2025+BSH指南：慢性淋巴细胞白血病的治疗

2025 British Society for Haematology Guideline for the treatment of chronic lymphocytic leukaemia

R. Walewska ${}^{1}$ | T. A. Eyre ${}^{2}$ | A. Bloor ${}^{3}$ | G. Follows ${}^{4}$ | S. Iyengar ${}^{5}$ |R. Johnston ${}^{6}$ | H. Marr ${}^{7}$ | N. Martinez-Calle ${}^{8}$ | A. McCaig ${}^{9}$ | H. McCarthy ${}^{1}$ T. Munir ${}^{10}$ | H. M. Parry ${}^{11,12}$ | N. Parry-Jones ${}^{13}$ | A. Pettitt ${}^{14}$ | J. Riches ${}^{15}$ | I. Ringshausen ${}^{16}$ | A. Schuh ${}^{2}$ | P.E. M. Patten ${}^{17,18}$

Correspondence

R. Walewska, Cancer Care, University Hospitals Dorset NHS Trust, Castle Lane East, Bournemouth BH7 7DW, UK Email:renata.walewska@nhs.net

KEYWORDS

BCL-2 inhibitor, Bruton tyrosine kinase inhibitor,CD20 antibodies,chemoimmunotherapy,CLL treatment,vaccinations

METHODOLOGY

These guidelines were prepared following the BSH process(https://b-s-h.org.uk/media/16732/bsh-guidance-developme nt-process-dec-5-18.pdf). The Grading of Recommendations,Assessment, Development and Evaluation(GRADE) nomen-clature was used to evaluate the levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradleworkinggroup.org.

Recommendations are based on a review of the litera-ture using Medline/PubMed. Search terms included are CLL treatment, randomised, clinical trial, FCR(fludar-abine, cyclophosphamide, rituximab), TP53 disruption,Bruton tyrosine kinase inhibitor, covalent, noncovalent inhibitors, BTK degraders, BCL2 inhibitor, rituximab,obinutuzumab, vaccination and COVID-19. The search was limited to English language publications and confer-ence abstracts from the date of publication of the previous CLL guideline from 2021 to July 2025. Titles/abstracts ob-tained were curated and manually reviewed by the writing group who conducted additional searches using subsection heading terms.

Policy on Treatment Inclusion in Recommendations:

1. Licensed and approved for National Health Service(NHS)use, such as via the National Institute for Health and Care Excellence(NICE) or Scottish Medicines Consortium(SMC) technology appraisals.

2. Licensed by the Medicine and Healthcare products Regulatory Agency(MHRA), the European Medicines Agency(EMA) or the Food and Drug Administration(FDA) but not yet NHS approved, if supported by robust Phase 3 data.

3. Unlicensed, but with strong clinical justification, includ-ing compelling evidence from pivotal Phase 3 studies,par-ticularly when relevant for UK-based practice.

Inclusion of such therapies does not imply endorsement for off-label use, but reflects their emerging role and clinical relevance in specific scenarios.

Review of the manuscript was performed by the BSH Guidelines Committee Haemato-Oncology Task Force, the BSH Guidelines Committee and the Haemato-Oncology sounding board of the BSH. It was also posted on the mem-bers section of the BSH website for comment. This guide-line has also been reviewed by patient representatives from the UK CLL Support Association(https://www.cllsupport.org.uk).

INTRODUCTION

The diagnostic work-up for chronic lymphocytic leukae-mia(CLL) has not changed; please refer to the International Workshop on chronic lymphocytic leukaemia(iwCLL)guideline.

2025 BSHM CLL GUIDELINE

 Licensed treatments for CLL in 2025 include inhibitors of B-cell lymphoma-2, BCLi(venetoclax), covalent inhibitors of Bruton tyrosine kinase, cBTKi(ibrutinib, acalabrutinib and zanubrutib) used as monotherapy or in combination with anti-CD20 monoclonal antibodies(rituximab and, in first only,binututizumab). Treatment regimens are either continuous(given until intolerance or progression) or fixed duration. These targeted agents have superseded chemo-immunotherapy, which is no longer recommended except where targeted agents are unavailable or contraindicated.

# CLINICAL OBSERVATION(ACTIVE MONITORING)

The International Workshop on chronic lymphocytic leu-kaemia(iwCLL) criteria for starting treatment were es-tablished in the era of chemoimmunotherapy and, until recently, there were no data to support their use in the era of targeted therapy. To address this knowledge gap,the CLL12 trial compared ibrutinib monotherapy with placebo in patients with asymptomatic early-stage CLL at high risk of progression based on the German CLL Study Group score, with overall survival(OS) as the primary end-point. After a median follow-up of 69.3 months, ibru-tinib demonstrated a significant progression-free survival(PFS) advantage over placebo[HR 0.174(95% CI 0.12-0.24)].Still, there was no evidence of an OS benefit,2 with 5-year OS rates of 93.3% and 93.6% in the ibrutinib and placebo groups respectively. Furthermore, patients in the experimental arm experienced more adverse events due to known toxicities of ibrutinib. The results of CLL12, there-fore, confirm that an active monitoring/‘watch-and-wait’/approach remains appropriate for patients with asympto-matic, early-stage CLL including those at high risk of early progression.

For many patients, the active monitoring period will likely extend into years before treatment is required; there-fore,this‘waiting time’ should be utilised to optimise general health status. All newly diagnosed patients should be offered prehabilitation when available and advised on healthy eat-ing, exercise, increasing physical activity and emotional well-being as well as optimising co-existing medical prob-lems.3 There is emerging evidence that increased physical activity through exercise can improve not only physical functions but also anxiety, quality of life and symptom burden.4-10

Both the National Health Service(NHS, Physical activ-ity guidelines for adults aged 19-- NHS) and the Centers for Disease Control and Prevention(CDC, Older Adult Activity:An Overview|Physical Activity Basics|CDC) encourage im-proving physical activity, including a minimum of 150 min-utes per week of moderate intensity or 75 minutes of vigorous intensity physical activity(or a mixture of both), a minimum of two sessions of strengthening exercises per week, and ac-tivities improving balance," as long as the patient is able to undertake this.

# Recommendations regarding clinical observation and commencing treatment

● There remains no evidence to treat asymptomatic CLL where iwCLL treatment criteria have not been met(GRADE 1A).

● All newly diagnosed CLL patients should be offered pre-habilitation if locally available or given advice on preha-bilitation(GRADE 2C).

CHEMOIMUMUNOTHERAPY IS NO LONGER RECOMMENDED

Chemoimmunotherapy(CIT) with FCR has been a standard of care for younger patients without co-morbidities, with excel-lent long-term outcomes for a subgroup of patients with IGHV-mutated(mIGHV) CLL and no adverse cytogenetic/molecular features who can achieve undetectable measurable residual disease(uMRD) status.12 It is difficult to identify these patients before starting treatment and more importantly, FCR is associ-ated with a small but significant(1.5%-3%) risk of developing therapy-related myelodysplastic neoplasm/acute myeloid leu-kaemia(MDS/AML).13,14 Crucially,data from three randomised controlled trials(E1912, FLAIR and CLL13) have shown that PFS is longer with either brutinib- or venetoclax-based therapy compared to FCR, with E1912 and FLAIR also showing a sur-vival advantage for brutinib+rituximab.14-17 While targeted agents are not without toxicity, adverse events can be mini-mised by considering relevant co-morbidities when deciding which regimen to use, and by taking appropriate precautions.Consequently,FCR is no longer indicated when other treatment options are available.The same applies to other chemotherapy-based treatments(e.g. rituximab+bendamustine(BR) or obinutuzumab-chlorambucil(CO)) where randomised con-trolled trials(RCTs) have shown clear inferiority compared to targeted agents.18-20

Recommendations

● Chemoimmunotherapy(including FCR, BR or CO)is no longer routinely recommended for treatment-naive or relapsed/refractory CLL(GRADE 1A) unless both BTKi and BCL2i therapies are unavailable or contraindicated.

