Professor Stephan Stilgenbauer explains how BTK inhibitors remain the gold standard of treatment for the slow-growing haematological malignancy
The most common leukaemia in the Western world – some 220 adults will be diagnosed with chronic lymphocytic leukaemia (CLL) in Ireland each year.1 Like other haematological malignancies, CLL now has a range of targeted treatments offering enhanced outcomes and better quality of life.2 Unlike other blood cancers, the treatment for many newly-diagnosed patients will be simply to watch and wait.3
The concept of this cancer as a chronic condition that does not necessarily require early aggressive treatment can still be difficult for patients to grasp, admits Professor Stephan Stilgenbauer, Professor of Medicine and Medical Director of the Comprehensive Cancer Centre at Ulm University Medical Centre in Germany.
Professor Stephan Stilgenbauer
Having spent more than three decades immersed in research and care pertaining to CLL, he has seen the field dramatically transform, with a host of effective therapies now available for patients who are seeing their disease progress.4
In fact, the model of genomic risk assessment developed by Prof Stilgenbauer and his colleagues almost 30 years ago remains the mainstay of risk assessment in CLL. His supervising professor Peter Lichter at the German Cancer Research Centre in Heidelberg had returned from the US having worked on this new technique. Stilgenbauer points out that the model of genomic risk assessment developed by the lab in Heidelberg was published by the New England Journal of Medicine in the year 2000 and remains the mainstay of risk assessment in CLL.5
Yet at the time, treatment choice for patients with progressing disease was limited.6 Chemotherapy was typically the only option, and a crude one. A swell of research activity saw the disease biology carefully interpreted, and sophisticated, more targeted treatments developed as a result.7
Prof Stilgenbauer explains, “Our disease understanding of CLL developed a lot with the knowledge of the genomic abnormalities, the gene mutations, the immunoglobulin rearrangement and the hypermutation status of the immunoglobulins as a very important prognostic marker.8 With the subsequent development of B-cell receptor signalling inhibitors including the BTK inhibitors such as ibrutinib and BCL2 targeting agents such as venetoclax, the field radically improved.”9
“With ibrutinib being available in clinical practice it played a truly transformative role in our treatment paradigm.10 Then later venetoclax as the lead compound with regard to BCL2 inhibition, making this a totally different treatment paradigm for patients.”11
Regarding efficacy, the professor notes that the primary endpoint of progression-free survival (PFS) improvement with BTK inhibitors such as with ibrutinib was met in all trials when compared to chemotherapy.12
Some 220 adults will be diagnosed with chronic lymphocytic leukaemia (CLL) in Ireland each year
“Chemotherapy was efficacious but toxic,” he points out. “Suddenly, we were changing from an intravenous, intense chemo immunotherapy to a well-tolerated once daily oral tablet that can really make a difference by acting more specifically, targeting characteristics of disease biology that this tumour depends on.”12 Tolerability is particularly improved with these targeted agents, with life-threatening adverse events such as neutropenia, neutropenic infection, and high-grade infection in general, now largely avoidable. “These things that we really are in fear of are much improved with targeted treatment.”
There is now a wealth of long-term data on ibrutinib in CLL, with some patients on it for almost a decade.13 For example, ibrutinib has consistently demonstrated durable efficacy benefits across several patient subgroups, including high-risk patients with del(17p), TP53 mutations, or unmutated IGHV and unmutated IGHV.12
Yet the insights on the first-generation BTK inhibitor keep coming, with a paper presented at ASH 2025 offering fresh evidence on sustained efficacy, its safety profile and the long-term benefits.14
“With a chronic disease like CLL, long-term follow-up, long-term experience and evidence is very important,” Prof Stilgenbauer asserts. “It is very reassuring to see that with a ten-year follow-up from the RESONATE 2 study, things still look unchanged. There are few, mostly low-grade adverse events and there’s continuous efficacy, so this is very reassuring to see.”12 Long-term immunophenotyping also points to the clinical benefits of immune restoration with ibrutinib in CLL, with reduced susceptibility to opportunistic infections observed in both clinical trials and real-world studies.15
With long-term treatment, retention strategies become a crucial aspect of disease management to ensure optimum patient outcomes. “We are now afforded the situation that these targeted treatments are so well tolerated and so efficacious that patients start asking if they need to continue treatment. It is very important to make clear that the benefit is derived from this continuous treatment.” Educating patients on the possibility of mild side effects such as diarrhoea or nausea can also help them better manage these when they occur, he adds.16
Prof Stilgenbauer says it has been well-documented that the vast majority of patients who experience adverse events can be managed by dose reduction and can successfully be kept on treatment with appropriate dose holds or dose modifications in the longer run.17
“There are clear strategies to pause treatment for a while until mild adverse events have resolved to re-start treatment or reduce the dose by a third or by even two-thirds, depending on the duration or the number of recurrences of adverse events and their severity. Many patients can eventually re-escalate to the full dose.”
