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Lymphoma Hub Symposium | The value of BTK inhibitors for the treatment of patients with R/R CLL

Oct 16, 2020

The Lymphoma Hub looks forward to hosting a virtual satellite symposium (Sunday, November 8, 2020, at 15:50–16:50 CET) at this year’s European School of Haematology (ESH) conference, ‘How to Diagnose and Treat Lymphoma.’ The aim of this symposium is to provide expert views on how to treat patients with relapsed/refractory (R/R) lymphoma. The symposium will be led by Lymphoma Hub Chair Gilles Salles and a panel of international experts: Marie José Kersten, Kieron Dunleavy, Francesc Bosch, and Astrid Pavlovsky. The group will focus on the existing and emerging treatment approaches for patients with R/R disease, and the challenges faced when considering patient prognosis in this setting.

In the leadup to the satellite symposium, the Lymphoma Hub is highlighting the treatment landscape of R/R chronic lymphocytic leukemia (CLL), which has seen great advances in the past decade following increased understanding of disease biology and the subsequent development of targeted therapies.1,2 Introduction of Bruton's tyrosine kinase (BTK) inhibitors has played an important role in prolonging progression-free survival (PFS) and overall survival (OS) in patients with R/R CLL who have otherwise limited treatment options.2 Here, the Lymphoma Hub outlines the journey of BTK inhibitors into the clinic and provides a compilation of previous hub content for their use in R/R CLL.


B-cell receptor signaling has been identified as a major contributor to the initiation, progression, and survival of B-cell malignancies. Preclinical knockout studies established the B-cell receptor kinase, BTK, as a particularly important driver of CLL, and it became an attractive therapeutic target. This led to the development of a number of a small-molecule agents, which inactivate BTK and are orally bioavailable.2

The most extensively investigated BTK inhibitors are ibrutinib, acalabrutinib, and zanabrutinib. Ibrutinib is a first-in-class, irreversible BTK inhibitor which, although efficacious, has been associated with a number of off-target effects, such as non-specific kinase inhibition and interference with anti-CD20 monoclonal antibodies.3 In an effort to overcome this, second-generation BTK inhibitors were designed. Acalabrutinib and zanubrutinib are both highly selective, second-generation BTK inhibitors which have demonstrated fewer off-target effects and low affinity for alternative kinases compared with ibrutinib in preclinical models.3,4


Since ibrutinib was launched in clinical trials in February 2009, it has been investigated in various clinical trials as well as in the real-world setting; below is a summary.2


The single-arm, open-label, multicenter PCYC1102-CA trial (NCT01105247) evaluated the safety and efficacy of once-daily ibrutinib for patients with CLL/small lymphocytic lymphoma (SLL). The study contributed towards the accelerated approval of ibrutinib by the U.S. Food and Drug Administration (FDA) in February 2014 for the treatment of patients with CLL/SLL who have received ≥ 1 prior therapy.2


A condition of the accelerated approval of ibrutinib was that it underwent further investigation in a randomized controlled trial.2 The RESONATE study (NCT01578707) was the first randomized, multicenter, open-label trial to evaluate ibrutinib vs ofatumumab in patients with R/R CLL.5 The Lymphoma Hub provided the latest update from the RESONATE 6-year final analysis.

In the RESONATE study, ibrutinib demonstrated superior PFS, OS, and overall response rates (ORRs) compared with ofatumumab in patients with high-risk R/R CLL. Superior outcomes with ibrutinib over rituximab have been also reported from the NCT01973387 trial in patients with R/R CLL in the Asia–Pacific region.

Results from the RESONATE trial provided the grounds for regular approval by the FDA in July 2014 for patients who have received ≥ 1 prior therapy for the treatment of CLL and for patients with CLL harboring the 17pDel mutation.  

Ibrutinib combination therapies

In light of positive data surrounding single-agent ibrutinib for R/R CLL, a number of studies set out to determine the value of different ibrutinib combination regimens.


The phase III, randomized HELIOS study (NCT01611090) was designed to evaluate the efficacy of ibrutinib in combination with bendamustine + rituximab (BR) vs placebo + BR. The 5-year final analysis uncovered the benefit of ibrutinib with BR, which demonstrated prolonged survival over placebo + BR in patients with R/R CLL/SLL. The efficacy data, along with the encouraging safety and toxicity findings, support the continued use of ibrutinib in this setting.