TREATMENT-NAIVE CLL

cBTKi and BCL2i(+/- monoclonal anti-CD20), as mono-therapy or in combination, have consistently demonstrated superiority against CIT in both fit and unfit patients(Table 1; Figure 1). While age and fitness remain impor-tant concepts, categorising patients as‘fit’ or‘unfit’ for treatment decision-making is no longer appropriate. We have, therefore, separated first-line treatment according to the intention to give fixed-duration/venetoclax-based or

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TABLE 1 Decision tool for first-line treatment of chronic lymphocytic leukaemia(CLL) patients.

|Determining factors||Acalabrutinib|Zanubrutinib|V+O|V+I|A+O|MRD V+I|V+A+/-O| |---|---|---|---|---|---|---|---|---| |CLL-related factors|IGHV mutated(not subset 2|+|+|++|++|++|++|Insufficient F/U| |CLL-related factors|IGHV unmutated or subset 2|++|++|+|+|++|++|Insufficient F/U| |CLL-related factors|TP53 mutation/17p deletion|+|+|+/-|+|+|-a|$$\begin{array}{l}\\ \\ \\ \\ \\ \\ \\ \\ \end{array}$$| |CLL-related factors|Bulky Disease|++|++|+|++|++|++|Insufficient F/U| |Patient vulnerabilities|Infection risk during treatment|+/-|+/-|-|+/-|-|-b|| ||Cardiac disease(risk of arrhythmia)|+/-|+/-|++|-|+/-|-|+| ||Hypertension|+/-|+/-|+|+/-|+-|-|+/| ||Bleeding history/anti- coagulant use|-|-|+|-|-|-|-| ||Renal disease|+|+|+/-|+/-|+|+/-|+/-| |Patient priorities and|Minimise initial hospital visits|++|++|-|+/-|-|+/-|-b| |preferences|Minimise cumulative toxicities|-|-|+|+|-|+/-|+| ||Fixed treatment duration|-|-|++|++|-|++|++| ||Continuous treatment|++|++|-|-|++|++|-|

Note: The following symbols are used:++=Very good choice;++=Good choice;+/-=Neutral/consider with caution;-=-Not recommended.These grades represent the authors' expert opinion and should not be interpreted as precise rankings. The order of therapies reflects the timing of UK funding approval and is grouped into continuous and fixed-duration regimens. A+O, MRD-directed V+I and V+A are included but are not currently funded in UK NHS practice. The table reflects relative efficacy and key clinical considerations for CLL-related factors. Importantly, no head-to-head comparisons exist between these regimes; differences in apparent efficacy may reflect trial design, follow-up duration, treatment strategy(fixed-duration vs. MRD-guided vs. continuous) and population differences as much as true differences in treatment effect. Continuous BTKi(alaacrabutirib) or ranubritin) may be preferred for TP53-mutated/17p-deleted disease due to longer observed responses. For patients with bulky disease, better disease control may be achieved with continuous BTKi or fixed-duration V+I or V+A(+/-O), which provide greater cytoreduction than V+O. Efficacy must be balanced against treatment incoherence risk, particularly in vulnerable patients. Infection risk varies between regimens: V+O carries a higher early risk but improves after treatment completion, while continuous therapies may lead to long-term immunosuppression. Arrhythmia and hypertension risks depend on drug-specific and duration-related factors, with brinuxitin carrying the highest cardiovascular risk. All BTKi increase bleeding risk. Venetoclax is less suited for patients with significantly impaired renal function due to TLS risk, requiring close monitoring, especially with the V+O regimen. Overall selection should be guided by shared decision-making, considering patient priorities, balancing efficacy, toxicity, comorbidities and treatment burden.

aNo data to inform decision.

b+/-if treatment used without O.

continuous BTKi therapy. Given the distinct outcomes of patients with TP53 disruption, the design of studies and the differences in the availability of regimens available, the data for outcome for such patients are considered separately. For all regimens, the key outcome data are presented, with ad-ditional considerations as to why one regimen may be pre-ferred over another presented in the section‘choosing the optimal first line therapy'.

Therapy for treatment-naive patients without TP53 disruption

Fixed-duration therapy

Venetoclax-based regimens

BCL2 overexpression is a molecular hallmark of CLL, consti-tuting an optimal target for therapeutic drug development.Venetoclax, the first-in-class BCLi2, constitutes the back-bone of all fixed-duration regimens for CLL treatment.

Since publication of the 2022 guideline, the fixed-duration 15-month ventoclax-ibrutinb(V+I) and the fixed duration venetoclax-acalabrutinib+/-obinutuzuman(V+A+/-O) regi-mens have been licensed, and data on the venetoclax-obinu-tuzumab(V+O) regimen in across all age ranges have been updated.

Venetoclax-Ibrutinib(V+I)

V+I has been compared with CIT, demonstrating superior PFS for all patient subgroups. For younger, fit patients(under 70 years of age with creatinine clearance>60 mL/min), the CAPTIVATE trial of a 15-month fixed-duration approach with V+I found a 5-year PFS of 67%(95% CI 59-74) and a 5-year OS of 96%(95% CI 91-98) with uMRD in peripheral blood being found in 77% of patients 3 months after treat-ment, with the greatest MRD benefit seen in patients with unmutated IGHV(uIGHV) disease.21

CAPTIVATE-FD included patients with TP53 disrup-tion(considered in'therapy for TN CLL patients with TP53 disruption'); therefore, caution should be exercised when

2025 BSHC PLL GUIDELINE

First line treatment algorithm for CLL

1. Reimbursed only for patients≥ 65 years and/or CIRS>6 and/or CrCL<70 m/min, or in TP53-mutated/17p-deleted disease(continuous therapy preferred in this setting)

2.15 months duration or MRD guided(the latter currently not re-

3. Licensed in the UK, but not NICE/SMC approved at the time of

![1. Reimbursed only for patients ≥ 65 years and/or CIRS > 6 and/or CrCL <70 m/min, or in TP53-mutated/17p-deleted disease(continuous therapy preferred in this setting) 2.15 months duration or MRD guided (the latter currently not re- 1. imReimbursed only for patients ≥ 65 years and/or CIRS > 6 and/or CrCL <70 m/min, or in TP53-mutated/17p-deleted disease(continuous therapy preferred in this setting) 3. Licensed in the UK, but not NICE/SMC approved the publication. 4. Leaue in the UK, but not NICE/SMC approved 5. Only for TP53 disrupted patients in whom BTK therapy is unsuitable 4. Particularly important if TP53 disrupted 6. Particularly important if TP53 disrupted [17p(del), TP53 mutation, IGHV status] 6.CIRS: Cumulative lIness Rating Scale: CV cardiovascular CrCL: Creatmine clearance; IHD: Ischemic heart disease 2.2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2.\n](2/aj0YEe4oUhYkBdfpda0fYP/figure922f5bdd3f0b479397519c1ed8c76316_0_5.png) FIGURE 1 First-line treatment algorithm for chronic lymphocytic leukaemia(CLL).

assessing these results compared to other V+I cohorts that did not include such patients.

For older(age≥65)+/- unfit patients(CIRS[Cumulative Illness Rating Score]>6, creatinine clearance<70mL/min),15-month fixed-duration V+I was compared to CO in the GLOW trial.20 There was improved PFS with the V+I com-bination, HR 0.26(95% CI 0.17-0.38), with 54-month PFS 66.5% vs. 19.5% and OS HR 0.45(95% CI 0.26-0.79). Both mutated IGHV(mIGHV) and uIGHV subgroups derived PFS benefit from the V+I combination(54-month PFS mIGHV 90% vs.40%; uIGHV 59% vs.8%). MRD negativity(using a cut-off of 10-4) was 54% for the whole cohort and correlated with PFS. Biologically, the uIGHV and mIGHV appear to be different: In GLOW, after 15 months I+V, 50%of uIGHV patient had disease relapse within 3 years whereas achieving deep remission did not seem to be important for PFS in patients with mIGHV.22

A young and fit patients' cohort studied in the CAPTIVATE and the FLAIR trials14,17 demonstrated improved PFS and high rates of MRD negativity with venetoclax combined with irubinitin. FLAIR utilised an MRD-guided approach with specific stopping rules, resulting in a median duration of therapy of 35 months. At 3 years, 60.4% of patients had stopped therapy, increasing to 73.1% by 5 years. At a median follow-up of 62.2 months, the 5-year PFS was 93.9% with V+I(HR 0.13 vs. FCR; HR 0.29 vs. ibrutinib), compared to 79.0% with ibrutinib monotherapy and 58.1% with FCR. PFS benefit with V+I was most marked in patients with iUGHV(HR 0.20 vs. Ibrutinib; HR 0.07 vs. FCR), while in mIGHV,PFS was similar to brutinib(HR 0.51) but superior to FCR

(HR 0.36). Undetectable MRD in bone marrow at 2 years was achieved in 66.2% of V+I patients, 0% with ibrutibin alone and 48.3% with FCR. The combination also improved overall survival, with 5-year OS of 95.9% for V+I(HR 0.26 vs. FCR;HR 0.41 vs. ibrutinib), compared to 90.5% with ibrutinib and 86.5% with FCR.17

Venetoclax-Acalabrutinib(V+A) and Venetoclax-Acalabrutinib-Obinutuzumab(V+A+O)

The efficacy of venetoclax-acalabrutinib(V+A) and vene-toclax-acalabrutinib-obinutuzumab(V+A+O) in compari-son to chemoimmunotherapy(FCR/BR) was assessed in a phase 3 AMPLIFY. At a median follow-up of 41 months, there was significant improvement in PFS with a HR 0.65 for V+A(p=0.0038) and 0.42 for V+A+O(p<0.0001) versus CIT. The median PFS for both these arms was not reached(estimated 3-year PFS was 76.5% and 83.1%, respectively), compared to 47.6 months for the CIT comparator(66.5% 3-year PFS). There was also a survival advantage for V+A over the control arm(HR 0.33,p<0.0001).23

Venetoclax-Obinutuzumab(V+O)

The regimen of 12-month venetoclax given with 6 months of obinutuzumab(V+O) has been studied in an older unfit cohort(CLL14) and a younger fit cohort(CLL13) of patients.

