Dr Bhat on Choosing Between Pirtobrutinib and Liso-Cel for R/R CLL Management

“How do we choose pirtobrutinib vs CAR T-cell therapy? We look at certain [factors like] the logistics, patient characteristics, [and] comorbidities.”

Seema A. Bhat, MD, a hematologist at The Ohio State University Comprehensive Cancer Center—James; as well as an assistant professor in the Department of Internal Medicine in the Division of Hematology at The Ohio State University, discussed factors that she considers when choosing between pirtobrutinib (Jaypirca) and CAR T-cell therapy for the treatment of patients with double-refractory chronic lymphocytic leukemia (CLL).

The CAR T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi) is now an 

FDA-approved treatment modality for patients with CLL

 and represents the only agent in this class approved for this indication, Bhat began. The FDA granted approval for liso-cel in patients with CLL who are considered “dual-refractory,” meaning they have previously been treated with at least 2 prior lines of therapy, including both a covalent BTK inhibitor and a BCL-2 inhibitor. This indication is similar to that for pirtobrutinib, which is also 

 in the third-line setting following treatment with a BTK inhibitor and a BCL-2 inhibitor, Bhat explained.

Ongoing investigations continue to explore ways to optimize outcomes with CAR T-cell therapy in patients with CLL, Bhat said. Notably, an update from the phase 1/2 TRANSCEND CLL 004 study (NCT03331198)—the trial that led to liso-cel’s FDA approval in CLL—was presented at the 2024 ASH Annual Meeting, she highlighted. In the update, liso-cel had enhanced efficacy when administered concurrently with the BTK inhibitor ibrutinib (Imbruvica). Treatment with the combination resulted in a doubling of complete response (CR) rates, a particularly promising finding that highlights the potential of this synergistic strategy, according to Bhat.

When selecting between pirtobrutinib and CAR T-cell therapy for patients with CLL who have progressed following covalent BTK inhibition and venetoclax (Venclexta), several clinical factors should be considered, Bhat emphasized. These include treatment logistics, the patient’s overall fitness, and the presence or absence of comorbidities, she noted. For instance, in a younger, fit patient with no significant comorbid conditions and access to a specialized treatment center offering CAR T-cell therapy, liso-cel may be preferred due to the potential for durable remissions, she stated. The TRANSCEND-CLL-004 trial has shown that patients achieving CRs with liso-cel often experience sustained disease control, she added.

Conversely, for patients who are medically frail, have multiple comorbidities, or are unable or unwilling to travel to a center that offers this modality, pirtobrutinib may be a more feasible treatment option, Bhat reported. Additionally, in scenarios involving rapidly progressing disease, initiating CAR T-cell therapy may not be practical due to the manufacturing timeline of this therapy, which can take approximately 3 to 4 weeks, she continued. In such urgent clinical contexts, immediate initiation of pirtobrutinib may be warranted to control disease progression and bridge to other potential therapies, Bhat concluded.

Videos

Seema A. Bhat, MD, discusses disease features and patient characteristics that inform the choice between pirtobrutinib and liso-cel for CLL.

With the emergence of additional therapies for patients with relapsed/refractory chronic lymphocytic leukemia (CLL), suitable treatment selection and sequencing practices, including the consideration of patient preference and rate of disease progression, have become more important than ever, according to Seema A. Bhat, MD.

“The goal of therapy for our patients with CLL is to appropriately sequence the available drugs and get the best mileage from each of them [in order] to extend survival,” Bhat, an associate professor in the Division of Hematology, Department of Internal Medicine, at The Ohio State University Comprehensive Cancer Center—James in Columbus, said in an interview with 

The most recent FDA approvals for patients with relapsed/refractory CLL include the CAR T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi) and the BTK inhibitor pirtobrutinib (Jaypirca). 

In March 2024, the FDA approved liso-cel for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL)

 who received at least 2 previous lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

In December 2023, pirtobrutinib earned approval for the same indication

The approval of liso-cel was supported by data from the phase 1/2 TRANSCEND CLL 004 study (NCT03331198), which demonstrated that patients who received the agent (n = 65) achieved a complete response (CR) rate of 20% (95% CI, 11.1%-31.8%) with a median duration of response (DOR) that was not reached (NR; 95% CI, 15 months-NR) among those with a CR.

