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Expanding Options in CLL/SLL: What Hematology/Oncology Nurses Need to Know

Newly Diagnosed CLL/SLL

Amy Goodrich: Let us dive into newly diagnosed CLL/SLL.

[00:04:01]

Overview of CLL/SLL

Let us look at a little overview. I am sure you are all aware this is the most common leukemia in the Western world. It is chronic, generally incurable. Today, most people are diagnosed on routine blood work, with all of the routine blood work that our population gets for various reasons. Many patients are not symptomatic at the time of diagnosis.

They are often observed for a period until they meet criteria for therapy. We will talk about those criteria in a minute. You can see this is a group of older folks, although younger people do get diagnosed with CLL, most are on the older side, just under 25,000 cases expected, and under 5,000 deaths. That five-year survival is really nice at almost 90%. With the growing number of therapies, these people do very well for a very long time.

[00:05:00]

Diagnosis and Prognosis

Diagnosing CLL is done on flow cytometry. Bone marrow biopsies, or tissue biopsies, are not necessary. They do happen at times, but most people are diagnosed just on peripheral blood flow cytometry. CLL and SLL small lymphocytic lymphoma are identical diseases. CLL has more than 5,000 circulating lymphocytes in the peripheral blood.

The SLL version of that is mainly nodal or with splenomegaly and not having that lymphocytosis component. Unfavorable prognostics, and I do not care what disease you have that TP53 mutation and/or deletion 17p are always high risk. Unmutated IGHV is high risk. We are going to talk about that in a second, as is 11q and ZAP-70 but favorable is mutated IGHV mutation status, and that deletion of 13a as the sole abnormality. Then our neutral ones are normal cytogenetics or trisomy 12.

[00:06:13]

Prognostic Variables in CLL/SLL

Again, looking at prognostic variables. We talked about our FISH studies, our deletion 17q, trisomy 12, down to 17p. Looking at a complex karyotype, beta-2 microglobulin is a recommended test as well. We talked about our IGHV status and TP53 testing. Then, on the right, there are baseline and acquired mutations on the right side, but I want to take you to the bottom with the mutations that are associated with resistance to targeted therapies.

It is that C481S that is the most common BTK inhibitor mutation. There are a growing number of recognized mutations that make these BTK inhibitors and BCL2 inhibitors less effective or frankly ineffective. That number is just going to grow as we learn more about the molecular science behind these agents and the resistance mechanisms.

[00:07:28]

CLL: Dynamic Monitoring vs Treatment

Why do we watch patients with CLL? If you split CLL patients into thirds, only about a third will require therapy at or shortly after diagnosis. Another third are watched for a number of years. Some people are watched for 5, 10, 15 years before they require therapy. That means two-thirds of patients will eventually require therapy. That leaves a third of patients that never require treatment. This is really a large part of the reason why we do lots of observation if patients are doing well and feeling well.

[00:08:14]

Indications for Treatment

What are indications for treatment? First of all, if you have a patient who is eligible for a clinical trial, there are trials that get done in the population that would otherwise be observed. If patients have disease-related symptoms fever, unexplained weight loss, drenching night sweats, profound fatigue with no other cause, progressive lymph nodes, big spleens, cytopenias from the marrow getting more busy making CLL cells, and losing capacity to make normal cells, then the autoimmune cytopenias, and it is usually autoimmune hemolytic anemia, that prompts treatment of CLL.

[00:09:03]

CLL Pathophysiology

Here is our IGHV status. For those of you who hear these terms and do not really understand these terms, this is part of where the malignant hit occurs. This is what drives the IGHV status. I want to take your eye to the top. We start with a naive B cell and go to the top where that cell interacts with T cells and memory B cells.

If that is the line where the malignant hit occurs, that is a mutated IGHV status. That cell actually mutates when it is exposed to those other parts of the immune system. That is a more mature cell that becomes malignant. All of us have a point of reference who work in oncology, that the less mature and the less well defined a cell is when the malignant hit occurs in general, the more aggressive the disease is.

If you can just take that concept and go to the bottom, the naive B cell that may interact with parts of the immune system, but does not really interact with T cells. Does not interact with memory B cells. Gets around the block a little bit, but not the exposure, and that mutation of developing memory that the top develops. That is a less developed, less mature cell. If the malignant hit occurs there, they have an unmutated IGHV status. Those patients tend to have more problematic disease.

[00:10:52]

Prognostic Implications of IGHV Mutation Status in CLL

This is a slide showing us that. This is median overall survival. The unmutated folks are on the bottom. Those are the ones with the less developed cell at malignant hit versus mutated, which is the blue. The mutated folks do better.

[00:11:13]

Chromosomal Deletions/Duplications in CLL

Then why do all these FISH studies matter? They matter because in general, patients with 17P deletions, and that is our orange, really do not do as well as folks with other chromosomal abnormalities. If you look at first time to first treatment, the 17ps tend to need treatment sooner.