For patients previously deemed suitable for chlorambu-cil-obinutuzumab(CO)(i.e. unfit and/or with comorbidi-ties), CLL14 demonstrated significant improvement in PFS for V+O compared to CO. After 76months of follow-up,the HR of 0.4(95 CI 0.31-0.52) for PFS favoured the V+O

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combination. Six-year OS was 78.7% and 69.2% for the V+O and CO arms respectively[HR 0.69(95% CI 0.48-1.01)].The PFS benefit of V+O was maintained for both mIGHV and uIGHBV subgroups[uIGH: HR 0.3(95% CI 0.22-0.42),mIGHV: HR 2.66(95% CI 1.63-4.34)].24

CLL13 further demonstrated improved PFS with the V+O combination compared to chemoimmunotherapy(FCR for<65 and BR for>65 y). At a median follow-up of 50 months, both V+O(known as GV) and the triplet irbuti-nib-venetoclax-inbutemutumab(GIV) showed a PFS bene-fit compared to CIT, with HR 0.47(97.5% CI 0.32-0.69) for GV versus CIT and 0.3(97.5% CI 0.19-0.47) for GIV ver-sus CIT.16 Patients with uIGHV had significant PFS bene-fit with the novel agent combinations compared to CIT. In contrast, among the mIGHV subgroup, only GIV showed significant improvement in PFS compared to CIT HR 0.4(97.5% CI 0.17-0.92). One key finding of the CLL13 trial was the demonstration of obinutuzumab's superiority over rituximab when combined with venetoclax; HR for PFS of 0.57(97.5% CI 0.38-0.84) in favour of obinutuzumab. No overall survival difference between cohorts has been ob-served to date.16 Fixed-duration venetoclax regimens ap-pear to not lead to the emergence of mutations associated with venetoclax resistance(in BCL2, BIM, BAX, BCL2L1,MCL1). This has been specifically demonstrated in CLL1425 and in CAPTIVATE,26 including the absence of mutations in BTK and PLCG2, suggesting that limited time pressure on the CLL clones is insufficient to drive major clonal selec-tion, opening the possibility of retreatment with the same class of drug at relapse.

In summary, randomised controlled trials of V+I(fixed-duration and MRD-directed) have demonstrated superiority over CIT across all age groups. Similarly, V+O shows superior-ity over FCR/BR and CO. V+A(and in additional combination with obinutuzumab) has similarly shown efficacy over FCR/BR. Data from FLAIR support the efficacy of MRD-directed V+I over I alone,17 but there is otherwise no direct comparative data between these different combinations(especially com-pared to fixed duration regimens), and therefore, no specific recommendation in terms of treatment efficacy can be given between the current UK and globally approved regimens.Toxicity considerations are given below. While MRD-guided approaches utilising longer regimens of V+I appear promising,this approach remains investigational and unlicensed.

Continuous BTKi therapy

Three cBTKi(ibrutinib, acalabrutinib and zanubrutinib)are currently available for treatment-naive CLL, all of which have demonstrated superiority over CIT in large,randomised trials. Brlutinib and acalabrutinib are li-censed with anti-CD20 monoclonal therapy. Since the 2022 guideline, zanubrutinib has been licensed. These data and updated analyses for ibrutinib and acalabrutinib are discussed here.

Ibrutinib

Ibrutinib was the first-in-class BTKi licensed for treatment-naive CLL patients, given as continuous monotherapy or in combination with a monoclonal antibody. After 10 years follow-up, in the pivotal Phase III RESONATE-2 study, the brutinib arm displayed a superior median PFS of 8.9 years[HR 0.16(95% CI 0.12-0.22)] censored for crossover versus chlorabancium and a 9-year OS rate of 68% for brinitin.27 Two studies have investigated ibrutinib in combination with rituximab(IR), the ALLIANCE A04170719 and the UK FLAIR study,28 with the ALLIANCE study showing no addi-tional benefit in adding rituximab to ibrutinib. Both FLAIR and the E19122 study showed a PFS and OS benefit for ibru-tinib over FCR. In contrast, the ALLIANCE demonstrated no OS advantage for ibrutinib over BR. Despite these efficacy outcomes, concerns regarding the toxicity of long-term ibru-tinib have led to the preferential use of second-generation agents. As a result, ibrutinib is no longer recommended for first-line initiation, though patients already receiving it and tolerating it well may continue.

Acalabrutinib

Acalabrutinib is a second-generation BTKi, licensed with and without obutunuzumab for the treatment-naive CLL.The ELEVATE-TN trial evaluated acalabrutinib mono-therapy in comparison to the combination of obinutu-zumab-akalabrutinib(A+O) and to CO. Six-year PFS of acalabrutinib compared to CO was 62% vs. 17% [HR 0.24(95% CI 0.17-0.32)]. The A+O combination led to sig-nificant improvement in PFS versus acalbrutinib, with a HR of 0.58 (95% CI 0.39-0.86, 6-year PFS 78%), but at the expense of increased infections, neutropenia and the requirement for infusions.30 There was no difference in OS between the two acalbrutinib arms [HR 0.69 (95% CI 0.11-1.09)]. PFS at years was comparable for acalbruti-nib monotherapy and A+O according to IGHV mutation status and TP53 status, confirming observations previ-ously reported for ibrutinib.

Zanubrutinib

The pivotal SEQUOIA trial compared continuous zanubru-tinib with sixcycles of BR and established zanubrutinib as an available therapy. Patients with TP53 aberrations were excluded from the randomised trial and were enrolled in a separate single arm trial. Zanubrutinib showed better PFS compared to BR, with a HR 0.42(95% CI 0.28-0.63)31 and numerically 82% vs.50% at 42 months follow-up, regardless of IGHV status.18

In summary, both acalabrutinib and zanubrutinib mono-therapy are efficacious in patients with no TP53 disruption and are options for initial treatment in this setting and pre-ferred over ibrutinib. Both acalabrutinib and zanubrutinib are NICE/SMC recommended for use in treatment-naive CLL patients aged≥65 years and/or those with comorbidities(CIRSG score≥6). Despite extensive randomised data sup-porting ibrutinib-based treatment, it is not NICE/SMC rec-ommendation in this setting and is in addition less preferred

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2025 BSHM CLL GUIDELINE

due to concerns regarding toxicity. With no trials directly comparing any of the available, licensed cBTKis in the first-line setting no specific recommendation can be given between the choice of acalbrutinib versus zanubrutinib.Finally, despite the high efficacy of the A+O combination, it is not currently NICE/SMC recommended, and the regimen carries a higher risk of toxicities.

Patients with TP53 disruption

TP53 mutation and/or deletion in CLL has historically been associated with poor outcome due to a combination of chem-oresistance and genomic instability with an increased risk of Richter transformation.32 First-line treatment options for CLL patients with TP53 disruption include BTKi treatment and venetocl taxmonotherapy(the latter only where BTKi are con-traindicated). Idelalisib-rituximab can also be offered if both of the former classes of drug are unsuitable. Current evidence on fixed-duration V+O or V+I(discussed below) suggests that continuous therapy might be preferred, although studies com-paring retreat treatment with fixed-duration therapy versus contin-uous therapy are needed to establish this firmly.

Continuous therapy

The only randomised evidence demonstrating superiority of BTKi over CIT is the first-line therapy for TPS5 -disrupted CLL originates from the ELEVATE-TN trial, which included a sub-group of patients with TP53 disruption. Despite small numbers in each arm(23 for acalabrutinib and 25 for CO), 6-year PFS for patients with TP53 aberrations was 56% for acalabrutinib-56% for acalabrutinib-obinutuzumab(i.e. no benefit for addi-tion of obinutuzumab) and 18% for CO. For patients with TP53 disruption, outcomes with acalabrutinib were similar to those observed for the entire acalabrutinib cohort(6-year PFS 56%).30 Single-arm trials of ibrutinib and zanubrutinib(cohorts of 34 and 110 patients respectively) have shown a 6-year PFS of 61%for ibrutinib33 and a 79% PFS at 42 months for zanubrutinib.18

Data on venetoclax monotherapy in patients with treatment-naive, TP53 disrupted CLL are available mainly from retrospective studies(prospective studies are small34).The largest study(n=35)35 showed a 4-year PFS of 84%.Despite the low numbers and retrospective nature, venetoclax mono-therapy is effective in TP53 disrupted patients and is recom-mended by NICE/SMC for patients unable to tolerate BTKi.Data on idealisib-R include a phase 2 trial of treatment-naive patients(nine patients had TP53 aberration)36 and a phase 3 trial of relapsed CLL not suitable for chemoimmunotherapy(46 patients with TP53 aberrations were included.)

