Blood cancers

BTK Inhibitors: First head-to-head data revealed 

Tuesday, 28 Sep 2021

BTK Inhibitors: First head-to-head data revealed

Chronic lymphocytic leukaemia (CLL) is a generally indolent lymphoproliferative disorder that mostly affects people over 60 years of age. While patients can often remain asymptomatic for many years and a proportion of patients will never require therapy, the disease will usually progress in the majority of patients and require treatment.1 In recent years, the landscape of CLL treatment has shifted away from the previous exclusive reliance on chemoimmunotherapy as more effective targeted therapies have been developed.1,2 In particular, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has gained traction as standard of care for patients with both treatment-naïve and relapsed/refractory (RR) CLL.2 However, the use of ibrutinib can be limited by toxicities and adverse events, affecting tolerability and continuation of therapy.2 Enter acalabrutinib – a more selective second generation BTK inhibitor that may offer improved tolerability.2,3 At the recent European Hematology Association (EHA) Virtual Meeting held in June 2021, data from the first head-to-head clinical trial of these two BTK inhibitors was presented.4 We spoke with Professor John Seymour, Director of  the Department of Haematology at the Peter MacCallum Centre & Royal Melbourne Hospital in Victoria for his commentary on the trial results.

Goals of management for patients with RR CLL

Only a small proportion of patients undergo allogeneic transplant, thus CLL is a lifelong disease that unfortunately remains incurable for the vast majority of affected patients in which an allogeneic stem cell transplant is not an option.1,5 When patients experience disease progression after one or more lines of therapy, it can be challenging to bring the disease under control. Added to this challenge is balancing the treatment efficacy necessary to control the disease and prolong life while minimising toxicities and side effects that can reduce quality of life for the patient.2,5  Prof Seymour described the approach: “For many of these patients, it’s not simply about getting the disease under control at all costs – we have to recognise that quality of life is an important factor that must be considered. So, to be in a position where we can effectively control the disease with less toxicity and greater tolerability is a real step forward.”

Improving treatment tolerability can be crucial for helping patients receive effective doses of their medication and continue their therapy, which in turn facilitates better disease control.6 The advent of therapies that directly target critical oncogenic pathways in malignant B lymphocytes – inhibiting their survival and proliferation – has revolutionised treatment for CLL.1,2  Standard of care for RR CLL now favours the BTK inhibitors or B-cell lymphoma-2 (BCL-2) inhibitor, venetoclax, alone or in combination with anti-CD20 monoclonal antibodies.5,7

Improving selectivity may improve tolerability

Ibrutinib is a first-generation, first-in-class irreversible covalent BTK inhibitor.6,8 In clinical studies of patients with RR CLL, it has demonstrated improved survival and less toxicity than with chemotherapy and chemoimmunotherapy regimens.6 While the overall safety profile and tolerability of ibrutinib is generally acceptable, its use is associated with a number of specific cardiovascular toxicities (atrial fibrillation, hypertension, bleeding events, and – rarely – sudden death) that can result in treatment interruptions or even discontinuation of therapy.2,6 “This is problematic,” Prof Seymour explains, “because disease control with BTK inhibitors requires continual rather than fixed-duration or cyclic treatment. This means patients need to stay on a daily oral medication until either their disease progresses or they can no longer tolerate it.” 3,6Clinical and real-world studies suggest that 20% to 40% of patients discontinue ibrutinib because of cardiovascular toxicities and other side effects, including diarrhoea and arthralgia.2 These treatment-related side effects are thought to result from off-target effects of ibrutinib inhibition on other kinases.2,6

Acalabrutinib is a second-generation, highly selective, irreversible covalent BTK inhibitor. It has a narrower range of kinase inhibition than ibrutinib, resulting in reduced off-target activity.2,3,6 The improved selectivity of acalabrutinib is hypothesised to result in fewer treatment-related side effects than with ibrutinib, which may help improve outcomes for patients by improving tolerability and reducing discontinuations.2,6 As Prof Seymour states: “We’re now in a situation where we have two BTK inhibitors with demonstrated efficacy and safety in patients with RR CLL, but we were lacking direct comparative information to guide our choice between ibrutinib and acalabrutinib. This head-to-head trial provides that important data we’ve been missing – showing whether the greater selectivity of acalabrutinib can indeed improve tolerability without sacrificing effectiveness.”

First head-to-head data for acalabrutinib vs ibrutinib revealed

The study presented by Prof Hillmen at EHA provides the first comparative data for any BTK inhibitors in RR CLL. “This was an open label, randomised, noninferiority, phase 3 trial of acalabrutinib vs ibrutinib in 533 previously treated high-risk patients with CLL, with a median follow-up of 40.9 months, Prof Seymour describes, adding that “Importantly, the primary endpoint of noninferiority assessed by a blinded independent review committeee was met: acalabrutinib demonstrated noninferiority to ibrutinib, with a median progression-free survival of 38.4 months in patients across both treatment arms.4

After demonstrating noninferiority, the secondary endpoints of all-grade atrial fibrillation, grade ≥3 infections, Richter transformation, and overall survival were then evaluated in hierarchical order (Table 1). “We see that patients treated with acalabrutinib experienced a significantly lower incidence of all-grade atrial fibrillation than those treated with ibrutinib,” Prof Seymour notes. The incidences of grade ≥3 infections and Richter transformation were comparable between treatment arms. Median overall survival was not reached in either treatment arm, with mortality rates similar between groups.4

TABLE 1: Primary and secondary endpoints and treatment-related discontinuation rate4