These overall survival rates that you see down at the bottom, those pre-date our novel therapies that we are going to be talking about. In general, they still hold true that 71p deletions are our highest risk patients, and our 13q as a sole abnormality are our best risk patients.

[00:12:10]

Major Mechanisms of Action of Current Initial CLL Therapies

What are these new therapies that we are going to be talking about? If we come around from the left, we see CD20 there. We are all familiar with rituximab and obinutuzumab that they hook onto the cell, and they call in good fighting cells, NK cells, all cells to come and attack that whatever the CD20 is hooked on to. I forgot down here the DNA damage. That is our old bread and butter chemotherapy just knocks out DNA.

If we go back around by our CD20 and we go to the B cell receptor pathway inhibitors, the B cell receptor pathway is a critical pathway in CLL. It is responsible for both survival of cells and the maturation of cells and programed cell death. When the B cell receptor pathway goes wrong, the cells divide at higher rates than they should, and they do not die.

Our BTK inhibitors are covalent inhibitors are ibrutinib acalabrutinib zanubrutinib, and our non-covalent. Our FDA-approved agent is pirtobrutinib. They block BTK, turn off those grow and never die signals. Then PI3 kinase inhibitors have a similar mechanism of action but a different pathway. Those are idelalisib and duvelisib that we really rarely use today.

There was a time we used those more readily in CLL. Then, if you keep going around the circle, that is where our BCL2 inhibition comes, and that is our venetoclax. BCL2 is responsible for programmed cell death. When that pathway goes wrong, venetoclax blocks that [?] pathway and the concept of apoptosis or programmed cell death comes back to that cell.

[00:14:20]

Guideline-Recommended First-line Therapy for CLL/SLL

Let us look at guidelines for first-line therapy.

[00:14:23]

Case 1: Patient With Previously Untreated CLL

First, let us dive into a case study. Mr. A is a 69-year-old diagnosed about four years ago with CLL. He has got well controlled hypertension. He has got good risk disease. He has that mutated IGHV 17q deletion. No TP53 abnormality. He is watched for a number of years. His white count is now 189. There is no magic white count.

The issue is the bone marrow gets busier and busier, making CLL cells and loses its capacity to make normal cells crowds out the capacity to make normal cells. We see that hemoglobin dropping. It is 10. Platelets are consistently under 100,000. His spleen is palpable, and he has got lots of palpable lymphadenopathy. We recheck his prognostic variables. He is had no change. Treatment is appropriate at this point. He lives two hours from your office. He really wants to minimize his visits. He is the primary caregiver for his wife, who has dementia.

[00:15:34]

Pretest 1

In discussing treatment options, what do you think is going to be the optimal therapy for this guy? Is it going to be chemo immunotherapy, something like FCR or bendamustine and rituximab? Do you think it is going to be a first-generation BTK inhibitor or ibrutinib, a second-generation acalabrutinib or zanubrutinib, or do you think he is going to get venetoclax with obinutuzumab?

Dwight: Poll is open.

Amy Goodrich: And then the second part is how confident are you in your answer?

1. You are guessing;
2. You are probably right; or
3. You are sure.

Dwight: Five more seconds. We will close the poll and share the results.

Amy Goodrich: Let us see if this is the right answer. We will talk about this.

[00:16:48]

NCCN Guidelines for 1L Treatment of CLL/SLL

If we look at our NCCN guidelines for first-line treatment of CLL/SLL, it is broken out into with that 17p deletion or TP53 mutation. Our good risk patients versus our high risk patients, those with a 17p or TP53 mutation. You can see here they are broken out into BCL2 inhibitor-containing regimens and covalent BTK inhibitor regimens in both - with or without 17p deletions.

You can see we have got acalabrutinib with venetoclax with or without obinutuzumab, which is fixed duration on top and its measurable residual disease guided on the bottom. Venetoclax and obinutuzumab fixed duration is there for both of those. Some of them are similar. Then we have our continuous BTK inhibitors acalabrutinib with or without obinutuzumab and zanubrutinib.

I want to take your eye to other recommended. This is where our ibrutinib-containing regimens are. Because ibrutinib has more side effects, it is our first-generation BTK inhibitor, it has more side effects than our second-generation drugs of acalabrutinib or zanubrutinib. It is not a preferred single agent in with or without 17p deletions. We are really using in first-line acalabrutinib or zanubrutinib, and rarely using ibrutinib in the first line.

[00:18:33]

BTK Inhibitors for CLL/SLL

What are these BTK inhibitors? They are small molecule inhibitors. We talked about the B-cell receptor signaling pathway. Toxicities. Atrial fibrillation which these are in alphabetical order. It happens. It is uncommon. Very common is aspirin like antiplatelets effects with bruising and easy bleeding. That is a very common side effect.

