Reference: August 2026 | Issue 8 | Vol 12 | Page 53
A time is coming when chemotherapy will no longer be used to treat chronic lymphocytic leukaemia (CLL), according to Prof Peter Hillmen, Emeritus Professor of Haematology at the University of Leeds.
Prof Hillmen is former Chair of both the CLL sub-group and Haematological Oncology Research Group of the UK’s National Cancer Research Institute (NCRI). In 2017, he was awarded the Binet-Rai Medal for his outstanding contribution to CLL research. His group pioneered the use of measurable residual disease assessment in CLL.
Prof Hillman was in Dublin in March to address the inaugural Global Oncology and Haematology Congress, hosted by the Network for Collaborative Oncology Development & Advancement (NCODA).
He said new therapies have transformed outcomes for patients with CLL.
“Up until about 15 years ago, the only available treatment was chemotherapy, which was usually first-line, and monoclonal antibodies, which were often used in combination. And in those days, if a patient failed chemotherapy, they had a median survival of approximately a year. There were very few real options for those patients. We have seen a lot of change from about 2010 onwards, with the advent of specifically targeted therapy based on the biology of CLL,” he said.
Elucidation of the biology of CLL has identified two key therapeutic targets – Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2). The enzyme BTK, which is essential for healthy B-cell function and development, is overexpressed and constantly active in CLL cells, fuelling uncontrollable growth of malignant cells. BCL2, a key molecule of B cell apoptosis, is upregulated in CLL cells, preventing cell death.
“Targeting these two molecules has really changed the outlook for patients with CLL, to the point now that patients who are currently diagnosed with CLL, very few, if any, should die of CLL itself, provided these therapies are available,” Prof Hillman said.
He highlighted the phase 3 NCRI FLAIR trial, which compared the combination of ibrutinib with venetoclax to ibrutinib alone or standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy. At the five-year mark, 93.9 per cent of patients receiving the ibrutinib plus venetoclax regimen were alive, with no disease progression, compared to 58.1 per cent of those on standard FCR. The combination therapy successfully mitigated the aggressive disease progression previously seen in patients with poor-risk genetic markers, including unmutated IGHV, ATM, or NOTCH1 aberrations.
“So, if we use these therapies as front-line, most patients do extremely well. We have evidence now that we probably cure a proportion of these poor-risk patients with the first treatment, which is likely to be over 50 per cent in our current estimates, although we need further follow-up,” Prof Hillman said.
Unfortunately, resistance to BTK inhibitors can occur as a result of mutations in BTK which prevents ibrutinib from covalently binding.
In the FLAIR trial, no BTK mutations were found at baseline. Of the group of patients that progressed on ibrutinib-containing regimens, 21 per cent had a BTK mutation at the C481, T474, or L582 residues. When treatment was stopped prior to disease progression, the allelic burden of BTK mutations started to decrease. The median time to first detected BTK mutation was 67 months in previously untreated CLL and median time from first detected mutation to disease progression was seven months. No BTK mutations were detected in patients receiving the combination of ibrutinib with venetoclax.
Hence, Prof Hillman said, since BTK mutations often present later in the disease process, eradicating the disease earlier, with the combination of ibrutinib and venetoclax, would prevent the problem.
Another approach would be to use a reversible BTK inhibitor, he said. Non-covalent BTK inhibitors, such as pirtobrutinib, use a different BTK binding mechanism and do not bind to C481. Pirtobrutinib is approved in the US for the treatment of relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including prior BTK inhibitor.
In vitro study has shown that steady state plasma pirtobrutinib exposure corresponds to 96 per cent BTK target inhibition in in vitro models and CLL cells, with pirtobrutinib showing a half-life of about two hours.
Pirtobrutinib has demonstrated efficacy in patients with BTK mutations. In a 2022 study of patients pre-treated with a BTK inhibitor alone or in combination with venetoclax, the overall response rate (ORR) was approximately 80 per cent.
“But these patients do eventually develop mutations that lead to resistance to the reversible inhibitor, so that has led to the development of protein degraders which degrade the BTK,” Prof Hillman said.
He explained that these agents specifically bind to and ubiquitinate BTK, which leads to its digestion.
“A single degrader can degrade multiple copies of BTK. This overcomes any resistance, potentially, because it is not binding to the pocket where the mutations occur that lead to resistance to both the covalent and the reversible BTK inhibitors,” he explained
He highlighted the CaDAnCe-101 study of the BTK degrader BGB-16673 in patients with relapsed/refractory CLL or small lymphocytic lymphoma (SLL). BGB-16673 is a highly selective oral BTK protein degrader that mediates BKT degradation through the proteasome pathway. It disrupts both the catalytic activity of BTK and its protein scaffolding functions. BGB-16673 has broad sensitivity for BTK mutations associated with covalent and non-covalent BTK inhibitor resistance.
The study included 68 heavily pre-treated patients with high risk CLL features. The average number of prior treatments was four, with a maximum of 10 prior lines of treatment. More than a third had BTK mutations. In 66 response-evaluable patients, the ORR was 86.4 per cent, with a 4.5 per cent rate of complete response (CR)or CR with incomplete marrow recovery. Almost half (49.3 per cent) remained on treatment for ≥12 months, and responses deepened over time. Responses were seen in patients previously treated with a covalent BTK inhibitor (85.5 per cent) or non-covalent BTK inhibitor (71.4 per cent). Twelve-month progression-free survival rate was 79.2 per cent.
BGB-16673 was well tolerated, with three patients discontinuing treatment due to treatment-related adverse events, but there were no treatment-related deaths and no new toxicities were identified within a median treatment duration of 13.6 months.
BGB-16673 is now being evaluated in phase 2 and 3 studies in patients with relapsed or refractory CLL or SLL.
Another BTK degrader, bexobrutideg (NX-5948), has also demonstrated rapid and durable clinical responses in relapsed/refractory CLL in a phase 1a/b trial.
Unlike conventional BTK inhibitors that only block enzyme activity, bexobrutideg harnesses the body’s natural protein disposal system to selectively eliminate the entire BTK protein. This catalytic mechanism removes both the kinase and scaffolding functions of BTK, which allows it to effectively target both wild-type and treatment-resistant mutant forms of BTK.
Early clinical data has shown high objective response rates and a favourable safety profile in heavily pre-treated patients. In the phase 1a/b NX-5948-301 trial, bexobrutideg delivered an 80.9 per cent objective response rate in heavily pre-treated, relapsed/refractory CLL/SLL. Responses were durable and consistent regardless of prior BTK inhibitor or BCL2 inhibitor exposure or baseline mutations. Bexobrutideg crosses the blood-brain barrier and has demonstrated clinical activity in the CNS.
Bexobrutideg was well tolerated. There were no dose-limiting toxicities, and no systemic fungal infections or grade 4 infections of any kind. The most common adverse events included bruising, diarrhoea, and fatigue. There was a single case of new onset atrial fibrillation.
“The evolution of therapy has been really dramatic in the last 15 years. We’ve seen a major impact on the outcome of patients with CLL with the BTK and BCL2 inhibitors. I think these are going to have the most effect in the front-line because patients do become resistant. We are seeing the next generation drugs – the reversible inhibitors – which are now well into phase 3 trials or have been approved, and now we have the protein degraders,” Prof Hillman told the NCODA meeting.
“I think we’ll get to the point where we have fixed duration therapy… and, where these treatments are available, chemotherapy should be a thing of the past for almost every patient with CLL.”
