ESMO 2026丨From First-Line Treatment Selection to Resistance Testing: Professor Stephan Stilgenbauer Discusses the Current Decision-Making Framework for Precision Therapy in CLL

The 2026 Congress of the European Society for Medical Oncology (ESMO 2026) was held in Madrid, Spain, from October 23 to 27 local time.

FOCUS Clinical Scientists traveled to the congress site to bring frontline academic coverage. We specially invited Professor Stephan Stilgenbauer from University Hospital Ulm for an interview on targeted treatment strategies for chronic lymphocytic leukemia (CLL). Prof. Stilgenbauer shared his views on the basis for first-line treatment decisions, the timing of testing for BTK pathway resistance mutations, and the changing prognostic significance of TP53 abnormalities/del(17p) in the era of time-limited targeted therapies.

 

FOCUS Clinical Scientists: What are the key factors that should guide the choice of first-line therapy for CLL in the current treatment landscape?

Prof. Stephan Stilgenbauer: In chronic lymphocytic leukemia (CLL), we today have a great range of treatment options. This is not chemotherapy anymore, but targeted therapy focusing on CD20 antibodies, BTK inhibitors, and BCL-2 inhibitors. With these regimens, we have great outcomes for our patients. Nevertheless, the tolerability profile of these agents is diverse. Moreover, there are disease characteristics—in particular, genetic factors of the disease—that influence outcome.

First, we know that del(17p) and/or TP53 mutation is associated with the most inferior outcome in the era of chemoimmunotherapy, but also with time-limited treatments based on BCL-2 inhibitors. Outcome for this subgroup is better with continuous BTK inhibitor monotherapy, such as acalabrutinib or zanubrutinib. On the other hand, combinations of BTK inhibitors such as ibrutinib plus venetoclax or acalabrutinib plus venetoclax produce very good results for patients with mutated IGHV, so that time-limited treatments are the preferred choice. For patients with unmutated IGHV, we know that all options are quite favorable—there is a slightly better progression-free survival with continuous BTK inhibitor monotherapy, but time-limited BCL-2 inhibitor-based treatment is also a valid option, with the chance of retreatment later on.

The other important factor when it comes to treatment choice is comorbidities and coexisting conditions of our patients. Cardiac coexisting conditions and comedications such as anticoagulation are adverse factors for BTK inhibitors, because they increase bleeding risk and the risk of cardiovascular events. On the other hand, renal comorbidities are adverse with regard to BCL-2 inhibitor-based therapy, because there is a risk of tumor lysis syndrome at treatment initiation.

All in all, a balance of patient-specific factors and disease-specific factors must influence our treatment choice. Last but not least, there is the point of patient preference—whether the patient prefers continuous or time-limited treatment must be factored in. All in all, we have to have shared decision-making together with our patients, outlining the pros and cons of all treatment options and making a decision together with the patient about the best treatment option.

 

FOCUS Clinical Scientists: With resistance mutations emerging in the BTK pathway, should routine genomic testing for resistance mechanisms be considered at the time of CLL progression?

Prof. Stephan Stilgenbauer: We know that genetic disease factors largely underlie the response, as well as progression-free survival and overall survival, in CLL with targeted therapy. Traditionally, del(17p) and/or TP53 mutation and unmutated IGHV are adverse factors, while mutated IGHV represents the most favorable outcome group.

However, after continuous treatment with BTK inhibitors or BCL-2 inhibitors, resistance mutations in the target genes have emerged. In particular, BTK mutations at position C481 generate resistance to all covalent BTK inhibitors, such as ibrutinib, acalabrutinib, or zanubrutinib. This leaves room for the non-covalent BTK inhibitor pirtobrutinib as a treatment option. However, we know that under pirtobrutinib, other BTK mutations—such as those at positions 474, 428 or 528—may emerge and cause resistance to that agent. And these mutations can also already be induced by covalent inhibitors.

This brings into play the critical question of testing for BTK mutations and PLCγ2 mutations at the time of relapse or disease progression on continuous BTK inhibitor therapy, because this will influence our treatment choice. If we find, for instance, after covalent BTK inhibitor treatment, a 474, 428 or 528 mutation, this implies that there will likely be no good response to pirtobrutinib treatment. We could then prefer the choice of venetoclax plus rituximab, which is another licensed treatment option in the relapsed/refractory setting that does not rely on the BTK pathway.

Therefore, testing for resistance mutations at progression on continuous covalent BTK inhibitor monotherapy is important, because it may guide treatment choice next to other factors.

 

FOCUS Clinical Scientists: In the era of time-limited targeted therapies, how has the prognostic significance of TP53 abnormalities/del(17p) changed?

Prof. Stephan Stilgenbauer: Traditionally in CLL with chemoimmunotherapy, del(17p) and/or TP53 mutation was the most adverse prognostic factor, associated with non-response and poor overall survival. The outcome has been dramatically improved by targeted therapy—with both BCL-2 inhibitor-based and BTK inhibitor-based treatments.

However, we still know that time-limited BCL-2 inhibitor-based therapy—whether BTK inhibitor plus BCL-2 inhibitor, or CD20 antibody plus BCL-2 inhibitor—still produces somewhat shorter progression-free survival times in patients with del(17p) and/or TP53 mutation. Outcome with regard to progression-free survival is a bit better with continuous BTK inhibitor monotherapy. So overall, the primary choice in that patient subgroup is in preference of continuous BTK inhibitor monotherapy agents, such as acalabrutinib or zanubrutinib.

Nevertheless, time-limited BCL-2 inhibitor-based therapy also produces quite good results. So patients who are poor candidates for BTK inhibitor monotherapy—i.e., patients with cardiac coexisting conditions or on anticoagulation—can still benefit from this treatment option.

 

Expert Profile

Prof. Stephan Stilgenbauer

University Hospital Ulm

Prof. Stephan Stilgenbauer is a world authority on high-risk CLL biology and therapy, particularly del(17p)/TP53-mutated disease. His pivotal M13-982 venetoclax monotherapy trial in del(17p) CLL led directly to the FDA approval of venetoclax in this difficult-to-treat population.