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We will start with Frontline Therapy Selection: Aligning Guidelines and Risk Stratification to Select Targeted Therapies for CLL/SLL in the Frontline Setting.

Interactive Case Question: First-Line Treatment

We will do an interactive case question. This is a patient we are deciding first-line treatment for. This is Mr. Green. He is a 63-year-old man who presents for treatment after being diagnosed with CLL previously. Mr. Green has a past medical history of hypertension and diabetes, and he is coming in today because he has now developed symptoms and lab abnormalities with cytopenias.

His testing has revealed that he is wild-type 17p, TP53 and has immunoglobulin heavy chain gene mutation. The patient preference is to have a fixed-duration all-oral regimen because of his career as a truck driver and difficulties coming in for infusion.

Pretest3

In this scenario, what treatment would you recommend? Again, it is summarized here on the left. Would you advise:

1. Acalabrutinib and venetoclax;
2. Acalabrutinib and obinutuzumab;
3. Obinutuzumab and venetoclax;
4. Pirtobrutinib or zanubrutinib.

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

Dr. Maddocks: Okay. A mix here, but the majority of people did pick the first choice of acalabrutinib and venetoclax. Again, in this situation, there is not necessarily a wrong answer with several of these can be chosen. This is taking into consideration both the medical perspective and then the patient preference to not have to come in for infusions with the obinutuzumab.

NCCN Guidelines Version 2.2026

Before we talk about the clinical trials, I just want to highlight the NCCN guidelines. This is the tables from the guidelines looking at suggested treatment regimens in the frontline setting. As you can see, they are divided by, on the top there, patients without deletion 17p or TP53 mutations. On the bottom, those with deletion 17p or TP53 mutations. Many of the preferred other recommended are actually fairly similar now in these boxes.

If you looked at preferred recommendations for those patients without deletion 17p and TP53, you have choices between both BCL2-containing regimens and covalent BTK-based regimens or a combination.

With the BCL-2, venetoclax/acalabrutinib such as what was just presented, plus or minus the obinutuzumab with fixed duration therapy, or venetoclax/obinutuzumab with fixed duration therapy.

Then covalent BTK-based regimens, continuous acalabrutinib plus or minus the obinutuzumab and then continuous zanubrutinib.

When you look at patients with 17p deletions or TP53 mutations, fairly similar. They do put the obinutuzumab/venetoclax and then the venetoclax/acalabrutinib/obinutuzumab with an MRD-guided approach or venetoclax/zanubrutinib with an MRD-guided approach, and then the continuous therapy with acalabrutinib plus or minus obinutuzumab or zanubrutinib.

Then in the top box, there are the MRD-guided approaches and venetoclax/ibrutinib for 17p.

Risk Stratification in CLL/SLL: TP53 and IGHV Mutation Status

When we look at the transition from chemotherapy to targeted agents, most of that came with trials that had compared chemoimmunotherapy regimens to targeted therapies. A lot of those initial trials looked at continuous targeted therapy. While we knew that targeted therapy was effective in beating chemo immunotherapy, there was also a question about do these targeted therapies need to be given in continuous fashion or as fixed duration therapy with targeted therapies adequate, particularly in certain risk patient populations.

The CLL17 study set out to look at that question was giving fixed duration therapy with either obinutuzumab and venetoclax or ibrutinib and venetoclax in inferior to treatment with continuous BTK inhibitor in this trial in the form of ibrutinib.

What they showed is fixed duration therapy with these targeted therapies was not inferior to continuous ibrutinib in terms of the trial endpoint of three-year progression-free survival.

If you look across different risk subgroups that held for those patients with TP53, although the numbers of these patients were small and the follow-up is short, so this will benefit from longer follow-up.

Then looking at that by IGHV status, the same thing. Although there was, if you look in 88% three-year PFS for those patients with the mutated IGHV in the VO arm, suggesting they do very well, but showed that you could get these fixed durations and be noninferior to a continuous BTK inhibitor, which is the options that we see in the frontline treatment for the guidelines.

Measurable Residual Disease (MRD) Considerations in CLL

The other thing that we think about when looking at frontline treatment for CLL is the ability to achieve measurable residual disease. The CLL14 study did show with these fixed duration treatments that for patients who achieve an undetectable measurable residual disease, that they do have improvement in their progression-free survival at the end of that treatment compared to those who continue to be MRD positive by a pretty significant margin. So achieving this in this fixed duration therapy.