 Data from the phase 1/2 BRUIN trial (NCT03740529) supported the approval of pirtobrutinib; patients who received the agent (n = 108) experienced an overall response rate of 72% (95% CI, 63%-80%) with a median DOR of 12.2 months (95% CI, 9.3-14.7).

In the interview, Bhat discussed treatment selection considerations for patients with relapsed/refractory CLL, the current role of pirtobrutinib, and how the approval of liso-cel has affected the treatment paradigm.

What characteristics do you consider when deciding whether a patient with CLL is a good fit for pirtobrutinib?

: Pirtobrutinib is a new tool in our kit. It’s a selective, non-covalent BTK inhibitor which is approved by the FDA for patients [with CLL] who have previously been treated with a covalent BTK inhibitor and a BCL-2 inhibitor and [who experience] disease progression. [Signs of] disease progression may [include] cytopenia, low hemoglobin or platelet [counts], new or enlarging lymphadenopathy or splenomegaly, or constitutional symptoms.

We make the decision to switch therapies based on the International Workshop on Chronic Lymphocytic Leukemia [iwCLL] criteria, [which] we’ve always used in the frontline and relapsed/refractory settings. Individual patient preferences are important when selecting [or] switching treatments because we have options. For patients who have received a prior covalent BTK inhibitor and [a BCL-2 inhibitor] with disease progression, CAR T-cell therapy is also now approved.

How do we choose between the two? Patients with rapidly progressing disease may not be able to wait for CAR T-cell [therapy] manufacturing, so pirtobrutinib would be preferred in those cases. In some cases, patients may not have access to a specialized center where CAR T-cell therapy is administered, so pirtobrutinib is [also] a good option for those patients. [These agents also] have different adverse effects [AEs]. The AE profiles of these drugs are important [to consider]. For some patients with multiple comorbidities who may or may not be candidates for CAR T-cell therapy, we prefer pirtobrutinib.

Are there distinct treatment selection considerations for patients with asymptomatic disease?

For patients who are doing well on their current treatment, be it a covalent BTK inhibitor or venetoclax [Venclexta], there is no rationale for switching to pirtobrutinib, or any other agent for that matter, solely based on the availability of a drug or theoretical benefit. Preserving therapeutic options for the future is key to [achieving] the maximum benefit from each treatment [in order to] extend the survival of our patients.

For patients who have previously received a covalent BTKinhibitor or a BCL-2 inhibitor, is there a role for rechallenge with either class of agents?

For patients who [experience disease] progression with a covalent BTK inhibitor, [such as] ibrutinib [Imbruvica] or zanubrutinib [Brukinsa], we must switch to another class of drugs, [such as] a BCL-2 inhibitor or a noncovalent BTK inhibitor. This is very important; one cannot switch to a different covalent BTK inhibitor.

For example, if a patient has disease progression with acalabrutinib [Calquence] you cannot switch [their treatment] to zanubrutinib because the mechanisms of resistance are shared between the covalent BTK inhibitors; they bind to the BTK molecule at the same site. So, if [a patient] develops resistance to one [of these agents] the [tumor] cells become resistant to all other covalent BTK inhibitors. This is when switching therapies becomes important.

However, for venetoclax-based, time-limited therapy, you can rechallenge after the initial therapy depending on the duration of treatment. For example, if a patient has good outcomes with a venetoclax-based [regimen] that lasted more than [approximately] 2 years, you could rechallenge them. In the ongoing [phase 2] ReVenG study [NCT04895436], patients with CLL who had prior treatment with venetoclax in combination with the anti-CD20 monoclonal antibody obinutuzumab [Gazyva] are being rechallenged [with that regimen].

For patients who were [being treated with] a covalent BTK inhibitor and have stopped for intolerance and not [disease]progression, you can rechallenge them with a different covalent BTK inhibitor because the reason for stopping the previous covalent BTK inhibitor wasn’t [disease] progression, so no mutations are involved. They may be able to tolerate another covalent BTK inhibitor.

[In terms of] targeted agent doublets such as acalabrutinib plus venetoclax time-based therapy, no data are available yet. However, since the drug exposure time is short, the probability of developing resistance is low and retreatment with either agent is an option.

Where does CAR T-cell therapy fit into the treatment paradigm in light of the established role of these BTK inhibitors?

