Although second-line therapy for patients with chronic lymphocytic leukemia (CLL) remains largely dependent on the frontline treatment choice, the potential emergence of the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) into the second-line setting could offer patients an additional treatment option, according to Jennifer A. Woyach, MD. 

“For most patients who [first] received a continuous BTK inhibitor, they could either receive venetoclax [Venclexta] plus obinutuzumab [Gazyva] or rituximab [Rituxan] as their next line [of therapy],” Woyach, the coleader of the Leukemia and Hematologic Malignancies Program and a professor in the College of Medicine at The Ohio State University Comprehensive Cancer Center–James in Columbus, said in an interview with 

®. “Pirtobrutinib is [also] now an option in the second-line setting, which is a pretty easy transition from a covalent BTK inhibitor.”

Pirtobrutinib is currently indicated by the FDA for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) following at least 2 prior therapies, including a BTK inhibitor and a BCL2 inhibitor.

 was informed by data from the phase 1/2 BRUIN trial (NCT03740529), which showed that patients who received the agent (n = 108) experienced an overall response rate of 72% (95% CI, 63%-80%).

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for CLL/SLL also recommend pirtobrutinib as an option in the second line for the treatment of patients with resistance or intolerance to prior covalent BTK inhibitor–based regimens, opening the door for its use in the second-line setting.

In the interview, which took place during Blood Cancer Awareness Month in September, Woyach parsed treatment options in second-line CLL, the current standing of pirtobrutinib in the treatment paradigm, and future research directions in the space.

How do you approach treatment selection in the second-line setting of CLL?

: We have a lot of options for the frontline CLL treatment, and second-line therapy generally is determined by what the patient received for their frontline regimen. A patient who has gotten [first-line] chemotherapy has a different set of options than one who was receiving a covalent BTK inhibitor that was given continuously.

One of the big unanswered questions is, how effective is retreatment going to be with a venetoclax-based regimen? We have options for venetoclax/obinutuzumab, venetoclax/acalabrutinib [Calquence], or all 3, in the frontline setting. There are studies that are being done to try to figure out how effective and durable remissions are going to be with those retreatment options.

That’s the biggest question for me right now. But for a patient who has received a venetoclax-based therapy, another fixed-duration therapy in the second-line setting—provided they’ve gotten a good remission the first time—is a good option.

What factors right do you weigh when considering a potential rechallenge in the second-line setting?

The biggest one is [considering] how long of a remission they had with their first treatment. A patient who received a venetoclax-based regimen and had only a 2-year remission after is very different from one who experiences a 5-year remission. We would expect that the next remission is going to be shorter if you do the same thing again. For a patient who had a 2- or 3-year remission duration after a venetoclax-based regimen, I might still use a venetoclax-based regimen but might change the combination partners. Or, if it was available, give a triplet rather than a doublet. That’s also a patient I would think about a clinical trial for.

How are you using pirtobrutinib in practice since its approval and inclusion in the NCCN guidelines?

This is potentially going to change in the future, given the topline data that’s been released in the frontline setting with pirtobrutinib. [In terms of] pirtobrutinib for relapsed/refractory CLL right now, it’s patient dependent.

For a patient who chose a covalent BTK inhibitor in the frontline setting, did very well with it, and didn’t mind taking the continuous treatment, it’s probably the easiest thing to switch those patients to a noncovalent BTK inhibitor at that point. Pirtobrutinib is well tolerated and easy to take, so that’s a natural transition for a patient who did well on a covalent BTK inhibitor.

That being said, if that patient had a desire to try something time-limited and maybe they didn’t have the opportunity the first time to do a venetoclax-based regimen, this is the time to do it. It’s probably not waiting until the third-line setting—it’s probably doing that in the second-line setting. In that case, I would use pirtobrutinib after a venetoclax-based regimen. [However], we don’t have a lot of data to tell us which one of those [approaches] is going to be the better second-line option.

What are some of the factors you consider when determining whether a patient is ready for subsequent therapy?

Again, it depends on the therapy they were receiving prior. In patients who receive a covalent BTK inhibitor, in general we see relapses occur slowly at first. You might see months, maybe even a year, of just increasing lymphocyte count. If a patient only has an increase in lymphocyte count with no other signs of disease and feels well, I will just let that rise until we see some other signs of disease progression, because at some point it does tend to accelerate rather quickly, and you’re trying to avoid that from happening.

For a patient who received a fixed-duration regimen in the frontline setting we generally would recommend the same criteria to start therapy in the second-line setting as we do in the frontline setting: wait until symptom onset. I generally don’t let it go as long as I would prior to the first therapy, because you know that person is going to be needing therapy, and you’re likely not doing much except for accelerating their symptoms [if you wait to intervene].

For a patient who’s getting treated in the third-line or later setting, I generally don’t let any symptoms develop. There we just look for any signs of disease progression and then switch [therapy] when convenient.

If pirtobrutinib eventually does reach the frontline setting, how do you see that shaking up the CLL treatment paradigm?

The biggest question in my mind is, are we eliminating the use of covalent BTK inhibitors by using a noncovalent inhibitor first? We’re not going to know [the answer to] that for a while. We’re going to have to wait until [we see] relapses on those frontline studies before we understand if the mechanism of relapse is different in the frontline setting than it is in a patient who is taking pirtobrutinib for relapsed CLL.

I’m going to assume that you probably won’t use a covalent BTK inhibitor after a noncovalent BTK inhibitor. Then, there are some populations that might greatly benefit from pirtobrutinib in the frontline setting, especially the older, more frail patients who will likely tolerate pirtobrutinib better than a covalent BTK inhibitor. We know that we can use venetoclax as an option after. Once we better understand what the median duration of remission is going to be for pirtobrutinib in the frontline setting, we can strategize. Should a patient who’s in their 80s receive pirtobrutinib first? If the remissions are as long as those from a covalent BTK inhibitor, then it opens up even more options, because then you still have venetoclax to use afterward and we assume that there’s going to be even more therapeutic options in the future.

If covalent BTK inhibitors are off the table, are there novel agent classes that you can turn to?

BTK degraders are certainly something that we’re seeing work after covalent and noncovalent BTK inhibitors. It’s not off the table if you start with a noncovalent BTK inhibitor, and I see that as a very good option. We also have seen more data with bispecific antibodies alone and in combination, and that’s something that also is likely to play a role in the future. For some patients, CAR T-cell therapy [is also an option]. These are not exactly the same patients who I suggested might get the most benefit from pirtobrutinib in the frontline setting, but there may be patients who are candidates for CAR T and could benefit from not [experiencing] the same adverse effect profile as the covalent BTK inhibitors.

What future research directions in CLL are you the most excited about?

[BTK] degraders, bispecific antibodies, and CAR T-cell therapy are coming forward. There are also other new targets that are being evaluated in CLL, and as we learn more about the biology of the disease, hopefully we’re going to have the next ibrutinib [Imbruvica] and the next venetoclax coming soon. We might even get to the point where we’re able to cure patients, rather than what we can do now, in most cases, which is sometimes functionally cure them, where the remissions outlive the natural lifespan. [We may] get to the point where we are eradicating the disease such that it won’t come back.

FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed September 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic

Jaypirca. Prescribing information. Eli Lilly and Company; 2023. Accessed September 25, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059s001lbl.pdf

NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 3.2025. Accessed September 25, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf

Articles

Jennifer A. Woyach, MD, discusses the potential of pirtobrutinib as a second-line option for patients with CLL.

Pirtobrutinib Offers Potential Second-Line Treatment in CLL

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, we had the pleasure of speaking with Asad Dean, MD, about treatment selection for patients with chronic lymphocytic leukemia (CLL) in the second-line setting. Dean is a physician at the Texas Oncology-Fort Worth Cancer Center.

In our exclusive interview, Dean discussed the roles of covalent Bruton tyrosine kinase (BTK) and BCL-2 inhibitors in managing CLL. He highlighted the importance of molecular profiling for treatment rechallenge decisions and the potential for resistance mutations in this disease. He also noted the role of pirtobrutinib (Jaypirca) in overcoming treatment resistance, along with clinical signs indicating that patients may need a therapy change. Dean also mentioned the high response rates seen with CAR T-cell therapy in patients with CLL and explained the possibility of combination regimens in CLL. Additionally, he expressed optimism about BTK degraders and bispecific antibodies.