Fixed-duration venetoclax-based therapy

There are limited data supporting the use of V+I as initial therapy for CLL patients with TP53 disruption. Analysis of 29

patients with del(17p) or TP53 mutation in the CAPTIVATE trial of V+I in younger, fitter patients showed CR/CRi(com-plete remission/complete remission with incomplete count recovery) and bone marrow uMRD of 52% and 45%, respec-tively, at 36 months26 and 45% PFS at 54 months.38

Among 46 patients with TP53 mutation/deletion in-cluded in the CLL14 trial, V+O conferred a better outcome(median PFS and TTNT(time to next treatment) of 57.3 and 51.9months, respectively) than CO.24

Despite PFS being shorter than for continuous therapy with BTKi, V+O or V+I remains a valid choice depend-ing on patient factors. There are currently no data directly comparing V+O with V+I in patients with TP53 disruption.Venetoclax combined with zanubrutib has shown prelim-inary 24 months PFS of 92%.39

In summary, both continuous BTKi and venetoclax monotherapy are options for the treatment of TP53 dis-rupted patients(the latter only when BTKi are contraindi-cated). The fixed-duration regimes(V+O and V+I) are also licensed and funded in the United Kingdom for this group although, noting small sample size, efficacy appears lower than for continuous BTKi and is an important consideration when making treatment choice in partnership with the pa-tient(Tables 1 and 2). Of the continuous therapies, idealis-ib-R is rarely indicated due to excess toxicity over BTKi or venetoclax. As for patients without TP53 disruption, ibru-tinib is no longer recommended for first-line initiation al-though patients already on treatment and tolerating it well may continue.

CHOOSING THE OPTIMAL FIRST-LINE THERAPY

The large number of approved options for untreated CLL provides clinicians with the challenge of choosing from a range of highly effective regimens. Important factors to consider are risk factors relating to CLL biology, past medical history/co-morbidity, concomitant medication and patient choice(Figure 1, Table 1). Prior to initial ther-apy, all patients should be tested for TP53 disruption(by mutation analysis and FISH for del(17p)) and for IGHV mutation status to guide treatment choice and inform prognosis.

The patient should be invited to participate actively in the decision-making process, and their carer if the patient so wishes(NG197, Overview|Shared decision-making|Guidance|NICE). Data regarding each of these fea-tures are discussed below to inform the decision-making;a full discussion should include the results of any relevant investigations(e.g. genomic results), the availability of any appropriate clinical trials, the potential benefits and disad-vantages of each regimen with respect to efficacy and toxic-ity and the patient's personal preferences.

Finally, it is important to note that while randomised controlled trials have established the efficacy of each available regimen compared to CIT, there are very limited

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head-to-head comparisons between these treatment options.Differences in apparent efficacy across studies may reflect differences in trial design, patient population, treatment du-ration and follow-up and must therefore be interpreted with caution.

BIOLOGICAL FACTORS INTRINSIC TO CLL

The relevance of TP53 aberrations has been discussed al-ready. Among other biological prognostic factors, IGHV status remains the most important for CLL progression and outcome in the non-CIT era. 14,16,18,22,40-42 It is recom-mended that all CLL patients are tested for IGHV mutation status prior to initial therapy. Since IGHV mutational status is fixed at the point of malignant transformation and not altered by therapy,43,44 testing does not need to be repeated.Despite the underpowered subgroup analysis employed in most studies, unmutated IGHV is consistently associated with earlier disease progression after fixed-duration ther-apy but seems to have less impact in the setting of continu-ous therapy. In contrast, patients with mIGHV have long durable remissions with all therapies, being especially the case for those patients receiving the fixed-duration regi-mens of V+O and V+I. Therefore, although there are no prospective studies demonstrating improved outcome for patients with uIGHV who receive continuous therapy, it is nevertheless reasonable to take IGHV status into account when choosing treatment, particularly if other considera-tions are finely balanced(Table 1).‘Bulky disease’, that is,lymph nodes>5cm have been shown to be an independ-ent negative prognostic factor for treatment with V+O,45 whereas similar PFS, OS and undetectable MRD rates are achieved in patients with bulky disease treated with V+I.21 Other biological determinants of outcome following CIT(del(11q),trisomy 12 and del(13q) have little or no prognos-tic value in the context of BTKi and BCL2i) therapy and are not required.

TOXICITY

Regarding the safety of venetoclax-containing fixed-duration regimens, the most important toxicities are neu-tropenia, diarrhoea and tumour lysis syndrome(TLS).Neutropenia/febrile neutropenia associated with the V+O regimen were 51.9%/4.2% in CLL14 and 61%/7.8% in CLL13.16 For patients receiving V+1, grade≥3 neutropenia/febrile neutropenia occurred in 34.9%/1.9% in the GLOW study and 33%/0.6% in CAPTIVATE. In clinical practice,weekly GCSF is commonly used to manage neutropenia.However, it should be noted that there is no prospective evi-dence that this approach prevents infections in the context of these combinations.

Diarrhoea of any grade/grade≥3 diarrhoea associated with V+O were 27.8%/1.8% in CLL14 and 32.9%/1.8% in

CL13. For V+I, the corresponding figures were 50.9%/10.4%in GLOW and 62%/3% in CAPTIVATE.22,42

Risk of TLS can be mitigated by delaying the start of venetoclut until after a full cycle of obinutuzumab(V+O)or 3 months of ibrinib (V+I). The incidence of TLS was 11% in CLL1 (1.7% clinical TLS) and 1.4% biochemical TLS(no clinical TLS) in CLL14. No cases of TLS were reported in GLOW or CAPTIVATE. Please refer to the Summary of Product Characteristics and BSH guideline on TLS on how to avoid and manage TLS risk(https://onlinelibrary.wiley.com/doi/10.1111/bjh.70092).

V+I was well tolerated in CAPTIVATE and FLAIR, which enrolled younger, fitter patients. The incidence of key ad-verse events such as grade 3 neutropenia and sudden death(n=4) was higher in GLOW, which enrolled older, less fit patients. In GLOW, grade 3 and 4 adverse events associated with V+I and CO were neutropenia(34.9% vs. 49.5%), infec-tions(17% vs. 11.4%) and diarrhoea(10.4% vs. 1%). 22.6% of participants discontinued V+I due to toxicity.20 The higher early treatment-related mortality in the V+I arm of GLOW compared with the control arm highlights the need for cau-tion when using the regimen in older, less fit patients and the importance of considering cardiovascular comorbidities that are relevant to ibrutinib.16,20,42

Finally, the most common reported adverse event re-ported in the AMPIFY trial assessing A+V, A+V with obinutuzumab(A+V+O) and the CIT comparator was neu-tropenia 26.8%(A+V), 35.2%(A+V+O), 32.4%(CIT) infec-tions(all grades/grade>3) A+V 51%/12%, A+V+O 54%/24%,CIT 32%/10%. Atrial fibrillation was infrequent: A+V: 0.7%,A+V+O: 0.8% and CIT: 0.8%; hypertension rates(grade 3)were A+V: 2.7%, A+V+O: 2.1% and CIT: 0.8%.23

The safety profile of BTKi is well described. Non-haematological toxicities include diarrhoea, fatigue, upper respiratory tract infection, atrial fibrillation and hyper-tension. A meta-analysis of 15 large clinical trials showed a pooled rate of grade≥3 diarrhoea of 1%(95% CI, 1-2%),grade≥3 upper respiratory tract infection 1%(95% CI,0-2%),grade≥3 atrial fibrillation 1%(95% CI, 1-2%) and hypertension 4%(95% CI, 2-7%). Neutropenia was the most reported haematological adverse event, with a pooled rate of grade≥3 neutropenia of 17%(95% CI, 13-22%).46

A lower incidence of atrial fibrillation/flutter(9.4% vs.16%; p=0.02), hypertension(9.4% vs. 23.2%) and bleeding events(38% vs. 51.3%) for acalabrutinb compared to ibru-tinib, with discontinuation due to toxicity of 14.7% and 21.3%, was observed in a trial comparing second-generation BTKi with ibrutinib ELEVATE R/R. ${ }^{47}$ In the ALPINE trial,zanubrutinb was associated with less atrial fibrillation/flutter(5.2% vs. 13.3%) but not hypertension(24% vs. 23%)compared to ibrutinib, with discontinuation due to toxicity in 14.5% vs. 22.2%. ${ }^{48}$ Interestingly, the incidence of hyper-tension associated with zanubrutinib in the ASPEN trial of Waldenstrm macroglobulinaemia was lower both in abso-lute frequency and relative to ibrutinib(15% vs. 26%).

