Navigating the Treatment Landscape for Relapsed/Refractory CLL

Even with the available agents and knowledge of when to select which option, there is an unmet medical need in the chronic lymphocytic leukemia landscape, according to Jennifer R. Brown, MD, PhD.

There are multiple options for treating patients with chronic lymphocytic leukemia (CLL) after initial treatments. Homing in on patients with disease progression on a Bruton’s tyrosine kinase (BTK) inhibitor or continuous BCL-2 inhibition with venetoclax (Venclexta), the other available agent is the best option, according to Jennifer R. Brown, MD, PhD.1

“The landscape of relapsed CLL has become increasingly complicated, because as we know, historically, patients would relapse after minimal therapies like [monoclonal antibodies] or chlorambucil, or after effective chemoimmunotherapy. And these remain the patients who have been studied in most all of our clinical trials,” explained Brown, director, Chronic Lymphocytic Leukemia Center, institute physician at Dana-Farber Cancer Institute, and a Worthington and Margaret Collette professor of medicine in the Field of Hematologic Oncology at Harvard Medical School, during a virtual presentation at the 26th Annual International Congress on Hematologic Malignancies, hosted by Physician’s Education Resource®.

The landscape for CLL is ever-changing, making the options for next-line CLL treatment plentiful. Data supporting this strategy come from multiple phase 3 studies, including RESONATE (NCT01578707), ASCEND (NCT02970318), ELEVATE RR (NCT02477696), ALPINE (NCT03734016), and MURANO (NCT02005471).

BTK Inhibitor Efficacy and Safety

Six-year follow-up data from the randomized, multicenter, open-label, phase 3 RESONATE study confirmed the robust efficacy of the BTK inhibitor ibrutinib (Imbruvica) in patients with relapsed or refractory CLL and small lymphocytic lymphoma. Its benefit over ofatumumab (Kesimpta) was observed regardless of high-risk or genomic features.2

The median progression-free survival (PFS) observed with ibrutinib was 44.1 months (95% CI, 38.5-56.2) compared with 8.1 months (95% CI, 7.8-8.3) in the ofatumumab treatment arm (HR, 0.148; 95% CI, 0.113-0.196).1 Brown highlighted, however, that 1 concern with this BTK inhibitor is the adverse event profile. In RESONATE specifically, the most common grade ≥ 3 hematologic AEs were neutropenia (25%), thrombocytopenia (10%), and anemia (9%). Among the grade ≥ 3 nonhematologic AEs, the most common pneumonia (21%), hypertension (9%), urinary tract infection (7%), diarrhea (7%), and atrial fibrillation (6%).2This safety profile has led to interest in next-generation BTK inhibitors, according to Brown. Acalabrutinib (Calquence) and zanubrutinib (Brukinsa) are 2 examples of next-generation BTK inhibitors that are still covalent but appear to target BTK more specifically, Brown explained.

ASCEND was a randomized, multicenter, open-label, phase 3 study of acalabrutinib versus investigator’s choice of either idelalisib (Zydelig) in combination with rituximab (Rituxan) or bendamustine plus rituximab.1,3

“We recently had [a] 3-year update demonstrating about a 60% to 65% progression-free survival at 3 years, regardless of the presence of 17p or unmutated IGVH,” explained Brown.

In terms of the safety of acalabrutinib, the any-grade AE that occurred in ≥ 20% of patients with CLL was headache. Grade 3 and 4 AEs were observed in 45% of the patients treated with acalabrutinib monotherapy versus 86% of those treated with idelalisib/rituximab, and in 43% of those who received bendamustine/rituximab.3

Results from ASCEND led to the head-to-head comparison of ibrutinib and acalabrutinib in the randomized, multicenter, open-label, non-inferiority, phase 3 ELEVATE RR study. The study showed that acalabrutinib was noninferior to ibrutinib for the treatment of CLL based on PFS data. The median PFS was 38.4 months (95% CI, 33.0-38.6) with acalabrutinib versus 38.4 months (95% CI, 31.0-41.6) with ibrutinib (HR, 1.00; 95% CI, 0.79-1.27).4

Further, safety data showed that acalabrutinib resulted in fewer cardiovascular AEs compared with ibrutinib (9.4% vs 16.02%; P = .02). Grade ≥ 3 events appeared comparable between acalabrutinib versus ibrutinib with infections having occurred in 30.8% versus 30.0%, respectively, and Richter transformations having been observed in 3.8% versus 4.9%.