Now, if you look at the CLL17 study, we know that you do not see that level of MRD with the continuous therapy, but that therapy is given until progression.

Discussion Point for Initial Therapy Selection

Really, when we just went through the guidelines and there were other situations or select situations that we did not go through. Really the primary recommendations now for CLL, both in the 17p deletion, TP53-mutated patients and those without that are to consider therapy with these targeted therapy-based regimens.

In the interest of how we are set up with a virtual talk, I am just going to throw this out there for people to think about, and then of course if you want to type anything in the chat.

Just thinking about are there circumstances in which you would still consider using chemoimmunotherapy for treating a patient who requires initial therapy for their CLL/SLL, as we have pretty much transitioned to targeted therapy approaches.

Targeted Therapies in the Frontline Setting and Key Trials

Let us move on to further data for these targeted approaches in the frontline settings and just review some of the key trials.

Frontline Treatment Selection in CLL/SLL

When we are approaching frontline treatment really, as we discussed with the guidelines, we are weighing, are we thinking about BTKi alone or with CD20 antibody combinations? Are we thinking about venetoclax-based combinations, either with CD20 or CD20 and BTK or just with BTKi.

When we are thinking through this and balancing it and talking to a patient, we know that the BTKis have been shown to be superior to chemoimmunotherapy. We will briefly review that. It does by itself require continuous dosing. There is more cumulative data and long-term data in the patients with those 17p deletions, TP53 mutations.

As I mentioned, the CLL17 study, looked at three-year PFS, but we do not have long-term follow-up there.

There is convenience to this. If you are giving it alone without the CD20, there is no infusions for patients to come in. There is no need to monitor for TLS or prophylaxis for that. Then there are the cardiac and bleeding events that can occur with BTKi. We know that this is better with second-generation BTKis than it was with ibrutinib, but it is not nonexistent and still something to consider.

Then looking at the BCL-2 or venetoclax-based different regimens also shown to be superior to chemoimmunotherapy. Give patients the potential for time-limited therapy. So not being on treatment for the duration can decrease toxicity, can decrease cost for patients and just gives them a therapy free window. Potential for cost savings, requires a ramp-up period with monitoring and prophylaxis, so depending on the risk of the patient. Still requires that the therapy is escalated and that is monitored carefully.

Still if you use a combination of the BCL-2 and the BTK inhibitor, then you get the risks of both medications. So higher toxicity profile, but then also tumor lysis and cardiac or bleeding risks.

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

Just taking a look at the data here. For frontline acalabrutinib plus or minus obinutuzumab, which was one of the recommended therapies. This came from the ELEVATE Treatment-Naive trial.

This trial looked at frontline acalabrutinib in the form of continuous therapy, plus or minus obinutuzumab versus time-limited chemoimmunotherapy.

Now, some of these chemoimmunotherapy trials that will be discussed were compared to chlorambucil and obinutuzumab and not perhaps the best control arm. Nevertheless, these were the studies.

This trial was for patients with untreated CLL, ECOG performance of zero to two. They were stratified by deletion 17p. This randomized patients to one of three arms:

• The obinutuzumab/chlorambucil;
• Continuous acalabrutinib; or
• Acalabrutinib continuously plus the fixed duration of obinutuzumab.

The primary endpoint of this trial was progression-free survival. They showed that both acalabrutinib arms had a significant improvement in the progression-free survival over that of the fixed duration chemoimmunotherapy with PFS of 78% in the acalabrutinib arm and 62% in the acalabrutinib arm for median PFS and 17% in the chemoimmunotherapy arm.

AMPLIFY: Fixed-Duration Acalabrutinib + Venetoclax ± Obinutuzumab vs CIT for Previously Untreated CLL

Sticking with acalabrutinib, looking at the AMPLIFY study. This looked at fixed duration acalabrutinib and venetoclax, plus or minus obinutuzumab versus chemoimmunotherapy. This was randomized, open-label, phase III trial. Patients with untreated CLL, no high-risk deletion 17p or TP53 mutation. Again, a little over 500 patients.

The primary endpoint of this trial was to actually look at the PFS with AV versus chemoimmunotherapy with the key secondary endpoint of PFS with AVO versus chemoimmunotherapy.

Acalabrutinib/venetoclax/obinutuzumab versus acalabrutinib/venetoclax versus chemoimmunotherapy with FCR or BR for six cycles.

This trial showed that both the AV and the AVO were associated with significant improvements in progression-free survival over that of chemoimmunotherapy.

When you looked at toxicity profiles, there was similar number of serious AEs in the patients with the AV and the chemoimmunotherapy, but there was a higher incidence in the AVO group of serious adverse events.

AMPLIFY: OS

Looking at in terms of overall survival, the three-year overall survival was statistically significantly improved or prolonged with that of the AV over that of the chemoimmunotherapy with FCR or BR.

Now when you look at part of the survival here, again, as mentioned, there was a higher rate of toxicity, particularly in high-grade infectious toxicities with the addition of the CD20 to the AV regimen. There was a much greater number of COVID deaths in the patients with the AVO.

The AMPLIFY study is what led to the FDA approval of acalabrutinib in combination with venetoclax for the frontline treatment of CLL.

CLL14: PFS and OS With First-line Obinutuzumab + Venetoclax or Chlorambucil (Time Limited)

Switching from the BTK inhibitor acalabrutinib combination and fixed duration BTK plus BCL-2, we will go to the CLL14 study and look at just BCL-2 in CD20 antibody combination.

The CLL14 study looked at randomized patients with untreated CLL, a little over 400 patients, to treatment with obinutuzumab/chlorambucil versus that with obinutuzumab/venetoclax for all time-limited therapy.

The primary endpoint of this trial was progression-free survival, and that was statistically significantly improved with the obinutuzumab/venetoclax over the obinutuzumab/chlorambucil with a median overall survival not reached in either arm, but a six-year overall survival of 69% in the obinutuzumab/chlorambucil and 79% in the venetoclax/obinutuzumab arm.

CLL14 6-Yr Follow-up: PFS With 1L Obinutuzumab + Venetoclax or Chlorambucil

Again, primary endpoint was progression-free survival. This was statistically significant in terms of doubling the median progression-free survival.

When they looked at PFS by the TP53 mutation status, the numbers were small. Again, there were 25 patients. There was significantly better PFS in those patients who did not harbor the TP53 mutation or 17p deletion.

SEQUOIA: Frontline Zanubrutinib (Continuous) vs Bendamustine/Rituximab (Time Limited)

Now to take look at the SEQUOIA study looking at other BTK therapies. This looked at frontline zanubrutinib given in a continuous fashion versus time-limited therapy, again with chemoimmunotherapy, as most of these agents were approved based on trials randomized to chemoimmunotherapy.

This was a randomized phase III study. It actually had multiple cohorts. What we are going to talk about or focus on is cohort one, which was patients without 17p deletion who were randomized to either continuous zanubrutinib or fixed duration chemoimmunotherapy with the BR regimen.

There was separate cohorts then in patients looking at continuous zanubrutinib in patients who had 17p deletion, but these were not randomized to the chemoimmunotherapy.

The primary endpoint of this trial was progression-free survival.

SEQUOIA 5-Yr Follow-up: PFS With Zanubrutinib vs BR

Again, similar to what we saw with the other targeted therapies versus chemoimmunotherapy, the continuous BTK with zanubrutinib had statistically significant improvement in progression-free survival over that of BR with a median PFS not reached versus 44.1 months. As you can see here, looking at it by the IGHV mutation status in mutated or unmutated patients with those patients doing better significantly with the zanubrutinib in both arms.

Frontline Treatment Selection in CLL/SLL

Just taking a step back to how we are looking at balancing. Thinking about the same things, but in the front-line treatment, preferred options. If you are going to do continuous BTK, include acalabrutinib and zanubrutinib.

We did not go over most of the front-line ibrutinib data because it has now been shown that when you look at acalabrutinib and zanubrutinib in randomized trials compared to ibrutinib, that there is an improved toxicity profile, particularly in terms of the cardiac and bleeding events with these second-generation BTK inhibitors.

However, if a patient is preferring time-limited therapy, thinking about a BCL2-based regimen, either venetoclax in combination with obinutuzumab, venetoclax in combination with acalabrutinib, or venetoclax in combination with both acalabrutinib and obinutuzumab. This is where patient preference might come into play if there is concerns about going in for infusion or if there is concerns about toxicities from the BTK inhibitor.

Interactive Case Question: First-line Treatment

Now we are just going to go back to Mr. Green, who was our first-line treatment patient who was coming in with symptomatic CLL and cytopenias, wild-type TP53, IGHV-mutated. He wants fixed-duration, all-oral regimen because he is on the road a lot. What treatment would you recommend?

