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

Seema A. Bhat, MD

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 OncLive®.

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.1 In December 2023, pirtobrutinib earned approval for the same indication.2

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.1,3 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).2

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.

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

Bhat: 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 2024 ASH Annual Meeting and Exposition, 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.

References

1. 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
2. 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
3. Breyanzi. Prescribing information. Bristol Myers Squibb; 2024. Accessed May 22, 2025. https://packageinserts.bms.com/pi/pi_breyanzi.pdf