That’s all we have for today! Thank you for listening to this episode of 

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Dean discusses the role of BTK inhibitors in the management of CLL and the importance of molecular profiling for treatment rechallenge decisions.

The Evolving Role of Noncovalent BTK Inhibition Informs CLL Treatment Selection: With Asad Dean, MD

Dr Woyach on When to Initiate Subsequent Therapy in Patients With CLL

“[Initiating subsequent therapy in patients with CLL] depends on the [prior] therapy…For patients on a covalent BTK inhibitor, we generally see that [disease] relapses occur slowly at first. We may see months, maybe even a year, of just increasing lymphocyte count.”

Jennifer A. Woyach, MD, coleader of the Leukemia and Hematologic Malignancies Program and a professor in the College of Medicine at The Ohio State University Comprehensive Cancer Center–James, discusses when additional therapy should be initiated for the treatment of patients with chronic lymphocytic leukemia (CLL).

Woyach began by underscoring that subsequent therapy for patients with relapsed/refractory CLL is largely dependent on the prior therapy that they received. Patients who are first treated with a covalent BTK inhibitor tend to experience slower disease relapse compared with those treated with other agents in the frontline, she explained. Increasing lymphocyte count can occur in these patients over the course of months or even up to a year, she added. For patients who only display an increasing lymphocyte count with no other signs of recurrent disease, Woyach will hold further treatment until other signs of disease progression emerge, she said.

For patients treated with a fixed-duration regimen in the frontline setting, the same criteria are generally required to begin second-line treatment, Woyach explained. This includes waiting until symptom onset; however, waiting as long as one would for their first therapy is not always ideal because it is understood that the patient will need additional therapy at some point, Woyach noted.

Treatment in the third line and beyond should not be held until additional symptoms develop, Woyach said. In this setting, any signs of disease progression indicate that a patient should switch to a new therapy when it is convenient for them, she concluded.

Videos

Jennifer A. Woyach, MD, discusses when to initiate subsequent therapy in patients with CLL.

Although pirtobrutinib (Jaypirca) is currently only indicated by the FDA for the treatment of patients with chronic lymphocytic leukemia (CLL) following at least 2 prior lines of treatment, the noncovalent could still have a role in the second-line setting of the disease for certain patients, according to Asad Dean, MD.

In December 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.

 The approval was supported by data from the phase 1/2 BRUIN trial (NCT03740529), which demonstrated that patients who received pirtobrutinib (n = 108) achieved an overall response rate of 72% (95% CI, 63%-80%) and a median duration of response of 12.2 months (95% CI, 9.3-14.7).

However, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for CLL/SLL recommend pirtobrutinib as an option in second-line therapy in the event of resistance or intolerance to prior covalent BTK inhibitor–based regimens.

“The pirtobrutinib [FDA] indication is following prior a covalent BTK inhibitor, as well as prior BCL2 [therapy],” Dean said in an interview with 

. “However, the way it is designated in the NCCN guidelines is that following a covalent BTK inhibitor, you have that option [to use pirtobrutinib]. I like that flexibility because we don’t have an indication for combination BTK plus BCL2 inhibition in the frontline setting. [The combination] is recognized by the NCCN, but we do not have an FDA approval. Based on NCCN as a platform and foundation, I find it advantageous to be able to move to a noncovalent, reversible BTK inhibitor like pirtobrutinib following progression on a covalent BTK inhibitor.”

Dean is a physician at Texas Oncology as well as an assistant professor in the Division of Hematology/Oncology at UT Southwestern Medical Center, both in Dallas.

In the interview, which took place during Blood Cancer Awareness Month in September, Dean discussed the treatment landscape of second-line CLL, the role of pirtobrutinib, and other agents of interest in the space.

How do you approach treatment selection in the second line for a patient with relapsed/refractory disease? What are some of the unmet needs in that setting?

