Applications, Future Directions of BTK Inhibitors in Blood Cancers and Autoimmune Disorders

Bruton tyrosine kinase (BTK) inhibitors are relatively new drugs that have been successful in the treatment of various B-cell malignancies, and BTK is a promising target in inflammatory diseases. A review published in the Journal of Hematology & Oncology summarized the current landscape of BTK inhibitors (BTKis) in both hematological cancers and inflammatory disorders.

Ibrutinib was the first BTKi to gain FDA approval when it was indicated for the treatment of relapsed and refractory mantle cell lymphoma (MCL) in 2013. This introduced the concept of nonchemotherapy treatment for hematological cancer. Now, second- and third-generation BTKis have been developed with reduced off-target toxicities and to mitigate the issue of acquired resistance to therapy in patients on continuous treatment with BTK inhibition. Acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib are additional BTKis that have either been approved or received accelerated or conditional approval for various B-cell malignancies.

BTK has more recently been found to play a role in inflammatory diseases, and autoimmune diseases in particular. Abnormal B-cell activation and autoreactive antibodies both occur in the pathogenesis of autoimmune disorders, and BTK is a key aspect in production of inflammatory cytokines in innate immune cells. It may therefore contribute to chronic inflammation or acute hyperinflammation, and targeting it might be a feasible strategy in autoimmune conditions. Both preclinical and clinical studies suggest that BTKis may reduce inflammation and autoantibody production, and the BTKi evobrutinib was first used for active relapsing–remitting multiple sclerosis in 2019 with positive results.

Like any treatment, BTKi use has pros and cons. One issue that may arise with ibrutinib, the first approved BTKi, is nonspecificity. This can lead it to bind to and inhibit kinases other than BTK, potentially causing off-target activity and treatment-related adverse events. Selectivity of treatment has been a focus as new BTKis are developed to mitigate off-target toxicity.

Second-generation BTKis, including acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib, are optimized to reduce off-target activity and have generally shown more tolerable toxicity than ibrutinib. However, they have varied safety profiles that clinicians should take into consideration on a case-by-case basis. A number of BTKis are under investigation, aiming to build upon progress and improve selectivity as well as overall efficacy.

BTKis have been and are being investigated in a range of cancers. The review highlights several disease areas in which these treatments are currently used or have potential: chronic lymphocytic leukemia, small lymphocytic lymphoma, MCL, Waldenstrom macroglobulinemia, marginal zone lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma. BTKis have significantly impacted the treatment landscape for B-cell malignancies overall, reducing the need for chemotherapy in many cases.

As the breadth of evidence suggesting BTKis may be a viable strategy in inflammatory diseases grows, potential applications are under investigation. This includes BTKi use in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, pemphigus, and other autoimmune conditions. There is less research on BTKis in the autoimmune disease arena, but the strategy is promising based on preclinical and early clinical trials. Considering many patients with autoimmune conditions do not have severe symptoms, the authors note that newer BTKis with fewer adverse effects would be the preferred route in this patient population.

Future research directions for BTKis should include head-to-head studies aiming to determine the best agents in each disease type and for certain types of patients, as well as further effort to overcome known obstacles such as toxicity and acquired resistance. There may also be potential for broader applications of BTKis, but more research is needed to allow for approval for other indications.

“Close cooperation between scientific research institutions, pharmaceutical companies, and medical institutions may accelerate the discovery of new drugs and the optimization of current treatment options,” the authors concluded.

Reference

Alu A, Lei H, Han X, et al. BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies. J Hematol Oncol. Published online October 1, 2022. doi:10.1186/s13045-022-01353-w