Positive data on the combination of ibrutinib and venetoclax also continues to emerge.18 The CLL17 study, which had several Irish sites, for the first time compared continuous BTK inhibitor monotherapy with ibrutinib against the two fixed duration treatment paradigms of obinutuzumab plus venetoclax and ibrutinib plus venetoclax.17
A three-year follow-up showed no significant difference with regard to progression free survival between the three different treatment paradigms.17 Prof Stilgenbauer explains, “This clearly underlines that ibrutinib as a continuous BTK inhibitor monotherapy is a valuable and efficacious treatment, but fixed duration combination treatments are of similar value. While they are more intense to begin with, patients do enjoy a treatment-free interval.”
Tolerability is even better in patients who are given this combination in the first line setting, when compared to relapsed/refractory patients.17 Prof Stilgenbauer notes that, in general, later lines of treatment are usually associated with somewhat lower efficacy because the prior treatment has led to the selection of some resistance mechanisms but are usually also associated with an increase in adverse events.19
“This is because the past treatment has already led to an infection compromised immune system,” he explains. “Also, the patient is ageing. In other words, it is good to benefit from that front line situation and use our best treatment option first.”
Prof Stilgenbauer notes there can often be misconceptions in relation to CLL, with some thinking its status as a chronic condition suggests a relatively benign disease.20
“As the name says, it is chronic but a leukaemia nevertheless,” he says. “A few years after diagnosis, with virtually all patients, there’s compromise of their daily activity and wellbeing and this makes treatment necessary.”1
Yet ‘watch and wait’ remains the mainstay of treatment for those diagnosed with CLL who remain symptom-free. Prof Stilgenbauer points out that there is no data yet to support the earlier use of treatment in terms of improving overall survival.21
With a host of agents available, treatment choice is ultimately influenced by disease characteristics such as genetics – whether 17P deletion, P53 mutation, IGHV mutational status – but also by patient characteristics such as comorbidities, overall health, and even logistical reasons.22
Newer treatments are also in the pipeline, such as non-covalent BTK inhibitors, and so-called BTK “degraders”.23
“We have very good treatments available in routine practice already, but these additional developments will almost certainly lead to further improvement for our patients,” Prof Stilgenbauer states.
“To me, cure is achieved when patients are not dying of this disease and live free from complaints due to their disease, which is today already a truly realistic goal in a very good proportion of patients and will improve even further in the near future.” 
References:
Irish Cancer Society, Chronic lymphocytic leukaemia (CLL). Available at: https://www.cancer.ie/cancer-information/cancer-types/chronic-lymphocytic-leukaemia-cll. Last accessed April 2026.
Blood Cancer United, People with CLL are living longer than ever before, and cures are on the horizon. Available at: https://bloodcancerunited.org/resources/blog/people-cll-are-living-longer-ever-and-cures-are-horizon. Last accessed April 2026.
CLL Ireland. Managing Treatment. Available at: https://clli.ie/treatment/managing-treatment/. Last accessed April 202.
Medical Independent, Chronic lymphocytic leukaemia: Latest approaches to diagnosis and treatment. Available at: https://www.medicalindependent.ie/clinical-news/chronic-lymphocytic-leukaemia-latest-approaches-to-diagnosis-and-treatment/. Last accessed April 2026.
Döhner, H., et al., Genomic Aberrations and Survival in Chronic Lymphocytic Leukemia, N Engl J Med 2000;343:1910-1916. DOI: 10.1056/NEJM200012283432.
