Pirtobrutinib Adds Effective Option to CLL Treatment Landscape, Underscoring Treatment Selection Considerations

Nitin Jain, MD

The emergence of pirtobrutinib (Jaypirca) has added an additional treatment option for patients with relapsed/refractory chronic lymphocytic leukemia (CLL); however, the growing wealth of choices requires careful consideration of patient needs and disease characteristics in order to select the appropriate therapy, according to Nitin Jain, MD.

In December 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of patients with CLL/small lymphocytic lymphoma who received a minimum of 2 prior lines of treatment, including a BTK and a BCL-2 inhibitor.¹ The approval was supported by data from the phase 1/2 BRUIN trial (NCT03740529), which demonstrated that patients who received the agent (n = 108) achieved an overall response rate of 72% (95% CI, 63%-80%); all responses were partial. Additionally, the median duration of response was 12.2 months (95% CI, 9.3-14.7). The most common any-grade adverse effects reported in at least 20% of patients included fatigue, bruising, cough, and musculoskeletal pain.

“[Regarding] pirtobrutinib, I think [about] how the treatment [paradigm] for CLL has evolved,” Jain said in an interview with OncLive^®. “Most patients initially receive a covalent BTK inhibitor, venetoclax [Venclexta]-based therapy, or one after the other in a sequential manner. There are also data [that indicate] you can combine covalent BTK inhibitors with venetoclax-based therapy. Right now, most of the data for pirtobrutinib [are in] patients who have had previous exposure to these drugs. Those patients are appropriate for pirtobrutinib-based therapy.”

Jain is a professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston.

In the interview, Jain discussed initial treatment selection considerations for pirtobrutinib in patients with CLL, when he decides to switch therapies, and the role of CAR T-cell therapy in the present treatment landscape.

OncLive: How do you determine which patients with CLL are eligible for pirtobrutinib?

Jain: Pirtobrutinib is a non-covalent BTK inhibitor. We have multiple covalent BTK inhibitors approved [by the FDA]: ibrutinib [Imbruvica], zanubrutinib [Brukinsa], and acalabrutinib [Calquence]. Pirtobrutinib does not bind to BTK C481, meaning that it works well in patients who are resistant to covalent BTK inhibitors, and that’s where most of the clinical data are.

The initial approval of pirtobrutinib included patients who have been exposed to or experienced disease progression with a BCL-2 inhibitor, namely venetoclax. However, more recent data suggest that any patient with relapsed/refractory CLL who [received] a prior covalent BTK inhibitor can be treated with pirtobrutinib. In my opinion, any [patient with] relapsed/refractory CLL who has received a covalent BTK inhibitor would be an appropriate candidate for pirtobrutinib-based therapy.

Are there any important conversations that need to be had with patients when considering pirtobrutinib?

I should also mention that the CAR T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi) is also FDA-approved for patients who [experienced disease progression on] or been exposed to a BTK inhibitor and venetoclax. Oftentimes in the clinic, [we have] conversations among patients who are double exposed and are considering pirtobrutinib-based therapy or CAR T-cell therapy. Logistically, pirtobrutinib is much easier because it is [orally administered]. Many patients are increasingly being prescribed pirtobrutinib in this setting.

When may it be appropriate to switch treatment to pirtobrutinib in the later-line settings?

If a patient is responding to ongoing therapy, whatever it might be, I don’t believe there’s a need to immediately switch to pirtobrutinib if they’re responding and the therapy is well tolerated. However, if they’re not responding, showing resistance to treatment, or if they’re experiencing adverse effects [AEs] such as increasing joint pain, bleeding issues, bruising, increased neutropenia, or myelosuppression, pirtobrutinib could be considered. However, if a patient is responding to ongoing therapy without any major AEs, I don’t believe there is a need at that time to switch to pirtobrutinib.

If a patient is asymptomatic and their blood counts are normal or improving, there’s no pirtobrutinib. However, if they’re having intolerance to whatever therapy they’re receiving or showing signs of resistance, including rising white blood cell counts, increasing lymph node [involvement], or worsening fatigue, then one could argue to look into starting pirtobrutinib, especially there’s a bona fide relapse on current therapy.

For patients who have previously received a BCL-2 inhibitor or a covalent BTK inhibitor, is there a role for rechallenge with these agent classes?

This is an important question. What has traditionally happened with covalent BTK inhibitors is that most patients would generally have been receiving these agents in a continuous manner, and they may be on it for many years before they have disease progression. If they [experience] disease progression, they are on a covalent BTK inhibitor, it doesn’t make sense to switch to another covalent BTK inhibitor because they just progressed on that [agent class].

However, venetoclax is known for its time-limited duration, and patients, many times, will complete the treatment and be in remission. Then they will be off therapy for a while, and then years down the line they could [have] disease progression. In those situations, you can retreat, and there are data emerging for retreatment with venetoclax in this situation.

I would also say that for a patient who stopped [treatment with] a covalent BTK inhibitor for intolerance some time ago, [then experienced] disease progression, and now you want to retreat, if they were receiving, for example, ibrutinib before they had intolerance, you can go to a second-generation BTK inhibitor, [such as] a acalabrutinib or zanubrutinib, because the patient was not highly resistant. They were intolerant to a prior covalent BTK inhibitor.

What is the present role of CAR T-cell therapy given the established roles of BTK inhibitors?

The issue is that we have a relatively lower number of patients treated with CAR T-cell therapy compared with pirtobrutinib. Also, CAR T-cell therapy is slightly more intensive early on, at least in the first month, because it requires hospital admission for most patients and has some toxicities associated with it. However, CAR T-cell therapy does allow the potential for a long-term treatment [break], and there is a curable fraction of patients who may achieve long-term, durable remissions with CAR T-cell therapy.

It remains to be seen what the cure fraction might be after CAR T-cell therapy. Having said that, we have two excellent options available for patients with relapsed/refractory CLL: pirtobrutinib and [liso-cel]. I discuss both options with my patients, and many patients elect for pirtobrutinib just because it’s an easier [treatment] initiation. However, with both of these therapies, you have to be prepared [to administer] the next line of therapy because many of these therapies, unfortunately, do not last for a long time. However, they can provide, for a short span of time, a good quality of life and disease control for patients.

Reference

FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed June 5, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic