Molecular risk profile: only TP53 and IGHV change first-line choices¶
Two kinds of marker.
- A prognostic marker describes how the disease is likely to behave.
- A predictive marker tells you which treatment will work better.
The Swedish guideline is explicit that predictive markers are "betydligt färre" (far fewer). At present, only del(17p)/TP53 mutation and IGHV status "har visat starkt prediktivt värde" (have shown strong predictive value). Stage, IPS-E, CLL-IPI, β2-microglobulin, lymphocyte doubling time and karyotype are treated as prognostic (VP8.2 §8.4) [E]. EHA 2026 agrees, and calls tests for genes other than TP53 "research purposes only" (EHA 2026).
How common. TP53 aberrations are found in 5–10% of patients at diagnosis and 10–20% of those starting first-line treatment. About 50–60% of patients have mutated IGHV (M-CLL) and 40–50% unmutated (U-CLL) (VP8.2 §8.4.5).
6.1 Marker by marker¶
| Marker | Prognostic? | Predictive? | Changes first-line therapy in 2026? | When to test | Repeat before later lines? |
|---|---|---|---|---|---|
| del(17p) (FISH) | Yes: shorter time to treatment, PFS and OS. In the chemoimmunotherapy (CIT) era, median survival was 2.5–4 years after treatment | Yes: CIT fails. PFS is shorter after fixed-duration venetoclax (CLL14 within-arm; CAPTIVATE 5.5-year PFS 30–36%; CLL17 HR 1.20, underpowered) | Yes. No CIT. Sweden and EHA favour continuous BTKi, preferably second-generation | Before first treatment (Sweden); optional at diagnosis | Yes, before every line: clones evolve |
| TP53 mutation (sequencing, NGS preferred) | As del(17p). Low-VAF (<10%) mutations are adverse after CIT | As del(17p). The effect of low-VAF mutations under targeted therapy is "yet to be defined" (ERIC 2024) | Yes | Same sample as FISH | Yes |
| IGHV (unmutated = ≥98% identity) | Yes: time to treatment and PFS. With targeted drugs, IGHV lost independent OS significance; TP53 kept it | Yes, for how long fixed-duration and CIT responses last (CLL14 HR 2.66 U vs M; CAPTIVATE 5.5-year PFS 55% vs 79%). Little effect under continuous BTKi (E1912 HR 0.27 in both groups; RESONATE-2 9-year OS 70% U vs 69% M) | Yes. M-CLL: fixed-duration preferred; EHA says continuous therapy "should be avoided" (II, A). U-CLL: fixed-duration first in Sweden, continuous BTKi "kan övervägas" (may be considered) | Once, before first-line; may be done earlier for IPS-E | No (stable) |
| Borderline IGHV (97–97.99%) | Behaves like M-CLL for time to treatment, except in subset #2 | Unknown | No | Reported with IGHV (two decimals) | No |
| Subset #2 (IGHV3-21/IGLV3-21) | Aggressive whatever the IGHV status | Inconclusive; CLL12 hints at reduced ibrutinib effect (exploratory) | No | From the IGHV sequence (Lund reports #2 and #8) | No |
| Subset #8 | Poor prognosis, high Richter risk (HR 24.5 in one series) | — | No | From the IGHV sequence | No |
| del(11q)/ATM | Adverse | CLL12: ibrutinib improved EFS (no OS benefit) | Internationally no. In Sweden it matters: continuous BTKi "kan övervägas", and TLV subsidises first-line acalabrutinib or ibrutinib monotherapy for del(11q) | FISH panel before treatment | Optional |
| del(13q) alone | Favourable | No | No | FISH | No |
| Trisomy 12 | Intermediate; complex karyotype with +12,+19 is indolent | No | No | FISH | No |
| Complex karyotype (≥3 aberrations; "high-CK" ≥5) | High-CK is independently adverse; 3–4 aberrations are adverse mainly with TP53 | Suggested shorter PFS with venetoclax combinations (EHA: "not robust enough") | Contested: EHA no testing outside trials; Onkopedia treats as high risk; S3 says test | Before treatment, if done | S3: before each therapy |
| NOTCH1 | Yes; also a Richter risk factor | Only for CIT (no rituximab benefit in CLL8). AMPLIFY acalabrutinib-venetoclax 36-month PFS 57.1% (NOTCH1-mutated) vs 79.0% (wild-type) (exploratory, secondary) | No (EHA: research only) | Not routine; the Lund TP53 panel reports it anyway | — |
| SF3B1 | Yes | No established role | No | Not routine; reported by the Lund panel | — |
| BIRC3 | Yes, after FCR (retrospective) | CIT only, unvalidated | No | Not routine | — |
| β2-microglobulin | Yes (CLL-IPI >3.5 mg/L) | No | No | Not routine in Sweden | — |
| CLL-IPI, IPS-E | Yes | No | No; explicitly not a reason to treat | Optional, for counselling | — |
| BTK, PLCG2, BCL2 mutations | Relapse biology | May guide the next line | Not applicable | Only at progression | At relapse |
| MRD (<10⁻⁴) | Strong after treatment | Used in trials to set treatment length; unlicensed | No | After fixed-duration therapy, in trials; not routine in Sweden | — |
Sources: VP8.2 §8.4; EHA 2026; ERIC TP53 2024; ERIC IGHV 2022; CLL14 6-year; RESONATE-2 final; Langerbeins 2024 (abstract only); Baliakas 2019 (abstract only); Stilgenbauer 2014 (abstract only); CLL12 genetics (abstract only); Rossi 2009 (abstract only); TLV Calquence 2025.
