The 2026 treatment landscape: fixed-duration versus continuous, and BTK inhibitors are not interchangeable¶

This section maps the options so that readers can follow a specialist's reasoning. It does not recommend any of them for an individual patient: the right choice depends on individual clinical and molecular data. Three layers decide what a patient in Sweden can actually receive, and they often disagree:

EU marketing authorisation from the EMA and European Commission.
Swedish reimbursement, through TLV for prescription drugs, or NT-rådet's recommendations for hospital drugs.
The Swedish national guideline's preference (VP8.2).

7.1 Approval, reimbursement and preference, drug by drug¶

Drug	EU authorisation for CLL	Swedish reimbursement (TLV) / NT-rådet	Swedish guideline VP8.2 (Jan 2026)
Venetoclax (Venclyxto)	Untreated CLL: with obinutuzumab (EC 9 Mar 2020), with acalabrutinib ± obinutuzumab and with ibrutinib (both added to the Venclyxto label, EC 27 May 2026). Relapsed: with rituximab. Monotherapy only in restricted settings	General subsidy (no restriction) from 24 Mar 2026	VO for 12 months recommended "i första hand" (+++). AV preferred over IV among all-oral fixed-duration options. Monotherapy only if alternatives are unsuitable
Acalabrutinib (Calquence)	Untreated: monotherapy or with obinutuzumab (5 Nov 2020); with venetoclax ± obinutuzumab (EC 2 Jun 2025). Relapsed: monotherapy	Restricted. First-line monotherapy only with del(17p)/TP53, unmutated IGHV or del(11q). With venetoclax in untreated CLL from 25 Nov 2025. Not subsidised with obinutuzumab	AV for 14 months recommended first-hand (+++). Second-generation BTKi preferred for continuous therapy
Ibrutinib (Imbruvica)	Untreated: single agent or with rituximab, obinutuzumab or venetoclax (venetoclax combination EC 2 Aug 2022)	Restricted: previously treated or del(17p)/TP53; monotherapy with unmutated IGHV or del(11q); with venetoclax in untreated CLL (from 25 Aug 2023)	IV approved and subsidised (+++), but AV preferred for cardiovascular reasons. Second-generation BTKi preferred over ibrutinib
Zanubrutinib (Brukinsa)	Monotherapy in any line (EC 15 Nov 2022); 160 mg tablets (EC 14 Aug 2025)	Restricted (decision 17 Nov 2023, capsules): first-line monotherapy with del(17p)/TP53 or unmutated IGHV; previously treated. No del(11q) clause. Subsidy for the tablet form not verified	Preferred second-generation option for continuous therapy; indirect data favour zanubrutinib (graded ++)
Pirtobrutinib (Jaypirca)	Monotherapy for adult CLL in any line (CHMP 25 Jun 2026; EC 29 Jul 2026). Conditional authorisation, renewed (EC 12 Aug 2026)	Only as monotherapy for relapsed/refractory CLL already treated with a BTKi, from 1 Oct 2026	Predates both events; describes the drug as "under utredning för subvention" (under review for subsidy), now outdated
Obinutuzumab (Gazyvaro)	Own label: CLL only with chlorambucil. VO and AO are authorised through the Venclyxto and Calquence labels	Hospital (requisition) drug outside TLV; NT-rådet has made no CLL statement	Part of VO; the guideline recommends a reversed start (7.6)
Liso-cel (Breyanzi, CAR-T)	No EU CLL indication	NT-rådet recommendations for LBCL and MCL only	CAR-T "not approved for use outside clinical trials" in CLL

Sources: EMA Venclyxto EPAR; Calquence EPAR; Imbruvica EPAR; Brukinsa EPAR; Jaypirca procedural steps; Breyanzi EPAR; TLV Venclyxto 2026; TLV Calquence 2025; TLV Imbruvica 2026; TLV Brukinsa decision 2023; TLV Jaypirca 2026; NT-rådet Gazyvaro; NT-rådet Breyanzi; VP8.2 ch. 11–12.

A note on zanubrutinib reimbursement. An earlier TLV assessment (May 2023) covered first-line TP53-aberrant disease only. The November 2023 decision text adds unmutated IGHV, and we rely on that later decision.

[I] What the three layers mean in practice:

Continuous BTKi for M-CLL without high-risk genetics is EU-approved but neither subsidised nor recommended in Sweden.
BTKi plus anti-CD20 antibody is EU-approved but not subsidised. The guideline says the antibody adds "begränsad tilläggseffekt" (limited added effect).
AVO: it is unclear whether Calquence's subsidy wording ("i kombination med venetoklax", in combination with venetoclax) covers it.

7.2 First-line regimens at a glance¶

Regimen	Schedule and burden	Key trials (latest follow-up)	Efficacy headline	Characteristic toxicity
VenO (venetoclax + obinutuzumab), fixed 12 cycles (~11 months)	Oral venetoclax with a 5-week ramp-up (from cycle 1 day 22 per the EU product information, the SmPC), plus 8 obinutuzumab infusions over 6 cycles (9 visits counting the split first dose). Pre-treatment CT for TLS risk, hydration, allopurinol, early blood checks	CLL14 (older/comorbid, ~9 years), CLL13 (fit, 5 years), CLL17 (mixed, 3 years), CRISTALLO	CLL14 vs chlorambucil-obinutuzumab: median PFS 76.2 vs 36.4 months; 6-year OS 78.7% vs 69.2% (p=.052). 9-year final: 76.6 vs 37.9 months; OS HR 0.80, NS (conference/secondary). CLL17: 3-year PFS 81.1%, non-inferior to continuous ibrutinib	Grade 3–4 neutropenia ~50%; infections (CLL17: 12 infection deaths, 7 from COVID-19; 3-year OS 91.5% vs 95.7% with ibrutinib, HR 1.67, NS); infusion reactions; TLS 1.4–4.1%, mostly laboratory only; AF low (3.7%)
AV (acalabrutinib + venetoclax), fixed 14 cycles (~13 months), all oral	Acalabrutinib 100 mg twice daily throughout; venetoclax ramp-up from cycle 3; no infusions	AMPLIFY (fit; TP53 excluded; median age 61; 41 months)	36-month PFS 76.5% vs 66.5% with chemoimmunotherapy (HR 0.65). OS 94.1% vs 85.9% at the primary analysis; at a later cut in the EU label, OS HR 0.42 "not significant after adjusting for multiplicity". Undetectable MRD (ITT) 34%	Grade ≥3 neutropenia ~32%; grade ≥3 infections 12%; fatal infections 3.1% (mostly COVID-19); AF 0.7%; grade ≥3 hypertension 2.7%; laboratory TLS 0.3%; headache
AVO (triplet), 14 cycles	AV plus 8 obinutuzumab doses (cycles 2–7)	AMPLIFY	36-month PFS 83.1%; undetectable MRD 67%; IGHV gap closed (83% vs 84%)	25 COVID-19 deaths; fatal infections 6%; fatal serious adverse events 11.6% in older patients (conference/secondary); OS HR vs chemoimmunotherapy 0.75, NS
IV (ibrutinib + venetoclax), fixed 15 cycles, all oral	3 cycles of ibrutinib lead-in, then 12 cycles of both. The lead-in cut the share at high TLS risk from 21% to 1% (CAPTIVATE)	GLOW (older/unfit; TP53 excluded; 67 months), CAPTIVATE (≤70; 5.5 years), CLL17	GLOW: 66-month PFS 51.7% vs 18.1% (HR 0.27), OS 79.0% vs 60.8% (HR 0.46). CAPTIVATE: 5.5-year PFS 66%. CLL17: 3-year PFS 79.4%	CLL17: AF 12.5%, cardiac disorders 23.8%. Pooled meta-analysis: AF 10.8%, hypertension 19%. GLOW: 4 sudden cardiac deaths, all in patients with high cardiovascular risk. Less neutropenia than VenO
Acalabrutinib, continuous ± obinutuzumab	Twice-daily tablets, indefinitely	ELEVATE-TN (≥65 or comorbid; TP53 included; 6 years)	72-month PFS 61.5% (acalabrutinib), 78.0% (with obinutuzumab), 17.2% (chlorambucil-obinutuzumab); OS HR 0.62 for the combination	AF 7.3–8.9%; hypertension 11.2%; major bleeding 5.6% (alone) and 9.0% (with obinutuzumab); headache; about half still on drug at 6 years; 18–21% stopped for adverse events
Zanubrutinib, continuous	320 mg a day, once or twice daily	SEQUOIA (≥65 or comorbid; 5–6 years); ALPINE (relapsed disease, vs ibrutinib)	60-month PFS 75.8% vs 40.1% with BR; 72-month 74% vs 32% (conference/secondary). OS 85.8% vs 85.0%. TP53 subgroup: 60-month PFS 70.7%, OS 82.3%	AF 7.1%; hypertension ~20% (19.6% or 22.9%, unresolved); any bleeding 52% (grade ≥3: 7.5%); bruising
Ibrutinib, continuous ± anti-CD20	Once-daily tablets	RESONATE-2 (~10 years), E1912, A041202, iLLUMINATE	Median PFS 8.9 years; 9-year OS 68%. E1912: OS HR 0.47 vs FCR	Most AF and hypertension (A041202: AF 18%, hypertension 55%). Sudden or cardiac deaths (FLAIR: 8 sudden deaths on ibrutinib alone). 33% stopped for adverse events over ~10 years. Adding rituximab gave no benefit
Pirtobrutinib, continuous (non-covalent BTKi)	200 mg once daily	BRUIN CLL-313 (vs BR, no del(17p)); CLL-314 (vs ibrutinib; interim)	24-month PFS 93.4% vs 70.7% (HR 0.199). Untreated subgroup vs ibrutinib: PFS HR 0.24 (immature)	AF 2.4% vs 13.5% with ibrutinib; grade ≥3 neutropenia 25.3% vs 17.5%; raised liver enzymes added to the label in 2025
Chemoimmunotherapy (FCR, BR, chlorambucil-obinutuzumab)	6 cycles	Many	Lower PFS than targeted therapy in every modern trial; FCR had worse OS than IR (E1912) and IV (FLAIR)	Myelosuppression, infections, therapy-related myeloid neoplasms (6.3% after FCR). FCR removed from VP8.2; BR only for M-CLL without high-risk genetics when VO/AV is not tolerated

