Teaching pack: Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia is a slow accumulation of mature B cells in blood, marrow, and lymph nodes, diagnosed at a median age of 70 and often found incidentally. Prognosis is set at diagnosis by IGHV mutational status, TP53 status (del(17p) or mutation), and karyotype, and by the CLL-IPI. Around a third of patients never need treatment; the rest are watched until symptoms, cytopenias, or bulky or rapidly progressive disease meet iwCLL criteria.

Treatment abandoned chemotherapy within a decade. Continuous BTK inhibitors (ibrutinib 2014, then the better-tolerated acalabrutinib and zanubrutinib) and the BCL-2 inhibitor venetoclax replaced FCR and BR after RESONATE, ELEVATE-TN, SEQUOIA, CLL13, and CLL14. Two strategies now compete in first line: indefinite BTK inhibition, or fixed-duration therapy for 12-15 months with venetoclax-obinutuzumab (CLL14) or a BTK inhibitor plus venetoclax (acalabrutinib-venetoclax, the first all-oral fixed-duration regimen approved in the US in February 2026). Undetectable MRD at the end of fixed-duration therapy predicts years of treatment-free remission. Patients with del(17p)/TP53 aberration receive continuous BTK inhibition or venetoclax-based therapy and are excluded from chemoimmunotherapy entirely.

• Chemotherapy-free care with near-normal life expectancy for many.
• Chemotherapy is essentially obsolete in CLL; median survival for most patients now approaches that of the general population.
• Two first-line philosophies with phase 3 support: indefinite BTK inhibition (acalabrutinib, zanubrutinib) or fixed-duration venetoclax combinations (venetoclax-obinutuzumab; acalabrutinib-venetoclax approved February 2026).
• Head-to-head data rank the BTK inhibitors: zanubrutinib beat ibrutinib on PFS and safety (ALPINE); acalabrutinib matched it with less cardiotoxicity (ELEVATE-RR).
• Sequencing works: BTKi → venetoclax → pirtobrutinib gives years of additional control; pirtobrutinib fully approved December 2025.
• uMRD at end of fixed-duration therapy is the key prognostic readout and is being tested as a stopping rule.

1. 1975Rai staging system
2. 1999IGHV mutational status predicts outcome
3. 2000Döhner hierarchical FISH model
4. 2010FCR: first regimen to improve survival
5. 2013Obinutuzumab approved; ibrutinib debuts
6. 2014Ibrutinib approved
7. 2014Ibrutinib approved in CLL; RESONATE
8. 2016Venetoclax approved
9. 2016Venetoclax approved (del(17p)); ibrutinib first line
10. 2019Fixed-duration therapy: CLL14; acalabrutinib approved

• Venetoclax (product)
• Sonrotoclax (product)
• BGB-16673 (product)
• Nemtabrutinib (product)
• CELESTIAL-TNCLL (trial)
• CaDAnCe-304 (trial)
• BELLWAVE-011 (trial)
• Pirtobrutinib (product)
• Lisocabtagene maraleucel (product)
• MRD-guided treatment duration in CLL (idea)
• BTK degraders to pre-empt resistance in frontline CLL (idea)
• BTK inhibitor + venetoclax, fixed duration (pairing)

• AMPLIFY (phase 3, n=867): Progression-free survival at 3 years: 76.5% vs 83.1% vs 66.5%
• ALPINE (phase 3, n=652): Progression-free survival: pending
• ELEVATE-TN (phase 3, n=535): Progression-free survival (median, 6-year follow-up): 27.8 months
• SEQUOIA (phase 3, n=590): Progression-free survival (cohort 1): pending
• CLL14 (phase 3, n=432): Progression-free survival (median): 76.2 months vs 36.4 months, HR 0.4
• RESONATE (phase 3, n=391): Progression-free survival: pending

• Double-refractory disease.
• Richter transformation.
• Richter transformation: median survival still under a year for clonally related cases; no approved therapy.
• Double-refractory disease after BTKi and venetoclax: pirtobrutinib gives ~1 year; CAR-T complete responses are only ~20%.
• Fixed duration versus continuous therapy has never been compared head to head for OS; MAJIC and CLL17 will inform.
• Infections remain the leading cause of death; vaccine responses are blunted and COVID-19 mortality was high.

1. What is CAR-T and which cancers is it approved for?
   Answer

   A patient's T cells are engineered with a synthetic receptor, multiplied, and returned. Approved CD19 products treat B-cell lymphomas and leukaemias; BCMA products treat multiple myeloma; the first solid-tumour approval (Claudin 18.2, gastric) is in China.
2. Why does venetoclax work in leukaemia?
   Answer

   It blocks BCL-2, the protein that stops leukaemia cells from self-destructing, so the built-in death programme (apoptosis) can run; used in CLL (fixed duration with obinutuzumab) and AML (with azacitidine).
3. What is in vivo CAR-T and why is it exciting?
   Answer

   Targeted lipid nanoparticles or viral vectors deliver CAR-encoding mRNA or DNA to T cells inside the patient, avoiding manufacturing, lymphodepletion, and wait time and allowing redosing; first-in-human data in 2025-26 show B-cell depletion. AbbVie bought Capstan for up to $2.1B.

• NCCN CLL/SLL Insights v2.2026: https://jnccn.org/view/journals/jnccn/24/3/article-p68.xml
• iwCLL guidelines (Blood 2018): https://ashpublications.org/blood/article/131/25/2745/36953
• Wikipedia: https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478
• Guideline: https://jnccn.org/view/journals/jnccn/24/3/article-p68.xml