The APLC expert consensus recommendations on the management of chronic lymphocytic leukaemia in Asia

ABSTRACT

Introduction: Targeted therapies have significantly transformed the management of chronic lymphocytic leukaemia (CLL), yet most recommendations continue to reflect Western practice patterns. Variations in disease biology, healthcare resources and treatment accessibility across the Asia-Pacific (APAC) necessitate region-specific guidance. The Asia-Pacific Leukaemia Consortium (APLC) therefore developed updated consensus statements to support standardised, context-appropriate care for patients with CLL.

Methods: A modified Delphi process was conducted with 17 haematology experts from multiple APAC regions. A systematic literature search (i.e. MEDLINE via PubMed) covering publications from 2016 onwards informed the development of 29 statements across 3 domains: diagnosis, treatment and long-term management. Panel members rated each statement using a 5-point Likert scale. Consensus was defined a priori as a mean score ≥3.5. Statistical measures and iterative expert discussions guided refinement of the final recommendations.

Results: Twenty-nine statements reached consensus with key recommendations addressing: (1) appropriate use of genetic and prognostic testing, particularly TP53 and immunoglobulin heavy chain (IGHV) status; (2) first-line and relapsed/refractory treatment selection, including the role of Bruton’s tyrosine kinase (BTK) inhibitors, B-cell lymphoma 2 inhibitors, combination strategies, cellular therapies and emerging modalities; and (3) long-term monitoring, toxicity surveillance and management of complications such as autoimmune cytopenias. Region-specific considerations—such as variable access to novel agents and diagnostic platforms—were incorporated throughout.

Conclusion: These updated APLC consensus recommendations provide clinicians across the APAC with an evidence-based, pragmatic framework for managing CLL. They aim to support treatment consistency, optimise sequencing strategies and address gaps in diagnostics, access and long-term survivorship care across diverse healthcare settings.

CLINICAL IMPACT

Clinical Impact

What is New

• Provides the first updated Asia Pacific (APAC)-focused consensus on CLL management since 2023.
• Integrates recent data on Bruton’s tyrosine kinase inhibitors and B-cell lymphoma 2 inhibitors therapy, sequencing strategies and emerging options such as chimeric antigen receptor T-cell and next-generation agents.

Clinical Implications

• Offers actionable recommendations for diagnosis, treatment selection and long-term monitoring tailored to APAC healthcare systems.
• Supports more consistent, evidence-aligned practice despite variations in access, resources and patient profiles across the region.

Relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL) is a mature B-cell neoplasm characterised by the accumulation of monoclonal B lymphocytes in the bone marrow, peripheral blood and lymphoid organs. It predominantly affects older adults, with a median age at diagnosis above 70 years, and exhibits a highly variable clinical course influenced by genetic and microenvironmental factors.^1,2 In 2019, there were an estimated 100,000 new CLL cases and 44,000 related deaths worldwide.³ CLL remains the most common leukaemia in Western countries, accounting for 25–35% of all leukaemia cases in the US, with an annual incidence of approximately 4.9–4.92 per 100,000 persons.^1,4 Although incidence is 5- to 10-fold lower in Asian populations compared to Western cohorts,^3,5 the absolute burden is rising with ageing populations and expanding diagnostic capacity. Moreover, the biological and clinical features of CLL in Asian populations may differ from those reported in Western studies, such as immunoglobulin heavy chain (IGHV) mutation status and high MYD88 mutation rate, underscoring the need for region-specific recommendations.^6,7 The reasons for these epidemiological differences are not fully understood, though genetic factors have been proposed.^8,9,10

To date, most evidence guiding CLL management is derived from Western populations, while data from Asia remain limited. This dearth in the literature creates challenges in adapting international guidelines to diverse healthcare infrastructures in Asia, with variable access to diagnostics and differences in treatment availability. Recognising these gaps, the Asia-Pacific Leukaemia Consortium (APLC) published consensus recommendations in 2023 tailored to the region’s needs.¹¹ Since then, the therapeutic landscape has evolved rapidly, with novel targeted agents, combination strategies and emerging sequencing approaches reshaping treatment paradigms.

This updated consensus builds on the previous framework, focusing on 3 domains: (1) diagnosis, (2) treatment and (3) long-term management. The recommendations presented in this paper reflect expert consensus intended to support clinicians in adapting current evidence to the heterogeneous healthcare environments across the Asia-Pacific region. By integrating recent evidence with collective regional experience, this document aims to provide practical, evidence-informed guidance that supports consistent and high-quality care while recognising variations in healthcare resources and patient circumstances. As with all consensus-based guidance, these recommendations should be applied alongside individual patient factors and clinical judgement.