Sources: CLL14 6-year, Blood 2024; CLL14 9-year, OncLive (conference/secondary); CLL17, NEJM 2026 (abstract only) and ASH 2025 abstract; CLL17 manufacturer summary (promotional); AMPLIFY, NEJM 2025 (abstract only); Calquence SmPC; Venclyxto SmPC; AMPLIFY QoL/age, AJMC (conference/secondary); GLOW 67-month (abstract only); GLOW sudden deaths; CAPTIVATE; Hofstetter 2026 meta-analysis (abstract only); ELEVATE-TN 6-year; SEQUOIA 5-year; SEQUOIA 6-year, OncLive (conference/secondary); SEQUOIA TP53 pooled (abstract only); RESONATE-2 final; E1912; A041202; FLAIR 2025 (abstract only); BRUIN CLL-313; BRUIN CLL-314; ANZ consensus 2026; VP8.2 §11.1.

7.3 Safety domains compared¶

Domain	Fixed-duration venetoclax regimens	Continuous second-generation covalent BTKi (acalabrutinib, zanubrutinib)	Ibrutinib	Pirtobrutinib
Infections	Highest with obinutuzumab (CLL17 VenO: grade ≥3 infections 34.9% vs 24.8% with ibrutinib (secondary)); AV 12%	Ongoing grade ≥3 infections of about 5–7% per year on continuous BTKi	Similar	Grade ≥3 infections 17.0% vs 16.6% with ibrutinib
Neutropenia	Grade 3–4 about 50% with VenO, mostly within the first year	About 10–12% grade ≥3 in monotherapy trials	—	25.3% grade ≥3
Atrial fibrillation (AF)	VenO 3.7%; AV 0.7%; IV 10.8–12.5%	Acalabrutinib 9.4% vs 16.0%; zanubrutinib 7.1% vs 17.0% (head-to-head with ibrutinib)	Highest	2.4% vs 13.5%
Hypertension	VenO 11.5% vs 24.2% with ibrutinib; AV grade ≥3 2.7%	Acalabrutinib lower than ibrutinib (9.4% vs 23.2%). Zanubrutinib not lower in ALPINE (27.2% vs 25.3%); Sweden reads this as "samma ökade risk" (the same raised risk)	Threefold raised risk (VP8.2)	10.6% vs 15.1%
Ventricular arrhythmia / sudden death	No venetoclax signal; the ibrutinib in IV carries one	Rare; conflicting data for acalabrutinib; a class effect is suspected	About 6–8 per 1,000 person-years (VP8.2); specific warning in the SmPC	No dedicated analysis
Bleeding	No venetoclax bleeding warning. Obinutuzumab can cause sudden, deep platelet falls	Bruising common; serious bleeding 1–4%, similar across covalent BTKi (VP8.2); no warfarin; stop 3–7 days around surgery	Same; SmPC says avoid fish oil and vitamin E	EU: stop 3–5 days around surgery; warfarin "not studied"
Tumour lysis (TLS)	Ramp-up needed; 0.3–4.1%; lower after debulking	Not usually	—	Rare
Kidneys	No venetoclax dose change down to dialysis, but more intensive TLS prophylaxis if creatinine clearance <80 mL/min	No change above 30 mL/min; little data below	Same	No change for mild to severe impairment; no dialysis data
Drug interactions	Strong CYP3A inhibitors contraindicated at start and during ramp-up; avoid grapefruit, Seville orange, starfruit	Acalabrutinib: avoid strong CYP3A inhibitors; capsules must not be taken with proton-pump inhibitors (tablets can). Zanubrutinib: fixed dose reductions	Most CYP3A-sensitive; avoid grapefruit and Seville orange	EU: no CYP3A dose change; raises levels of rosuvastatin, dabigatran and digoxin
Monitoring burden	Heavy for 1–3 months (ramp-up blood tests, infusions), then ends	Lifelong visits with blood pressure, pulse and ECG checks	Same	Same
Quality of life and daily life	Venetoclax-anti-CD20 regimens gave the fastest QoL gains in CLL13; toxicity is time-limited, followed by treatment-free years	Cumulative bruising, AF and hypertension; headache at start with acalabrutinib; less joint pain than ibrutinib	More joint and muscle pain	Short follow-up

