BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

(2022) 15:138 Alu et al. Journal of Hematology & Oncology https://doi.org/10.1186/s13045-022-01353-w Open Access REVIEW BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies Aqu Alu†, Hong Lei†, Xuejiao Han, Yuquan Wei and Xiawei Wei* Abstract Bruton’s tyrosine kinase (BTK) is an essential component of multiple signaling pathways that regulate B cell and myeloid cell proliferation, survival, and functions, making it a promising therapeutic target for various B cell malignancies and inflammatory diseases. Five small molecule inhibitors have shown remarkable efficacy and have been approved to treat different types of hematological cancers, including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib. The first-in-class agent, ibrutinib, has created a new era of chemotherapy-free treatment of B cell malignancies. Ibrutinib is so popular and became the fourth top-selling cancer drug worldwide in 2021. To reduce the off-target effects and overcome the acquired resistance of ibrutinib, significant efforts have been made in developing highly selective second- and third-generation BTK inhibitors and various combination approaches. Over the past few years, BTK inhibitors have also been repurposed for the treatment of inflammatory diseases. Promising data have been obtained from preclinical and early-phase clinical studies. In this review, we summarized current progress in applying BTK inhibitors in the treatment of hematological malignancies and inflammatory disorders, highlighting available results from clinical studies. Keywords: BTK, Inhibitors, Hematological malignancies, Inflammatory diseases, Signaling pathways, Clinical trials Background Bruton’s tyrosine kinase (BTK) was firstly reported to be related to the inherited immunodeficiency disease x-linked agammaglobulinemia (XLA) in 1993, mutations of which cause a disorder in the transformation of pre-B cells in the bone marrow into mature peripheral B cells [1, 2]. At first, BTK was thought to be expressed only in B cells since no significant developmental and functional † Aqu Alu and Hong Lei contributed equally to this work *Correspondence: Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China defects were observed in other immune cells of XLA patients. In consistent, a point mutation in the BTK gene led to the X-linked immunodeficiency (XID) phenotype in mice, which showed B cell-specific abnormality characterized by the inability to produce antibodies [3, 4]. Soon after, scientists discovered that stimulation of B cell receptors (BCR) can induce the tyrosine phosphorylation and activation of BTK in mature B cells [5–7]. BTK is also constitutively phosphorylated in pre-B cells and plays a functional role in pre-BCR signaling [7]. The pre-BCR is an immature form of BCR, which transduces signals for cell growth and differentiation [8]. Therefore, in XLA patients, defects in BTK’s function resulted in hampered pre-BCR signaling and B cell development. © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Alu et al. Journal of Hematology & Oncology (2022) 15:138 Then, it is demonstrated that besides normal B cells, BTK is also expressed in malignant B cells [9, 10]. BTK is not only indispensable for B lineage development and function but inhibits Fas/CD95-induced apoptosis in lymphoid B cells [11, 12]. These results inspired the development of BTK inhibitors (BTKi) in treating B cell malignancies. In 1999, Mahajan et al. rationally designed the first BTKi named LFM-A13, which showed synergistic anti-leukemia effects with ceramide or vincristine in vitro [13]. After that, plenty of upgraded BTKi have been developed gradually, with higher efficacy and selectivity. Ibrutinib was the first-in-class BTKi that received its first approval by the U.S. Food and Drug Administration (FDA) in 2013 for the treatment of relapsed and refractory (R/R) mantle cell lymphoma (MCL). The approval of ibrutinib has an epoch-making significance since it offered the concept of chemotherapy-free treatment of hematological cancers. It is so popular that the global market size of ibrutinib grew to about 9.44 billion dollars in 2020 and was estimated to reach 66.28 billion dollars by 2030. It ranked fourth in the list of the top10 cancer drugs by sales in 2021. The success of ibrutinib promoted the exploration of second- and third-generation BTKi, aiming to reduce off-target toxicities and overcome acquired resistance, which is common in patients receiving continuous BTKi treatment. Among those inhibitors, acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib have received accelerated or conditional approval for the treatment of multiple B cell malignancies (Fig. 1). BTK is also expressed in many other hematopoietic cells, including macrophages, granulocytes, mast cells, osteoclasts, etc. [10, 14]. Meanwhile, BTK is involved Page 2 of 35 in other signaling pathways, including Toll-like receptor (TLR) signaling, chemokine receptor signaling, and Fc receptor (FcR) signaling [15–17]. Recent studies revealed that BTK plays a significant role in the pathogenesis of inflammatory diseases, especially autoimmune diseases. Autoimmune disorders are characterized by a loss of self-tolerance, abnormal B cell activation, and subsequent generation of autoreactive antibodies [18]. Animal models indicated that BTK is essential for defining the threshold for B cell activation and counterselection of autoreactive B cells via BCR signaling [19]. Transgenic mice overexpressing BTK spontaneously formed systemic lupus erythematosus (SLE)-like autoimmune pathology involving multiple organs. BTK is also critical for the production of inflammatory cytokines in innate immune cells [20]. Thus, B (...truncated)