METHODS

The APLC assembled a core panel comprising 5 haematology-oncology experts with an appointed chair. Subsequently, this consensus statement was developed using a modified Delphi method with a panel of 17 haematology-oncology experts from 9 Asia-Pacific regions: Australia, Hong Kong, Japan, Malaysia, People’s Republic of China, Singapore, South Korea, Taiwan and Thailand.

To identify the scope of this consensus statement, a comprehensive literature search was conducted using the MEDLINE database (via PubMed) to identify English-language research articles published from January 2016 until December 2024. Keywords included “chronic lymphocytic leukaemia,” “diagnosis,” “risk stratification,” “treatment,” “prognosis,” “Bruton’s tyrosine kinase inhibitor (BTKi),” “B-cell lymphoma-2 inhibitor (BCL-2i),” “TP53” and “immunoglobulin heavy chain variable region (IGHV) mutation,” among others. Relevant publications were reviewed to inform the survey design.

Based on the literature review findings and the clinical experience of the core panel, a qualitative survey was developed comprising 28 statements organised into 3 sections: (1) diagnosis, (2) treatment and (3) management. Panel members rated their agreement with each statement using a 5-point Likert scale (1 = strongly disagree, 2 = disagree, 3 = neutral, 4 = agree, 5 = strongly agree).

The statements were classified based on mean scores as follows:

• Consensus: Mean score ≥3.5
• Near consensus: Mean score of 3.25–3.49
• No consensus: Μean score ≤3.25

The consensus development process is illustrated in Fig. 1. Survey responses were recorded and analysed to determine consensus levels for each statement. Following survey completion, a virtual meeting was held on 16 July 2025 to present results and facilitate discussion among the entire panel. The meeting allowed the entire panel to review the final statements and provide additional feedback. The meeting led to the division of 1 consensus statement into 2 distinct statements (Statements 18 and 19). Statements 18 and 19 were initially combined and reached consensus during the survey; however, the panel agreed that separating them would provide greater clarity. In addition, Statement 4, which had reached near consensus during the survey, was reworded during the meeting and subsequently achieved consensus. Following thorough discussion and evidence review, 29 consensus recommendations were finalised. Table 1 summarises all recommendations with their corresponding statistical measures. The consensus recommendations and the supporting literature are discussed in the subsequent sections.

Fig. 1. Consensus process using a modified Delphi method.

Table 1. Summary of key consensus statements for APLC expert consensus on the management of chronic lymphocytic leukaemia in Asia.

Statistical analysis

For each statement, the mean, median and interquartile range (IQR) we calculated. The IQR measures statistical dispersion by capturing the difference between the upper and lower quartiles, representing the middle 50% of responses. An IQR ≤1 indicates that more than half of all responses fall within 1 point on the scale, demonstrating good consensus on a 5-point Likert scale, a standard and rigorous measure commonly used in Delphi studies.¹³

RESULTS AND DISCUSSIONS

Diagnosis

Timing of treatment initiation

For the majority of newly diagnosed CLL patients (over 80%), the disease is asymptomatic and early-stage (Rai 0 or Binet A). Only 30–50% of such cases will progress to advanced, symptomatic disease requiring therapy, while the rest may never need treatment in their lifetimes.¹⁴ Major guidelines, including the 2018 International Workshop on CLL (iwCLL) consensus, recommend that patients with early-stage, asymptomatic CLL should be monitored without treatment outside of clinical trials, since no overall survival (OS) benefit has been demonstrated for treating these patients prior to progression.^12,15,16

Notably, multiple randomised trials have demonstrated no OS benefit from early treatment in this population.^17,18 The CLL7 trial, which evaluated frontline FCR (fludarabine, cyclophosphamide, rituximab) in asymptomatic patients with high-risk Binet A disease, showed improved event-free survival but no OS advantage.¹⁹ Additionally, the phase III CLL12 trial confirmed that early intervention with ibrutinib delayed disease progression in biologically high-risk patients but did not confer a survival benefit and carried known toxicities.²⁰ High-risk early-stage patients, such as those with unmutated IGHV, TP53 abnormality or elevated beta-2 microglobulin, may be considered for clinical trials of early intervention, but outside such settings, surveillance remains the standard of care.¹⁹