Sources: ELEVATE-RR; ALPINE final; BRUIN CLL-314; EU SmPCs for Venclyxto, Imbruvica, Calquence, Brukinsa, Jaypirca and Gazyvaro; VP8.2 ch. 12; CLL13 5-year (abstract only); ANZ 2026.

7.4 BTK inhibitors are not equivalent¶

Three randomised head-to-head trials against ibrutinib show the next-generation drugs are at least as effective and safer [E]:

Acalabrutinib (ELEVATE-RR): PFS non-inferior (HR 1.00); less AF and less hypertension; more headache.
Zanubrutinib (ALPINE): PFS superior (final HR 0.68, del(17p)/TP53 subgroup HR 0.51); AF 7.1% vs 17.0%; no cardiac deaths vs 6 with ibrutinib.
Pirtobrutinib (BRUIN CLL-314): response rate non-inferior; AF 2.4% vs 13.5%.

No trial has compared acalabrutinib directly with zanubrutinib. Indirect comparisons conflict and are often sponsor-funded. A meta-analysis found ibrutinib carried more AF (OR 2.50), heart failure (OR 2.08) and cardiac discontinuations (OR 3.32) than second-generation BTKi, with no difference in all-cause mortality (Mushtaq 2026).

EHA recommends acalabrutinib or zanubrutinib over ibrutinib for all new patients starting continuous therapy (I, A). It also says patients doing well on ibrutinib "should not be switched" (EHA 2026). Sweden says second-generation BTKi "bör väljas i första hand" (should be chosen first) (VP8.2 §12.1).

[I] Practical differences between acalabrutinib and zanubrutinib:

Dosing: acalabrutinib twice daily; zanubrutinib once or twice daily.
Side-effect emphasis: early headache with acalabrutinib; hypertension similar to ibrutinib with zanubrutinib.
Resistance mutations: T474I appeared with acalabrutinib; L528W was enriched after zanubrutinib (ELEVATE-RR genomics; Blombery 2022).
Swedish first-line subsidy: acalabrutinib covers TP53, unmutated IGHV and del(11q); zanubrutinib covers TP53 and unmutated IGHV.
Formulation: acalabrutinib capsules lose absorption with proton-pump inhibitors (AUC −43%); the tablets do not. Which form Swedish pharmacies dispense was not verified.

