EvidenceChronic lymphocytic leukaemia

AMPLIFY delivered the first all-oral, fixed-duration doublet for front-line CLL and supported its approval, giving fit patients a way to avoid both chemotherapy and years of continuous BTK inhibitor. It does not settle whether a doublet or triplet is best, or how AV compares with venetoclax-obinutuzumab. Patients with TP53 aberration were excluded and still need different strategies.

Watch and wait remains the standard of care for early-stage chronic lymphocytic leukaemia irrespective of risk factors, even with a targeted drug available.

ELEVATE-TN put a more selective BTK inhibitor into first-line CLL and, with the head-to-head ELEVATE-RR trial, showed it is as effective as ibrutinib with fewer cardiac side effects. Continuous acalabrutinib became one of the two main front-line options alongside fixed-duration venetoclax combinations. The trade-off is indefinite therapy and cost versus a time-limited course.

CLL14 established the first chemotherapy-free, fixed-duration regimen for front-line CLL and made MRD-guided thinking mainstream in the disease. Patients get a year of treatment and then a treatment-free period rather than indefinite therapy. The choice today is between fixed-duration venetoclax combinations and continuous BTK inhibitors, with no proven survival difference.

MURANO made fixed-duration venetoclax the standard for relapsed CLL and showed that stopping therapy after a deep response is safe for most patients. It also established MRD at end of treatment as a practical guide to who is likely to stay in remission. Retreatment with venetoclax at relapse appears feasible.

This paper is the proof-of-concept for a living drug: a single infusion of a patient's own engineered T cells could eradicate leukaemia that had survived chemotherapy, transplant and antibody therapy. It defined cytokine release syndrome and its antidote, tocilizumab, and revealed antigen-loss relapse. It led directly to the first approved gene-modified cell therapy three years later.