Complex R/R CLL Treatment Landscape Braces as Noncovalent Inhibitors Emerge

Targeted Therapies in OncologyMay 2022
Volume 11
Issue 7
Pages: 35

Targeted agents, such as Bruton tyrosine kinase inhibitors, PI3K inhibitors, B-cell lymphoma 2 inhibitors, and venetoclax, have delivered improvements in quality of life, progression-free survival, and overall survival for relapsed/refractory chronic lymphocytic leukemia.

With the arrival of targeted therapies for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), efforts to identify noncovalent inhibitors are progressing. Today, targeted agents, such as Bruton tyrosine kinase (BTK) inhibitors, PI3K inhibitors, B-cell lymphoma 2 inhibitors, and venetoclax (Venclexta), have delivered improvements in quality of life, progression-free survival (PFS), and overall survival (OS).

“We’re in a period where the majority of patients are treated with several targeted therapies, rather than chemotherapy, as a standard of care,” Anthony Mato, MD, MSCE, said during his presentation during the National Comprehensive Cancer Network 2022 Annual Conference.1 His presentation provided a historical perspective on how far the fi eld has come in the past several decades, spanning the use of glucocorticoids and alkylating agents, the era of combination chemotherapy and chemoimmunotherapy, and the recent advent of several targeted agents.

To begin, Mato noted the 3 main treatment options for chemotherapy-free pathways in the frontline setting: ibrutinib (Imbruvica), acalabrutinib (Calquence), and venetoclax.2-5 However, in the R/R setting, there are 5 approved targeted agents, with the potential for 120 treatment sequences. “When thinking about treatment in the [R/R] setting, we always need to consider what was used during an earlier line of therapy,” Mato said, who is the director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York, New York.

Given the complex treatment landscape in the R/R setting, Mato offered tips on developing an optimal treatment plan for patients. “First, always select the best frontline approach for patients,” Mato said. When the disease progresses, 3 considerations to keep in mind are the reason for discontinuation of the therapy, the available treatment options, and the levels of evidence to support the decision. These considerations apply to 2 groups of patients. The first group consists of patients who were treated with frontline BTK inhibitors and the second group consists of patients who were treated with frontline venetoclax, he said.

For patients who are novel-agent naïve in the R/R setting, Mato asked which novel agent—a BTK inhibitor, PI3K inhibitor, or venetoclax—should be administered first. He said in all circumstances, when clinically acceptable, the data support a BTK inhibitor or venetoclax before an approved PI3K inhibitor. “There is, however, no definitive comparative data to support venetoclax over a BTK inhibitor as a first novel agent in novel agent–naïve R/R CLL, but limited real-world evidence data are intriguing,” Mato said.

Three BTK Inhibitors

Further adding to the complexity is the availability of 3 BTK inhibitors that are indicated in the R/R setting—ibrutinib, acalabrutinib, and zanubrutinib (Brukinsa). Which BTK inhibitor to choose? Mato’s short answer was to select a second-generation BTK inhibitor over ibrutinib. In particular, he cited findings from the ALPINE trial (NCT03734016), a phase 3 study comparing zanubrutinib vs ibrutinib in patients with R/R CLL/small lymphocytic leukemia (SLL).6

At a median follow-up of 15 months, objective response rate (ORR) was signifi cantly higher with zanubrutinib vs ibrutinib (78.3% vs 62.5%, 2-sided P = .0006 compared with a prespecified α of 0.0099 for interim analysis). ORR was higher in patients with 11q deletion (83.6% vs 69.1%, respectively) and 17q deletion (83.3% vs 53.8%) with zanubrutinib, as were overall 12-month PFS rates (94.9% vs 84.0%) and OS rates (97.0% vs 92.7%).6

In the ELEVATE-RR trial (NCT02477696) that evaluated acalabrutinib vs ibrutinib, patients were randomized 1:1 to receive 100 mg of acalabrutinib or 420 mg of ibrutinib.7 The primary end point was independent review committee–assessed noninferiority of PFS. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib, with a median PFS of 38.4 months in both arms (acalabrutinib, 95% CI, 33.0-38.6; ibrutinib, 95% CI, 33.0- 41.6; HR, 1.00; 95% CI, 0.79-1.27).

Mato also shared data from a study that evaluated the optimal sequencing of ibrutinib, idelalisib (Zydelig), and venetoclax in CLL.8 In the trial, 683 patients were evaluated, and investigators determined that with a median follow-up of 17 months (range, 1-60), median PFS and OS for the entire cohort were 35 months and not reached, respectively. Patients treated with ibrutinib (vs idelalisib) as first kinase inhibitor had a significantly better PFS in all settings: frontline (HR, 2.8; 95% CI, 1.3-6.3, P = .01), R/R (HR, 2.8; 95% CI 1.9-4.1; P < .001), and 17p deletion (HR, 2.0; 95% CI, 1.2-3.4; P = .008).

