Transformations in chronic lymphocytic leukaemia therapy

The Liam O’Connell Lecture at the Haematology Association of Ireland (HAI) Annual Meeting 2026 was delivered by Prof John Seymour, Consultant Haematologist and Clinician-Researcher, Haematology Department, Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Australia.

The lecture is hosted every year by the HAI in honour of Dr Liam O’Connell, Ireland’s first haematologist.

This year’s lecture was titled ‘BCL-2 inhibition in CLL: From undruggable target to standard of care’ and examined transformations in chronic lymphocytic leukaemia (CLL) therapy over the past 25 years.

According to Prof Seymour, the development of BCL-2 inhibition in CLL marked a major milestone in haematology.

He served as the lead investigator for landmark clinical trials evaluating venetoclax in CLL and has authored more than 700 peer-reviewed publications and over a thousand conference abstracts.

Prof Seymour noted that a hallmark of cancer is the ability of malignant cells to evade apoptosis (programmed cell death). He highlighted the fundamental differences in the mechanisms of BCL-2 dysregulation in CLL and follicular lymphoma.

Prof Seymour discussed the introduction of the BCL-2 inhibitor venetoclax, which he has investigated in clinical trials, including the MURANO trial.

The primary analysis of the phase 3 MURANO trial of venetoclax plus rituximab in relapsed/refractory CLL found a significantly higher rate of progression-free survival with venetoclax plus rituximab than with standard chemoimmunotherapy.

The 2026 European Haematology Association guidelines on first-line CLL state that time-limited targeted therapies are preferred for most patients, Prof Seymour noted.

He concluded that effective therapeutic targeting of apoptosis requires “understanding the cellular biology and BH3-mimetic mechanism of action and detailed profiling of cellular BCL-2 family of proteins and their binding partners”.

He added that there is substantial single-agent clinical activity in CLL and that resistance is multifactorial, but usually involves acquired BCL-2 mutations.

Deep remissions with CD20 mAb combinations allow time-limited treatment in CLL, while the apparently lower rate of resistance mutations enables effective retreatment, Prof Seymour stated.

“Synergy with BTKi and triplets have specific benefit in IGHV-unmutated disease,” he noted, adding that multiple front-line time-limited combinations are approved globally as standards of care.