[I] The Lund panel also reports NOTCH1 and SF3B1, so patients tested there may receive results that do not change treatment. Prognostic results obtained at diagnosis mainly set expectations and the follow-up interval. Under every guideline cited here, they never justify starting treatment early.
6.2 Where the guidelines differ¶
| Guideline (date) | When to test biology | TP53 method and VAF | Complex karyotype | Other genes | First line if TP53-aberrant |
|---|---|---|---|---|---|
| Sweden VP8.2 (Jan 2026) | Before treatment; IGHV optionally earlier | FISH, then sequencing if FISH is negative; VAF <10% "kliniskt relevant", <5% discuss with the lab | Not routine | Not routine | Continuous BTKi first; VO or AV as alternatives |
| EHA 2026 (Jun 2026; succeeds ESMO) | Not needed in asymptomatic early stage; before every line | FISH plus NGS per ERIC; no fixed VAF threshold | Not outside trials (III, B) | Research only | Continuous treatment suggested unless shared decision-making favours fixed duration (I, A); triplets "may add" benefit (III, B) |
| ESMO 2024 interim update | IGHV and TP53 before treatment | — | FCR only with a non-complex karyotype (<5 aberrations) | — | "Preferably a BTKi"; ibrutinib-venetoclax and VenO (III, A) as options |
| NCCN v2.2027 (version listed on nccn.org; professional text not verified) and the NCCN 2026 patient guideline | Patient version lists FISH, TP53, IGHV, karyotype and β2M as core tests | — | Karyotype listed | — | VenO, acalabrutinib ± obinutuzumab, zanubrutinib, AVO and venetoclax-zanubrutinib all "preferred" |
| ERIC (TP53 2024; IGHV 2022) | — | NGS preferred; no fixed VAF; each lab states its own detection limit | — | — | — |
| iwCLL 2018 | Before treatment ("Always") | Sanger-like ~10% VAF, now superseded by ERIC 2024 | "Not generally indicated" in practice | Prospective data needed | Predates current targeted regimens |
| BSH 2025 | Not verified (summary-level access only) | — | — | — | CIT "no longer recommended except where targeted agents are unavailable or contraindicated" |
| Germany S3 v2.0 (Dec 2024) + Onkopedia (Sep 2025) | "Kann" (may) at diagnosis; "soll" (shall) before each line; TP53 result ≤12 weeks old | FISH plus mutation analysis | S3: "sollte" (should); Onkopedia: high risk | Extended panel "kann" | Continuous acalabrutinib or zanubrutinib preferred |
Sources: VP8.2; EHA 2026; ESMO 2024; NCCN Guidelines for Patients 2026; ERIC TP53 2024; iwCLL 2018; BSH 2025 summary; S3 v2.0; Onkopedia.
[I] The disagreements that matter to a patient are four:
- Whether fixed-duration therapy is acceptable in TP53-aberrant disease. NCCN is the most permissive; EHA and Germany favour continuous BTKi.
- Whether to test for complex karyotype.
- Venetoclax-zanubrutinib, which NCCN prefers for TP53 disease but which is not licensed in the EU.
- First-line pirtobrutinib (section 7.5).
6.3 How Skåne runs these tests, and what to ask¶
[E] Region Skåne's lab catalogue lists all three core tests as done in-house in Lund by Klinisk genetik, patologi och molekylär diagnostik (AnalysPortalen, archived copies):
- FISH panel for del(11q), +12, del(13q) and del(17p). Accredited; answer in 7 days (3 if urgent).
- TP53. Run as a read-out of TP53, NOTCH1 and SF3B1 from the accredited Illumina TruSight myeloid NGS panel. Bone marrow is preferred; blood works if CLL cells circulate (archived entry).
- IGHV. Targeted amplicon sequencing with subset #2/#8 assignment. The catalogue entry is dated 2025-06-13, the test is not flagged as accredited, and the turnaround is listed as "35", with no unit given (archived entry).
Accreditation. Region Skåne holds ISO 15189 accreditation (Swedac no. 1309, latest decision 12 December 2025), which covers FISH and NGS methods generically (Swedac 1309). No Lund laboratory appears on ERIC's TP53 or IG certification lists. Those pages were modified 18 September 2026 and include certifications from April 2026, so the lists are maintained. In Sweden, the TP53-certified labs are Sahlgrenska, Karolinska Huddinge, Karolinska Solna, Umeå and Uppsala; the IG-certified labs are Sahlgrenska and Uppsala (ERIC TP53 network; ERIC IG network).
For comparison, Karolinska sends IGHV to Uppsala, with a turnaround of 3–4 weeks (Karolinska).
[I] What the missing ERIC listing means. It is not evidence of poor testing. It does mean three questions are reasonable:
- What is the detection limit of the TP53 assay?
- Does the lab take part in external quality schemes?
- If a result is borderline (IGHV 97–97.99%, or a TP53 VAF below 10%), would confirmation at an ERIC-certified lab add anything?
[I] What sample to use if this is SLL. ERIC 2024 asks for CD19 enrichment when the absolute lymphocyte count is 10×10⁹/L or less, because few clonal cells may be circulating. It is worth asking which material the genetic tests will be run on: node tissue, marrow or blood (ERIC TP53 2024).