7.5 Pirtobrutinib's new labels: EU, US and Sweden now disagree¶

EU [E]. The CHMP gave a positive opinion on 25 June 2026 and the European Commission decided on 29 July 2026. The indication now reads "Jaypirca as monotherapy is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL)", with no restriction by line of therapy or by del(17p) status (the US label excludes patients with known del(17p)). It rests on interim BRUIN CLL-313 and CLL-314 data. The authorisation remains conditional; its one-year renewal was decided on 12 August 2026 (EMA procedural steps; CHMP summary).
US [E]. On 2 October 2026 the FDA approved pirtobrutinib for previously untreated CLL or SLL "with no known 17p deletion", based on BRUIN CLL-313: 282 patients, PFS HR 0.20, median not reached vs 33.5 months. The notice does not call it an accelerated approval (FDA).
Sweden [E]. TLV subsidises pirtobrutinib from 1 October 2026 only for relapsed or refractory CLL previously treated with a BTKi. TLV's comparator was venetoclax-rituximab, and an indirect comparison judged the effect "jämförbar" (comparable) (TLV). VP8.2 (January 2026) predates all of this.
EHA (June 2026, before the EU decision). EHA declined to recommend pirtobrutinib first-line. It cited "the lack of data on subsequent successful use of cBTKi following ncBTKi", that is, of a covalent BTKi given after a non-covalent one (EHA 2026). Mutations that emerge on pirtobrutinib (T474I, L528W) can confer resistance to some covalent BTKi (Brown 2026, abstract only).

[I] In October 2026, first-line pirtobrutinib is EU-authorised but neither subsidised nor guideline-recommended in Sweden. Outside a trial (CLL18 pairs it with venetoclax), routine first-line use in Swedish public care is unlikely without a regional or NT-rådet decision.

7.6 Swedish particulars to raise with the specialist¶

AV for TP53-aberrant disease (conflict). VP8.2 lists AV for 14 months (+++) as an alternative in del(17p)/TP53-mutated CLL. AMPLIFY, however, enrolled only patients "without del(17p) or TP53 mutation" (EMA Venclyxto procedural steps), and the EU label carries no TP53 restriction [E]. [I] The +++ grade for this use appears to be extrapolated from other regimens. A patient found to be TP53-aberrant should ask what evidence supports AV.

The VO start order (conflict).

The EU SmPC follows the CLL14 schedule: obinutuzumab first (cycle 1, days 1–2, 8 and 15), then venetoclax ramp-up from cycle 1 day 22 (Venclyxto SmPC).
VP8.2 §11.1 recommends, "baserat på klinisk erfarenhet" (based on clinical experience), the reverse: venetoclax ramp-up first, then obinutuzumab, to avoid severe reactions. VP8.2 §16.1 adds that TLS risk is very low "vid start med venetoklax före obinutuzumab" (when venetoclax is started before obinutuzumab) (VP8.2 §16.1) [E].
The standard order uses obinutuzumab to shrink the disease first. In CRISTALLO, no patient remained at high TLS risk after obinutuzumab (CRISTALLO).
[I] The reversed order was not the order tested in the pivotal trial. This is a question to put to the specialist, not advice: if VO is ever chosen, which order will the clinic use, and why?

Anti-CD20 added to a BTKi. Not subsidised in Sweden. EHA says acalabrutinib-obinutuzumab is "more effective than acalabrutinib alone but with additional toxicity, and should not be preferred".

Triplets. No triplet is in the Swedish recommendation boxes. EHA says triplets "may add" benefit in TP53 disease (III, B). Other experts call triplets "premature" for TP53-aberrant disease and would consider them only for fit, fully immunised patients under 70 with unmutated IGHV and normal TP53 (McKeague & Seymour 2026, abstract only). The Australasian consensus says triplets "may be preferred" for younger IGHV-unmutated patients if infection risk is explained.

Regimen library. As of 7 October 2026, the national regimen library (Regimbiblioteket) listed VO, AV and continuous-BTKi regimens, but no IV or pirtobrutinib regimen (Regimbiblioteket KLL).

7.7 What happens at relapse, and does the first choice keep later options open?¶

After fixed-duration venetoclax therapy [E]:

Across 10 reports of venetoclax retreatment, response rates were 72–100% and median PFS 23–58 months (Castonguay 2026, abstract only).
Retreatment works best if the treatment-free interval exceeded 2 years (EHA, IV, B). Sweden uses about 36 months of remission as a rough guide (VP8.2 §15.1).
The BCL2 resistance mutations G101V and D103Y were not observed after fixed-duration therapy. No BTK or PLCG2 mutations appeared after fixed-duration IV (Jain 2024).
A BTKi is an equally recommended alternative (+++). Some patients in CLL13 (fit, without TP53 aberration) relapsed after first-line venetoclax-based treatment and were retreated with a venetoclax-based regimen. In that group, 2-year treatment-free survival, counted from the start of this second-line treatment, was above 80% (CLL13 5-year, abstract only).