Posttest 3

Same choices that we had as before.

1. Acalabrutinib/venetoclax;
2. Acalabrutinib/obinutuzumab;
3. Obinutuzumab/venetoclax;
4. Pirtobrutinib; or
5. Zanubrutinib.

We will see if anybody has changed their mind.

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

Dr. Maddocks: We do have some changes. About two thirds prefer acalabrutinib and venetoclax with a little bit of mix of the others.

We did go through data on acalabrutinib/venetoclax, acalabrutinib/obinutuzumab, obinutuzumab/venetoclax and zanubrutinib. Pirtobrutinib is not approved in the frontline setting at this time. This was lots of options. One, two, three, five. But just thinking about patient preference and not having a right answer in that time.

Posttest 3: Rationale

Again, that was the AMPLIFY trial.

Initial Therapy for CLL/SLL: Discussion Points 

I am just going to throw these out there as thought-provoking again, taking it back to this question was posed before. Are there scenarios where you still consider chemoimmunotherapy for a patient requiring initial therapy?

Looking at experience with adverse events when you are looking at some of these combination therapies. We do know cytopenias, infections, GI toxicity is increased when you give the combination of BTKi and BCL-2 over that of single-agent therapy. We see more infectious, particularly in terms of viral infections when we add that CD20 to this combination as well.

Thinking about if there are comorbidities that affect your treatment recommendations and why or how. We mentioned the bleeding, cardiac toxicities, even hypertension with the BTK inhibitors, maybe ability to tolerate tumor lysis when you are thinking about venetoclax and even other medication interactions.

Applying Current Guidelines and Expert Guidance to Treatment Selection and Sequencing for Patients With R/R CLL/SLL in the Second-/Third-line Settings

Now we are going to pivot from frontline therapy and talk about current guidelines and expert guidance and treatment selection and sequencing for patients with relapsed/refractory CLL/SLL in the second and then third-line or later settings.

Poll 5

We will take it back to some polling questions. I am confident in my ability to optimally select and manage therapies for patients requiring second-line treatment for CLL/SLL.

1. Strongly disagree;
2. Disagree;
3. Neither agree nor disagree;
4. Agree; or
5. Strongly agree.

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

Dr. Maddocks: Okay. Here we have a pretty even distribution, although most fall within neither agree nor disagree or agree.

Pretest 4

The next pre-test question. We are going to go back to a patient case. We have a 56-year-old man diagnosed with Rai stage IV CLL six years ago and was treated with venetoclax and obinutuzumab. He had progression at 19 months, so key time. At that time he was treated with zanubrutinib for 36 months. He presents with worsening symptoms, including adenopathy, cervical and axillary lymph nodes. No splenomegaly.

Which of the following approved therapies would you recommend as a treatment option for this patient with relapsed/refractory CLL?

1. Add a BCL-2 inhibitor to the ongoing BTK;
2. Switch to a degrader;
3. Switch to CAR T-cell therapy;
4. Switch to an alternate covalent BTK.

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

Dr. Maddocks: Okay. We actually have almost even split variability here between our answers. We will go through the data in relapsed/refractory.

NCCN Guidelines Version 2.2026

Again, we will take back to starting with the NCCN guidelines before we suggest the trial. At the top, second-line or subsequent therapy. This, of course, is going to, to some degree, depend on what the patient was treated within the front-line setting.

Preferred options in this setting include BCL2-containing regimens with venetoclax/obinutuzumab, covalent BTKi-based regimens with continuous acalabrutinib or zanubrutinib, or consideration of non-covalent BTKi with continuous pirtobrutinib. Then also possible venetoclax/rituximab or venetoclax/ibrutinib.

Then looking at for patients who have progressed after prior covalent BTKi and BCL2-containing regimens, probably the two best or most common options that we think of are either the non-covalent BTKi regimen with pirtobrutinib if it is not already been given or chimeric antigen receptor T-cell therapy with the CD19-directed product, liso-cel. You will note that says plus or minus ibrutinib with alternate or other potentials as listed.

Venetoclax-Based Treatment in R/R CLL/SLL

The initial data from venetoclax-based treatment in the relapsed/refractory setting for CLL came from the MURANO study, that once again was a comparison to chemoimmunotherapy even in the relapsed/refractory setting. In this trial, patients were randomized to treatment with venetoclax/rituximab versus six cycles of chemoimmunotherapy with bendamustine/rituximab.

