Chronic lymphocytic leukaemia: lines of therapy
12 standard-of-care settings across 6 lines and 3 biomarker subgroups. Rows come from the cancer page's standard of care; the grid places each on its line and subgroup.
| Line | All comers | FRα | TP53 / del(17p) |
|---|---|---|---|
| Early / localised | 1 | · | · |
| Advanced, first line | 3 | · | 1 |
| Second line | 3 | · | · |
| Third line and beyond | · | 1 | · |
| Special situations | 1 | · | 1 |
| Other settings | 1 | · | · |
Early / localised
| Subgroup | Setting | Approach | Products and trials | Guideline | Evidence |
|---|---|---|---|---|---|
| All comers | Early stage, asymptomatic (Rai 0-II, Binet A-B) | Watch and wait with periodic counts and examination; early treatment with ibrutinib (CLL12) delayed progression but did not improve survival and is not recommended. Vaccinations and infection prevention. | NCCN · Category 1 (observation) | 87 |
Advanced, first line
| Subgroup | Setting | Approach | Products and trials | Guideline | Evidence |
|---|---|---|---|---|---|
| All comers | Frontline | BTK inhibitor continuous or venetoclax-based fixed duration. | NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma | 85 | |
| All comers | First-line, continuous BTK inhibition | Acalabrutinib (± obinutuzumab, ELEVATE-TN) or zanubrutinib (SEQUOIA) until progression; ibrutinib where alternatives are unavailable. Preferred for del(17p)/TP53 and for patients who cannot manage venetoclax ramp-up or TLS monitoring. | NCCN · Category 1 (acalabrutinib, zanubrutinib pre… | 88 | |
| All comers | First-line, chemoimmunotherapy (limited role) | FCR only for young, fit, IGHV-mutated, TP53-intact patients who decline targeted therapy or lack access; BR in older patients likewise. Outperformed by targeted therapy in CLL13, ELEVATE-TN, SEQUOIA, AMPLIFY. | NCCN · Category 2A (select patients) | 83 | |
| TP53 / del(17p) | First-line, del(17p) or TP53 mutation | Continuous second-generation BTK inhibitor (zanubrutinib: 5-year PFS 72%; acalabrutinib) or venetoclax-obinutuzumab; never chemoimmunotherapy; consider clinical trial and early referral for transplant/CAR-T planning if young. | NCCN · Category 1 | 88 |
Second line
| Subgroup | Setting | Approach | Products and trials | Guideline | Evidence |
|---|---|---|---|---|---|
| All comers | Relapsed | Alternate class; pirtobrutinib; CAR-T. | NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma | 89 | |
| All comers | Relapse after fixed-duration venetoclax | Retreat with venetoclax-based therapy if remission lasted >2-3 years, or switch to a BTK inhibitor (acalabrutinib, zanubrutinib); pirtobrutinib if prior covalent BTKi as well. | NCCN · Category 2A | 87 | |
| All comers | Progression on a covalent BTK inhibitor | Venetoclax-based therapy (venetoclax-rituximab 24 months, MURANO) or pirtobrutinib (BRUIN CLL-321; traditional approval December 2025); BTK degraders (BGB-16673 vs pirtobrutinib, CaDAnCe-304) in trials. | NCCN · Category 1 (venetoclax-rituximab); Category… | 86 |
Third line and beyond
| Subgroup | Setting | Approach | Products and trials | Guideline | Evidence |
|---|---|---|---|---|---|
| FRα | Double-refractory (BTKi and BCL2i) | Pirtobrutinib if BTK-naive-to-noncovalent; lisocabtagene maraleucel CAR-T (TRANSCEND CLL 004; accelerated approval 2024); allogeneic transplant in fit patients; PI3K inhibitors (idelalisib, duvelisib) rarely; clinical trials of degraders, sonrotoclax, bispecifics. | NCCN · Category 2A | 82 |
Special situations
| Subgroup | Setting | Approach | Products and trials | Guideline | Evidence |
|---|---|---|---|---|---|
| All comers | Supportive care throughout | Infection prophylaxis and vaccination (non-live; reduced vaccine responses), IVIG for recurrent infections with hypogammaglobulinaemia, HBV screening before anti-CD20, skin cancer surveillance (second cancers), cardio-oncology review before ibrutinib, TLS prophylaxis with venetoclax. | NCCN · Category 2A | 79 | |
| TP53 / del(17p) | First-line, TP53-intact, fit or unfit, fixed duration | Venetoclax + obinutuzumab for 12 months (CLL14, CLL13), or acalabrutinib + venetoclax for 14 cycles (AMPLIFY; approved February 2026), or ibrutinib + venetoclax 15 months (EU; GLOW, CAPTIVATE). uMRD at end of treatment predicts durable remission; retreatment is effective. | NCCN · Category 1 (venetoclax-obinutuzumab); Categ…ESMO-MCBS · 4 (CLL14) | 89 |
Other settings
| Subgroup | Setting | Approach | Products and trials | Guideline | Evidence |
|---|---|---|---|---|---|
| All comers | Richter transformation | Biopsy to confirm and assess clonal relationship; chemoimmunotherapy (R-CHOP) has poor results; checkpoint inhibitor + BTK inhibitor (zanubrutinib-tislelizumab, RT1), pirtobrutinib, venetoclax-based regimens, CD20×CD3 bispecifics (epcoritamab, glofitamab), CAR-T; allogeneic transplant for responders. | NCCN · Category 2A (clinical trial preferred) | 83 |
Sequence and caution pairings
CautionApproved
Caution: chemoimmunotherapy in del(17p)/TP53 CLL
Chemotherapy-based regimens barely work when the p53 gene is lost; these patients need BTK inhibitors or venetoclax from the start.
CautionApproved
Caution: ibrutinib in patients with cardiac risk
Ibrutinib raises the risk of irregular heart rhythm, high blood pressure, and sudden cardiac events; second-generation BTK inhibitors are safer choices for patients with heart disease.
Regimens in the library
Lines and subgroups are parsed from the setting text of each standard-of-care row and can misclassify an unusual phrasing; the row’s own setting is always shown. Guideline chips reflect the NCCN category and ESMO-MCBS grade recorded on the cancer page, checked on its stated date. Not medical advice.