Sudden death/ventricular arrhythmia (VA) has been documented in patients receiving both first- and

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second-generation cBTKi with VA estimated to occur in 0.6-0.8 per 100 person-years for brinuxib, 490153(0.044 non-fatal excluding PVCs+0.109 fatal) per 100 patient-years of exposure for acalabrutinib50 and 0.24 per 100 patient-years of exposure for zanubrutinib.51 The low frequency of these events makes it impossible to determine relative risk between the drugs. We recommend that all patients receiving BTKi should be advised about the risk of sudden death.

Identifying and addressing side effects of BTKi is import-ant throughout treatment, and it is important to be aware of a cumulative increase in the incidence of serious effects such as hypertension, atrial fibrillation and serious infection risk. Clinical trial data have reported a 41% discontinuation rate at 5 years for brinuxinib27 which has been confirmed by‘real-world’ data(discontinuation in 42% at 17 months).52 Discontinuation rates for acalabrutinib are 25% for A+O and 30% for monotherapy.30 Long-term data from RESONATE and RESONATE-2 have demonstrated an ongoing incidence of new adverse events after 5 years of therapy with brinuxin,another factor to consider when counselling patients on treat-ment options and planning follow-up.27,53

No trials have directly compared available, licensed BTKis in the first-line setting but as above, comparisons have been made in patients with relapsed or refractory CLL through the ELEVATE RR (acalabrutinib vs. bributinib) and ALPINE(zanubrutinib vs. bributinib). These studies demon-strated that acalabrutinib and zanubrutinib are associated with less cardiovascular toxicity, and lower overall bleeding risk, but similar frequency of major bleeding events48,54 and it is reasonable to assume that these observations hold true irrespective of the number of lines of prior therapy.

OTHER MEDICAL CONDITIONS

Selection of CLL therapy should consider other medical conditions and their treatment. Pre-existing cardiovas-cular disease and ongoing need for anti-coagulation are important considerations that may influence the choice between BTKi and BCL2i and, if opting for a BTKi, the selection of one drug over another.55 To help with decision-making and optimise patient safety, a thorough evaluation of cardiovascular and bleeding risk at the time of treat-ment initiation is required, together with ongoing control of modifiable cardiovascular risks throughout treatment.The 2022 ESC Guidelines and App can help to quantify risk in this difficult area.

Since the cumulative risk of infection increases with drug exposure time, ${}^{57}$ with reported annual grade 3+ infection rates of~7% on long-term BTKi therapy ${}^{48}$ fixed-duration regimens that do not include anti-CD20 antibodies may be more attractive for patients having comorbidities that fur-ther predispose to infection, such as autoimmune disease,chronic obstructive pulmonary disease or chronic kidney disease, in order to limit the period of additional immuno-suppression from CLL therapy. Renal impairment increases the risk of TLS with BCL2i. BTKi are more permissive, with

reports of safe use in patients with CrCl<30mL/min.58 BTKi may, therefore, be a preferred option in patients with chronic renal impairment, especially if other risk factors for TLS are present, such as high tumour burden.

CONCOMITANT MEDICATION

Current medication should be carefully reviewed, with par-ticular attention to strong CYP3A inducers, or inhibitors,which should be stopped or replaced by other medication.Careful adjustment of dose for all targeted inhibitors is re-quired if they are taken concomitantly with moderate CYP3A and P-gp inhibitors. The reader is referred to a specific Summary of Product Characteristics(SmPC) and for guid-ance on the management of anti-coagulation/anti-platelet therapy, to the BSH good practice paper on‘Management of Cardiovascular Complications of Bruton Tyrosine Kinase Inhibitors'.55 It should be noted that any BTKi combined with anti-coagulation carries a risk of severe bleeding that exceeds that of BTKi and anti-coagulants individually.59 Patients should be counselled, and the risks and benefits of the combination carefully evaluated.

PRACTICAL CONSIDERATIONS

Delivery of fixed-duration regimes requires weekly dose escala-tion of venetoclax and close monitoring for TLS. This requires adequate infrastructure, staff and capacity on the haematol-ogy day unit and inpatient ward. Venetoclax dose escalation can also present logistical challenges for patients. These factors should be considered when making treatment decisions.

POTENTIAL BENEFITS OF A TREATMENT-FREE INTERVAL

Compared to continuous BTKi therapy, fixed-duration regimens are associated with a lower cumulative risk of de-veloping drug resistance25,26,60-61 potentially allowing the redeployment of the same drug(or class of drug) at disease progression. Fixed-duration treatment is also associated with a lower cumulative risk of the adverse events associated with BTKi, such as arrhythmias, hypertension, bleeding and infection.30,47

PATIENT CHOICE

The need to involve patients and their carers in shared decision-making on treatment cannot be over-emphasised. While this principle is universally applicable, it is especially important when objective considerations are finely balanced. In addition to ensuring that patients understand the full range of medical and practical considerations that feed into treatment choice,patient preference should be actively sought and respected.

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Only therapies meeting defined licensing or evidence-based criteria are included in the following formal Recommendations sections. Other approaches may be dis-sion criteria are outlined in the Methodology section.

TREATMENT OF CLL INVOLVING CENTRAL NERVOUS SYSTEM

CLL presentation in the central nervous system (CNS) is rare.When it occurs, it is not infrequently in the context of Richter syndrome, which should be excluded. There are no clinical studies investigating the best approach (CNS involvement is an exclusion to all recently published CLL trials), and there is no established standard of care. Therefore, treatment decisions should be individualised based on clinician judgement, and no overall recommendation can be made. A retrospective cohort of 30 patients treated with chemoinmotheruapy suggested that prognosis is related to biological characteristics of CLL rather than CNS localisation.63 The first-generation BTKi,ibrutin,has been shown to cross the blood-brain barrier and has been used successfully in CNS-involved CLL.64 Second-generation BTKi also cross the blood-brain barrier; zanubrutinib plasma and cerebrospinal fluid were analysed in 13 patients with diffuse large B-cell lymphoma, and in 22 of 23 samples, peak concen-trations were above IC50.65 In a retrospective multicentre study of 24 patients with Bing-Neel syndrome, 17 (81%) experienced clinical improvement. There are case reports of mantle cell lymphoma involving CNS to support the use of acalabrutib.67 Venetocl pharmacokinetics have been studied in paediat-ric patients. ${ }^{68}$ It binds preferentially to proteins, with less than 1% of free unbound drug. Some evidence suggests that veneto-clax may penetrate the blood-brain barrier. Rada et al. reported a venetoclax concentration close to the IC50 in CSF in a CLL patient on 400mg.69 Soumerai et al. describe a case who went into second remission after adding venetoclax 4 years later.70

Venetoclax pharmacokinetics have been studied in paediat-ric patients. ${}^{68}$ It binds preferentially to proteins, with less than 1% of free unbound drug. Some evidence suggests that veneto-clax may penetrate the blood-brain barrier. Rada et al. reported a venetoclax concentration close to the IC50 in CSF in a CLL patient on 400mg. ${}^{69}$ Soumerai et al. describe a case who went into second remission after adding venetoclax 4 years later.

Recommendations for Treatment-Naïve CLL

All Patients

● All patients should be tested for del(17p) and TP53 mu-tation to clarify treatment options and inform on re-sponse duration(GRADE 1A).

● All patients should be tested for IGHV mutation sta-tus to inform on response duration and use of fixed-duration therapy(GRADE 1B).

● Further assessment is recommended if uncertainty re-garding comorbidities that are relevant to BTKi(e.g.car-diovascular) or BCL2i(e.g. renal)(GRADE 2B).

● A shared decision-making approach should be adopted,where both fixed-duration and continuous treatment options should be discussed, taking into consideration disease characteristics, patient preference, safety profiles,co-morbidities, concurrent medication and the potential benefit of a treatment-free interval(GRADE 1D).

•All patients should be considered for a clinical trial if one is available(GRADE 1A).

● Patients with CNS presentation can be treated with tar-geted therapy,including BTKi or BCL2i,but no consen-sus exists on optimal duration(GRADE 2D).

First line treatment for patients without TP53 disruption

● Licensed and approved options are listed below.Where MHRA (Medicines and Healthcare products Regulatory Agency) approval exists, this is shown together with the National Institute for Health and Care Excellence (NICE) Technology Appraisal and Scottish Medicines Consortium (SMC) approval to indicate UK reimbursement; United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals are also shown where applicable.

