Treatment decision matrix: what the evidence says by situation, not a choice for any individual patient¶
This matrix shows how the guidelines and the evidence treat each situation that may apply once a patient's data are known. It does not choose a regimen for anyone. Most real patients sit in several rows at once, for example IGHV-unmutated and hypertensive and preferring fixed duration. The specialist weighs those rows together.
| Situation | Swedish VP8.2 | EHA 2026 | Strongest evidence | Main uncertainty | Swedish reimbursement |
|---|---|---|---|---|---|
| A. TP53-aberrant (del(17p) and/or TP53 mutation) | Continuous BTKi first-hand (+++); VO 12 months (+++) or AV 14 months (+++) as alternatives; venetoclax alone only if all else is unsuitable | Continuous therapy suggested unless shared decision-making favours fixed duration (I, A); second-generation BTKi; triplets "may add" benefit (III, B) | Ibrutinib (pooled): 4-year PFS 79%, OS 88%. Zanubrutinib: 60-month PFS 70.7%, OS 82.3%. VenO median PFS 49–52 months. CAPTIVATE 5.5-year PFS 30–36%. CLL17 subgroup HR 1.20 (0.40–3.59) | No adequately powered randomised comparison. AMPLIFY excluded TP53-aberrant patients, so AV here is extrapolated. Meaning of low-VAF mutations under targeted therapy undefined | Acalabrutinib, ibrutinib and zanubrutinib monotherapy subsidised |
| B1. IGHV-mutated, TP53 intact | VO or AV first-hand; BR only if VO/AV is not tolerated and genetics are low-risk | Time-limited preferred (I, A); continuous therapy "should be avoided" (II, A) | CLL14: VenO median PFS 104.9 months (conference). CLL13: VenO 5-year PFS 82.9% (secondary). CLL17: 3-year PFS VenO 87.6% vs ibrutinib 83.5% | No head-to-head AV vs VenO yet (MAJIC due ~2027) | Continuous BTKi not subsidised for this profile |
| B2. IGHV-unmutated, TP53 intact | VO or AV first-hand; continuous BTKi "kan övervägas" (may be considered) | Time-limited where possible, "considering renal function and ramp‐up process" | CLL17: 3-year PFS VenO 75.8% vs ibrutinib 79.7% (HR 0.98). Fixed-duration remissions shorter (CLL14 VenO median 64.7 months at 9 years, conference; AMPLIFY AV 68.9% at 36 months). AVO narrows the IGHV gap but at an infection cost. RESONATE-2 9-year OS 70% | CLL17 follow-up is short; EHA: picture "may change over time". Durability of retreatment unknown | Continuous acalabrutinib, ibrutinib or zanubrutinib subsidised |
| B3. del(11q) (relevant in Sweden) | Continuous BTKi "kan övervägas" | Not a separate stratum | CLL12: ibrutinib improved EFS (no OS benefit) | — | Acalabrutinib and ibrutinib monotherapy subsidised; zanubrutinib not |
| C. Younger/fit vs older/comorbid | No age or fitness split: "Även de äldsta äldre och patienter med hög samsjuklighet har oftast nytta av, och tolererar, målriktade behandlingar" (even the oldest and most comorbid usually benefit from and tolerate targeted treatment) | Choose by comorbidity (cardiac, renal, infections, co-medication), not calendar age | Pooled CLL13 + CLL14 VenO: 3-year PFS 86.4% (unfit) vs 87.5% (fit); venetoclax dose reductions below 70% linked to shorter PFS. AVO fatal serious adverse events 11.6% in older patients. GLOW sudden deaths clustered in high cardiac-risk patients | Trial ages differ widely (AMPLIFY median 61, CLL14 median 72) | — |
| D. Kidney impairment | Special attention to TLS with venetoclax when kidney function is reduced | Time-limited when possible "considering renal function" | Venetoclax: no dose change down to dialysis, but more intensive TLS measures if CrCl <80 mL/min; in severe impairment only if benefit outweighs risk. Covalent BTKi: no change above 30 mL/min. Pirtobrutinib: no change from mild to severe. Obinutuzumab: not established below 30. Fludarabine: contraindicated below 30. Onkopedia favours a BTKi if GFR <30 | No dedicated first-line kidney-subgroup analysis. CLL14 enrolled patients with CIRS >6 and/or CrCl <70 (median CrCl 66); CLL17 and CLL18 require ≥30 | — |
| E. Heart disease or anticoagulation | ECG before any BTKi; blood pressure controlled; AF "som regel ingen kontraindikation" (usually not a contraindication) to starting a BTKi; ventricular arrhythmia contraindicates continuing a BTKi; no warfarin, DOAC preferred; AV preferred over IV | BCL2 inhibitors favoured with heart disease or anticoagulation; avoid BTKi after ventricular arrhythmia or with uncontrolled heart failure | CLL17 cardiac disorders: VenO 13.9% vs ibrutinib 34.6%. ESC 2022 for BTKi patients: blood pressure every visit, weekly home readings for 3 months then monthly, pulse/ECG every visit, echocardiogram if high risk | First-line BTKi trials excluded warfarin and significant heart disease | — |
| F. Preference: fixed duration vs continuous | Fixed duration recommended first-hand when TP53 is intact; "patientens önskemål" (the patient's wishes) count | Time-limited preferred when TP53 is intact (I, A) | Fixed duration: toxicity concentrated in the first year, then treatment-free years (CLL14 median time to next treatment 91.9 months; 39.6% treatment-free at 9 years). Continuous: all oral, but lifelong side effects; 18–33% stop for adverse events over 5–10 years. Stopping a BTKi arbitrarily is not the same as fixed duration (STAIR: 1-year PFS ~53% after stopping vs 96% continuing) | No randomised proof that either sequence prolongs overall survival | PL 7 kap. 1 § gives a choice between evidence-based alternatives, subject to cost justification |
| Trial option | "Viktigt att beakta möjligheten att inkludera patienten i någon klinisk studie" (important to consider including the patient in a trial) | — | CLL18/MOIRAI at Lund, if treatment is indicated: all arms time-limited; TP53-aberrant and SLL patients eligible | Lund's current enrolment status must be confirmed | — |
Sources: VP8.2 §11–12; EHA 2026; CLL17; CLL14 6-year; Allan 2022; SEQUOIA TP53; Al-Sawaf 2025 pooled fit/unfit (abstract only); Venclyxto SmPC; Onkopedia; ESC 2022 cardio-oncology; STAIR registry record; Patientlag 7 kap. 1 §; CTIS CLL18.
[I] The daily-life angle. Fixed-duration venetoclax regimens avoid the cumulative bruising, AF and hypertension of continuous BTKi. They bring infusions (with VenO), the ramp-up logistics, and a year of neutropenia and infection risk. A BTK inhibitor raises bleeding concerns in everyday life (section 11). This is a framing for discussion, not evidence that one approach is better for any individual patient.