We now have the option of CAR T-cell therapy for our patients with CLL. Liso-cel is the only CAR T-cell therapy that is currently approved by the FDA for patients with CLL. Its [indication] is similar to pirtobrutinib in [that] it’s [approved] in the third-line setting. There’s ongoing research in this realm. During the 

, we saw an update from TRANSCEND CLL 004 in which [investigators] used ibrutinib to enhance the efficacy of [liso-cel]. The results showed that the addition of ibrutinib to CAR T-cell therapy doubled the CR rates [compared with liso-cel monotherapy], which is amazing. 

[When choosing] between pirtobrutinib and CAR T-cell therapy, we look at logistics and patient characteristics, such as comorbidities. If I [am treating] a young patient who has [received] a covalent BTK inhibitor and venetoclax with disease progression, no comorbidities, and access to a center with CAR T-cell therapy, I prefer CAR T-cell therapy. [Data from] TRANSCEND CLL 004 have shown that patients [can achieve] durable CRs [with liso-cel]. 

What is your advice for reducing the time from disease progression to the next line of treatment?

It’s important to recognize [disease] progression early. [Patient] education is a big part of what we do in our clinics. When patients come to see us, one of our main roles is to educate them about symptoms to look for and to sensitize them to constitutional symptoms such as fevers, chills, night sweats, unintentional weight loss, growing lymph nodes, or pain in the left side of the abdomen that could be a sign of splenomegaly. Following these patients very closely is also key.

When patients come in, you must ask those questions, examine them, and pay attention. You must monitor their counts, especially hemoglobin and platelets. If those are dropping, that’s a sign of disease progression. When we identify disease progression and confirm it, switching treatments promptly is key.

However, sometimes there are logistical issues to switching treatments, such as insurance coverage, copays, and drug delivery. Having a multidisciplinary team that’s working on all these fronts is important to getting the drug to the patient within a reasonable [amount of] time.

If a patient has disease progression on a covalent BTK inhibitor, sometimes we overlap the covalent BTK inhibitor until we start a new treatment. For example, if a patient has disease progression on acalabrutinib, I won’t just stop [treatment], I’ll continue [with therapy] until the day the patient is ready to switch to the next treatment. It’s key to continue to give those patients the covalent BTK inhibitor because there’s a phenomenon called ‘CLL flare,’ [which is] a rapid disease progression, if you stop a medication and do not start a new treatment right away. Being aware of these [aspects] and continuing [treatment with] the covalent BTK inhibitor [as you] overlap it with the next treatment can sometimes prevent that rapid disease progression.

US FDA approves Bristol Myers Squibb’s Breyanzi as the first and only CAR T cell therapy for adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). News release. Bristol Myers Squibb. March 14, 2024. Accessed May 22, 2025. https://news.bms.com/news/details/2024/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Breyanzi--as-the-First-and-Only-CAR-T-Cell-Therapy-for-Adults-with-Relapsed-or-Refractory-Chronic-Lymphocytic-Leukemia-CLL-or-Small-Lymphocytic-Lymphoma-SLL/default.aspx

FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed May 22, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic

Breyanzi. Prescribing information. Bristol Myers Squibb; 2024. Accessed May 22, 2025. https://packageinserts.bms.com/pi/pi_breyanzi.pdf

Articles

Seema A. Bhat, MD, discusses the current treatment landscape of chronic lymphocytic leukemia in light of the FDA approvals of liso-cel and pirtobrutinib.

Liso-Cel and Pirtobrutinib Add Options in R/R CLL, Underscoring the Importance of Proper Treatment Selection

Pirtobrutinib (Jaypirca)—the first noncovalent BTK inhibitor approved for patients with chronic lymphocytic leukemia (CLL)—has reshaped third-line treatment strategies in this disease space and prompted new considerations regarding treatment sequencing and patient selection as the paradigm grows more complex, according to Nicole Lamanna, MD.

 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 BCL-2 inhibitor.

 This decision was backed by data from the phase 1/2 BRUIN trial (NCT03740529), in which pirtobrutinib elicited an overall response rate of 72% (95% CI, 63%-80%) among patients with CLL/SLL (n = 108).

Subsequently, the confirmatory phase 3 BRUIN CLL-321 trial (NCT04666038) showed that 

 vs idelalisib (Zydelig) plus rituximab (Rituxan) or bendamustine plus rituximab.

