Page 21 - Haematologica Vol. 109 - July 2024

EDITORIAL
High-risk stays high-risk: Bruton tyrosine kinase inhibitors in B-cell malignancies
Othman Al-Sawaf
University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Germany, Cancer Institute, University College London, UK and Francis Crick Institute, London, UK
In this issue of Haematologica, Xu et al. present an overview of the genomic landscape of patients with B-cell malignan- cies who received the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib after prior intolerance to ibrutinib and/or aca- labrutinib.1 Based on a 106-gene targeted next-generation sequencing panel, they characterized baseline and relapse samples from 71 patients with relapsed/refractory B-cell malignancies. In line with previous reports on relapsed/ refractory B-cell malignancies, a high rate of mutations in genes such as TP53, SF3B1 and ATM was observed prior to the start of zanubrutinib. Patients with these alterations had a shorter progression-free survival under zanubruti- nib therapy than patients without these alterations. The authors also looked at the incidence and impact of BTK and PLCG2 mutations, which are known contributors to treatment resistance, particularly in the context of chron- ic lymphocytic leukemia. Three patients had BTK C481S mutations at different variant allele frequencies prior to starting zanubrutinib and had relatively short responses. Of nine patients with progression while receiving treatment with zanubrutinib, four had BTK C481S mutations, mostly accompanied by PLCG2 mutations. Overall, the authors concluded that the mutational landscape and particularly its prognostic relevance in terms of response and duration of response are important in the context of BTK inhibitors. The study contained a particular cohort of patients with intolerance to ibrutinib and/or acalabrutinib, who consti- tute up to 40% of patients with relapsed/refractory chronic lymphocytic leukemia.2 Given the availability of several covalent and non-covalent BTK inhibitors, questions re- garding their optimal sequencing are becoming increasingly relevant also for routine care. National and international treatment guidelines primarily recommend a switch to a different class of agents, e.g. Bcl-2 inhibitors, for patients with disease progression on a continuous covalent BTK in- hibitor.3 However, it is currently unclear which factors need to be considered for patients who develop intolerance to
a BTK inhibitor, e.g. due to toxicity, and therefore have to discontinue treatment. It was previously demonstrated that a switch from ibrutinib or acalabrutinib to zanubrutinib in patients who had intolerance, mostly due to fatigue, hyper- tension, arthralgia, rash or atrial fibrillation, is feasible and can reduce or avoid recurrence of toxicity.4 A general caveat regarding such analyses, which have also been conducted for acalabrutinib,5 is the lack of a standardized definition of intolerance, which can lead to uncontrolled biases that can influence clinical decisions, such as re-imbursement considerations, availability of studies or frailty of patients. Patients with relapsed/refractory B-cell malignancies com- monly present with a complex and heterogeneous muta- tional background, as the disease has been exposed to various selective pressures by treatments. The study by Xu et al. confirms this by demonstrating a high frequency of TP53, SF3B1, ATM and NOTCH1 mutations in up to a third of patients who had discontinued ibrutinib or acalabrutinib. Interestingly, when looking at the prognostic relevance of these alterations, apart from NOTCH1, they were associated with a significantly shorter progression-free survival under zanubrutinib, suggesting similar molecular vulnerabilities as with other covalent BTK inhibitors (Figure 1).
Recent studies have shed light on the functional impact of BTK mutations in the context of BTK inhibitor resistance. The BTK C481S mutation is the most frequent BTK mutation arising in patients undergoing continuous BTK inhibition.6 Functionally, this variant is associated with an altered binding site at the kinase domain of BTK, thereby leading to reduced affinity of covalent BTK inhibitors. Multiple other BTK mutations, such as T474I or T316A, have been described, which also confer treatment resistance and re- duced binding affinity. In addition, other mutations, such as L528W, affect the activity of BTK and confer a kinase-dead state, despite an unaltered binding site. Several studies have reported L528W mutations occurring particularly after zanubrutinib treatment, possibly more commonly than after
Haematologica | 109 July 2024
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Correspondence: O. Al-Sawaf othman.al-sawaf@uk-koeln.de
Received: Accepted: Early view:
February 14, 2024. February 29, 2024. March 7, 2024.
https://doi.org/10.3324/haematol.2024.285029
©2024 Ferrata Storti Foundation Published under a CC BY-NC license