Although major bleeding can happen, it is uncommon. Other side effects include infection, hypertension, cytopenias, and GI adverse events. Historically, we thought that patients who were on BTK inhibitors, anticoagulation was not contraindicated, but we were always nervous putting patients on BTK inhibitors who were on anticoagulants. What we are learning is antiplatelet therapy actually increases the bleeding risk more than anticoagulation. That is a philosophy shift based on the long-term data and long-term follow-up. Bleeding is always an issue and something that you are thinking about with BTK inhibitors.

[00:19:55]

Be Prepared to Review Dosing and Drug Interactions With BTK Inhibitors When Counseling Patients

I am not going over this. These are the doses. They are all CYP3A drugs. If you do not have a pharmacist in your practice, hopefully somebody is figuring out the dosing of these drugs when there are drug-drug interactions, and there are no issues with gastric acid-reducing agents for any of these drugs.

[00:20:17]

Overview of BTK Inhibitor Toxicities in CLL

Toxicities. Some common toxicities, we talked about some of these. Bleeding, atrial fibrillation is not common, but it is something that we talk about all the time with patients. Arthralgias, infection, diarrhea, hypertension derm changes fatigue. Patients rarely but can have ventricular arrhythmias and cytopenias. All of these side effects tend to reduce the longer the patient is on the drug, except hypertension. That peaks year three, four, or five. That tends to be something that happens later rather than earlier.

[00:20:58]

BCL-2 Inhibitors for CLL/SLL

What about BCL2 inhibitors? They target anti-apoptotic mitochondrial surfaces on the BCL2 protein. What happens is they turn on programmed cell death. That rapid apoptosis or programmed cell death can cause tumor lysis syndrome. Our only currently FDA-approved drug is venetoclax. We have got some others coming, and you can see them there.

Hopefully, when you think of BCL2 inhibitors or venetoclax, the first thing you think of is tumor lysis syndrome. We never had a drug before in CLL that worked so effectively and rapidly that we had overwhelming tumor lysis syndrome risks. It is very safe now. Those of you who treat CLL patients know that. We will talk about that in a bit.

BCL2 inhibitors were originally studied in combination with our anti-CD20 either rituximab or obinutuzumab, their combination oral IV. Then newer regimens include a BCL2 inhibitor with a BTK inhibitor. Those are our oral options. The issue with BCL2 inhibitors is that they induce very deep remissions. BCL2 inhibitor-based therapies are time limited. Because they again, get patients into very deep remissions.

The are fixed-duration measurable residual disease, typically measured by flow cytometry, those things. These regimens are superior over chemoimmunotherapy. Again, they are fixed duration, so patients get their therapy and then they are off therapy for a number of years, which is great. Again, side effects, tumor lysis syndrome, cytopenias, GI fatigue, arthralgias, other than that, tumor lysis syndrome, a pretty typical panel of issues.

[00:23:15]

Venetoclax Dosing and Administration Clearly Explain the Ramp-up Dosing Schedule

Initially, there were a couple episodes of fatal tumor lysis syndrome because patients started 400 mg on some of the early clinical trials. When that happened, and the investigators realized that this drug worked so rapidly, this ramp up was established where patients get 20 mg for a week. Then 50 a day for a week, 100 mg, 200 mg. Then it is that fifth week that they get up to 400 mg. There have been no episodes of fatal tumor lysis syndrome with this ramp-up. This has really become a very safe and effective drug to give.

[00:23:58]

Preferred Regimen Fixed-Duration Combinations for CLL: Initial Therapy

Fixed duration combinations. Just to show you some of this, and I am not going over this in great detail because you have the references. You can go back and look at this. Venetoclax and obinutuzumab is a one year therapy. AVO, acalabrutinib, venetoclax, and with or without obinutuzumab is 14 cycles. Then, with or without 17p deletions, it is 14 cycles or 15 cycles.

With a 17p deletion, it is all measurable residual disease driven. It stops based on whether there is still measurable residual disease, so you are really chasing those deep dive evaluations of those patients. Then the latest regimen, maybe not the latest, but venetoclax and zanubrutinib, which is also measurable residual disease guided. That is up to 28 cycles. They are all slightly different.

[00:25:02]

Choosing Between Treatment Options

How do you choose? There are patient factors. Who is the person in front of you. Like our guy who lives two hours away and takes care of his wife. He is not really looking to make trips back and forth for tumor lysis monitoring. What comorbidities do they have? What other drugs are they on? What are their prognostic showing.

Then the regimen, is it an oral drug? Is it oral and IV? Can the patient be adherent to the regimen? Are they interested in a regimen? All of these regimens work, and they work well. They have different side effects and different requirements for visits and monitoring. Really explaining that to patients, there is no right or wrong answers here. That is why the patient really has to be at the table deciding which of these therapies fit into their life best.

