Review on the use of BTK inhibitors

The beauty of BTK inhibitors is that they impair tumor development by blocking normal, unmutated BTK, causing many lymphoid tumors to be sensitive, as we have reviewed. Thus, for each tumor type a majority of patients respond, and escape mutants are rare; however, we have predicted the most common escape mutants, based on substitution scanning. Our ongoing investigations are both clinical and experimental. In a recent clinical trial (Br J Haematol, 2018) conducted at Karolinska, we have in collaboration with the clinical PI, Anders Österborg, studied ibrutinib-treated patients with CLL. In my lab we found that the rapid shrinkage of enlarged lymph nodes upon treatment coincides with similarly prompt reductions in serum levels of inflammatory proteins, including cytokines. Thus, the B-cell derived cytokines CCL3 and CCL4 were significantly decreased already 9 hours after patients took their first tablet. 50 proteins were significantly altered and 96% were down-regulated. Moreover, we have obtained detailed information about the effect of ibrutinib on tumor transcriptomes.
We also observed a reduction of plasmacytoid dendritic cells (pDCs) in CLL patients. The reduction of pDCs in the blood of CLL patients has been attributed to the fact that TNF-α secreted by CLL cells can suppress pDC development. We suggest that the increase in pDCs after ibrutinib treatment is secondary to the reduction in TNF-α, since this decrease is highly significant.
The purpose of the visit to STIAS is to write a review on the use of BTK inhibitors (ibrutinib, acalabrutinib and other) for the treatment of human disease. Currently, these drugs are only approved for the treatment of leukemia, lymphoma and graft-versus-host disease, but I anticipate that also certain forms of autoimmune disorders may have become approved indications until 2020. Irrespective of this, the field has essentially exploded and given the very high output of new articles it will be timely to review the status of the field.