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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
When chronic lymphocytic leukaemia returns, the usual move is to switch drug class: venetoclax-based therapy after a BTK inhibitor, or a BTK inhibitor after venetoclax. Pirtobrutinib (BRUIN) works after the older BTK inhibitors fail, and CAR-T is approved for patients who have run out of both classes.
Relapse is usually slow and treatment resumes only when iwCLL criteria are met again. The regimen depends on what was given first and why it stopped: progression on a covalent BTK inhibitor usually means a BTK C481 mutation or PLCG2 mutation and calls for venetoclax-based therapy or the non-covalent inhibitor pirtobrutinib; intolerance to one covalent BTK inhibitor can be managed by switching to another (ALPINE found zanubrutinib superior to ibrutinib in relapsed disease, progression-free survival hazard ratio 0.65, with less atrial fibrillation, 5.2 versus 13.3 percent); relapse a year or more after fixed-duration venetoclax can be treated with venetoclax again; TP53 aberrant disease and complex karyotype shorten every remission.
The landmark trials each defined a setting. RESONATE (2014) established ibrutinib against ofatumumab in relapsed disease (hazard ratio 0.22 for progression, median 44.1 versus 8.1 months on long follow-up). MURANO (2018) established two years of venetoclax-rituximab against bendamustine-rituximab, with two-year progression-free survival of 84.9 versus 36.3 percent and a survival gain, the first fixed-duration targeted regimen. BRUIN CLL-321 (2024) showed pirtobrutinib beat investigator's choice of idelalisib-rituximab or bendamustine-rituximab after covalent BTK inhibitor failure, and pirtobrutinib was approved in 2023 for patients previously treated with both a BTK and a BCL-2 inhibitor. Lisocabtagene maraleucel, a CD19 CAR-T, was approved in 2024 for the same double-exposed group after TRANSCEND CLL 004 (complete remission in about a fifth, undetectable MRD in the blood in two thirds).
| Setting | Approach | Guideline |
|---|---|---|
| Relapse after a BTK inhibitor | Venetoclax plus rituximab for two years (MURANO) or venetoclax-obinutuzumab; pirtobrutinib after covalent BTK inhibitor failure (BRUIN CLL-321). | not mapped |
| Relapse after venetoclax | Acalabrutinib or zanubrutinib (ALPINE) continuously, or ibrutinib; venetoclax retreatment if the prior remission lasted a year or more. | not mapped |
| Double-refractory after BTK inhibitor and venetoclax | Pirtobrutinib; lisocabtagene maraleucel CAR-T (TRANSCEND CLL 004); idelalisib-rituximab; clinical trials of BTK degraders, sonrotoclax and bispecifics; allogeneic transplant in fit young patients. | not mapped |