[00:26:01]

Frontline BTKi vs Ven + Obinutuzumab: Factors to Consider

Some other considerations if you are just using a BTK inhibitor, again, acalabrutinib, or zanubrutinib is what we are using. They are convenient. There is no infusions. There is no tumor lysis monitoring. We have got lots of long-term data. It is better than chemotherapy. We have a lot of data on using a BTK inhibitor and then going to a venetoclax-based regimen.

If you look at venetoclax with obinutuzumab it is a potential one year time limited therapy. There is no cardiac or bleeding risks. There is less long-term adherence issues because it is a year and out. Then there is a potential cost savings of that one year of therapy if they have an extended remission, which many patients do.

[00:26:55]

Goals of Continuous vs Fixed-Duration Therapy in CLL/SLL

Again, when explaining this to patients, really the goals of continuous therapy are disease control prolonged, progression free survival. We are not shooting for deep remissions. Patients they can be on these BTK inhibitors for years and years. If you do flow cytometry on their blood, you can find CLL.

They are not in deep remissions, but they are in durable remissions, versus fixed therapy that really eradicating disease at a very deep level where there is undetectable measurable residual disease is the goal. That equates into prolonged progression-free survival as well. Both of these options are great. It is just whatever sounds better to the patient.

[00:27:45]

Posttest 1

Back to our 69-year-old who is taking care of his wife and lives a couple hours away. In discussing treatment options, what do you think that he is most likely to get? Is it

1. Chemo immunotherapy;
2. A first-generation BTK inhibitor, ibrutinib;
3. Second-generation acalabrutinib or zanubrutinib; or do you think he is going to get
4. Venetoclax and obinutuzumab?

How confident are you in your answer?

Dwight: Poll is open. Five more seconds. We will close the poll and share the results.

Amy Goodrich: We did better. It is the second-generation BTK inhibitor acalabrutinib, or zanubrutinib. Remember, we are not really using ibrutinib much anymore. Then that venetoclax and obinutuzumab has a lot of back and forth visits, and this guy wants to minimize those.

[00:29:05]

Relapsed/Refractory CLL/SLL

Relapsed refractory.

[00:29:10]

Pretest 2

Which of the following most accurately describes the current FDA-approved indication for pirtobrutinib in CLL? Is it for

1. Newly diagnosed or relapsed refractory; is it for
2. Adults with relapsed refractory after a covalent BTK inhibitor;
3. Relapsed refractory after a covalent BTK inhibitor and a BCL2 inhibitor; or
4. Adults with relapsed refractory CLL after greater than two prior therapies, including a covalent BTK inhibitor and a BCL2 inhibitor.

Dwight: Poll is open.

Amy Goodrich: How confident are you? Sorry, I missed that.

Dwight: Five more seconds. We will close the poll and share the results.

Amy Goodrich: Pretty even. Hopefully we will up that.

[00:30:23]

Case 2: R/R CLL

Let us dive into a second case. Mr. B is an 85-year-old. He has got early stage prostate cancer that he had a prostatectomy for. He has got hypertension and diabetes, both well controlled on oral agents. He was diagnosed with CLL 12 years ago. Good risk disease mutated IGHV deletion 13q. He received acalabrutinib.

He had a good initial response. After five years on therapy, he progressed, and he was noted to have a C481S resistance mutation. Remember, that is the most common resistance mutation for patients with CLL on BTK inhibitors, covalent BTK inhibitors. What it really means is that there is a binding pocket.

When the C481S mutates, it cannot hook in anymore, and so there is no effect because the binding pocket mutates, and the drug cannot hook in there. That is how ibrutinib, acalabrutinib zanubrutinib, they all work through that same binding pocket. If a patient is resistant to one covalent BTK inhibitor, they are resistant to all of them. He has had no change in his prognostics.

He is watched for a while and then is treated with venetoclax with obinutuzumab. He has detectable measurable residual disease post-therapy, but gets a year of treatment and stops. Three years later, he is progressing, and his repeat prognostic testing reveals a new 17p deletion and TP53 mutation. Patients can have clonal evolution and start out with good risk or average-risk disease and then develop higher-risk features.

[00:32:26]

Pretest 3

Which of the following management approaches best incorporates patient-centered communication to address disease progression risks, benefits, and support adherence? Are you going to

1. Counsel him on treatment deferral with close monitoring because he is elderly; are you going to
2. Get him prepped for pirtobrutinib, and talk about adverse events and drug interactions; are you going to
3. Anticipate talking to him about chemo immunotherapy, or do you think that
4. He is going to restart his acalabrutinib because he did well for five years prior.

How confident are you?

Dwight: Poll is open. Five more seconds. We will close the poll and share the results.

Amy Goodrich: All over. Hopefully, we can improve on that, too.