Baseline genetic testing prior to therapy

TP53 status, defined by the presence of either a 17p deletion (detected by interphase fluorescence in situ hybridisation [FISH]) or a somatic TP53 mutation (identified via sequencing), is the most clinically actionable biomarker in CLL.^12,21 These abnormalities are typically mutually exclusive but occasionally co-occur.²² Testing for both is essential, as a subset of patients will harbour TP53 mutations without a detectable 17p deletion. TP53-disrupted CLL is associated with poor response to chemoimmunotherapy and reduced survival, even with novel agents.^23,24,25 Consequently, targeted therapies are now the preferred frontline approach in these patients, and identification of TP53 status is a prerequisite for appropriate risk-adapted management.¹² However, the expert panel recognised that the comprehensive assessment of TP53 may not be consistently available across the APAC region due to factors such as accessibility and affordability.

IGHV mutation status similarly stratifies patients by disease biology. IGHV-unmutated CLL carries a worse prognosis and responds poorly to chemoimmunotherapy, whereas IGHV-mutated CLL, especially in younger, fit patients, may achieve durable remissions with fixed duration.^26-28 As such, IGHV status directly informs treatment selection, and its assessment is now standard practice prior to therapy.

Conventional karyotyping, while less widely available in some countries across the APAC region, may offer additional prognostic information beyond FISH and sequencing. In particular, the presence of a complex karyotype (≥3 abnormalities) or high-complexity karyotype (≥5 abnormalities) has been associated with inferior outcomes across treatment modalities.²⁹ The iwCLL 2018 guidelines list karyotyping as desirable where feasible.¹² While not essential, it can be considered in centres with adequate laboratory capacity to refine risk assessment, particularly in patients with borderline or ambiguous molecular profiles.

Panel recommendations for the diagnosis of CLL:

1. Newly diagnosed, asymptomatic early-stage CLL should be managed with active surveillance until progression criteria are met, in line with iwCLL 2018 guidelines.
2. Baseline testing for TP53 mutation and 17p deletion should be performed before initiating therapy; both tests should be ordered simultaneously where possible to avoid missing TP53-disrupted disease.
3. IGHV mutation testing should be performed prior to treatment, as results directly guide regimen selection and long-term prognostication.
4. Conventional karyotyping can be considered where available to identify complex karyotype, which provides additional prognostic insight beyond standard molecular testing.
5. High-risk patients identified through biomarker testing should be counselled on the implications for treatment choice and prognosis at the time of diagnosis.

Treatment

Communication and patient expectations

CLL is typically an indolent, chronic leukaemia that is treatable but not curable in most cases. It requires lifelong monitoring and periodic treatment, making patient education and expectation-setting crucial. Engaging patients in treatment decisions and addressing their questions, values and lifestyle preferences help align long-term management plans with patient goals.^30,31 This collaborative approach is especially important in most countries across the APAC region, where historical norms tended towards physician-driven decisions; newer models encourage patient participation to improve satisfaction and adherence.

BTKi therapy precautions and perioperative considerations

BTKi therapies (e.g. ibrutinib, acalabrutinib, zanubrutinib) can impair platelet signalling and increase bleeding risk. If possible, patients on BTKi therapies should avoid other agents with antiplatelet or anticoagulant effects. Specifically, nonsteroidal anti-inflammatory drugs and aspirin-containing products can exacerbate BTKi-related bleeding and are generally discouraged.

It is important to recognise that the combination of BTKi therapy with both antiplatelet and anticoagulant agents (“triple therapy”) markedly increases the risk of serious bleeding and is generally contraindicated.^32-34 When dual antiplatelet therapy is mandatory (e.g. after coronary stenting), BTKi use should be deferred or alternate CLL treatments considered.^35-37

If only 1 additional agent (either antiplatelet or anticoagulant) is required, the risk-benefit decision should be individualised. BTKi therapy may be justified in patients with limited options, such as those refractory to venetoclax-based therapy or immunochemotherapy. If anticoagulation is required, guidelines recommend avoiding vitamin K antagonists (warfarin) and using a direct oral anticoagulant instead.³⁵ Patients should be counselled that supplements such as omega-3 fatty acids (fish oil) and vitamin E have mild antiplatelet effects. These should be stopped prior to elective surgeries and ideally avoided during BTKi therapy.³⁵

Expert consensus and pharmacodynamics data suggest withholding BTKi for 3 to 7 days pre- and post-procedure, depending on bleeding risk and the specific BTKi’s half-life.^38-41 Platelet function begins to normalise 2–3 days after stopping BTKi and fully recovers by 7 days.⁴² Thus, a 1-week interruption is appropriate for major surgeries.

First-line treatment selection

For the vast majority of patients requiring initial therapy, targeted agents should be considered the standard of care whenever available. Two main targeted strategies are now supported by phase III data: (1) continuous covalent BTK inhibition, and (2) fixed-duration venetoclax-based regimens. Selection among these approaches should be individualised according to comorbidities, patient preference for continuous versus time limited therapy, and regional access and reimbursement considerations across the Asia-Pacific region.^43-51

In cases where targeted agents are not available, chemoimmunotherapy with FCR, usually administered for 6 cycles, for young, fit patients with mutated IGHV and intact TP53 (no 17p deletion or TP53 mutation) may be considered. However, FCR can carry long-term risks, including approximately 5% risk of therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) in follow-up.²⁸ In some APAC countries, cost or availability issues may still lead to FCR use, but as novel agents become more accessible, this treatment choice is likely to become less commonly utilised.

The expert panel generally suggests the use of a second-generation covalent BTKi, such as acalabrunitib or zanubrutinib, over ibrutinib, whenever possible.⁵² Although there is no head-to-head comparison between acalabrutinib and ibrutinib in frontline setting, in the randomised phase III ELEVATE-RR trial, acalabrutinib demonstrated non-inferior progression-free survival (PFS) with fewer cardiovascular events compared to ibrutinib.⁵³ In the randomised phase III ALPINE trial, zanubrunitib resulted in higher overall response rate (ORR) and improved PFS compared to ibrutinib.⁵⁴ Rates of atrial fibrillation were also lower with zanubrutinib.

However, the expert panel also acknowledges several caveats when interpreting these trials. Notably, ALPINE observed lower PFS for ibrutinib than reported in the earlier RESONATE trial, despite enrolling a less heavily pretreated cohort.⁵⁵ This has prompted debate within the CLL community, as the reasons for ibrutinib’s underperformance in ALPINE remain unclear. Factors such as broader geographic recruitment, changing treatment landscapes and trial conduct during the COVID-19 pandemic may have contributed. Other studies, such as the Australian Pharmaceutical Benefits Scheme analyses and OSU cohort data, have also reported cardiac event rates and overall outcomes with ibrutinib that more closely resemble earlier trial benchmarks.^48,56 The expert panel generally suggests the preferential use of second-generation agents due to better safety profile, but in certain APAC regions, only ibrutinib is accessible.

Fixed‑duration venetoclax‑based regimens represent another therapeutic option in frontline CLL management, particularly for patients who prefer time‑limited therapy. Venetoclax plus obinutuzumab was tested in the CLL14 trial, where the regimen achieved high rates of undetectable MRD and durable remissions, with 6‑year follow‑up demonstrating sustained progression‑free survival benefit compared with chlorambucil–obinutuzumab.⁵⁷ Where available and feasible, venetoclax–obinutuzumab provides an effective time‑limited alternative to continuous BTK inhibition.

Covalent BTK inhibitors can be combined with venetoclax in chemotherapy‑free first‑line regimens, as demonstrated in the phase III GLOW trial (fixed‑duration ibrutinib–venetoclax versus [vs] chlorambucil–obinutuzumab) and the phase II CAPTIVATE trial (fixed‑duration ibrutinib–venetoclax in fit patients).^58-60 These studies have shown high rates of undetectable MRD and PFS outcomes superior to chemoimmunotherapy (GLOW) and high rates of sustained treatment-free remission (CAPTIVATE) in predominantly older/unfit and younger/fit treatment‑naïve patients, respectively. Recently published relatively short 3-year data from the CLL17 (front-line fixed-duration venetoclax-obinutuzumab vs venetoclax-ibrutinib vs continuous ibrutinib)⁶¹ showed non-inferiority, except for patients with TP53 dysfunction (7.6% of cohort) where venetoclax-obinutuzumab appeared less effective (62% venetoclax-obinutuzumab, 69% venetoclax-ibrutinib, 79% ibrutinib).

The assessment of cytogenetic and molecular risk factors, including molecular analysis to assess IGHV mutation status; sequencing to assess TP53 mutation status; FISH to assess 17p deletion, 11q deletion, 13q deletion and trisomy 12; and cytidine monophosphate guanosine oligodeoxynucleotide-stimulated metaphase karyotype or single-nucleotide polymorphism array to assess for karyotypic complexity, are crucial for understanding each patient’s prognosis.^62-65

Outcomes with chemoimmunotherapy in CLL patients with TP53 mutation/del(17p) are uniformly poor, and hence should not be used when targeted agents are available.⁶⁶ Continuous BTKi therapy demonstrates improved PFS compared with chemoimmunotherapy in subgroup analyses of patients with TP53 aberrant CLL from randomised studies in older, unfit patients,^45-48 and is recommended as first choice. Durability of response to time-limited therapy with venetoclax-obinutuzumab in this population is less well established. In CLL14, only 25 patients with a del(17p) or TP53 mutations received venetoclax-obinutuzumab,⁵⁷ and had inferior PFS compared to normal TP53. The ongoing CLL17 trial will compare the impact of venetoclax-obinutuzumab vs ibrutinib in the frontline setting.

Treatment in R/R CLL and sequencing strategies

Targeted therapies with continuous BTK inhibitors (BTKi) or fixed-duration venetoclax plus anti-CD20 monoclonal antibody therapy have established superiority over chemoimmunotherapy in R/R CLL and have become the preferred standard of care treatment.⁶⁵ The selection of therapies for patients with R/R CLL requires consideration of several factors including previous therapy, disease characteristics, the patient’s clinical status (including co-morbidities, concurrent medications, etc.), access to clinical trials and cost implications.⁶⁷

Covalent BTKis such as acalabrutinib, ibrutinib and zanubrutinib are approved for treatment of R/R CLL based on the results of phase III randomised studies (ASCEND, ELEVATE-RR, RESONATE, and ALPINE trials).^53-55,68 The PFS benefit compared with chemoimmunotherapy was seen across all patient subgroups including those with del(17p) or TP53 mutation.

After BTKi failure, venetoclax-based therapy is highly effective as the next-line treatment. In one multi-centre study, CLL patients who had disease progression on ibrutinib had significantly longer survival if their subsequent therapy included venetoclax, compared to those who received alternate agents (median OS approximately 30 months vs approximately 9 months).⁶⁹

Venetoclax plus rituximab is approved for the treatment of R/R CLL based on the results of the phase III randomised MURANO trial.⁷⁰ Venetoclax-rituximab was superior to bendamustine-rituximab with longer PFS across all subgroups of patients, including those with del(17p) or TP53 mutation (hazard ratio [HR], 0.21 for del(17p); HR, 0.25 for TP53 mutation], and undetectable measurable residual disease (uMRD) at the end of treatment was also higher for venetoclax-rituximab (62% vs 13% for bendamustine-rituximab).⁷¹

When possible, it is recommended to use venetoclax-obinutuzumab. In CLL13, venetoclax-obinutuzumab was associated with higher rates of uMRD with a cutoff of ≤10⁻⁴ (MRD4) compared with FCR or bendamustine-rituximab in fit patients with CLL/SLL without del(17p)/TP53 mutations, but venetoclax-rituximab was not.⁷² A real-world retrospective cohort of 40 previously treated CLL patients receiving off-label venetoclax-obinutuzumab reported a 90% ORR (complete remission/complete remission with incomplete count recovery 27.5%), 2-year PFS of 81.2% (95% confidence interval 69.5–94.8), and good tolerability, with no venetoclax-related tumour lysis syndrome and 3% laboratory tumour lysis syndrome with obinutuzumab initiation, supporting venetoclax-obinutuzumab as a reasonable option when used in R/R disease.⁷³

Venetoclax monotherapy resulted in an ORR of 77% (63% in patients who received prior therapy with a BTKi (ibrutinib) or PI3Ki (idelalisib) in patients with R/R del(17p) CLL.⁷⁴ The estimated 24-month PFS and OS rates were 54% and 73%, respectively, for the overall study population (50% and 55%, respectively, for patients who had received prior BTKi or PI3Ki).

Lisaftoclax (APG-2575) is a next-generation selective BCL2i that has recently been approved in China for R/R CLL. Approval was supported by a pivotal phase II trial in which lisaftoclax met the primary end point of ORR in patients with R/R CLL who received prior treatment with BTKi and/or chemoimmunotherapy. The agent also displayed a favourable safety profile; no cases of tumour lysis syndrome occurred during the trial.⁷⁵

It is important to note that when patients have disease progression on a covalent BTKi, abrupt discontinuation may result in rapid progression.⁷⁶ Therefore, for patients with progression on a covalent BTKi, and when venetoclax-based therapy is started, it is recommended that covalent BTKi therapy is continued until there is evidence of clinical/laboratory response.

An emerging question is whether venetoclax can be re-used after a drug-free interval. The final 7-year analysis of the MURANO trial (venetoclax–rituximab in R/R CLL) reported outcomes of a retreatment sub-study. Patients who had completed the initial 2-year venetoclax course and later progressed were retreated with venetoclax–rituximab: the OS rate was approximately 72%, and the median PFS on retreatment was approximately 23 months.⁷⁰ Long-term follow-up and retreatment data from the frontline CLL14 and CLL13 studies and the ongoing ReVenG trial will further refine the treatment-free interval to identify the optimal duration of remission after treatment cessation when considering venetoclax-based retreatment.⁷⁷ In this consensus, the expert panel agreed that a ≥3-year interval is appropriate. Retreatment is less effective if CLL relapse occurs quickly (e.g. within a year of stopping venetoclax), as such cases often harbour venetoclax resistance mutations (like BCL2 G101V).⁷⁸ Ongoing studies are needed to further explore venetoclax retreatment and combination strategies to overcome resistance.

In the second-line setting after frontline venetoclax-obinutuzumab, a second-generation covalent BTKi such as acalabrutinib or zanubrutinib may be considered. In 1 study, among 44 patients who were BTKi naïve and previously received venetoclax in the frontline (4%) or R/R (96%) setting, covalent BTKi had an ORR of 84% and median PFS of 32 months.⁷⁹ In another series of 23 patients who previously received venetoclax, covalent BTKi therapy had an ORR of 91% and median PFS of 34 months.⁸⁰

For patients with CLL who have had prior covalent BTKi, and especially those “double refractory” to covalent BTKi and BCL2i, non-covalent BTK inhibitors are a potential option if accessible.⁸¹ Non-covalent BTKi can inhibit BTK even in the presence of the C481S mutation that causes resistance to all covalent BTKi including ibrutinib, acalabrutinib and zanubrutinib.

The emerging class of BTK degraders, all currently in clinical trials, are also likely to be useful in the “double refractory” setting. BTK degraders, such as NX-5948 and BGB-16673 (in early-phase trials), use proteolysis-targeting chimeras to tag BTK for destruction. Initial phase I data show that BTK degraders have shown rapid tumour regressions in BTKi-resistant CLL patients, including those with prior pirtobrutinib exposure.^81,82

Although no bispecific antibody therapy is yet approved specifically for CLL, T-cell–engaging bispecific antibodies are emerging as an important option for patients whose CLL is refractory to both BTKi and BCL2i. These agents (e.g. epcoritamab, a CD3×CD20 bispecific antibody) recruit the patient’s T cells to attack CLL cells, and early trial results have shown promising efficacy even in heavily pretreated cases. In the ongoing EPCORE CLL-1 study, epcoritamab achieved high overall response rates with some patients attaining undetectable minimal residual disease, despite most patients having had prior BTKi and BCL2i therapy.⁸³

Role of patient preferences

Patient surveys indicate a general preference for fixed-duration treatment when efficacy is perceived as equivalent. In one survey of adults with CLL, the majority expressed that they would opt for a finite therapy that can be stopped (e.g. 12-month venetoclax-based regimens), rather than life-long medication (e.g. daily BTKi until progression), provided the expected 2-year remission rates were high.^84-86 Other factors such as frequency of clinic visits, need for IV infusions, cost and insurance coverage, travel ability, comorbidities and patient personality influence decision-making. Therefore, beyond clinical factors, physicians should proactively ask patients about their priorities and incorporate those preferences into the decision.

Cellular therapy

For patients with disease refractory to both covalent BTKi and BCL2i, allogeneic stem cell transplantation (allo-SCT) can be considered in highly selected cases, typically younger, fit patients with an available donor and no access to CD19-directed chimeric antigen receptor (CAR) T cell therapy such as lisocabtagene maraleucel.^87,88 Although CAR-T cell therapy has demonstrated promising efficacy in multiply R/R CLL, its limited availability across Asia necessitates continued consideration of allo-SCT as a last-line option in suitable candidates. This approach aligns with international guidelines that reserve allo-SCT for patients with high-risk or double-refractory CLL when no approved targeted therapies are viable.⁸⁹

Long-term monitoring and toxicity surveillance

CLL requires sustained monitoring during and after treatment to mitigate therapy-related complications. Infectious prophylaxis, particularly hepatitis B virus (HBV), is a critical priority in Asia. All patients should be screened for HBV (HBsAg and anti-HBc) before starting anti-CD20 monoclonal antibodies or targeted therapies.^90,91 Those with chronic or resolved HBV infection should receive antiviral prophylaxis in line with local guidelines. This is especially important for regimens containing obinutuzumab or rituximab. BTKi therapies have also been associated with rare HBV reactivation, and screening prior to use is recommended.⁹²

Infection risk should be stratified by comorbidities, prior infections and immunosuppression. Routine vaccinations (influenza, pneumococcal and herpes zoster) are advised. Prophylaxis against Pneumocystis jirovecii pneumonia and bacterial or fungal infections is not routinely required for BTKi or venetoclax monotherapy, though further research could help identify which particular patient groups are most at risk and which prevention interventions might be effective.^93,94 Immunoglobulin replacement can be considered in patients with hypogammaglobulinaemia and recurrent infections.⁹⁵

Cardiotoxicity is a known risk of BTKi therapy, especially with first-generation ibrutinib. Baseline and periodic cardiovascular assessments should be performed, with preference given to second-generation BTKis in patients with atrial fibrillation, hypertension or elevated cardiac risk. A multidisciplinary team is crucial to help manage emerging toxicities with the goal of maintaining BTKi therapy, if possible.⁹⁶

Surveillance for secondary malignancies as per general guidelines, including skin cancer and therapy-related MDS/AML, should be incorporated into long-term follow-up.⁹⁷ Routine cancer screening and skin examinations are recommended. Clinicians should also remain alert to signs of Richter transformation as CLL can transform into an aggressive lymphoma in 2–9% of patients.

Panel recommendations for the treatment of CLL:

1. Engage patients early in shared decision-making, clearly communicating disease chronicity, treatment goals and expected relapse patterns.
2. Avoid concomitant BTKi use with dual antiplatelet therapy; where unavoidable, alternative regimens should be considered. Hold BTKi therapy perioperatively according to surgical risk.
3. For patients with TP53 aberrations, targeted therapy with BTKi or venetoclax-based regimens is preferred over chemoimmunotherapy; choice should consider patient preference, toxicity profile and drug availability.
4. In settings without access to novel agents, FCR remains an acceptable option for fit patients with mutated IGHV and intact TP53, and can be considered for unmutated IGHV when no alternatives exist.
5. Second-generation BTKis are preferred over ibrutinib when accessible, due to lower cardiovascular toxicity and improved tolerability.
6. Treatment sequencing after chemoimmunotherapy should prioritise BTKi or BCL2i; choice should be individualised based on comorbidities, prior exposure and treatment goals.
7. Venetoclax retreatment can be considered if the treatment-free interval is ≥3 years; non-covalent BTKi or CAR-T-cell therapy may be appropriate for double-refractory disease where available.
8. Allo-SCT remains a consideration for fit patients with no access to CAR-T cell therapy and refractory to both BTKi and BCL2i (Fig. 2).

Management

Response monitoring and risk stratification

Treatment response monitoring should follow the iwCLL guidelines for response assessment, which provides definitions for complete remission, partial remission, stable disease, and progression based on clinical examination, blood counts, marrow evaluation and lymph node/spleen size.¹² Using iwCLL response guidelines in routine monitoring allows clinicians to objectively track disease status and make comparisons across studies.

Risk stratification in CLL is driven by key biological prognostic factors. The most relevant parameters for predicting outcomes are the IGHV mutational status, the serum β2-microglobulin (β2M) level and any disruption of the TP53 gene (either deletion 17p or TP53 mutation).¹² Applying iwCLL response criteria and incorporating IGHV, β2M and TP53 status into risk stratification represents current best practice in monitoring and prognostication.

Role of MRD

The expert panel agreed that current evidence is insufficient to use an MRD-driven approach in standard practice outside of clinical trials. While undetectable MRD is a valuable research endpoint, it has not been proven that altering therapy based on MRD (such as stopping or extending treatment) improves patient outcomes in the real-world setting. Further research and follow-up are needed to determine its role in routine clinical practice, both for prognostication and for guiding treatment decisions, before use in routine clinical practice.^98,99

Therapy-specific monitoring

Each targeted agent used in CLL requires tailored monitoring strategies due to distinct toxicity profiles. Patients on BTKi therapy (e.g. ibrutinib or acalabrutinib) should be monitored closely for cardiovascular and bleeding complications. Atrial fibrillation occurs in 6–16% of cases and may reach 30% with prolonged exposure. Regular pulse and blood pressure monitoring, electrocardiograms and vigilance for symptoms such as palpitations or dyspnoea are essential. BTKis also impair platelet function, increasing the risk of minor and major bleeding. Concomitant use of anticoagulants or antiplatelet agents should be approached with caution. Life-threatening arrhythmias or a history of ventricular tachycardia may warrant discontinuation or switching to alternative therapies.^96,100,101 BTKi therapy, especially ibrutinib, should also generally be avoided in patients with poorly controlled hypertension and those with a history of heart failure.^37,96 Overall, long-term BTKi therapy should be accompanied by proactive cardiovascular and bleeding surveillance.

Venetoclax carries a significant risk of tumour lysis syndrome, especially during initiation. A 5-week dose ramp-up with close biochemical monitoring is standard, guided by tumour burden risk stratification.¹⁰² Patients may require pre-emptive hospitalisation or outpatient blood tests at 6–8 and 24 hours post-dose. Prophylaxis with hydration and uric acid-lowering agents is recommended. In addition to tumour lysis syndrome, venetoclax is associated with high rates of cytopenias, particularly grade ≥3 neutropenia in approximately 40% of patients.^103,104 Full blood counts should be monitored regularly, especially during the initial treatment cycles. Supportive measures, such as granulocyte colony-stimulating factor and dose adjustments, may be necessary. Safe administration of venetoclax requires careful tumour lysis syndrome prevention and ongoing monitoring for haematologic toxicity.

Management of autoimmune cytopenias

Autoimmune cytopenias (AIC), including autoimmune haemolytic anaemia and immune thrombocytopenia, affect approximately 5–10% of patients with CLL.^105-107 First-line management involves immunosuppressive therapy, typically corticosteroids, with or without anti-CD20 monoclonal antibodies such as rituximab.¹⁰⁸ This combination achieves high response rates, though remissions may be transient. The iwCLL guidelines recognise steroid-refractory AIC as an indication for initiating CLL-directed therapy, even in the absence of other progression criteria.¹²

In cases where AIC is R/R, targeted agents such as BTK inhibitors (e.g. ibrutinib) and BCL2 inhibitors (e.g. venetoclax) have demonstrated efficacy. Ibrutinib, alone or with rituximab, has shown high response rates and sustained remissions in steroid-refractory AIC, with most patients achieving transfusion independence within weeks.¹⁰⁸ Venetoclax may also be considered in selected cases, particularly when BTKis are unsuitable.¹⁰⁹ Ultimately, the resolution of refractory AICs often depends on effective control of the underlying CLL. A stepwise approach (beginning with immunosuppression and escalating to targeted CLL therapy when needed) remains the standard of care.

Panel recommendations for the management of CLL:

1. Monitor treatment response according to iwCLL guidelines, integrating IGHV, β2-microglobulin and TP53 status into ongoing risk assessment.
2. MRD testing should not be used to guide treatment outside clinical trials; its role in routine care remains investigational.
3. Long-term BTKi therapy requires regular cardiovascular and bleeding risk assessment; avoid use in patients with prior ventricular arrhythmias or high cardiac risk where alternatives exist.
4. Initiate venetoclax with strict tumour lysis syndrome risk stratification and monitoring protocols; manage cytopenias with supportive measures as needed.
5. Autoimmune cytopenias should be treated initially with immunosuppression; escalate to targeted CLL therapy if refractory.
6. Long-term follow-up should include vaccination, infection prophylaxis for high-risk groups, and screening for secondary malignancies and Richter transformation.

Fig. 2. Flow diagram of the recommended treatment algorithm for CLL.

CONCLUSION

These updated consensus recommendations provide a framework for optimising CLL management in the APAC region, integrating evolving evidence with local practice considerations. By addressing diagnosis, treatment selection, sequencing and long-term management, they aim to support consistent, evidence-informed care despite variable access to novel agents. Ongoing collaboration among clinicians, policymakers and industry stakeholders will be essential to improve access, reduce treatment costs, and ensure that therapeutic advances translate into equitable benefits for patients across the region.

Supplementary Material

Table S1. Summary of NCCN, iwCLL and ESMO guidelines.

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