 The independent review committee–assessed median progression-free survival (PFS) was 14.0 months (95% CI, 11.2-16.6) in the pirtobrutinib arm (n = 119) vs 8.7 months (95% CI, 8.1-10.4) in the control arm (n = 119; HR, 0.54; 95% CI, 0.39-0.75; 

“[The role of] pirtobrutinib is shifting a bit,” Lamanna said in an interview with 

®. “It depends on where your patient started treatment and what prior therapies they received. [In the future], pirtobrutinib might fit into the third-line setting, like it does currently, or [in earlier lines] as more data emerge and patients receive alternative therapies in the frontline setting.”

In the interview, Lamanna discussed the current role of pirtobrutinib in the third-line relapsed/refractory CLL setting, considerations for sequencing CLL therapies based on patient symptoms, the importance of waiting for clear indications to initiate a treatment switch in asymptomatic patients, factors that affect decision-making between pirtobrutinib and lisocabtagene maraleucel (liso-cel; Breyanzi), and ongoing clinical trials investigating pirtobrutinib in earlier lines of therapy.

Lamanna is an associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at the Columbia University Herbert Irving Comprehensive Cancer Center in New York, New York.

: What are some of the patient and disease factors that you consider when potentially selecting pirtobrutinib as a treatment for patients with relapsed/refractory CLL?

: Pirtobrutinib is one of the newer tools we have to treat CLL. It's a noncovalent BTK inhibitor, which is different than [the other covalent BTK inhibitors] we currently have, [including] ibrutinib [Imbruvica], acalabrutinib [Calquence], and zanubrutinib [Brukinsa]. However, the noncovalent BTK inhibitors are reversible binders to BTK.

Part of [our traditional treatment decision-making depends on the order in which] these drugs were approved. We had covalent BTK inhibitors approved first, and then we had our first BCL-2 inhibitor—venetoclax [Venclexta]—approved. Now, pirtobrutinib is the first noncovalent BTK inhibitor approved, currently [indicated] in the third-line setting for patients who have progressed on a covalent BTK inhibitor and a BCL-2 inhibitor, although there are limited data [supporting the use of pirtobrutinib in] patients who are intolerant to covalent BTK inhibitors; you can use it in the intolerance setting as well. However, the BRUIN study [investigated this agent] mostly in patients who were either refractory or double refractory to both a covalent [BTK inhibitor] and a BCL-2 inhibitor. Currently, I tend to [use pirtobrutinib] in patients who are refractory to a covalent [BTK inhibitor] or a BCL-2 inhibitor—that [accounts for] most of the patients [to whom] you can offer it in that [third-line] setting.

Typically, we're still [making the decision to switch therapies based on] the same reasons [we have always used to choose treatments] in the frontline and relapsed settings. For patients who need therapy because they're developing cytopenias or progressive, bulky adenopathy, we're still looking for proper indications to treat. We're not necessarily jumping from one [agent] to another without having a reason. This comes up even when we think about other drugs.

A common question I get is: What if [a patient is receiving] a covalent BTK inhibitor? Should you switch? Our goal with CLL is always to consider how we sequence these therapies and how to get the most mileage out of therapies, because CLL is a chronic disease, and—maybe with the exception of some older patients who may only need 1 therapy—younger patients might go from one therapy to another. We are always thinking about sequencing.

If a patient is doing well on a therapy, I'm not necessarily switching [them to another therapy] because that is going to use up another class. If they have an intolerance [to their current BTK inhibitor], then you can move around [to other therapies]. But otherwise, [when deciding] whether to use pirtobrutinib or any other relapse treatment, I would normally [look for] the indications we would [use to choose] pirtobrutinib: progressive disease, cytopenias, new lymphadenopathy, and the constitutional symptoms that go along with that.

What may be the logic behind switching a patient to pirtobrutinib or another therapy vs continuing current treatment if the patient is asymptomatic?

Some patients might start to progress but are relatively asymptomatic. When we think about strategy, we are thinking about the long term. If a patient is currently receiving a BTK inhibitor and their white blood cell [WBC] count is starting to rise, they're starting to develop resistance. [In this case], you can send for resistance mutation testing to [see whether the patient has a] 

 C481S mutation or another mutation, [although this information is mostly just] educational right now.

However, not all patients with progressive disease may have an identifiable resistance mutation. We do this [testing] in the academic setting because there are data showing that besides 

 C481S, there happen to be other resistance mutations, and some of them may have overlapping [targets] between the covalent and noncovalent BTK inhibitors. The question is: In the future, as these tests become more mainstream, will they influence how we sequence therapies? [If we learn that a mutation] is a common [target] for both the noncovalent and the covalent BTK inhibitors, we may not go from [one of those agents to the other], and maybe we will then switch to venetoclax-based therapy. We don't have that granularity of data yet, so [we cannot make treatment decisions based on mutational test results].