In this real-world trial, Mato et al concluded that ibrutinib appeared superior to idelalisib as first kinase inhibitor. In the event of kinase inhibitor failure, an alternate kinase inhibitor or venetoclax therapy should be considered over chemoimmunotherapy combinations. Further, choosing venetoclax upon ibrutinib failure might be superior to idelalisib.

New Treatment Options

Noncovalent BTK Inhibitors

Turning to emerging treatment options, Mato focused on the development of resistance to BTK inhibitors that are attributable to mutations, notably C481 mutations that are detected at disease progression. In a presentation by Woyach et al,9 investigators reported that patients underwent deep sequencing every 3 to 6 cycles, using a digital droplet polymerase chain reaction assay for BTK C481S after receiving acalabrutinib. Investigators concluded that CLL relapse after acalabrutinib is mediated by mutations in BTK that are similar to ibrutinib. They recommended that further BTK resistance monitoring could offer the opportunity to intervene before symptomatic disease. This finding and others have spurred the development of several noncovalent BTK inhibitors, including vecabrutinib, AQQ-531, and LOXO305 (pirtobrutinib).

Mato touched on pirtobrutinib, which has shown to be highly selective for BTK as compared with other kinases. Pirtobrutinib has a different binding mode, “such that it has the opportunity to overcome resistance and seems well tolerated,” Mato said.10

In the phase 1/2 BRUIN study (NCT03740529), 323 patients were treated with pirtobrutinib across 7 dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day). Investigators reported that 0 dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events (AEs) in at least 10% of 323 patients were fatigue (20%), diarrhea (17%), and contusion (13%). The most common AE of grade 3 or higher was neutropenia (10%).

Cellular Therapies

For cellular therapies, the role of chimeric antigen receptor (CAR) T-cell therapy in CLL is undergoing evaluation. Mato spotlighted the TRANSCEND-CLL-004 trial (NCT03331198), which evaluated the CD19-directed CAR T-cell therapy, lisocabtagene maraleucel (Breyanzi), in patients with high-risk CLL or SLL who have previously progressed on ibrutinib. In the monotherapy cohort, the ORR was 82%, with a partial response of 36%. Median PFS was 18 months (95% CI, 3.0–not reached).11 “I’m quite encouraged cellular therapies will play a major role in the management of [R/R] CLL,” Mato said.

Allogeneic Hematopoietic Stem Cell Transplantation

There are encouraging data for allogeneic stem cell transplantation (alloHCT) in patients who received prior targeted therapies, according to a study by Roeker et al.12 In this trial, 29% (18 of 63) of patients received novel agents as CLL-directed therapy prior to undergoing alloHCT. The 3 most common novel agents used in any line of therapy prior to alloHCT were ibrutinib (82%), venetoclax (40%), and idelalisib (20%). The investigators reported that neither the number of novel agents nor the specific novel agent used prior to alloHCT had an impact on survival outcomes. “As we try the many targeted therapies, the pendulum may ultimately swing back to an increasing role for alloHCT,” Mato said.


1. Mato A. Optimizing treatment of patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia. Presented at: NCCN 2022 Annual Conference; March 31-April 2, 2022; Orlando, FL. Accessed April 15, 2022.

2. Burger JA. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020;383(5):460-473. doi:10.1056/NEJMra1908213

3. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43-56. doi:10.1016/S1470-2045(18)30788-5

4. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi:10.1056/NEJMoa1815281

5. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278- 1291. doi:10.1016/S0140-6736(20)30262-2

6. Hillmen , 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; June 9-17, 2021; virtual. Accessed April 20, 2022.

7. 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

8. Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5):1050- 1056. doi:10.1093/annonc/mdx031

9. Woyach J, Huang Y, Rogers K, et al. Resistance to acalabrutinib in CLL is mediated primarily by BTK mutations. Blood. 2019;134 (suppl_1): 504. doi:10.1182/blood-1029-127674

10. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5. doi:10.1016/S0140-6736(21)00224-5

11. Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: Phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Accessed April 20, 2022. https://bit. ly/3jYkiJz

12. Roeker LE, Dreger P, Brown JR, et al. Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents. Blood Adv. 2020;4(16):3977-3989. doi:10.1182/bloodadvances.2020001956

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