BTK Inhibition in CLL: Successes and Challenges

Virtually every medication carries pros and cons, and Bruton tyrosine kinase (BTK) inhibitors are no exception. An analysis published in Frontiers in Immunology addresses the breakthroughs and barriers that have changed the way these drugs, which first saw FDA approval in 2013 with ibrutinib, are used to treat chronic lymphocytic leukemia (CLL).

BTK inhibition has proven effective in treating CLL and other B-cell lymphomas by targeting the B-cell receptor (BCR) signaling pathway. BCR signaling is key to both normal B-cell development and malignant B-cell survival, and there are 2 types of BCR: chronically activated and tonic. BTK inhibitors are one way to target the BCR pathway, and subtypes of lymphoma with activated signaling, like CLL, are those that respond well to BTK inhibitors.

In total, 3 BTK inhibitors—ibrutinib, acalabrutinib, and zanubrutinib—are currently FDA approved to treat B-cell malignancies.

Ibrutinib, an orally bioavailable, covalent BTK inhibitor, was the first to be approved. This changed the approach for treating CLL in the clinical setting, with ibrutinib monotherapy showing better progression-free survival (PFS) and overall survival (OS) versus conventional single-agent chemotherapy or immunotherapy in treatment-naïve patients.

Ibrutinib is the most effective option for inhibiting BTK, but can also inhibit unintended targets like epidermal growth factor receptor (EGFR), ErbB2, inducible T-cell kinase (ITK), and TEC. This is a potential factor in ibrutinib toxicity given that bleeding and cardiac arrhythmia (both thought to be associated with TEC inhibition) are side effects of ibrutinib treatment.

The second-generation BTK inhibitors were formulated to reduce toxicity and improve tolerability. Acalabrutinib, another covalent BTK inhibitor approved for CLL and mantle cell lymphoma (MCL), carries less potent inhibition of TEC compared with ibrutinib and does not inhibit EGFR or ITK.

Zanubrutinib, approved for the treatment of MCL, Waldenström’s macroglobulinemia, and just recently for relapsed/refractory marginal zone lymphoma, is a BTK inhibitor with less potent ITK and EGFR inhibition. There are ongoing studies to determine whether these second-generation, more selective BTK inhibitors are safer and more effective than ibrutinib across cancer types, including in CLL.

Despite their effectiveness in overall disease control, the covalent BTK inhibitors ibrutinib or acalabrutinib alone do not typically result in undetectable minimal residual disease in CLL patients. Multiple trials are ongoing to test combination BTK inhibitor and chemoimmunotherapy regimens, including anti-CD20 monoclonal antibodies; fludarabine; bendamustine; FCR; fludarabine; cyclophosphamide plus obinutuzumab;and bendamustine plus rituximab to improve BTK inhibitor efficacy.

Where safety is concerned, BTK inhibitors increase the risk of side effects like bleeding, hypertension and atrial fibrillation that can complicate care and require intervention.

Another challenge associated with BTK inhibitors is drug resistance, which is one of the most common reasons CLL patients discontinue BTK inhibitor use. Long-term follow-ups on patients who received ibrutinib monotherapy showed a 70% to 92% 5-year PFS for those who received first-line ibrutinib compared with 40% to 44% 5-year PFS for patients with relapsed CLL. Patients displaying pretreatment risk markers, such as TP53 aberrations, complex karyotype, increased ß-2 microglobulin, and elevated lactate dehydrogenase, also have increased risk of progression.

The authors consider methods that may aid in preventing BTK inhibitor resistance, including stopping treatment with BTK inhibitors after a defined period, combining multiple agents with non-overlapping mechanisms of action.

“Critical to these approaches is the ability to monitor clonal evolution during and after treatment cessation in both investigational and control arms of these trials,” they wrote.

CLL that is resistant to BTK inhibitors and not treated with effective salvage therapy tends to take an aggressive course. Certain drugs such as venetoclax can achieve responses at first, but patients generally progress within 2 years. Studies are testing novel drug combinations in these CLL cases, like ibrutinib and venetoclax or umbralisib plus ublituximab.

They noted that immunotherapies can bypass resistance mechanisms in tumor cells, giving them an advantage over targeted therapy. They also raise the possibility of CD19 chimeric antigen receptor T-cell therapy in patients after ibrutinib failure, but no commercially available options are approved for CLL.

The authors concluded that the data conducted on BTK inhibitors thus far have produced research questions that, when examined, could play a critical part in optimizing BTK targeting. This includes more specific safety and efficacy profiles for each BTK inhibitor, novel targeted combinations with potential to produce deeper responses in CLL patients.

Reference

Ahn IE, Brown JR. Targeting Bruton’s tyrosine kinase in CLL. Front. Immunol. Published online June 23, 2021. doi:10.3389/fimmu.2021.687458