Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies

Abstract

The BTK inhibitors ibrutinib and acalabrutinib are FDA-approved drugs for the treatment of B cell malignances. Both drugs have demonstrated clinical efficacy and safety profiles superior to chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia. Mounting preclinical and clinical evidence indicates that both ibrutinib and acalabrutinib are versatile and have direct effects on many immune cell subsets as well as other cell types beyond B cells. The versatility and immunomodulatory effects of both drugs have been exploited to expand their therapeutic potential in a wide variety of human diseases. Over 470 clinical trials are currently registered at ClinicalTrials.gov to test the efficacy of ibrutinib or acalabrutinib not only in almost every type of B cell malignancies, but also in hematological malignancies of myeloid cells and T cells, solid tumors, chronic graft versus host disease (cGHVD), autoimmune diseases, allergy and COVID-19 (http:www.clinicaltrials.gov). In this review, we present brief discussions of the clinical trials and relevant key preclinical evidence of ibrutinib and acalabrutinib as monotherapies or as part of combination therapies for the treatment of human diseases beyond B cell malignancies. Adding to the proven efficacy of ibrutinib for cGVHD, preliminary results of clinical trials have shown promising efficacy of ibrutinib or acalabrutinib for certain T cell malignancies, allergies and severe COVID-19. However, both BTK inhibitors have no or limited efficacy for refractory or recurrent solid tumors. These clinical data together with additional pending results from ongoing trials will provide valuable information to guide the design and improvement of future trials, including optimization of combination regimens and dosing sequences as well as better patient stratification and more efficient delivery strategies. Such information will further advance the precise implementation of BTK inhibitors into the clinical toolbox for the treatment of different human diseases.

Ibrutinib in Refractory or Relapsing Primary Central Nervous System Lymphoma: A Systematic Review

“…TLRs, NLRP3, TREM-1, and Dectin-1 can activate monocytes, macrophages, and neutrophils, and ibrutinib can block this activation through BTK-dependent processes. Ibrutinib can also inhibits T-cell differentiation, effector function, and survival by inhibiting IL-2-inducible T-cell Kinase (ITK) on T-cells [ 30 ]. A recent in vitro study has also demonstrated that ibrutinib-associated BTK depletion impairs NFAT and NF-κB responses in macrophages, leading to impaired clearance of Aspergillus fumigatus [ 31 , 32 ].…”

Tetrabromobisphenol A effects on differentiating mouse embryonic stem cells reveals unexpected impact on immune system

“…The fact that BTK is a key mediator of innate immunity and inflammation ( Weber et al, 2017 ; Weber, 2021 ) strongly suggest that TBBPA has the potential to lead to a strong imbalance, which in turn could induce and/or aggravate damages to the BBB integrity ( Ní Chasaide and Lynch, 2020 ), and permeate TBBPA in the central nervous system with more direct effects. Of note, BTK inhibitor share a variety of clinical applications, ranging from treatment of B cell malignancies, to autoimmune diseases and COVID-19 ( Zhu et al, 2021 ; Malekinejad et al, 2022 ; Rezaei et al, 2022 ; Weis et al, 2022 ), which raise the question on whether TBBPA may interfere with these therapeutic actions. This will certainly require dedicated experimental exploration and validation.…”

Editorial: Autoimmunity, Infection and Cancer, an Inflammatory Relationship With Intimate Implication to Cancer Prevention and Immunotherapy

“…Zhu et al present a comprehensive review on their effect on a variety of immune cell subsets besides B cells, and illustrated their impact on BTK-dependent and -independent signaling. Given their broad effect, one can envision that they could be integrated into combinatory regimens to ameliorate autoimmune damage and/or to boost antitumor immunity (Zhu et al, 2021).…”