Growing Patient Population of Unmet Need

This is where a growing population of unmet need is with dual refractory CLL, where a patient has had both BTK inhibitor and a BCL-2 inhibitor. These patients unfortunately have very poor outcomes.

[00:50:43]

Guideline-Recommended Therapy for R/R CLL/SLL Prior BTK Inhibitor and Venetoclax-Based Therapy

In this group of patients is where after 2 prior lines of therapy with a BTK inhibitor and venetoclax is where pirtobrutinib or liso-cel, which is CAR T therapy, are really recommended.

[00:50:55]

Noncovalent BTK Inhibitors Can Overcome BTK Resistance

The rationale for this is that none of these newer non-covalent BTK inhibitors, so pirtobrutinib is one and nemtabrutinib is the other one. They do not bind to the site where these covalent BTK inhibitors bind, which is to the C481 residue. They bind in a different site, and they decrease the activation downstream signaling etc, by binding in a separate site. Therefore, irrespective of what the mutation might be at this site where the covalent BTK inhibitors bind, these molecules are expected to work.

[00:51:27]

BRUIN: Pirtobrutinib (Noncovalent BTKi) for Previously Treated CLL/SLL

In fact, these are data from the BRUIN study, where pirtobrutinib was used in a large set of patients, about 282, where you can nicely see the response rate in the waterfall plot on your right. This really was very impressive data.

[00:51:43]

BRUIN CLL/SLL: PFS

You can see that the median PFS, after the failure of both BTK inhibitor and BCL2 inhibitor was about 19 months. Now, it was longer in patients who did not receive venetoclax in the past, so about 22 months, compared to patients who did receive a BCL2 at about 16 months. But regardless, it just shows that this is an effective treatment option in patients who have had progression disease on both of these agents. This is really where you want to think about getting patients on pirtobrutinib.

Now, the challenge, of course, is that this is not a home run unfortunately, right? 19.6 months is great because previously before this drug was available and approved, this was not even an option. But this is still not something that you can tell of a 65-year-old patient, for example, that okay, this is great. You still need to think about what else you are going to do after this agent is going to not continue to work and that is where you think about liso-cel and other investigational agents.

[00:52:41]

BRUIN CLL/SLL: Pirtobrutinib Safety Profile

The safety profile of this drug was very good. The risk of hypertension, atrial flutter/atrial fibrillation was much lower compared to many of the other covalent BTK inhibitor, suggesting that this is a very safe drug. In fact, you see it in the clinic. A lot of patients take this and they do not even know that they are on the drug, which is really phenomenal.

[00:53:01]

Revisiting Case 2: Patient With Relapsed CLL After Inhibitor and Venetoclax-Based Therapy

Just revisiting this case, I think for the sake of time, I am not going to question you again. But again, this patient had ibrutinib, venetoclax and had progression of disease so we would switch to pirtobrutinib in this case.

[00:53:15]

BELLWAVE-001: Nemtabrutinib for R/R CLL

I will just maybe spend 2 more minutes and then I will be done. But these are data from a different non-covalent BTK inhibitor called nemtabrutinib. Again, this is similar to pirtobrutinib. It binds to a different site. It is not as far along in the development process yet as pirtobrutinib, but there are increasingly data becoming available that look at the efficacy of this drug in patients who have received both prior BTK and BCL2 inhibitors. You will note that they have an impressive overall response rate of about 60% and 40% in cohorts, with or without a prior BTK C481S mutation.

[00:54:01]

BELLWAVE-001: Nemtabrutinib AEs of Special Interest

There were several side effects noted. Note that rash was prominent, but not as prominent as some of the other side effects that were noted. Low risk of atrial fibrillation.

[00:54:13]

Select Ongoing Phase III Studies of Noncovalent BTK Inhibitors in CLL/SLL

There are many, many clinical trials ongoing at this time with the use of nemtabrutinib and pirtobrutinib, which are both non-covalent BTK inhibitors in CLL.

[00:54:24]

Posttest 1

Hopefully, this will get to the point where it will likely be approved. Although a lot more data need to be generated with this agent. I will just end with this posttest question. Which of the following accurately describes nemtabrutinib?

1. It binds to BTK target via C481S site;
2. It demonstrated activity after previous BTK inhibitor and BCL2 inhibitor;
3. It is approved in combination with the venetoclax; or
4. Rash is the most common adverse event.

Speaker: The poll is open. Please vote. Here are your results.

Dr Parikh: Okay. Wonderful. Thank you all very much for joining. I think I will not have time to go through the last few slides, but just a couple final questions.

[00:55:29]

Poll 3

Do you plan to make any changes in your clinical practice based on what you learned in today's program?

1. Yes;
2. No;
3. Uncertain.

Speaker: That poll is open. Please vote. Here are your results.

[00:55:54]

Poll 4

Dr Parikh: Okay. Thank you. Then, if you can please take a moment to text in 1 key change that you plan to make in your practice based on this education. The QR code is on your screen.

Speaker: Again, the text box is here. If you would like to type in your response, you are welcome to do that. In the meantime, I will open the floor to our moderator. Dr Parikh, if you will advance our slide for me, please, to the next slide. There you go. Right there, please. Our moderator will jump on and say a few more things for you. Okay. Since I am not hearing our moderator, I will say it.

[00:56:51]

Q&A

I think I saw 1 more question submitted to you. Did you see that?

Dr Parikh: No. I am looking at this. Tips for managing atrial fibrillation or bleeding risk. I mean, it is hard. It is not easy. I will mention 1 thing is that I will first question if a patient is on a BTK inhibitor, whether they really need to continue with it or not, if they develop 1 of these complications of bleeding or atrial fibrillation?

For example, in the front line E1912 study that compared ibrutinib and rituximab to FCR in CLL, if patients stopped ibrutinib because of toxicity, the average time to the need for retreatment was about 2 years. Similar data have been published from Ohio State University as well.

What this tells me is that if a patient develops a side effect from ibrutinib or any of the BTK inhibitors, such as atrial fibrillation or bleeding, I will first question, does the patient still need any treatment at all? Because they may have achieved a very good partial remission or a complete remission, which is rare, but does happen. Then I do not need to treat the patient with anything. I just stop the treatment. I will say, let us just monitor and see how things go, and we will deal with your CLL if and when it does come back, eventually.

In that patient population where you really have to continue BTK inhibitor, I will partner very closely with our cardio oncology colleagues and try to figure out how to best treat the atrial fibrillation. Then I will typically reduce the dose of the BTK inhibitor by 50% to prevent bleeding issues and particularly for patients on concomitant anticoagulation.

In short, I try to look for reasons not to continue the BTK inhibitor, but if I really have to, I will reduce the dose by 50%. I will partner very closely with cardio-oncology.