An ALPINE guide to covalent BTKis in CLL

In this issue of Blood, Brown et al¹ present the final comparative analysis of the ALPINE study, comparing zanubrutinib with ibrutinib for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).

The authors document that zanubrutinib provides a sustained benefit over ibrutinib for patients with R/R CLL for progression-free survival (PFS) and the advantage of an improved cardiac safety profile. The original publication in January 2023² had a median follow-up of 29.6 months, and the current report extends this by 11.3 months to a total of 40.9 months.

All covalent Bruton tyrosine kinase inhibitors (c-BTKis) block at the cysteine 481 adenosine triphosphate binding site. The major differences between the 3 widely available c-BTKis, namely ibrutinib, acalabrutinib, and zanubrutinib, lie in the higher BTK specificity of acalabrutinib and zanubrutinib and higher potency with zanubrutinib. An earlier trial comparing acalabrutinib with ibrutinib, ELEVATE R/R,³ showed noninferiority between acalabrutinib and ibrutinib but with an improved cardiac safety profile due to lower rate and a later onset of atrial arrhythmias with acalabrutinib. ALPINE is therefore the first head-to-head trial of c-BTKis in R/R CLL to show superior efficacy with a lower toxicity profile. The superior efficacy is consistent with the higher potency of zanubrutinib, combined with the twice daily dosage schedule, resulting in more a potent, complete, and continuous blockade of BTK.⁴ 

Cardiac toxicities are seen with all c-BTKis but were lower with zanubrutinib than ibrutinib, with atrial fibrillation or flutter occurring in 7.1% vs 17.0%, respectively, broadly comparable to the results in the ELEVATE R/R trial where acalabrutinib also had a lower cardiac toxicity rate. Arrhythmias are considered most likely due to “off-BTK” Tec kinase inhibition, hence are lower with the greater BTK specificity of the “second-generation” BTKis. The precise molecular mechanisms involved remain elusive. Hypertension is another class effect, but rates of hypertension were virtually identical in both arms of ALPINE and also similar to acalabrutinib, suggesting that, unlike arrhythmias, hypertension is not linked to specificity of BTK blockade.

Is increased BTK specificity always a good thing? Autoimmune cytopenias (AICs) are common in CLL, occurring in about a third of patients during their disease course, and can present difficult management issues. Patients with CLL with AIC are also often excluded from clinical trials, limiting our information for optimal management. It was noted early with ibrutinib therapy⁵ that AICs were distinctly less common, and it has been speculated this may be partly due to inhibition of inducible T-cell kinase, which zanubrutinib inhibits much less potently. In the ALPINE study, autoimmune hemolysis was rare in both arms of the study. These data are tantalizing but inadequate to answer the AIC and BTKi specificity question at present.

Another point of differentiation between BTKis, especially in R/R CLL, is the potential resistance mutations that might occur. With ibrutinib, the most common mutations are within the BTK C481 binding site itself (often C481S), and these render all c-BTKis ineffective. However, patients with C481 mutations still respond to the more recently developed noncovalent BTKis (nc-BTKis) such as pirtobrutinib. The principal concern is that zanubrutinib has been associated with “kinase-dead” L528 mutations,⁶ which make both c-BTKis and nc-BTKis ineffective, essentially losing a class of drugs for these patients.

ALPINE had the misfortune to overlap with the COVID-19 pandemic. As is widely known, patients with CLL are the most vulnerable to COVID-19 severity and mortality, and this risk is exacerbated by B-cell-directed therapies. Both arms of ALPINE suffered mortality due to COVID-19 in the 6% range.

The superior efficacy in ALPINE of zanubrutinib vs ibrutinib occurred across all parameters of PFS, at the index point of 36 months, and for the overall population was 65.4% vs 54.4%, for TP53 dysfunctional patients was 59.2% vs 38.5%, and for those on active treatment was a less marked difference of 78.7% vs 71.5%. Overall survival was identical between arms. There has been some debate in the CLL community regarding the apparent PFS underperformance of ibrutinib in ALPINE compared with the original RESONATE study in which the overall PFS at 36 months was 59%, and in patients with 17p-deleted ∼55%, when the trial was conducted a decade ago.

The authors note that ibrutinib real-world data are often similar to RESONATE. This may depend on when access became available. In Australia, a Named Patient Program (NPP)⁷ ran for 3 years (December 2014 to November 2017) with outcomes similar to RESONATE. This NPP ceased when the Australian Government funded ibrutinib on the Pharmaceutical Benefits Scheme (PBS). Analysis of a 10% sample (222 patients; December 2017 to March 2021, dates overlapping ALPINE) of PBS patients⁸ showed ibrutinib outcomes superior to RESONATE with 63.9% remaining on therapy at 36 months with older age (median 74 years) and 65.8% having only 1 prior line of therapy.

There are now 2 matching-adjusted indirect comparison publications that examine this apparent underperformance of the ibrutinib arm in ALPINE compared with RESONATE. The first is by a group of CLL clinicians⁹ and the second is by a subset of the ALPINE authors.¹⁰ The issue is addressed by Brown and the authors in their Discussion. There is agreement that patients recruited to RESONATE were more heavily pretreated and had few viable treatment options when it enrolled 391 patients from 67 centers in 2012-2013, while with ALPINE in 2018-2020, there was a wide range of highly effective alternatives. The authors highlight that ALPINE had a wider scale and breadth of recruitment of 652 patients from 150 sites across Europe, North America, Asia, and Australasia. Responses recorded in Brown et al's original publication’s supplementary Table 2A-B² show that patients from Australia and New Zealand had investigator-assessed outcomes that narrowly favored ibrutinib, while Europe narrowly favored zanubrutinib. In Asia and North America, the difference was more marked and significantly favored zanubrutinib. Thus, in ALPINE overall, zanubrutinib showed superior PFS efficacy and safety. There are some vagaries in every well-conducted clinical trial and yet they remain our gold standard upon which we do and should base our clinical decision making.

Conflict-of-interest disclosure: S.P.M. declares no competing financial interests.