Ibrutinib was also evaluated in comparison with zanubrutinib for the treatment of patients with relapsed or refractory CLL or SLL in the phase 3, randomized ALPINE study. The overall outcome of the interim analysis was that zanubrutinib had a better response rate of 78.3% (95% CI, 72.0%-83.7%) versus 62.5% (95% CI, 55.5%-69.1%) in the ibrutinib arm.1,5

Zanubrutinib also prolonged PFS in the study. The landmark 12-month PFS rate for the zanubrutinib-treated population was 94.9% versus 84.0% with ibrutinib (HR, 0.40; 95% CI; 0.23-0.69; 2-sided P = .0007). Moreover, cardiovascular AEs were fewer with zanubrutinib (2.5%) compared with ibrutinib (10.1%), showing a P value of .0014. Rates of major bleeding at 2.9% versus 3.9% were also lower with zanubrutinib.5

“I think these data really do establish that, at this point, our BTK inhibitor of choice is probably a second-generation BTK inhibitor. Zanubrutinib has not yet been approved in this setting either. But hopefully, based on these data, it will be soon,” said Brown regarding the ALPINE trial results.1

The final next-generation agent for the treatment of CLL is venetoclax. After 3 years of follow-up in the multicenter, phase 3, open-label, randomized MURANO study, investigators have shown that fixed-duration venetoclax plus rituximab provides durable PFS and overall survival (OS) benefit in patients with relapsed or refractory disease. Some patients in the study even achieve undetectable minimal residual disease (uMRD) status while on treatment, which was associated with improvement in PFS and OS.1,6

The median PFS with venetoclax/rituximab was 53.6 months (95% CI, 48.4-57.0) versus 17.0 months (95% CI, 15.5-21.7) with the comparator combination (HR, 0.19; 95% CI, 0.15-0.26; P < .0001). The median OS was not evaluable in either arm (HR, 0.40; 95% CI, 0.26-0.62; P < .0001).

Safety data for venetoclax/rituximab shows that the combination did not lead to serious AEs. Grade ≥ 3 AEs occurred in 58.8% of the venetoclax/rituximab arm compared with 39.9% of the bendamustine/rituximab arm. Richter transformation was uncommon in the study.6

Selecting Between Treatment Options

The lingering questions after reviewing data from these 5 clinical trials is whether to use a second-generation BTK inhibitor or the combination of venetoclax and rituximab. According to Brown, there are pros and cons on both ends of the spectrum.1

Some of the information favoring the use of a second-generation BTK inhibitor after disease progression on frontline therapy include longer follow-up data to reference and improved toxicity profiles, Brown shared. However, there are some factors that make venetoclax/rituximab more promising, including high rates of complete response, uMRD rates, time-limited therapy, cost, and the potential to re-treat patients.

Even with the available agents and knowledge of when to select which option, Brown says, there is an unmet medical need in the CLL landscape. More patients are developing disease progression on both BTK inhibitors and venetoclax, showing no true standard of care for these patients. To date, clinical trials are showing promise for noncovalent BTK inhibitors, combinations of BTK and BCL-2 inhibition, and time-limited therapy.


1. Brown JR. Treating CLL in subsequent lines of therapy. Presented at: 2022 International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma; February 23-25, 2022; Miami, FL.

2. Munir T, Brown JR, O’Brien SO, et al. Final analysis from RESONATE: Up to six years of follow‐up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94(12):1353-1363. doi:10.1002/ajh.25638

3. Ghia P, PLuta A, Wac M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355

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. Hillmen P, Eichhorst B, Brown JR, et al. First interim analysis of alpine study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: European Hematology Association 2021 Virtual Congress; June 9-19, 2021; virtual. Abstract LB1900.

6. Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. 2020;38(34):4042-4054. doi:10.1200/JCO.20.00948