Some of the similar mutations that both [covalent and noncovalent BTK inhibitors target] are infrequent and rare. In the BRUIN study of pirtobrutinib in the relapsed setting, [patients' mutational status] didn't affect their responses [with pirtobrutinib]. We don't have a lot of data yet on this, but in the future, resistance mutational testing will potentially be relevant and important, and this may influence the sequencing of drugs.

If a patient is receiving a BTK inhibitor and has a WBC count that is progressing, sometimes you can buy extra mileage out of the drug if they don't have cytopenias, and you do not need to switch them [to another therapy] so quickly. Otherwise, if their disease is progressing, eventually you're going to change therapy, and that could be to venetoclax-based therapy or some other therapy. If you start a venetoclax-based combination that is a time-limited approach where patients come off therapy, you could retreat them, depending on the duration of that treatment. For example, [if a patient had good outcomes with] venetoclax that lasted more than 2 years and they tolerated the therapy well, you could rechallenge them. If this is a relapse in the third-line setting, you could go to [a different agent, like] pirtobrutinib. You have more than one option.

If the patient is asymptomatic, I would still wait until you have a real indication for treating them. [You may not need to treat them] just because their WBC count is going up if their hemoglobin and platelet levels are [stable]. You're going to have the discussion [with the patient, telling them] that they’re eventually going to need treatment again. However, that doesn't mean you necessarily have to put them on therapy sooner.

I'm happy that we have all these targeted therapies and that toxicity issues are improved compared with when we used to give chemoimmunotherapy. However, all these agents [are associated with] potential adverse effects [AEs], including infectious issues. None of these therapies are curative, so if [the patient does not] have an indication to treat yet, I would err on the side of being conservative. I won't treat my patients just because they're starting to progress unless we prove that doing so meaningfully affects their survival, although some trials are trying to address [the potential benefits of] early intervention.

What factors influence your treatment decision-making for patients with CLL who are eligible for both pirtobrutinib and liso-cel?

It's been a long time coming for CAR T-cell therapy in CLL. We started research on this more than a decade ago, but because of the toxicity issues [associated with CAR T-cell therapy], and because we started getting other targeted therapies with far less toxicity, CAR T-cell therapy kept getting relegated further down the line. We're happy to finally have an approval [for CAR T-cell therapy] in CLL because there are many patients who, if they start their CLL journey when they are young, will receive more than 1 therapy. We see patients who relapse after a covalent BTK inhibitor, after venetoclax, and after pirtobrutinib, so we need newer therapies for patients with CLL. Having the [FDA] approval [for liso-cel], 

One of the benefits of CAR T-cell therapy is that it's a time-limited therapy, in a way. [However, it is still associated with] cytokine release syndrome and potential neurologic toxicity. Thankfully, because CAR T-cell therapy has been around for so long in other disease states, our colleagues who administer CAR T-cell therapy have gotten good at mitigating some of these potential AEs, which has improved with a lot of supportive care and better management.

The problem in CLL is that, unfortunately, in studies like the phase 1/2 TRANSCEND CLL 004 study (NCT03331198), which led to the approval of liso-cel, like many relapsed/refractory studies that we do when we investigate new agents for this disease, some of these patients are on their fourth, fifth, or later lines of therapy—a heavily pretreated group and not a good risk group. In the [TRANSCEND CLL 004] study, 20% of the patients achieved a complete response, and among those 20%, [responses were] durable. [However], for [all other patients, this treatment] falls short.

An update to the TRANSCEND CLL 004 study [presented at] the 

 investigated using a BTK inhibitor to augment response to CAR T-cell therapy for patients with CLL. That [combination] doubled the response [rate vs liso-cel alone]. We still have a lot of work to improve upon responses to CAR T-cell therapy in CLL. It's important to get a good response in CLL from CAR T-cell therapy because it will [likely] be durable.

Now that both [liso-cel and pirtobrutinib] are approved [by the FDA], we still consider the patient's comorbidities and how old the patient is. If a patient has progressed on a covalent BTK inhibitor and venetoclax-based therapy, you have to consider other therapies. All other therapies—even pirtobrutinib in [the third-line] setting—are probably going to [yield] limited [responses]. Even in the BRUIN study with pirtobrutinib, the median PFS in double-refractory patients was less than 2 years, so you're going to have to consider other agents.