[00:33:42]

NCCN Guidelines for R/R CLL

In the relapsed refractory world, so you can see we have got second-line or subsequent therapy in general. Then we have relapsed refractory disease after prior covalent BTK inhibitor and BCL2 inhibitor. If you look at the top second line and beyond, we have got our - you know if you did not use Ven-O initially, you can use it second line.

If you did not use a covalent BTK inhibitor at initial therapy, you can use it second line. This is a change. Pirtobrutinib is now FDA-approved for patients who are intolerant or resistant to a prior covalent BTK inhibitor-based therapy. It used to be that they had to have had a BTK inhibitor and a BCL2 inhibitor.

Now all you have to do is have had ibrutinib, acalabrutinib, zanubrutinib, and either be resistant or intolerant. Remember, our guy is resistant. He does meet the criteria for pirtobrutinib. Then, after a covalent BTK inhibitor and BCL2 inhibitor regimens, this is where we are seeing again pirtobrutinib is an option there as well. Then that is where CAR T comes in. We will talk about that in a minute. Then there is lots of other things. Lenalidomide comes in alemtuzumab or Campath, some different options come in.

[00:35:21]

Sequencing of Novel Therapies in CLL

Sequencing our novel therapies again, much of it depends on what a patient has received before. Have they gotten a covalent BTK inhibitor with or without an anti-CD20? Have they relapsed after both covalent BTK inhibitor and BCL2 either in sequence or in combination? Then this is really the population that we need, a growing number of therapy options. There are bispecifics being tested, but this is where CAR T comes in. We really need more novel approaches for those folks who have had all of these drugs and are still needing more therapy.

[00:36:04]

Key Biomarker Testing to Inform R/R CLL/SLL

Biomarkers. Remember, if patients do not have high-risk disease, if they do not have a 17p deletion or a TP53 mutation, checking makes sense because it is prognostic. If they are having clonal evolution and developing more abnormalities, that makes them higher risk. IGHV does not change. That does not need to be repeated. The FISH studies definitely should be repeated if they are not high-risk.

[00:37:53]

Summary of Pivotal Studies With Covalent BTK Inhibitors and Venetoclax in R/R CLL

Amy Goodrich: Pivotal studies with our covalent BTK inhibitors and venetoclax. You can see here. I am not going through this. This is in the relapse refractory data on acalabrutinib, zanubrutinib, as well as venetoclax. All of these drugs work very well. Again, our BTK inhibitors alone are continuous therapy. When we are folding in a BCL2 inhibitor, it is always time-limited.

[00:38:25]

Rationale for Combining BTK Inhibitors With Venetoclax

Why do we combine these drugs? They have different mechanisms of action. Remember that cell we saw? They have non-overlapping toxicity profiles. They act on different compartments of CLL cells. Then the synergy potentially deepens the response. Then, in most of these combination regimens, actually all of them, the BTK inhibitor is given for a number of months before the venetoclax is started, so patients get debulked. Then that tumor lysis syndrome risk is reduced when you start the venetoclax.

[00:39:09]

What Strategies Can We Use in Heavily Pretreated or Double-Refractory CLL

What can we do for these heavily pre-treated or double-refractory patients? If they have gotten a non-covalent BTK inhibitor, then they are eligible pirtobrutinib. If you see this bold in December 2025, approval expanded to patients previously treated with just a covalent BTK inhibitor. They do not have to have had venetoclax to be eligible for pirtobrutinib. We have got CAR T coming. When patients are resistant or have progressed through a BTK inhibitor and venetoclax, all of the things on the right are very unlikely to work. PI3 kinase inhibitors, chemo immunotherapy, more covalent BTK inhibitors, unlikely to benefit.

[00:40:00]

With Covalent BTK Inhibitors, Resistance Mutations Are a Major Driver of CLL Progression

What are these resistance mutations? These are a major driver of why patients are not staying on BTK inhibitors long-term. They develop resistance. You can see in this pie chart that there are a number of resistance mutations that are being recognized. C481 is the most prevalent, but there are others being recognized.

[00:40:33]

Noncovalent BTK Inhibitors Can Overcome BTK Resistance

This is where pirtobrutinib comes into play. If you go to the right, you can see where the covalent binding happens in C481. That is where ibrutinib, acalabrutinib zanubrutinib bind. Remember, I talked about that pocket, and then when the pocket mutates the drug cannot hook on, and they stop working. If you go to the right our non-covalent BTK inhibitors, and this is pirtobrutinib, it does not bind in at that C481 pocket. It does not matter if that is normal or mutated. It hooks on elsewhere on the cell. When patients progress through our covalent drugs because they develop a resistance mutation, pirtobrutinib is effective because it does not bind in at that same place.

[00:41:28]

What Are the Implications of Covalent and Noncovalent BTK Inhibitor Selectivity for Off-Target Effects?