From what we know, not surprisingly, very significant improvement in terms of the median PFS with the venetoclax/rituximab over chemoimmunotherapy approaching 55 months versus 17 months, median PFS with a five-year PFS of about a little over a third of patients.

Then looking at the single-arm CLARITY trial. This was a phase II trial that looked at BTK/BCL- combination using the first-generation BTK, ibrutinib, so ibrutinib plus venetoclax. This was a 50-patient study. This showed a little over half patients achieved a CR that had undetectable MRD with 60 months survival approaching 80%.

Venetoclax Retreatment in Patients With R/R CLL Achieving Deep Response Following Venetoclax + Rituximab

Venetoclax-based therapy in the second-line setting. What about venetoclax retreatment for patients who have had venetoclax in the frontline setting? Patients who want to had a fixed duration therapy in the frontline setting now have relapsed and really prefer to maintain that fixed duration therapy over thinking about now going on continuous therapy plus BTK inhibitor.

There is some data for venetoclax retreatment in patients with relapsed/refractory CLL following initial therapy with venetoclax-based regimen.

This is data from nine patients who were treated with venetoclax and rituximab and had a response to therapy, so time-limited venetoclax/rituximab. Discontinued therapy and then subsequently progressed.

You can see here the time off therapy from the venetoclax and then the time that they re-responded. Really showing for those patients who got longer remission durations, they could achieve again very good and durable remissions with venetoclax retreatment if they did that the first time.

If you look at progression-free survival from initial treatment to PD and then from retreatment to PD, of course, not as good, but you see again some patients achieve long responses if they had long responses initially. Median overall survival being not reached with initial treatment to seven years with retreatment.

Outcomes With Venetoclax Retreatment

There is retrospective study looking at initial therapy with venetoclax-based regimens and then subsequent therapy with venetoclax. The MURANO data, when patients were treated with venetoclax/rituximab and then subsequently received venetoclax/rituximab again and then combination with venetoclax/CD20 and then receiving subsequent therapy with venetoclax/obinutuzumab.

What you see is small numbers, but overall response somewhere between 70% and 80% of patients with a median progression-free survival of about two years. So reasonable option again, for those patients who get a good duration of response to the initial venetoclax treatment.

BTKi-Based Treatment for R/R CLL

Looking at BTKi-based treatment for relapsed/refractory CLL. Multiple studies have shown improved progression-free survival with the use of continuous BTKi compared to chemoimmunotherapy or even targeted therapy in the form of the PI3 kinase inhibitor with idelalisib/rituximab.

On the left, you see the data from the RESONATE study showing a continuous ibrutinib had significantly better progression-free survival than that with ofatumumab. The ASCEND trial showed acalabrutinib had a significantly improved progression-free survival over both chemoimmunotherapy with BR and targeted therapy with rituximab and the PI3K, idelalisib.

BTKi-Based Treatment for R/R CLL

We have also seen in addition to those ibrutinib studies, the second generation, which are now again more commonly used acalabrutinib and zanubrutinib.

The ELEVATE-RR trial looked at acalabrutinib versus ibrutinib, and the ALPINE trial looked at zanubrutinib versus ibrutinib. Really what they showed was that while in the ELEVATE trial, the median progression-free survival was actually the same, but the toxicity profiles with both the second-generation BTK inhibitors were improved over that with ibrutinib, making these really the preferred treatment here where we have the availability of all of these.

Venetoclax After Prior Covalent BTK Inhibitor in R/R CLL

In terms of sequencing, thinking about second-line therapy after first-line therapy, venetoclax has shown to be effective. You can reuse venetoclax.

This is just data looking at venetoclax after prior covalent BTK inhibitor, phase II venetoclax monotherapy on the left. So a prospective study and then a multicenter retrospective study of venetoclax-based therapy after prior covalent BTK inhibitors, so prospective and retrospective, showing that the patients did have an improvement in terms of progression-free survival and their response to venetoclax and those patients who had not previously progressed on a BTK inhibitor versus those who had not progressed on a BTK inhibitor.

BRUIN CLL – 321: Pirtobrutinib for R/R CLL/SLL Previously Treated With cBTKi

Most often, one was going to be used in the frontline, and one is going to be used in the second-line, but what about other options potentially in the second-line but for third-line and beyond.