Jain P, Thompson PA, et al. Long-term outcomes for patients with chronic lymphocytic leukemia who discontinue ibrutinib. Cancer. 2017;123(12):2268-2273. DOI:10.1002/cncr.30596.
Timofeeva, N., & Gandhi, V.,Ibrutinib combinations in CLL therapy: scientific rationale and clinical results. Blood Cancer Journal, 11(4), 79. https://doi.org/10.1038/s41408-021-00467-7.
Rosenquist, R., Ghia, P., Hadzidimitriou, A. et al. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations. Leukemia 31, 1477–1481 (2017). https://doi.org/10.1038/leu.2017.125.
Jacobs RD et al., Outcomes in high-risk subgroups after fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia/small lymphocytic lymphoma: up to 5.5 years of follow-up in the phase 2 CAPTIVATE study, EHA poster 2024.
Dartigeas C, et al. Final results on effectiveness and safety of Ibrutinib in patients with chronic lymphocytic leukemia from the non-interventional FIRE study. Ann Hematol. 2025;104(2):1079-1093. DOI:10.1007/s00277-024-05666-3.
Constantine S Tam., et al., Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort, Blood (2022) 139 (22): 3278–3289. https://doi.org/10.1182/blood.2021014488.
Burger, J.A., Barr, P.M., Robak, T. et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia 34, 787–798 (2020). https://doi.org/10.1038/s41375-019-0602-x.
ASH Publications, Final analysis of the RESONATE-2 study: up to 10 years of follow-up of first-line ibrutinib treatment for CLL/SLL. https://ashpublications.org/blood/article/146/18/2168/546415/Final-analysis-of-the-RESONATE-2-study-up-to-10. Last accessed April 2026.
Onco Nexus, ASH 2025: Emerging Clinical Evidence and Pivotal Trials in Lymphoma: Key Insights Shaping Modern Practice. https://oncologynexus.com/ash-2025-emerging-clinical-evidence-and-pivotal-trials-in-lymphoma-key-insights-shaping-modern-practice. Last accessed April 202.
Solman,G., I., et al., Impact of long-term ibrutinib treatment on circulating immune cells in previously untreated chronic lymphocytic leukemia, Leukemia Research, Volume 102, 2021, 106520, ISSN 0145-2126. https://doi.org/10.1016/j.leukres.2021.106520. Last accessed April 2026.
Medicines.ie, IMBRUVICA. https://www.medicines.ie/medicines/imbruvica-140-mg-280-mg-420-mg-and-560-mg-film-coated-tablets-34809/spc. Last accessed April 2026.
Pharmacy Times, Real-World Study Supports Ibrutinib Dose Reduction for Managing Adverse Events in CL. https://www.pharmacytimes.com/view/real-world-study-supports-ibrutinib-dose-reduction-for-managing-adverse-events-in-cll. Last accessed April 2026.
Kater AP., et al., Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities, New England Journal of Medicine. DOI: 10.1056/EVIDoa220000.
George B, et al. Ibrutinib Resistance Mechanisms and Treatment Strategies for B-Cell lymphomas. Cancers (Basel). 2020;12(5):1328. Published 2020 May 22. DOI:10.3390/cancers12051328.
Westbrook, T. D., et al., Illness Perceptions in Chronic Lymphocytic Leukemia: Testing Leventhal’s Self-regulatory Model. Annals of behavioral medicine : a publication of the Society of Behavioral Medicine, Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC6696900/. Last accessed April 2026.
Rule, S., et al., Long-Term Outcomes with Ibrutinib Versus the Prior Regimen: A Pooled Analysis in Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) with up to 7.5 Years of Extended Follow-up, Blood (2019) 134 (Supplement_1): 1538. https://doi.org/10.1182/blood-2019-124691.
Health Tree Foundation, CLL Genetic Features. https://healthtree.org/cll/community/cll-treatment-resistant-genetic-features. Last accessed April 202.
ASH Publications, Phase 1/2 studies of DZD8586 in CLL/SLL patients after COVALENT and non-COVALENT BTK inhibitors and BTK degraders – extended follow-up report. https://ashpublications.org/blood/article/146/Supplement%201/3889/550916/Phase-1-2-studies-of-DZD8586-in-CLL-SLL-patients. Last accessed April 2026.
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