- Fixed-duration venetoclax-obinutuzumab(V+O),(MHRA[NICE TA663/SMC C2293], FDA, EMA)

- Fixed-duration venetoclax-ibrutinib(V+I),(MHRA[NICE TA891/SMC2543], EMA)

- Continuous acalbrutinib (MHRA [NICE TA689],FDA,EMA)

- Continuous zanubrutinib (MHRA [NICE TA931/SMC2600], FDA, EMA)

- All have GRADE 1B evidence over their comparator CIT regimens.

● No single overall recommendation can be made between these regimens.

● If a fixed-duration regimen is chosen, no specific recom-mendation can be given between V+O or V+I. However,the use of V+I in older patients with comorbidities should be carefully weighed against the potential risk of cardio-vascular complications; patients with mIGHV respond particularly well to V+O(GRADE 1A).

● Fixed-duration venetoclax-acalabrutinib with or with-out obinutuzumab(V+A+/-O, EMA/MHRA) is an ad-ditional fixed-duration regimen(GRADE 1A). Limited follow-up duration means long-term efficacy, durability of response and MRD kinetics remain uncertain.

● If a continuous treatment regimen is chosen, no specific recommendation can be given between acalbrutinib or zanubrutinib(GRADE 2D).

● Acalabrutinib-obutinutuzumab(A+O,MHRA[no NICE TA/SMC], FDA, IEMA) is a first-line treatment option for all patients without TP53 disruption and has higher efficacy but increased toxicity compared to acalabruti-nib monotherapy(GRADE 1B).

●V+I with duration guided by serial MRD measurement appears highly effective with an acceptable toxicity pro-file but is currently unlicensed (GRADE 1B).

First line treatment for patients with TP53 disruption

● Licensed and NICE TA-recommended options are continuous acalbrutinib(MHRA [NICE TA689/

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SMC2347], FDA, EMA), zanubrutinib(MHACE TA931/SMC2600], FDA, EMA), ibrutinib(MHRA[NICE TA429/1151/16], FDA, EMA), idealalisib-rit-uximab(MHRA[NICE TA359/1026/15], FDA,EMA) and venetoclax monotherapy(MHRA[NICE TA796/1249/17], FDA, EMA),(for those with a contra-indication to a B-cell receptor inhibitor) and fixed-duration V+O(MHRA[NICE TA663/SMC2293], FDA,EMA) and V+I(MHRA[NICE TA891/SMC2543], EMA)(GRADE 1B).

● Continuous cBTKi regimens may be preferred over fixed-duration regimens due to the longer responses ob-served in this setting(GRADE 2A).

● Among continuous treatment options, second-generation cBTKi(acalabrutinib or zanubrutinib) are preferred to britisunib due to their improved safety pro-file(GRADE 1A).

● Irbutinib is not recommended for new treatment initia-tion but may be continued in patients already receiving it and tolerating it well. Idiselis-rituximab is least preferred due to higher toxicity(GRADE 2A).

● Venetoclax monotherapy remains an option for patients for whom a BTKi or idelisab-rituximab is contraindi-cated(GRADE 2B).

● Acalabrutinib-obinutuzumab(A+O, MHRA[no NICE TA/SMC], FDA, EMA) is a first-line option for patients with TP53 disruption(GRADE 1B). However,subgroup analysis from ELEVATE-TN showed no PFS advantage over aclabrutinib monotherapy in this population, and the combination carries a higher tox-icity burden.

RELAPSED/REFRACTORY CLL

Licensed therapies for relapsed CLL are BTKi(ibrutinib,calastrubinib, zanubrutinib), BCL2i(venetoclax mono-therapy or in combination with rituximab) and phos-phoinositide 3-kinase inhibitors(PI3Ki)(idelisib and rituximab).37,53,71-73 The key outcome data are presented for these regimens, with additional considerations as to why one regimen may be preferred over another presented in the section‘choosing second-line therapy and beyond’.In all studies listed below, patients had been treated with chemoimmunotherapy in first line. Therefore, the PFS may not reflect what is being observed post-first-line tar-geted therapies.

At disease progression, repeat testing for TP53 disruption(mutation and/or deletion) is recommended to guide treat-ment selection. Additional evaluation, such as karyotype,FISH or genomic sequencing, may provide useful informa-tion in selected cases(e.g. where atypical disease progression is observed or when considering novel therapies). In patients progressing on covalent BTKi, testing for BTK and PLCG2 mutations may provide useful information on resistance mechanisms and help guide sequencing of further therapy.The role of routine mutation testing after other regimens re-mains less well defined.

Ibrutinib

Ibrutinib showed superior efficacy in R/R CLL compared to single-agent ofatumubin in RESONATE, with an overall re-sponse rate(ORR) of 91% and a CR of 11% after 6 years of follow-up. The median duration of therapy was 41 months,with 22% still on ibrutinib at study closure. The median PFS for brutinib was 44.1 months vs.8.1 months respectively.

Acalabrutinib

Acalrabutinib was non-inferior to ibrutinib in the large, ran-domised phase 3 ELEVATE-RR trial of patients with high-risk features47 with a median PFS of 38.4 months on both arms after median follow-up of 40.9 months. As previously noted, atrial fibrillation or flutter, hypertension, diarrhoea,arthralgia and bleeding events of any grade were less fre-quent in the acalabrutinib group.

Zanubrutinib

In the phase 3 ALPINE trial, over 600 patients with previ-ously treated CLL/small lymphocytic lymphoma(SLL) were randomised to receive continuous therapy with zanubru-tinib or brutinib. Patients with previous BTKi exposure were excluded. PFS at 3 years was superior for zanubrutinib(65.4% vs.54.4%(HR 0.68, CI(0.54-0.84))) with a benefit for zanubrutinib in patients with TP53 disruption(HR 0.51, CI(0.33-0.78)). Fewer cardiac events including arrhythmias were observed in the zanubrutinib group, but hypertension,bleeding, infection and neutropenia were similar. A recently published phase 2 trial suggests that zanubrutinib is safe and effective in patients who have stopped either brutinib(n=57) or acalabrutinib(n=10) due to intolerance.

Venetoclax-rituximab

After 7-year follow-up of the MURANO study in which pa-tients with relapsed CLL were randomised between veneto-clax-rituximab(Ven-R) and bendamustine-rituximab(BR),median PFS in patients treated with Ven-R was 54.7 months versus 17 months.75 only 1.5% of patients received a prior BTKi.High-risk genetic features had an adverse impact on outcome(28.7% vs.72.7% 5-year PFS for unmutated vs. mutated IGHV;27.3% vs.42.5% 5-year PFS for disrupted vs. wild-type TP53),but all subgroups had superior PFS with Ven-R compared to the chemoimmunotherapy comparator.33 Undetectable MRD(<10-4) at the end of treatment predicted improved PFS and OS compared to patients with high levels of MRD(≥10-2).

Venetoclax monotherapy

Venetoclax monotherapy has been evaluated in a pooled analysis of Phase 1 and 2 studies,76 as well as in a Phase

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3B trial." The treatment has shown efficacy in both BTK inhibitor-naive and BTK inhibitor-pretreated patients.With a median follow-up of 49 months, CR or CR with in-complete marrow recovery was observed in 35% (95%):27.8%-41.8%) of patients who were BTK inhibitor-naive,and in 27% (95% CI: 16.8%-39.1%) of patients who were BTK inhibitor-pretreated.

Idelalisib-rituximab

Idelalisib-rituximab remains a licensed and funded treat-ment option for R/R CLL which in a randomised study ver-sus placebo-rituximab showed ORR 81% with median PFS 19.4months.37,78 Patients had all received prior chemomim-monotherapy with a median of three prior lines of treat-ment, but none had previously received a BTKi.Toxicities of idelalisib include colitis, pneumonitis and cytomegalovirus(CMV) reactivation which was observed in 1.8% of the study patients; CMV polymerase chain reaction(PCR) monitoring is required.

Pirtobrutinib

Pirtobrutinib is a highly selective, noncovalent BTKi(ncBTKi) with high activity in patients with the c481s BTK mutation which confers resistance to cBTKi. It has been granted FDA approval for use in R/R CLL after at least two prior lines of therapy including prior cBTKi and BCL2i.More recently,EMA/MHRA approval has been given for use in any relapsed refractory patients who have been previously treated with a cBTK inhibitor, following the results of the pivotal BRUIN321 phase 3 study showing significant efficacy in heavily pretreated patients.79 One hundred and nineteen patients achieved a median PFS of 15.3 months, with a post hoc analysis showing a median time to next treatment of 29.5months for patients who were venetoclax-naive versus 20months for venetoclax-treated patients. These findings build on the earlier phase 1/2 BRUIN study, where 247 pa-tients treated with a prior cBTKi achieved an ORR of 82.2%with pirtobrutinib; median PFS was better for venetoclax-naive patients(20.3 months vs. 15.9 months)80; in contrast to BRUIN321, response rates were similarly high in patients who had also received a BCL2i and those who had not.81

CHOOSING SECOND-LINE THERAPY AND BEYOND

Choice of treatment for relapsed or refractory disease de-pends on prior therapy (fixed-duration or continuous and agents used), response duration and (where applicable) time off from therapy, as well as the patient-related and biological disease factors that apply to choosing first-line treatment. A distinction must be made between those patients with CLL who progress due to intolerance of therapy (and who have

therefore discontinued), in which case an alternative drug from the same class could be chosen, compared to those who progress while off therapy. Therapy for first relapse will gen-erally be a choice between a continuous second-generation cBTKi(acalabrutinib or zanubrutinib) regimen or the 24-month venetoclax-rituximab regimen. In addition, there will remain a group of patients who have received chemoim-munotherapy as first-line treatment; for these patients, the same principles of choice of therapy will overall apply(See Figure 2 and Table 2).