The BRUIN CLL-321 trial looked at the non-covalent BTK inhibitor, pirtobrutinib, for relapsed/refractory CLL/SLL, previously treated with covalent BTKi and have a randomized phase III study, where patients were randomized to either pirtobrutinib or idelalisib plus rituximab or bendamustine/rituximab, and then were allowed to cross over with the primary endpoint of being progression-free survival.

BRUIN CLL–321: PFS and OS

Initially, I will step back a minute based on the single-arm data for progression on covalent BTK inhibitors in CLL. The initial accelerated approval for pirtobrutinib came for patients who had progressed on both covalent BTKi and BCL-2 inhibitor.

This randomized trial showed that pirtobrutinib significantly improved median progression-free survival over that of the idelalisib/rituximab or bendamustine/rituximab.

This led to the full approval of pirtobrutinib for patients who had previously been treated with a covalent BTKi inhibitor.

BRUIN CLL-314: Pirtobrutinib vs Ibrutinib in Treatment-Naive and R/R CLL/SLL

The BRUIN CLL-314 trial looking at pirtobrutinib versus ibrutinib included both relapsed/refractory and treatment-naive patients. This was a randomized, phase III, international trial. Patients were randomized to treatment with pirtobrutinib versus ibrutinib with a non-inferiority of overall response in the intention-to-treat or relapsed/refractory population.

BRUIN CLL-314: ORR

As you can see here in the ITT population, the treatment-naive and even relapsed/refractory, pirtobrutinib consistently showed higher overall response rates across all populations and all pre-specified subgroups.

BRUIN CLL-314: PFS by INV in ITT and R/R Populations

These are the PFS curves looking at pirtobrutinib versus ibrutinib, which was statistically significant in their intention-to-treat portion of the analysis.

Before I move on, I will just mention, not in the slides, but just presented at the recent meetings was relapsed/refractory BRUIN study looking at pirtobrutinib plus venetoclax /rituximab versus venetoclax/rituximab. That was also a positive study showing a statistically significant improvement with the addition of pirtobrutinib, which held true across arms of high-risk patients, people with TP53 mutations, people who had prior covalent BTKi. So probably more to come in the pirtobrutinib arena.

TRANSCEND CLL 004: Lisocabtagene Maraleucel in R/R CLL/SLL

Then the TRANSCEND CLL 004 study. This looked at chimeric antigen receptor T cells, so the liso-cel product in relapsed/refractory CLL. We know CD19 CAR T cells have been very effective in numerous B-cell malignancies. This was patients who were ineligible or had progressed on prior BTKi, had high-risk disease.

They were treated with the liso-cel product. About half of the patients responded. So an overall response rate of close to 50% with a median CR of about 20% and bone marrow MRD of about 60%.

TRANSCEND CLL 004: PFS by Response in BTKi Progression/ Venetoclax Failure Subset at DL2

Looking at PFS for patients with liso-cel, again, these are patients who progressed on prior BCL-2 and BTK inhibitors. Median PFS was about a year with median overall survival of 30 months. Like we see in other diseases for those patients who achieve a CR, they have a much better outcomes in terms of progression-free survival.

Liso-cel + Ibrutinib: Outcomes by Response Group

Now this was a trial that looked at the addition of ibrutinib, so BTK inhibitor to CD19 CAR T cells. Median progression-free survival in this was 31 months, so not randomized if you compare to these two single-arm trials suggest by overall response, CR rate, undetectable MRD and PFS that maybe there is a benefit to the BTK inhibitor added to the CD19 CAR T-cell and also potentially in terms of improving toxicity or CRS.

Factors Influencing Sequencing of Therapies in R/R CLL

When we looked at thinking about sequencing therapies in relapsed/refractory disease, sequencing treatment really begins in the frontline setting. When you are thinking about that initial therapy, thinking about how you potentially might sequence these patients, of course, lots of things change over time in our therapies that are available.

Increasing the use of fixed-duration novel therapies does offer potential for retreatment if remissions are long. If patients have a progression-free survival of over the three years, responses to that venetoclax-based regimens very reasonable to use venetoclax-based regimens again.

Thinking about relooking at genomic risk factors, comorbidities, medications before each line of treatment and then thinking about clinical trials, of course, across all diseases.