After continuous covalent BTKi [E]:

Sweden recommends a gap-free switch to venetoclax plus an anti-CD20 antibody (++). TLV treats venetoclax-rituximab as the Swedish standard after BTKi.
Pirtobrutinib is now subsidised for this setting. In BRUIN CLL-321, median PFS was 14.0 vs 8.7 months (HR 0.54) against an outdated comparator (idelalisib-rituximab or BR). OS was not improved (HR 1.09), confounded by crossover (BRUIN CLL-321).
Acquired BTK C481 or PLCG2 mutations explain about 65–85% of progressions (Bonfiglio 2023; Woyach 2017).
Sweden treats resistance to one covalent BTKi as resistance to all. Intolerance, by contrast, is managed by switching to another BTKi.

Double-refractory disease (progression on both drug classes) [E]:

Outlook is poor: median OS 3.6 months in a small Australian series; median next-line PFS 9.2 months in US data (Lew 2021; Eyre 2023).
Sweden: trials first, plus contact with CLL expertise. Idelalisib-rituximab is the authorised fallback. Duvelisib's EU authorisation was withdrawn on 16 February 2026 (EMA Copiktra).

CAR-T [E]:

The US granted liso-cel accelerated approval on 14 March 2024, after at least two prior lines including a BTKi and a BCL2 inhibitor.
In double-exposed patients: complete remission about 20%, overall response about 45%, median PFS about 12 months (Siddiqi 2023, abstract only; US label).
There is no EU CLL indication. The global phase 3 trial, which had planned Swedish and Norwegian sites, was withdrawn in 2024 ("Business objectives have changed") (NCT06205290).
Sweden restricts CLL CAR-T to trials. SUS does run CAR-T for lymphoma.

Allogeneic stem-cell transplantation [E]:

It remains the only established potentially curative therapy.
Sweden says it "bör diskuteras" (should be discussed) when a BTKi or venetoclax fails and the plan is to switch targeted therapy, and for clonally related Richter transformation, with early contact with a transplant centre (VP8.2 §15.3).
EBMT 2025 rates it a "clinical option" (CO/II) in double-refractory CLL and standard of care (S/II) in clonally related Richter (EBMT 2025).
Retrospective outcomes after novel agents: 2–3-year PFS about 60–70%, OS 80–87%, non-relapse mortality 7–18%. Prior targeted therapy did not raise transplant risk (Roeker 2020; Kim 2020; both abstract only).

Emerging agents [E]: BTK degraders, next-generation BCL2 inhibitors, nemtabrutinib and bispecific antibodies. None is EU-approved for CLL.

Tacabrutideg (degrader): response 85–94% in heavily pretreated patients, with few complete remissions (3–6%); median PFS 24.4 months (OncLive, EHA 2026, conference/secondary).
Bexobrutideg (degrader): response 83%, median PFS 22.1 months (Nurix filing, press release).
Sonrotoclax (BCL2 inhibitor): conditionally approved only in China for relapsed CLL (January 2026) (Drugs 2026).
Epcoritamab (bispecific) in relapsed CLL: response 61%, complete response 39%, with frequent cytokine-release syndrome (ASH 2024 abstract, conference).
Phase 3 trials are not expected to read out before 2028–2032.

Trial eligibility can depend on what came before [E]. The two large degrader phase 3 trials require prior covalent BTKi and exclude patients who have had pirtobrutinib or a degrader. The sonrotoclax relapse phase 3 excludes patients previously given a BCL2 inhibitor unless their remission lasted at least 3 years and at least 2 years have passed since the last dose (NCT06943872; NCT07516093).

[I] Does the first choice preserve later options?

Fixed-duration venetoclax therapy appears to keep both drug classes available: few resistance mutations emerge, and the BTKi is still unused.
Continuous covalent BTKi leaves venetoclax combinations and pirtobrutinib, with possible cross-resistance to the latter.
First-line pirtobrutinib raises the open question of whether a covalent BTKi still works afterwards.
No randomised sequencing trial proves any of this. Overall survival has not differed so far between fixed-duration and comparator arms in CLL13, CLL14 or CLL17.
Taking a BTKi or venetoclax first does not appear to make a later transplant less safe.