: We have revolutionized therapy for [patients with] CLL. When I was a fellow 25 years ago, [the standard of care] was fixed-duration chemoimmunotherapy. The advent of BTK inhibition has revolutionized the way we approach treatment.

In my practice, most of my patients in the frontline setting are receiving a covalent BTK inhibitor. There are some patients who are hesitant to be on continuous therapy, and for those patients in the frontline setting, I have used fixed-duration anti-BCL2 therapy along with anti-CD20 therapy. These have both proven to be effective regimens in the frontline setting; however, as is the case in other malignancies, resistance can develop.

In the second-line setting [following] a covalent BTK inhibitor, [in the event of] disease progression, I will then change to a BCL2-directed therapy. With that being said, NCCN guidelines recommend consideration, following a covalent BTK inhibitor, of either a BCL2 inhibitor or a noncovalent, reversible BTK inhibitor.

Is there a role for rechallenge with a covalent BTK inhibitor or BCL2 inhibitor in the second line?

If a patient is intolerant to one covalent BTK inhibitor, then rechallenge can certainly be possible [without] losing efficacy. I would also say that molecular profiling is important. It is very important to know if [a patient] has deletion 17p, deletion 11q, [or] a 

 mutation. If they have unmutated or mutated immunoglobulin heavy chain status, that could also influence consideration of a rechallenge.

The problem with rechallenge upon [disease] progression is the development of resistance mutations. Those mutations for the BTK inhibitors most commonly happen in the C481 binding region of the 

 enzyme. However, [a patient] can also have 

 mutations, so you have to be careful about rechallenge because of the of binding of the particular enzyme. If [

] is mutated, it’s unlikely to respond to a treatment within the same class.

How do you weigh rechallenge vs moving to a new therapy if there is an approved and indicated option?

For me, rechallenge makes most sense if a patient is intolerant because it’s unlikely that you have been able to exhaust the lifespan of a particular treatment. Therefore, the mechanistic approach would continue to work.

What could signal that a patient may be ready to move on to pirtobrutinib?

The beauty of the advent of pirtobrutinib is having noncovalent, reversible binding, which allows you to overcome resistance. If a patient is progressing clinically, they could have worsening blood counts, cytopenias, anemia, thrombocytopenia, or their white [blood cell] count could be escalating. It is important to note that you do get a transient lymphocytosis following initial initiation of a BTK inhibitor due to discombobulation and egress into the peripheral blood, but that subsides in time. If you’re seeing after months or years on a BTK inhibitor and the white [blood cell] count is starting to elevate, that could mean you’re losing response.

If a patient develops progressive or worsening lymphadenopathy, it’s important to biopsy to make sure that they’re not transforming to a higher-grade lymphoma. If they are getting progressive splenomegaly, or they’re having recrudescence of B symptoms [such as] fevers, night sweats, weight loss, or worsening fatigue, those would all be indicators that you are losing response or developing resistance, indicating a need to change therapy.

Where does CAR T-cell therapy fit alongside pirtobrutinib as it’s currently being used?

CAR T-cell therapy is a remarkable way to harness an individual’s immune system to combat their cancer. Within CLL, it’s [used] in heavily pretreated patients. It is important to note that the response rate can range anywhere from [approximately] 40% to 90%, and the complete response [CR] rate is [approximately] 18% to 68%.

Also, studies have shown that if you are able to obtain a CR in the first year, your progression-free survival [rate] is much better at five years. There have also been data to suggest that you can have improved response by combining it with a BTK inhibitor such as ibrutinib [Imbruvica]. The data are forthcoming, and we will need to see in time where CAR T-cell therapy fits.

It is an expensive therapy, although the advantage is that your treatment is done in a fixed timeframe, and, if you can achieve that type of response, then it’s unlikely to develop the resistance that we see with continued usage of BTK and BCL2 inhibitors. You can also develop resistance to pirtobrutinib as well. The promise of CAR T is taking that out of the equation, but it is still far from being moved into an earlier setting.

What other areas of research or novel agents could also help improve treatment options within the second-line setting and beyond in CLL?

I’m particularly excited about research looking at BTK degraders through ubiquitination, [which is] essentially proteasome destruction. That is an exciting class that is presently under investigation.