For example, if I have a young patient who has progressed on a covalent BTK inhibitor and venetoclax-based therapy—truly double refractory—I am going to get them evaluated by my colleagues who administer CAR T-cell therapy, but I'm also probably going to strategize to get their disease better under control because CAR T-cell therapy can be important if you can get them into a good response. Oftentimes, I'll [decide to] get the patient evaluated [for CAR T-cell therapy] and then put them on pirtobrutinib. Sometimes I'll even bridge with pirtobrutinib to CAR T-cell therapy for some of my younger, fitter patients. The good news is, we also have clinical trials, so there are lots of other drugs I might be exploring.

However, when you're [just considering] what's approved—[covalent BTK inhibitors, venetoclax], pirtobrutinib, and liso-cel—you have to evaluate the potential [of each therapy]. If I have an older, frailer patient who I feel may not be able to receive CAR T-cell therapy, I'm going to give them pirtobrutinib. However, for my younger patients, I'm [considering their need for] other therapies down the line; I need to think ahead for them because [their current therapy is] not going to last forever.

For the older patients, if they're not receiving CAR T-cell therapy, I'm considering pirtobrutinib, but then I need to think about what I can do for those in whom the response duration may not last as long. Can you go back to older therapies? Can you add an antibody? You need to become artsy with combinations if you can't get them on a clinical trial with newer agents like BTK degraders, bispecific antibodies, or other agents coming down the pike.

When thinking about pirtobrutinib vs CAR T-cell therapy, you have to consider your patient. What are the goals of treatment? Are they eligible for CAR T-cell therapy? If you're thinking about CAR T-cell therapy [in the future], you should try to have the patient evaluated, because you can collect their cells and freeze them if CAR T-cell therapy is a potential option, because the pirtobrutinib may only last so long, depending upon how heavily pretreated they are.

How might the role of pirtobrutinib in CLL continue to evolve going forward?

There have been lots of studies that are starting to move pirtobrutinib into earlier lines of therapy. There are also clinical trials that have been reported with pirtobrutinib plus venetoclax or pirtobrutinib plus venetoclax and obinutuzumab [Gazyva]—doublets or triplets that are time limited. We may see a lot more time-limited approaches with pirtobrutinib, similar to what we're seeing with covalent BTK inhibitor and venetoclax combinations that have moved into the frontline setting. Some of those have already been included in the National Comprehensive Cancer Network [NCCN] Guidelines. 

Ibrutinib plus venetoclax was approved in Europe

[based on data] from the phase 3 GLOW study [NCT03462719]. And now we have the phase 3 AMPLIFY trial [NCT03836261] regimen of acalabrutinib plus venetoclax with or without obinutuzumab, and that's now on the NCCN Guidelines as well, although it is not yet FDA approved. Studies with pirtobrutinib have moved into both the second- and first-line settings.

We will see a lot of clinical trials read out over the next several years positioning pirtobrutinib as a potential time-limited approach. How then are we going to sequence those kinds of therapies? Do we go from a covalent BTK inhibitor to venetoclax to a noncovalent BTK inhibitor, which is how it is now? What if [pirtobrutinib moves into earlier lines] and is time limited? We have more work to do regarding the potential role of sequencing and where to position pirtobrutinib, either in the frontline or second-line settings.

There are newer agents coming about as well. We will see clinical trials combining these agents with [those with] newer targets, such as BTK degraders or bispecific antibodies. Some clinical trials are adding pirtobrutinib into multiple arms and combining it with different agents. Stay tuned.

The field of CLL is getting a little trickier. I am grateful that we have lots of agents we can use for patients with CLL, but we still have to figure out the best sequencing approach or the best combinations, although there's more than one combination we can [use]. The field is moving quickly, but we still have a lot of data gaps that we need to [fill].

Jaypirca (pirtobrutinib) now approved by U.S. FDA for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. News release. Eli Lilly and Company. December 1, 2023. Accessed May 9, 2025. https://investor.lilly.com/news-releases/news-release-details/jaypircar-pirtobrutinib-now-approved-us-fda-treatment-adult

Sharman JP, Munir T, Grosicki S, et al. BRUIN CLL-321: Randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. 