Choosing Therapy: Expert Algorithm for R/R CLL After Initial Therapy With BCL-2i + Anti-CD20 mAb

We just have a few algorithms for choosing therapy in the relapsed/refractory setting. When a patient has received initial therapy with a BCL-2 inhibitor and a CD20 monoclonal antibody. You have got this time-limited treatment in the first-line setting. Now you need second-line therapy.

We are wanting to consider if there is progression on treatment, if there is a short duration of response, if there was any intolerance or there is now concerns about comorbidities, then we are picking a covalent BTK inhibitor.

If they have a very prolonged response to this BCL-2 and anti-CD20, then we can think about reusing BCL-2 inhibitor-containing regimens or still can go to that covalent BTK inhibitor.

If you reuse this regimen, then you have the covalent BTK inhibitor available in the third-line therapy. Then thinking about moving on to the non-covalent BTK or CD19 CAR, again, always thinking about clinical trials as well.

Expert Algorithm for R/R CLL After Initial Therapy With BCL-2i + cBTKi ± Anti-CD20 mAb

If we are giving BCL-2 covalent BTK and/or CD20 in the frontline setting. Similar thought here in terms of if there is progression on treatment, then we are thinking about non-covalent BTKi inhibitor therapy. If we have this long duration of response, then we are maybe thinking about using reusing BCL-2 inhibitor containing regimens. Or if there is intolerance to either drug potentially reusing the alternate drug and then thinking about moving onto non-covalent BTK and/or the CD20 CAR product.

Again, if you have these long durations, retreatment can be considered but we still encourage clinical trial participation.

Expert Algorithm for R/R CLL After Initial Therapy With cBTKi ± Anti-CD20 mAb

Then if the first-line therapy is a continuous BTKi, plus or minus the CD20, if patients progress on treatment, moving to BCL-2 inhibitor or non-covalent BTKi. If they respond, we continue until progression or intolerance.

If they have progression or intolerance, thinking about BCL-2 inhibitor-containing regimen. For intolerance, you can potentially try a different covalent BTKi or switch to a non-covalent BTKi.

Posttest 4

We are going to take it back to our 56-year-old man who had venetoclax/obinutuzumab, then progressed at 19 months, went on to be treated with zanubrutinib. He has now got symptomatic progression. Would you:

1. Add a BCL-2 inhibitor;
2. Switch to a degrader;
3. Switch to CAR T-cell; or
4. Switch to a non-covalent BTK inhibitor.

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

Dr. Maddocks: A mix here. Probably ideally progressed on venetoclax-based treatment and only got 19 months, so out of that therapy and then actively progressing on a covalent BTK. Maybe thinking about CAR T-cell therapy here.

Therapy for R/R CLL/SLL: Discussion Points 

Okay. Just to summarize, things to think about from this are your patients who experience disease progression, are you testing for mutations? What other testing is recommended for patients who relapse? How are you using MRD, or if you are using it, what are some of the medications to be aware of for interactions?

On the Horizon: Emerging Therapies in Development and Next Steps for CLL/SLL

Then just real quickly thinking about some emerging therapies and next steps in CLL.

BRUIN CLL-313: Pirtobrutinib vs Bendamustine + Rituximab in Untreated Patients With CLL/SLL

The BRUIN CLL-313 trial. This is frontline pirtobrutinib. This randomizes patients to this chemoimmunotherapy, but is an international randomized phase III trial looking at patients without 17p deletions, randomizing them to continuous pirtobrutinib versus fixed duration chemoimmunotherapy with BR. There is a crossover in primary endpoint is progression-free survival. PFS favorable. OS not significant but trending that way.

Nemtabrutinib: Reversible ncBTK Inhibitor in CLL

We talked a lot about pirtobrutinib, but nemtabrutinib is another reversible non-covalent BTK inhibitor that is showing activity in relapsed/refractory CLL, both as a single-agent and then in combination with venetoclax. Probably more to come on that.

BTK Degraders: Mechanism of Action

BTK inhibitors have been very effective, BTK degraders. Resistance mutations in BTKi can reduce the enzymatic activity.

These mutations are still susceptible to BTK degrader, so essentially targeted BTK in a different way. There is different ones of these that have been in development and showing activity in early clinical trials.

BTK Degrader NX-5948 (Bexobrutideg): Activity

This compound has an overall response rate of a little over 80%.

CADENCE: BTK Degrader BGB-16673

This compound, again, has an overall response rate of over 80%, including in high-risk subgroups.