The CLARITY clinical trial (ISRCTN13751862) is a phase II, multi-center study investigating the safety and efficacy of ibrutinib in combination with the BCL-2 inhibitor, venetoclax, for patients with R/R CLL. Results from a 21.1-month follow-up suggest that the combination is both efficacious and well tolerated in patients with R/R CLL. The high rates of measurable residual disease negativity observed in patients receiving ibrutinib + venetoclax suggest that the combination may only require a short administration period.

In the video below, Nitin Jain, The University of Texas MD Anderson Cancer Center, outlined what population of patients with CLL may benefit most from ibrutinib + venetoclax.

Which population of patients with CLL might benefit most from venetoclax plus ibrutinib?

Challenges associated with real-world ibrutinib use

Despite the encouraging clinical efficacy demonstrated by ibrutinib in the treatment of CLL, there are a number of factors which limit its continuous use. The Lymphoma Hub provided a comprehensive summary of ibrutinib-mediated toxicities that may lead to treatment discontinuation in patients with CLL across the United States. Increased risk of serious infection is one of the hurdles associated with long-term treatment with ibrutinib, which you can read more about here.

Guidance on how to manage patients who discontinue treatment is limited. The Lymphoma Hub reviewed the real-world outcomes of patients following ibrutinib discontinuation for CLL. This analysis revealed that approximately 25% of patients who discontinue treatment with ibrutinib demonstrate rapid disease progression and, therefore, outlined an area of unmet clinical need.

Second-generation BTK inhibitors



The ASCEND trial (NCT02970318) evaluated the efficacy of acalabrutinib vs investigator’s choice of rituximab + idelalisib or rituximab + bendamustine for patients with R/R CLL. At a 16.1-month follow-up, median PFS was significantly longer in patients receiving acalabrutinib vs investigator’s choice (not reached vs 16.5 months; p < 0.0001), and acalabrutinib demonstrated a reasonable safety profile in patients with R/R CLL.6 Data from the ASCEND trial supported the FDA approval and Committee for Medicinal Products for Human Use (CHMP) positive opinion of acalabrutinib for patients with R/R CLL.


Results from an additional phase Ib/II, multicenter study (NCT02029443) confirmed the efficacy, durability, and tolerability of acalabrutinib in patients with R/R CLL or SLL. Acalabrutinib demonstrated a favorable adverse event profile, supporting its use in combination regimens, and high ORR irrespective of patient genomics; read more here.



The pivotal single-arm phase II study (NCT03206918) investigated the safety and efficacy of zanubrutinib in patients with R/R CLL/SLL. As a result of the promising patient responses observed in this study (ORR, 62.6%), zanubrutinib was granted approval by China’s National Medical Products Administration (NMPA) in June 2020.


BTK inhibitors have improved patient prognosis in the R/R CLL setting, offering hope to patients with high-risk disease and those who have exhausted alternative treatment options. However, treatment approaches for R/R CLL are not limited to BTK inhibitors, as outlined by Jennifer Woyach in an interview with Lymphoma Hub. Please take part in the poll below to let us know what you think is the most promising emerging agent in R/R CLL.

Thinking beyond BTK inhibitors, what do you think is the most promising novel drug class for patients with R/R CLL?

PI3K inhibitors


CAR T-cell therapy


BH3-mimetic (venetoclax)


Bispecific antibodies


7 votes

  1. Cuneo A, Foà R. Relapsed/refractory chronic lymphocytic leukemia: chemoimmunotherapy, treatment until progression with mechanism-driven agents or finite-duration therapy? Mediterr J Hematol Infect Dis. 2019;11(1):e2019024. DOI: 4084/MJHID.2019.024
  2. de Claro A, McGinn KM, Verdun N, et al. FDA approval: ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Cancer Res. 2015;21(16). DOI: 10.1158/1078-0432.CCR-14-2225
  3. Isaac K, Mato A.R. Acalabrutinib and its therapeutic potential in the treatment of chronic lymphocytic leukemia: a short review on emerging data. Cancer Manag Res. 2020;12:2079-2085. DOI: 10.2147/CMAR.S219570
  4. Song Y, Zhou K, Zou D, et al. Treatment of patients with relapsed or refractory mantle-cell lymphoma with zanubrutinib, a selective inhibitor of Bruton's tyrosine kinase. Clin Cancer Res. 2020;26(16):4216- DOI: 10.1158/1078-0432.CCR-19-3703
  5. Byrd J, Brown J, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213-223. DOI: 10.1056/NEJMoa1400376
  6. Ghia P, Pluta A, Wach 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