Primary endpoint

Progression-free survival


38.4 months


38.4 months

Secondary endpoints

All-grade atrial fibrillation

Grade ≥3 infections

Richter transformation

Overall survival





Not reached





Not reached

Mortality 23.5% 27.5%
Treatment-related discontinuations 14.7% 21.3%


“When looking at the most common treatment related-adverse events of any grade, we see that, acalabrutinib was associated with a lower incidence of hypertension, arthralgia, and diarrhoea but a higher incidence of headache and cough than ibrutinib, Prof Seymour describes (Table 2). “And these adverse events led to fewer treatment discontinuations in patients treated with acalabrutinib than with ibrutinib.” 4

TABLE 2: Any-grade adverse events occurring in ≥20% of patients in either treatment arm4





Hypertension 9.4% 23.2%
Arthralgia 15.8% 22.8%
Diarrhoea 34.6% 46.0%
Headache 34.6% 20.2%
Cough 28.9% 21.3%

In addition, the study identified that among any-grade adverse events, cardiac events, including atrial fibrillation, hypertension, and bleeding events, occurred less frequently in patients treated acalabrutinib than those treated with ibrutinib (Table 3).4

TABLE 3: Any-grade and grade ≥3 selected adverse events of clinical interest4





All cardiac events 24.1% 8.6% 79.0% 9.5%
Atrial fibrillation 9.4% 4.9% 16.0% 3.8%
Hypertension 9.4% 4.1% 23.2% 9.1%
All bleeding events 38.0% 3.8% 51.3% 4.6%
Major bleeding events 4.5% 3.8% 5.3% 4.6%
Infections 78.2% 30.8% 81.4% 30.0%

Understanding the clinical importance of improved safety and tolerability

When asked about the importance of these new findings for patients with RR CLL, Prof Seymour explained: “Overall, this head-to-head comparison shows that acalabrutinib offers equivalent efficacy to ibrutinib in terms of progression-free survival, but with significantly less cardiovascular toxicity and fewer discontinuations from treatment side effects. But when we take a closer look at those side effects, there are two themes that emerge. First, we saw that acalabrutinib significantly reduces the risk for some serious clinical issues that concern doctors – atrial fibrillation, hypertension, and bleeding events. But secondly – and perhaps more importantly for some patients – acalabrutinib was also associated with lower rates of nuisance side effects such as diarrhoea and arthralgia that can substantially affect patients’ quality of life.” 4

Where does acalabrutinib fit into treatment sequencing for RR CLL?

The most recent international guidelines for treatment of symptomatic RR CLL, all developed before the results of this study were available, recommend either continuous therapy with ibrutinib or acalabrutinib, or fixed-duration therapy with venetoclax (a BCL-2 inhibitor) plus rituximab (anti-CD20 monoclonal antibody).5,7 “So while BTK inhibitors as a class are now considered one of the top options for treating patients with RR CLL, the current guidelines don’t recommend one over the other or offer any guidance for choosing which BTK inhibitor to use for your patients,” says Prof Seymour.

When it comes to treatment sequencing for RR CLL, choice of therapies should be individualised based on patient circumstances and preferences. As well as factors such as patient preferences for treatment duration (fixed vs continuous) and administration (daily oral tablet vs incorporating intravenous infusions) that can affect compliance, each patients’ response to or tolerance for previous lines of therapies and their comorbidities and risk for complications play a large role in determining the right approach.2,5 As Prof Seymour explains, “We can use the known side effect profiles of each agent to help evaluate if it’s the right fit for a certain patient, taking into account their own personal priorities. For example, BTK inhibitors may be less suitable for patients with cardiovascular comorbidities or a higher risk for bleeding, while BCL-2 inhibitors may be less suitable for those with higher risk for tumour lysis syndrome and impaired renal function.” 1

In terms of the place of BTK inhibitors in therapy, Prof Seymour explains, “To date, the choice of BTK inhibitor was likely determined solely by availability, as we had no direct evidence for one over the other. These new data provide support for selecting acalabrutinib over ibrutinib for patients who are at greater risk for bleeding or cardiac events such as atrial fibrillation and hypertension, or for those patients who want to minimise side effects such as arthralgia and diarrhoea. But for a patient who suffers from troublesome headache, or has adherence issues with twice daily dosing, ibrutinib may be preferable to acalabrutinib.” 4

So, what’s the take home message for treating patients with RR CLL? “More options can only benefit our patients. By improving the tolerability and safety of treatment, we can help promote adherence. And the longer we can maintain our patients on therapy, the better we can help keep their disease under control,” concluded Prof Seymour.

This article was sponsored by Astra Zeneca. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Calquence® (acalabrutinib)  product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.


  1. Pérez-Carretero C, et al. The evolving landscape of chronic lymphocytic leukemia on diagnosis, prognosis and treatment.Diagnostics (Basel). 2021;11(5):853.
  2. Patel K, Pagel JM. Current and future treatment strategies in chronic lymphocytic leukemia.J Hematol Oncol. 2021;14(1):69.
  3. Calquence (acalabrutinib) Approved Product Information. 22 November 2019.
  4. Byrd JC, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial. J Clin Oncol; 2021:accepted in press.
  5. Eichhorst B, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2021;32(1):23-33.
  6. Abbas HA, Wierda WG. Acalabrutinib: A selective bruton tyrosine kinase inhibitor for the treatment of B-cell malignancies.Front Oncol. 2021;11:668162.
  7. Wierda WG, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma, Version 4.2020, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2020;18(2):185-217.
  8. Imbruvica (ibrutinib) Approved Product Information. 13 April 20021.


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