. 2024;144(suppl 1):886-886. doi:10.1182/blood-2024-198147

Nicole Lamanna, MD, discusses pirtobrutinib decision-making in the relapsed/refractory CLL setting and ongoing earlier-line research with the agent.  

Patient Symptoms and Disease Features Guide Pirtobrutinib Use in R/R CLL

Dr Lamanna on Considerations for Pirtobrutinib Use in Pretreated CLL

"Our goal is always to think about how we sequence these therapies and how we can get the most mileage out them for patients with CLL. The indications that we would think about [when considering] which patients to choose for pirtobrutinib would be [those with] progressive disease, cytopenias, new lymphadenopathy, and constitutional symptoms that go along with that."

Nicole Lamanna, MD, a hematologic oncologist at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian/Columbia University Irving Medical Center, discussedtolerability and disease considerations when determining whether to initiate treatment with pirtobrutinib (Jaypirca) for patients with pretreated chronic lymphocytic leukemia (CLL).

Pirtobrutinib represents a key addition to the therapeutic landscape for chronic lymphocytic leukemia (CLL) as the first non-covalent BTK inhibitor to receive regulatory approval, Lamanna began. In December 2023, 

the FDA granted an accelerated approval to the agent

 for the treatment of adult patients with CLL or small lymphocytic lymphoma who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.

Its clinical utility is largely informed by findings from the phase 1/2 BRUIN trial (NCT03740529) study, which evaluated the agent in heavily pretreated populations, particularly those refractory to both covalent BTK inhibitors and BCL2 inhibitors, Lamanna detailed. In current practice, pirtobrutinib is primarily used in this double-refractory setting, where most patients now eligible for the agent, she explained.

Treatment indications in the relapsed setting remain consistent with frontline decision-making criteria, focusing on evidence of disease progression, such as cytopenias or symptomatic lymphadenopathy, rather than shifting therapies in the absence of clinical need, Lamanna noted. This is particularly relevant in the context of CLL’s chronic nature, where therapeutic sequencing is critical to maximize long-term disease control, she added.

A frequent clinical question pertains to switching therapies in patients who are doing well on covalent BTK inhibitors. In such cases, Lamanna emphasized that there is no rationale for transitioning to pirtobrutinib or another agent solely based on drug availability or theoretical benefit. Preserving therapeutic options for future use is a key principle, particularly for younger patients expected to require multiple lines of therapy over time, she stated. However, for patients experiencing intolerance to a BTK inhibitor, a switch to a different agent within the same class—or to pirtobrutinib—may be warranted, she clarified.

Ultimately, the choice to initiate pirtobrutinib should be guided by clear clinical indications, such as disease progression marked by worsening cytopenias, new or enlarging lymphadenopathy, or emergence of constitutional symptoms, Lamanna concluded.

Nicole Lamanna, MD, shares key considerations for the use of pirtobrutinib in the management of chronic lymphocytic leukemia.

! I’m your host today, Ashling Wahner.


, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, OncLive 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 Nicole Lamanna, MD, about patient selection considerations for the use of pirtobrutinib (Jaypirca) in the management of chronic lymphocytic leukemia (CLL). Dr Lamanna is a hematologic oncologist at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian/Columbia University Irving Medical Center in New York, New York.

In our exclusive interview, Dr Lamanna discussed how disease progression, treatment intolerance, and prior therapy exposure inform the decision to initiate pirtobrutinib in patients with CLL. She also highlighted important clinical features that guide the use of noncovalent BTK inhibitors—including sequencing strategies following covalent BTK and BCL-2 inhibitors, and emphasized the importance of balancing treatment efficacy with tolerability to optimize long-term disease management in CLL.

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

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Podcasts

Dr Lamanna discusses how disease progression, treatment intolerance, and prior therapy exposure inform the decision to initiate pirtobrutinib in CLL. 

Diving Into Therapeutic Decision-Making in Later-Line CLL | Supplements and Featured Publications

Dr Bhat on Choosing Between Pirtobrutinib and Liso-Cel for R/R CLL Management

Liso-Cel and Pirtobrutinib Add Options in R/R CLL, Underscoring the Importance of Proper Treatment Selection

Patient Symptoms and Disease Features Guide Pirtobrutinib Use in R/R CLL

Dr Lamanna on Considerations for Pirtobrutinib Use in Pretreated CLL

Disease Features and Treatment Intolerance Inform Pirtobrutinib Use in Pretreated CLL: With Nicole Lamanna, MD