RETREATMENT AFTER PROGRESSIVE DISEASE

Data are available to support the effectiveness of retreatment with targeted agents even when previously used.

CAPTIVATE analysed for mutations in BTK and PLCG2(known to confer resistance to cBTKi) and in BCL2 (known to confer resistance to venetoclax) in 40 patients whose CLL had progressed after first-line V+I.38 No mutations in BTK or PLCG2 were detected, and only one mutation of unknown significance was detected in BCL2. Twenty-eight patients received retreatment with ibrutinib monotherapy or V+I, achieving an overall response rate of 86% and 83%,respectively.

In the MURANO trial, patients with progressive disease were followed up for response to next-line therapy. Twenty-five patients who had received V+R were retreated with the same regimen and had an ORR of 72.0%(CR 24%) and a me-dian PFS(95% CI) of 23.3 months (15.6-24.3). Responding patients included those with unmutated and mutated IGHV.75 An international retrospective study of retreatment with venetoclax-based therapy in high-risk R/R CLL patients demonstrated similar results(ORR of 79.5%, CR of 33%, me-dian PFS of 25 months). ${}^{82}$

These studies suggest that fixed-duration BCL2i-based or cBTKi-BCL2i therapy does not preclude retreatment at relapse. The role of mutation testing for cBTKi and BCL2i remains incompletely defined but may provide value in se-lecting therapy in the future.

The phase 3b VENICE-1 trial investigated venetoclax monotherapy in R/R CLL, CR/CRi was 35% in patients who were BTKi naive and 27% in patients who were previously exposed to BTKi.77

The optimal sequencing of targeted agents in patients with R/R CLL remains a challenging area, and treatment decisions should be guided by patient preference, prior ex-posure and toxicity profile of available agents.

Recommendations for relapsed or refractory CLL

•At disease progression, repeat evaluation of TP53 dis-ruption is recommended to inform treatment selection(GRADE 1A).

• Covalent BTKi or venetoclax alone (MHRA [NICE TA796/1249/17], FDA, EMA) or in combination with

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|||||||||||||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |Pirrobutrinitin||||||||||||||| |See legend|See legend|++|++|+/-|+/-|+/-|+ -|+|+|+|+|+|-|| |See legend|++|++|++|+ (if1br)/cal inoligerant)|++|++|+/-|+ -|-|+|+|-|+|| |Zanubutrinitin|++|++|++|+ (if1br)/cal inoligerant)|++|+/-|+/-|+ -|+|+|+|+|-|| |Zanubutrinitin|++|++|+ +|+/-|+/-|+/-|+ -|+|+|+|+|+|-|| |++|++|+/-|+ +|+/-|+/-|+/-|+|+|+|+|+|+|+|| |++-|++|+/-|+ -|+/-|+/-|+/-|+|+|+|+|+|+|+|| |++-|+/-|+/-|+/-|+/-|+/-|+/-|+|+|+|+|+|+|+|| |Endirection|on cTBI|||||||||||||| |TP53 mutation/tp deletion|Progression|0||||||||||||| |Infection risk during treatment||||||||||||||| |Cardiac disease (risk of||||||||||||||| |Hyperension||||||||||||||| |Boed||||||||||||||| |Realution||||||||||||||| |Realysis|||0|+/-|+|+/-|+|+|+|+|+|+|+|+| |Realactic disease (risk of||||||||||||||| |Realural dislocation||||||||||||||| |Realution||||||||||||||| |Realust||||||||||||||| |Realust||||||||||||||| |Discontinuum or obliability||||||||||||||| |Discontinuum treatment||||||||||||||| |Discontinuum or obliability to octific visits||||||||||||||| |Disothant tissue||||||||||||||| |Topelaction||||||||||||||| |Topelaction distribution||||||||||||||| |Topelaction distribution||||||||||||||| |Topelaction distribution||||||||||||||| |Topelaction distribution||||||||||||||| |Topelaction distribution||||||||||||||| |Topelaction distribution||||||||||||||| |Topelaction distribution||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top||||||||||||||| |Top|||||||||||||||

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Second and Subsequent lines

 $$\text{1.Post fixed duration Venetoclax therapy}$$

FIGURE 2 Second and subsequent lines.

rituximab(MHRA [NICE TA561/SMC2166], FDA,EMA) are the treatments of choice for relapsed CLL and should be offered ahead of idelalisib-rituximab(MHRA[NICE TA359/1026/15], FDA, EMA). Acalabrutinib(MHRA [NICE TA689/SMC2348], FDA, EMA) and zanubrutinib(MHRA [NICE TA931/SMC2600], FDA,EMA) are preferred over Ibrutinib(MHRA [NICE TA429/1151/16]) due to improved safety profiles(GRADE 1A).

•Patients whose CLL progresses on a covalent BTKi should be offered either a venetoclax-based regimen, ir-respective of TP53 status(GRADE 1B) or Pirtobrutinib(Grade 1B, EMA, MHRA approved). The optimal se-quencing of BTKi, BCL2i and pirtobrutinib remains under investigation.

•Patients whose CLL progresses after a fixed-duration venetoclax-containing regimen should be offered either a covalent BTKi(GRADE III) or a venetoclax-based reg-imen depending on prior response, tolerance and pa-tient preference(GRADE 1B).

•Patients with a history of ibrutinib intolerance should be offered venetoclax-based therapy, acalabrutinib or zanubrutinib depending on the nature of the intolerer(GRADE 1B).

● Idelalis-rituximab remains an option for patients who are refractory to BTKi- and BCL2i-based treat-ment, or for whom these treatments are unsuitable(GRADE 2B).

● To prevent disease acceleration, patients whose CLL is progressing on continuous therapy should not stop treatment until the next line of therapy is started(GRADE 1C).

•All patients should be considered for clinical trials if one is available(GRADE 1A).

ROLE OF ALLOGENEIC TRANSPLANT AND CAR-T

Allogeneic transplantation remains an option for select patients with high-risk features including multiple treat-ment failures especially in the context of TP53 disruption.However, the consideration of transplantation has become increasingly complex and individualised. The role of trans-plantation needs to be considered in the context that CIT is no longer recommended for any patient and that alternative therapies are continually emerging.

Chimeric antigen receptor T-cell(CAR-T) therapy is an area of ongoing investigation, with regulatory approval by the FDA for patients who have failed both BTKi and BCL2i therapies. ${}^{83}$ However, the optimal sequencing of CAR-T rel-ative to other new agents, such as non-covalent BTKi and emerging approaches such as BTK degraders and bispecific antibodies, remains uncertain. For patients with Richter's transformation, CAR-T is available for standard indications for diffuse large B-cell lymphoma.

What constitutes treatment failure continues to remain unclear. Given the complexity, close liaison with a transplant centre with expertise in CLL is necessary when considering patients who are deemed suitable for transplantation in light of remission status, patient age, performance status, comor-bidity, patient preference, donor status and availability of al-ternative treatments. These factors are equally relevant when considering CAR-T.

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Recommendations

● Consideration for allogeneic transplantation and cellu-lar therapy should be made in close conjunction with a transplant centre experienced in CLL.

● Allogeneic stem cell transplantation remains an option for suitably fit young patients with high-risk CLL; refer-ral should be made early, before all lines of treatment are exhausted(GRADE 2B).

● CAR-T remains investigational, and while it may be considered in select cases, its optimal sequencing rela-tive to other licensed and emerging therapies remains uncertain(GRADE 2C, FDA, No MHRA licence or reimbursement).