Then what about side effects? We talked about ibrutinib being our first-generation BTK inhibitor, and then acalabrutinib and zanubrutinib being our second and pirtobrutinib being our third generation. In general they are more selective as each iteration has come and have less off target effects.

If you go to the bottom, tech is one of the off-target effects that is thought to be responsible for bleeding and cardiac toxicity. Those of you who are seeing solid tumor patients, all about EGFR, the rashes, the diarrhea, the arthralgias. You guys know this like the back of your hands. Those are off-target effects with these BTK inhibitors. Again, really, each drug that has come to market has had fewer off-target effects and better tolerance. We still have more work to do, that is really why ibrutinib has fallen out of favor, because it has the most off-target effects.

[00:42:34]

BRUIN CLL-321: IRC-Assessed Progression-Free Survival

Let us look at pirtobrutinib. This study looked at pirtobrutinib versus idelalisib with rituximab or bendamustine rituximab for CLL patients. You can see those curves splitting, and the pirtobrutinib patients are doing better here.

[00:42:53]

BRUIN: Pirtobrutinib Safety Profile

Safety profile. Even though it is our third-generation drug and it has the best safety profile, it really has a lot of those similar toxicities, just lower incidence. I want to go to bleeding - with ibrutinib, acalabrutinib zanubrutinib, up to 50% of patients will have bleeding. It is into the 30s with pirtobrutinib. Also, the hypertension AFib, a-flutter neutropenia rates, those are all better with pirtobrutinib than the first and second generation drugs.

[00:43:32]

CART T-Cell Therapy for CLL/SLL

How about CAR T? Liso-cell is our only FDA-approved CAR T agent. It is approved for third line and beyond. Patients have to have had a covalent BTK inhibitor, and they have to have had a BCL2 inhibitor. I am not going to get into the mechanisms of action of CAR T therapy. If you are doing it, you know it. If you are sending patients in for it you know that they can have lots of toxicities.

By the time they get back to you, the acute things are over, and you are dealing with the hypogammaglobulinemia and infections, and maybe low blood counts. There is a cytokine release happens, neurotoxicity happens. This is an emerging option for CLL patients. We are all trying to figure out the right patients for CAR T with CLL, but this is a great option for them. Their bispecifics are in studies with CLL. I am hoping that those will be options as well at some point, like we have with our lymphoma patients.

[00:44:41]

Posttest 2

Let us go back to pirtobrutinib. Where is Pirtobrutinib FDA-approved? Is it for newly diagnosed or relapsed refractory disease? Is it approved after a covalent BTK inhibitor? Is it approved after both a covalent BTK inhibitor and a BCL2 inhibitor, or do patients have to have more than two lines of prior therapy that include a covalent BTK inhibitor and a BCL2 inhibitor? Then how confident are you?

Dwight: Poll is open. Thank you. We will close the poll and share the results.

Amy Goodrich: 56% are correct. Just a covalent BTK inhibitor. Again, that did change relatively recently, just in December, so hot off the press.

That is our correct answer.

[00:46:00]

Posttest 3

Here is another. Which of the following management approaches best incorporates patient-centered care to address disease progression risks, benefits, and support adherence.

1. Are you going to counsel them - this guy on the - do you think he is just going to continue to be watched because he is old and he is had a lot of therapy?
2. Do you think he is going to start pirtobrutinib, and you are counselling him on that.
3. Do you think he is going to start bendamustine and rituximab, and you are going to start counselling on that?
4. Do you think he is going to restart his acalabrutinib because he had a five-year remission?

How confident are you?

Dwight: Poll is open. Five more seconds. We will close the poll and share the results.

Amy Goodrich: 53% are correct. Remember he is gotten acalabrutinib venetoclax, and obinutuzumab. He has a resistance mutation, so pirtobrutinib is the best option for him.

[00:49:30]

Case 3: Managing AEs

Managing adverse events. Miss Z is a 59-year-old. She started acalabrutinib as her initial therapy. She comes in for a nurse visit two weeks after starting therapy. She has new headaches, new joint aches. She has daily headaches. They are not severe, but they are low-level. They are bothersome. Her joint aches are intermittent, and they are worse in the evening or after she is super active.

[00:49:57]

Pretest 4

What is the optimal management of this patient's adverse event? Do you think

1. Acetaminophen 650 as needed;
2. Ibuprofen every eight hours for three days. Then, as needed;
3. Oxycodone is needed; or
4. Do you think she needs a steroid pulse?

Again started acalabrutinib. New headaches, new arthralgias, and myalgias.

Dwight: Poll is open. Five more seconds. We will close the poll and share the results.