There have also been promising phase 1 data looking at bispecific therapies, specifically epcoritamab-bysp [Epkinly]. In the [phase 1b/2] EPCORE CLL-1 trial [NCT04623541], which included heavily pretreated and high-risk patients with CLL with a primary end point of ORR. The excitement of bispecific therapy and tempered toxicity related to immune effector cell–associated neurotoxicity syndrome is an issue that we have to contend with. As we become more comfortable with bispecific therapies in other diseases, it will help us when the time comes to fit them into the equation for CLL.

With September being Blood Cancer Awareness Month, what is your main message for colleagues on the current state of the second-line setting of CLL?

It’s an exciting time for patients and for research development taking place in CLL. This is a disease that tends to affect older patients. Ultimately, the goal is to provide safe, effective treatment that doesn’t hinder quality of life or create undue risk that would outweigh benefits, since we’re treating an older population.

That being said, there are also younger patients who may develop [CLL], and intensified, aggressive approaches are necessary in order to ensure greater longevity and improvement in overall survival. I feel optimistic about how the science continues to develop, and as a practicing oncologist in the community, I’m so gratified by how I have seen the approach to CLL change during my career, and having oral targeted agents available is tremendous. It helps patients be able to take control of their lives, empowers them to take charge of their health, and provides a convenient way to have effective treatment that is not only tolerable but safe. The future is incredibly promising, and I look forward to seeing how some of the therapies that I mentioned weigh into our considerations for our patients to improve their lives.

FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed September 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic

Jayprica. Prescribing information. Lilly; 2023. Accessed September 19, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059s001lbl.pdf

NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic leukemia, version 3.2025. Accessed September 19, 2025. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

Asad Dean, MD, discusses the evolving role of pirtobrutinib in chronic lymphocytic leukemia.

Pirtobrutinib Expands Potential Second-Line Options in CLL

Dr Dean on the Role for Pirtobrutinib in Second-Line CLL

“Based on the NCCN [guidelines] as a platform and foundation, I [would] move on to a noncovalent, reversible BTK inhibitor like pirtobrutinib following disease progression on a covalent BTK inhibitor.”

Asad Dean, MD, a physician at Texas Oncology and an assistant professor in the Division of Hematology/Oncology at UT Southwestern Medical Center, discusses the role of pirtobrutinib (Jaypirca) for the second-line treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL). 

Dean began by stating that he sees pirtobrutinib playing a role in the second-line setting for patients with CLL. The agent is currently indicated by the FDA for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor, he noted. Data from the phase 1/2 BRUIN trial (NCT03740529), which supported the agent’s approval in this setting, showed that patients treated with pirtobrutinib (n = 108) experienced an overall response rate of 72% (95% CI, 63%-80%) and a median duration of response of 12.2 months (95% CI, 9.3-14.7). According to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for CLL/SLL, pirtobrutinib is also recommended as a second-line therapy in the event of resistance or intolerance to prior covalent BTK inhibitor–based regimens, he added.

Dean added that the flexibility offered by the inclusion of pirtobrutinib in the NCCN guidelines benefits patients since there are currently no FDA approvals for a frontline BTK inhibitor and BCL2 inhibitor combination regimen in CLL. This approach is also recognized by the NCCN guidelines, he said. It is advantageous to use the NCCN guidelines as a foundation to allow the use of a noncovalent, reversible BTK inhibitor such as pirtobrutinib following disease progression on a first-line covalent BTK inhibitor, he concluded.

Asad Dean, MD, discusses the role of pirtobrutinib in second-line CLL.

Navigating Second-Line Treatment Decisions in CLL | Supplements and Featured Publications

Pirtobrutinib Offers Potential Second-Line Treatment in CLL

The Evolving Role of Noncovalent BTK Inhibition Informs CLL Treatment Selection: With Asad Dean, MD

Dr Woyach on When to Initiate Subsequent Therapy in Patients With CLL

Pirtobrutinib Expands Potential Second-Line Options in CLL

Dr Dean on the Role for Pirtobrutinib in Second-Line CLL