TREATMENT OF AUTOIMMUNE COMPLICATIONS OF CLL

Autoimmune haemolytic anaemia(AIHA) and, to a lesser extent, immune thrombocytopenia(ITP), are relatively frequent in CLL(5%-7%). Autoimmune cytopenias(AIC)can be classified as‘simple’ when they occur in the con-text of otherwise stable CLL, or‘complex’ when there is concomitant CLL progression.84 90% of autoimmune dis-orders in CLL are caused by non-malignant B lymphocytes that produce polyclonal high-affinity IgG which opsonises red blood cells and/or platelets leading to their destruc-tion via antibody-dependent cellular cytotoxicity. In gen-eral, CLL patients with simple AIC should be managed in the same way as patients with primary AIHA or ITP in accordance with current guidelines.85-87 Most patients with AIC, specifically those with warm auto-antibodies,respond to high-dose corticosteroids. For patients not re-sponding to corticosteroids, rituximab monotherapy and/or thrombopoietin agonists in the case of ITP(e.g. romi-plostim, elstrombopil, avatrombopag) are recommended second-line options. Patients with cold AIHA respond poorly to steroids, so the first-line choice is rituximab in transfusion-dependent cases who fail thermal protection measures. For refractory cases, complement inhibition with sutlimibab(anti-C1S monoclonal antibody) is an effective option.88,89 AIC poorly responsive to corticos-teroids and rituximab remain as an indication for CLL treatment.1 Currently, there are limited data regarding the use of targeted therapies for patients with complex autoimmune cytopenias and CLL progression. However,there have been a few reports of B-cell receptor signal-ling inhibitors, principally irrebutinib, demonstrating effec-tive control of the cytopenias and disease in this context,which may reflect the long-term suppression of poly-clonal IgG production.90,91 Combinations of venetoclax with anti-CD20 antibodies would also be expected to be effective due to the deeper remissions and impact on hu-moral immunity. In a retrospective study of 815 patients treated with targeted therapy(including 572 ibrutinib, 100

venetoclax), 104 had pre-existing AIC and this improved in 80% of patients. Treatment emergent AIC rates were low following ibrutin(1%) but higher post-venetoclax(7%); however, the majority of these were given venetoclax monotherapy.92 Therefore, treatment with either BTKi monotherapy, BTKi/BCL2i combinations or BCL2/anti-CD20 antibody combinations are recommended options.Consideration should be given to enrolling patients in a clinical trial if available.

Recommendations

● CLL patients with simple AIC should be managed in the same way as patients with primary AIHA or ITP(GRADE 1D).

● AIC poorly responsive to corticosteroids& rituximab remain as an indication for CLL treatment(GRADE 1D).

● Treatment with BTKi monotherapy, BTKi/BCL2i com-binations or BCL2/anti-CD20 antibody combinations are recommended options a recommended option(GRADE 2B).

VACCINATIONS

All patients should have their total serum immunoglobul-in levels checked at diagnosis and repeated with the onset of frequent infections to ascertain if hypogammagiobuln-naemia is present. The updated vaccination booklet for patients at diagnosis, is available in supplementary docu-ments. Currently, vaccination against pneumococcus is recommended at diagnosis with Prevenar(PCV) 13 or 15,followed 2 months later by Pneumovax23. However, sin-gle dose PCV20 is anticipated to replace both of these vac-cines by early 2026. https://assets.publishing.service.gov.uk/media/684b1fbc1c8d5c94e201abae/Green_Book_Chapter_25_pneumococcal_12_6_25.pdf.93,94 Where Pneumovax23 has already been given, wait at least 1 year before administering PCV13,15 or 20(Administering Pneumococcal Vaccine: For Providers|CDC). Where the his-tory and records are unclear, a pragmatic approach should be taken and vaccination given as per newly diagnosed patients.In patients with a history of frequent or serious infection,checking functional antibody responses 6 weeks following vaccination with pneumovax23(polysaccharide vaccine)can be helpful and can facilitate access to immunoglobu-lin replacement therapy if required(https://igd.mdsas.com/wp-content/uploads/ccp-for-the-use-of-therapeutic-immun oglobulin-england-2025.pdf).

For patients aged 18 and over, two doses of Shingrix(re-combinant varicella zoster vaccine), a minimum of 8 weeks apart is also recommended Shingles Green Book chap-ter 28a.95 Annual influenza vaccination should continue to be recommended, and COVID-19 vaccination, according to the Department of Health guidance, to all patients and adult

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household members. The RSV vaccine is also advisable for those aged 75-79 years of age Respiratory syncytial virus(RSV) vaccination programme-GOV.UK.96

The IMPROVE study reported no evidence that pausing BTKi therapy around the time of vaccination improves vac-cine responses. Patients due to start therapy should ensure vaccination history is optimised where possible, prior to commencing therapy.97

ANTIMICROBIALS

The use of antimicrobials should be individualised. Disease status, treatment history, co-morbidities and infection his-tory are important factors to be taken into account. No data exists to support the routine use of antimicrobial prophy-laxis in the era of targeted therapies, but it should be con-sidered in anyone with a history of serious or recurrent infections and in the relapsed/refractory setting where im-mune suppression may be more pronounced. For those re-quiring prophylaxis, local microbiology advice should be consulted over the choice of antibiotic. For those with re-current lower respiratory tract infections, a CT chest will help to identify the presence of bronchiectasis which can be associated with hypogammaglobulinaemia and a CLL diag-nosis.°8 For those with a history of VZV/HSV1 reactivation,acyclovir prophylaxis may be used. Patients should always be screened for hepatitis B, C and HIV before starting therapy.For those with evidence of prior hepatitis B infection, anti-viral prophylaxis is recommended to prevent reactivation.99 Always take into account potential drug interactions be-tween specific antibiotics and BTKi as well as BCL2i.00 For those continuing to get infections following a 6-month trial of antibiotics, immunoglobulin replacement therapy should be considered(https://igd.mdsas.com/wp-content/uploads/ccp-for-the-use-of-therapeutic-immunoglobulin-england-2025.pdf).

Recommendations

● Prevenar followed 2 months later by Pneumovax23, or a single dose PCV20.

● Two-dose Shingrix course at diagnosis(1A).

● Influenza and COVID-19 as per DOH campaigns(1).

● Respiratory syncytial virus(RSV) is currently available for those aged 75-79(DOH guidance)(1A).

AUTHOR CONTRIBUTIONS

All authors contributed to the writing of the guideline.

AFFILIATIONS

${}^{1}$ Cancer Care, University Hospitals Dorset NHS Trust, Bournemouth, UK

${}^{2}$ Department of Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

${}^{3}$ The Christie NHS Foundation Trust,Manchester,UK

${}^{4}$ Department of Haematology, Addenbrookes, Cambridge, UK

${}^{5}$ Department of Haemato-Oncology, The Royal Marsden NHS Foundation Trust,London,UK

${}^{6}$ University Hospitals Sussex Royal Sussex County Hospital, Brighton, UK

'Freeman Hospital, Newcastle, UK

${}^{8}$ Clinical Haematology, Nottingham University Hospitals NHS Trust,Nottingham, UK

9Queen Elizabeth University Hospital,Glasgow,UK

${}^{10}$ St.James's Institute of Oncology, Leeds Institute of Cancer and Pathology,

University of Leeds, Leeds, UK

${}^{11}$ Institute of Immunology and Immunotherapy, University of Birmingham,

Birmingham, UK

${}^{12}$ University Hospitals Birmingham NHS Trust, Birmingham, UK

${}^{13}$ Department of Haematology, Aneurin Bevan University Health Board, Wales, UK

${}^{14}$ The Clatterbridge Cancer Centre NHS Foundation Trust, University of Liverpool,Liverpool,UK

${}^{15}$ Queen Mary University of London, London, UK

University College London, London, UK

${}^{17}$ Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences,

King's College London, London, UK

18Department of Haematology, King's College Hospital NHS Trust, London, UK

ACKNOWLEDGEMENTS

The authors thank the Richmond CLL meeting attendees(8-9 May 2024)-Drs.R. Allchin,N.Chavda,N.Elmusharaf,F. Forconi,M. Furtado,S.Gohil,N.Kalakonda,S. Marshall,G. Preston and S. Williams-for invaluable discussion and also thank Dr. D. Bartlett for guidance on the importance of exercise in CLL patients. Thank you to O. Hofer for improving figures.

ORCID

R. Walewska 90 https://orcid.org/0009-0007-5693-2789

T.A.Eyre https://orcid.org/0000-0002-6631-9749

A. Bloor ❾https://orcid.org/0000-0003-4550-220X

N. Martinez-Calle https://orcid.

.org/0000-0002-5184-9464

T. Munir 90 https://orcid.org/0000-0002-2901-0769

H.M.Parry $\theta$ https://orcid.org/0000-0002-9707-8167

N. Parry-Jones https://orcid.org/0000-0002-3878-4467

A. Pettitt https://orcid.org/0000-0002-0907-8950

J. Riches https://orcid.org/0000-0002-3425-7686

P.E.M. Patten ❶https://orcid.org/0000-0003-3320-3034

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SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

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How to cite this article: Walewska R,Eyre TA, Bloor A,Follows G,Iyengar S,Johnston R,et al.2025 British Society for Haematology Guideline for the treatment of chronic lymphocytic leukaemia. Br J Haematol.2025;00:1-18.https://doi.org/10.1111/bjh.70100

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