EPCOR CLL1: Epcoritamab Bispecific Ab in CLL

Then the bispecific antibodies which have made their way into the treatment for B-cell malignancies. The EPCOR CLL1 looked at single-agent epcoritamab in CLL, a small number of patients, but showed overall response rates of 60% with complete response rates of 40% and same undetectable MRD with median progression-free survival a little over a year.

Shared Decision-making in Action: Optimal Strategies for Partnering With Patients and Improving Care Outcomes

Then lastly, this focuses on shared decision-making and patient preference, so optimal partnering with patients to improve outcomes.

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

Just thinking about when we are deciding between these different regimens because we are fortunate enough to have options, what adverse events can be expected and how are they managed? What do patients need to be looking for and calling in for? Making sure that we are aware of all the medications they are on and any new medications that are started, any procedures that patients are going to undergo.

I explain to patients, how long they should hold their drug before and after, just so they have that awareness, but also that they should call me before anything is done, so I can remind them thinking about making sure that we are vaccinated against viral things, particularly ideally prior to initiation of treatment and then screening for more serious adverse events.

Understanding Challenges to Adherence and Persistence With Oral BTK Inhibitors

Of course, when we think about problems with adherence and persistence, particularly for oral medications, I would say in general, but those that are continued indefinitely. The cost of these medications sometimes, you will have patients that wean them out for a longer period. Thinking about just expectations, again, when to call, what is expected or not expected.

Thinking about pill diaries or ways to remember, taking pills and the resources that we can provide patients.

Patient Support and Resources

Patient support and resources. Here is a link to NCCN guidelines for patients.

QR Code for the CLL Experts’ Discussion Forum

Here is a QR code for the CLL Experts’ Discussion Forum to ask questions of expert faculty.

Let's Revisit the Questions

Just to re-go through our questions quickly.

Posttest 1

Now that we have talked about the data, the indication for pirtobrutinib.

1. Newly diagnosed or relapsed/refractory disease;
2. After covalent BTKi;
3. After covalent BTKi and BCL-2;
4. After more than two treatments and covalent BTKi and BCL-2.

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

Dr. Maddocks: Okay. Now, it is after prior treatment with covalent. Most people provided the answer. Remember, this was a more recent change.

Posttest 2

I consistently discuss pros and cons of all recommendations with my patients.

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

Dr. Maddocks: Okay. Most people agree.

Poll 6

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

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

Speaker: Poll is open. Please vote. Five more seconds. Thank you. We will close the poll and share the results.

Dr. Maddocks: Okay. About three fourths of people said yes. That is good.

Poll 7

If you said yes, you could scan the QR code and enter what that key change is.

Q&A

While you are thinking about that, I am going to go ahead because we are running short on time. I do want to look at these questions and answers.

How do you manage progression on a covalent BTKi in patients with prior venetoclax intolerance?

If they are still concerned for this, then I am going to think about now the availability of the non-covalent BTKi with pirtobrutinib. I am giving that medication right up to the time I am switching and then I am transitioning from the covalent to the non-covalent BTKi in terms of pirtobrutinib.

I am also thinking about potential for clinical trials which we discussed. Then when I actually am transitioning a patient to pirtobrutinib, I am thinking about is this a patient that is going to be a candidate for a CD19 CAR? I am not necessarily giving it at that point, but I am thinking about the time that I am going to be able to keep them on pirtobrutinib and if I need to have that discussion and start preparing that.

For patients with recurrent infections, how do you weigh those modification against switching therapy?

This can be tricky. If a patient has had a good response to treatment and has otherwise tolerated it well outside of the infection, I do really try to keep them on that medication and use dose modifications and then amping up prophylaxis as much as I can to try to prevent infections from that standpoint as well. Then really save totally switching therapy if I struggle with that.

I will say if you look at the data for BTK inhibitors, they can all cause infections. There is more neutropenia seen with zanubrutinib. If I am struggling from that standpoint, then that might be where I switch the BTK inhibitor because they all have the potential for the same side effects. Sometimes you can switch covalent for intolerance or even think about pirtobrutinib in that setting.

Another questions following about NCCN highlights infection rates. The zanubrutinib PI suggests using G-CSF to address infection. Do you use growth factor in these patients?

It depends on the situation. I try to manage with like dose reductions or potentially switching therapies. Yes, I have also used growth factor support when I felt indicated or needed.