[00:51:04]

Common and Important BTK Inhibitor Toxicities in CLL

Amy Goodrich: Common toxicity is of special interest are those arrhythmias, AFib, ventricular arrhythmias, bleeding, hypertension infections. Our most common issues are anemia, arthralgias, myalgias, cough, diarrhea, headaches neutropenia. Patients can have cytopenias, nail changes, nausea, rash, lymphocytosis.

[00:51:35]

Managing Bruising and Hemorrhage

I am not going through this in great detail. This is showing you how common that bruising and easy bruising is up to 50%, but very few major hemorrhage. The really important things are dose reductions holding. Then if patients are having invasive procedures, any procedures you are holding three days before and after minor procedures, seven days before and after major procedures. Then we talked about the blood thinners and anti-platelet agents that may increase bleeding risk arrhythmias.

[00:52:16]

Managing AF and Cardiac Arrhythmias

Again, atrial fibrillation is the most common. You can see this is relatively low volume, less than 5% for all of these. It is not an indication to discontinue. You can continue treatment if the atrial fibrillation is controlled. If you are having a really hard time, if your cardiologists are having a really hard time controlling the atrial fibrillation, you can either dose, reduce, or go to a more selective agent, but really teaching on signs and symptoms of atrial fibrillation is important.

[00:52:57]

Managing Other cBTKi-Related AEs

Other BTK inhibitor-related adverse events you can see here diarrhea, hypertension, infection, neutropenia, thrombocytopenia, and what you do about those. Our case study had headaches. Acalabrutinib has the highest incidence of headaches, and usually last a month or two. It is acetaminophen and caffeine that help the most. You should avoid NSAIDs, things like ibuprofen, because they increase bleeding risk as well as the drug. Really avoiding any NSAIDs that are going to increase bleeding risk. Then, musculoskeletal pain, really just treating that symptomatically. You may need dose reductions or dose interruptions there.

[00:53:47]

Patient and Caregiver Discussions: What AEs to Expect/Monitor While Taking BTK Inhibitors

Patient education, really discussing those adverse events, talking about the bleeding and bruising. They should be monitoring for GI bleeding, blood in stools, blood in urine, blood in their sputum. If they are having significant bleeding and bruising, I have a patient who plays pickleball, and he will come with these massive hematomas on his legs. He stresses me out.

Then wallet cards, they should be carrying a wallet card. Then really talking about all new medications. Again, there is CYP3A pathway drugs. They interact with lots of things. They should not get live vaccines, and typically that is MMR, but they should be getting their annual COVID boosters, their shingles vaccines, their flu shots, those are definitely acceptable. The recommendations in the NCCN guidelines is to do a cardiovascular risk assessment on patients.

We are trying to get into the habit of doing a baseline EKG. You could think about going back to your practice and discussing doing baseline EKGs because it is recommended that you do this risk assessment. The NCCN guidelines do not tell you what to do. Baseline EKG seems like a reasonable thing.

[00:55:15]

Understanding Challenges to Adherence and Persistence With Oral BTK Inhibitors

Challenges to BTK inhibitors. These are oral drugs. Cost is an issue. Health literacy. Managing side effects so that patients do not stop taking their drug because it makes them feel bad. Really, educating them. Trying to have patients get into a routine, whether it is a diary or an app or something to remind themselves, shared decision making is really important because we know that when patients are part of decision making, they are more adherent to their regimen. Then, really maximizing the benefit trying to keep patients on drug. You are the ones who are doing the education, and patients are really honest with you about what is going on. That is critically important.

[00:56:07]

Most Frequent Grade ≥3 AEs with Venetoclax + Obinutuzumab

We are going to jump into venetoclax and obinutuzumab. Again, major side effects, neutropenia, thrombocytopenia, but very few episodes of febrile neutropenia.

[00:56:18]

Venetoclax for CLL: TLS Risks Stratification and Prophylaxis

This is the tumor lysis syndrome risk stratification and prophylaxis. This is in the prescribing information. Low and medium-risk patients are - if it is based on lymph node size and absolute lymphocyte count, those get outpatient dosing for patients at high risk. They are typically admitted for their first two doses, their first 20 mg and their first 50 mg dose. They get more intensive tumor lysis monitoring. I really look at this often. I try not to just memorize this, but everyone should get allopurinol. Everyone should get hydration of some sort.

[00:57:04]

Key Questions to Ask When Considering Fixed-Duration Regimens

When you are thinking about starting venetoclax, you have got to make sure that the patient can stay hydrated. That they are compliant with meds, with the ramp-up. Do they have transportation back and forth because there is lots of blood draws? Those first two months are pretty intensive. Then do they have support at home? Patients can have late obinutuzumab infusion reactions. Those are some of the things you are thinking about.

[00:57:30]

Building Trust: Shared Decision-making

Shared decision-making, we talked about this a little bit. It is really important that patients are part of the team here because they are more adherent, they have better outcomes. They are more satisfied if they are part of the team. We have to empower them to understand their options so that they can make the decision that works best for them. Again, these are all great options for patients.

[00:57:54]

Patient Engagement: Considerations Among a "Menu" of Treatment Options for CLL/SLL

We have got this menu. We have got oral. We have got infusion, we have got combinations. We have fixed duration, we have continuous. We have disease control versus deep remission. The toxicities are different. We may guide a patient to one option or another based on comorbidities. There are cost issues that we are always thinking about for our patients.

[00:58:19]

Posttest 4

Let us go back to our last patient who started acalabrutinib. New headaches. New arthralgias and myalgias. Started acalabrutinib two weeks ago, comes in to see you. What are you going to tell them? They are having new headaches, new joint aches. Are you going to use

1. Acetaminophen as needed;
2. Ibuprofen running for three days, then as needed;
3. Oxycodone;
4. Pulse steroids.

Are you guessing? Are you sure? You think you are right, or you know you are right? Hopefully, everybody knows this one.

Dwight: Poll is open. Five more seconds. We will close the poll and share the results.

Amy Goodrich: 82% are correct. That is the correct answer.

Ibuprofen that is the drug of choice because it does not cause bleeding and it works very well. Acetaminophen and caffeine.

[00:59:38]

Poll 4

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

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

Dwight: Poll is open. Five more seconds. We will close the poll and share the results.

Amy Goodrich: Yes, and uncertain, that is wonderful.

[01:00:22]

Poll 5

Poll five. If you would take a moment to enter one key change that you plan to make based on this education, that would be really important. I would be interested, is there something that we did not cover that you would like covered too? If one change is great and - much feedback as you can give is important.

Dwight: Once again, you can scan the QR code and text in your response, or we do have a polling box open where you can simply just type in your response. Amy, we will leave the polling box open, and we can go ahead and move forward. Great.

[01:01:00]

Q&A Session

Amy Goodrich: This is our question and answer. If anybody has questions, I am happy for you to shout them out, put them in the chat. I thank you for attending. Wendy is going to close out with all this content. If anybody has questions, please let me know.

Wendy: Thanks so much, Amy. We are now taking questions. Please, for those online, use the Q&A function in Zoom to submit your questions. Adrian, if there are questions from the in-person group in North Carolina, will you please open the mic and let us know?

Adrian (DCE): I have no questions in the room.

Wendy: Thank you so much. Amy, I do see a couple of questions that are submitted in the Q&A. If you can see the Q&A on your side. Dwight, if you will please pull up the QR codes. While you are looking for that, we are going to pull up the QR codes. In addition to the QR codes that we are pulling back up, I did put the links to the evaluation and the program resources directly in chat. You will have that information there. Just a reminder, you do need to be logged in to or create and log in to your DCE account at deceraclinical.com/education, and then these will work for you.

Amy Goodrich: I see these questions. There are three questions. What patient education do you feel is most important at diagnosis? I think just the fact that it is a chronic disease and really explaining the prognostics and what those mean to patients is really important, and then making sure they understand what monitoring that we are going to be doing.

I find that it is much easier for patients to wrap their head around CLL if they know somebody with prostate cancer, because this is very similar. There is a lot of observing. Really, it is just making sure they understand their prognostics and the fact that this is a chronic disease, and observing is really the backbone unless they are having symptoms.

How do you counsel a patient who is anxious about starting treatment, despite having a - about not starting treatment? Yes. We have lots of data that shows that we do not help patients have better outcomes treating them early versus waiting until they actually need treatment. Remember that that little one-third, one-third, one-third.

A third will need treatment shortly after diagnosis. A third can be watched for an extended period of time, and a third never need treatment. I do talk to patients about that to make sure that they understand that there is a third of a chance they may never need therapy, but then letting them know that we really do have very effective and well-tolerated treatments.

Then what side effects or adherence challenges do you anticipate with pirtobrutinib? It is still a BTK inhibitor. I find that some of the most difficult issues for patients are the GI side effects initially. Making sure that they know to take Imodium, that they have got their antiemetics with them. By the time patients get to pirtobrutinib, typically, they have had a few regimens.

They tend to have some count issues. Those can be challenging. Again, remember that is our third generation. It is got the lowest side effect profile of any of them. Patients tend to tolerate pirtobrutinib relatively well compared to the others, although it is really hit or miss what side effects patients have. Just really educating them and watching them like a hawk when they first start. I think those are all the questions we have had. I went five minutes over. I am very sorry.

Wendy: Thank you so much, Amy. Thanks to everybody who joined us today. As we close out our webinar, we will leave the QR codes up on the screen here for a couple of minutes for everyone to get. Ensure that you have time to grab that and go online and complete your evaluation and claim your credit. Thanks again for your teaching today, Amy. We appreciate your time, and thanks to everyone who joined us. With that, we will close our program.

[END OF TRANSCRIPT]