Poll Responses Show Preference Among Expanding Relapsed CLL Therapies

Effective treatment options for relapsed and refractory chronic lymphocytic leukemia (CLL) continue to expand, which is an exciting development for patients, though it poses unique challenges to the practicing hematologist/oncologist. Specifically, among the preferred treatment regimens suggested by the National Comprehensive Cancer Network (NCCN) guidelines, there is a paucity of head-to-head prospective trials to define a single, superior approach, often leaving the decision for therapy between the patient and the provider.¹ Shared decision-making remains a critical part of optimal care for patients with CLL. Important factors to determine the most appropriate therapy include which therapy the patient received previously, how well the patient responded to this regimen, and how well it was tolerated, in addition to disease-specific features (ie, IGHV and TP53 status) and patient-specific features (ie, age, comorbidities, and patient preferences).

To understand treatment patterns and preferences, a series of expert-led Case-Based Roundtable events were conducted over the past year, during which over 200 practicing hematologists/oncologists were surveyed on their preferred patterns of treating patients with CLL in both the second- and third-line settings. The focus was on relapsed CLL for which 2 cases were discussed—a second-line and a third-line case of relapsed CLL.

Covalent Bruton tyrosine kinase (BTK) inhibitors are preferred in the second line for high-risk patients who are naive to novel agents (Polling Question 1).

Participants were presented with a case of a 68-year-old man who was diagnosed with CLL, then eventually treated with bendamustine/rituximab (Rituxan) with relapse 4 years later (when the patient was 78 years old). His only comorbidity was hypertension, controlled with lisinopril. His workup at the time of symptomatic relapse was notable for the presence of a 17p deletion. When asked to select preferred therapy at the time of this relapse, the majority of respondents favored a covalent BTK inhibitor—specifically, 46% preferred zanubrutinib (Brukinsa) and 25% preferred acalabrutinib (Calquence). Less preferred time-limited approaches included a venetoclax (Venclexta)-based regimen (21%) and chemoimmunotherapy (0.4%). Interestingly, 7.4% of respondents selected pirtobrutinib (Jaypirca) even though this patient would not meet the current NCCN- or FDA-approved use of pirtobrutinib, which necessitates a prior covalent BTK inhibitor or prior BTK and BCL-2 inhibitor, respectively.^1,2 No respondents selected ibrutinib (Imbruvica).

Overall, there is not a single appropriate right answer for this question, although the vast majority of respondents selected highly reasonable approaches, whether it was the use of a continuous covalent BTK inhibitor in this high-risk patient or the use of a venetoclax-containing regimen. Although venetoclax-based regimens may lead to shorter time to progression in the setting of 17p deletion, there is the benefit of some time off therapy, which would be reasonable if this was in line with the patient’s preferences.³ Both zanubrutinib and acalabrutinib have demonstrated excellent efficacy in the relapsed setting in high-risk patients and improved safety when compared with ibrutinib, though there is no prospective head-to-head comparison of these 2 preferred agents to suggest which of these agents is truly superior.^4,5

Polling Question 1.

What second-line treatment do you or would you prescribe for this patient with relapsed/refractory CLL?

In patients with prior treatment of covalent BTK inhibition and venetoclax, pirtobrutinib is favored over chimeric antigen receptor (CAR) T-cell therapy (Polling Question 2).

Participants were presented with a case of a 70-year-old patient with relapsed CLL who had previously been treated with acalabrutinib for 3 years (and progressed while on it), then a venetoclax/rituximab regimen (and progressed 6 months following completion of the regimen). This patient’s only comorbidity was type 2 diabetes on insulin. Workup at the time of relapse was notable for the presence of a TP53 mutation. Pirtobrutinib was overwhelmingly the preferred therapy for this patient at the time of relapse, selected by 80.9% of respondents. CAR T-cell therapy was the second most selected answer, selected by 10.4% of respondents.

Though both are listed as preferred regimens in the NCCN guidelines, the audience commonly cited ease of use, high response rate, and excellent safety profile as reasons for preferring pirtobrutinib over CAR T, which is in line with the presented data from the phase 1/2 BRUIN trial (NCT03740529) and the recently published BRUIN CLL-321 trial (NCT04666038), which studied pirtobrutinib in exclusively postcovalent BTK inhibitor–treated patients.⁶ For those who selected CAR T-cell therapy, the long durability of responses was cited as a significant benefit, though many cited lack of access to specialized centers as a major barrier.⁷

Importantly, very few respondents selected zanubrutinib (4.8%) or rechallenge with venetoclax or acalabrutinib (1.6%), neither of which would be expected to lead to prolonged response, due to a shared resistance mechanism for zanubrutinib and acalabrutinib and to short duration of time off therapy for venetoclax.

Polling Question 2.

Since this patient responded well to both prior treatments, what third-line therapy are you most likely to recommend for relapsed/refractory CLL?

Overall, effective therapies for patients with CLL in the relapsed setting are multifold, and the community oncologists who participated in this Case-Based Roundtable event demonstrated an excellent understanding of the evolving options. Further research should aim to continue to refine the role of many outstanding questions/debates within the field: the potential role for minimal residual disease testing, novel agent sequencing in relation to resistance mechanisms, and efficacy of retreatment with venetoclax-based regimens in light of evolving time-limited frontline options that will impact therapeutic options in the relapsed setting.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia and small lymphocytic lymphoma; version 1.2026. Accessed October 13, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf}

_{2. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 1, 2023. Updated December 7, 2023. Accessed October 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic}

_{3. Kater AP, Harrup R, Kipps TJ, et al. The MURANO study: final analysis and retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL. Blood. 2025;145(23):2733-2745. doi:10.1182/blood.2024025525}

_{4. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210}

_{5. Brown JR, Eichhorst B, Lamanna N, et al. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE. Blood. 2024;144(26):2706-2717. doi:10.1182/blood.2024024667}

_{6. Sharman JP, Munir T, Grosicki S, et al. Phase III trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. 2025;43(22):2538-2549. doi:10.1200/JCO-25-00166}

_{7. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023;402(10402):641-654. doi:10.1016/S0140-6736(23)01052-8}