Consensus guidelines for the management of treatment-naïve chronic lymphocytic leukaemia in Singapore (2024)

ABSTRACT

Introduction: Chronic lymphocytic leukaemia (CLL) has a heterogeneous disease course and a variable prevalence across populations. Appropriate management for achieving optimal outcomes requires consideration of multiple factors, including disease-related factors like genomic alterations, patient characteristics and fitness, availability and access to treatments, and logistics/cost. This review aims to provide comprehensive and pragmatic recommendations for the management of treatment-naïve (TN) CLL that are relevant to Singapore’s clinical context.

Method: Clinical consensus statements were developed by an expert panel of haematologists from Singapore through a 2-round modified Delphi process. Statements were drafted using recent evidence-based guidelines and published literature. Panel members reviewed draft statements, provided anonymised feedback and proposed modifications where relevant. A physical meeting was held to facilitate discussion, voting and endorsement of the final consensus statements.

Results: The final consensus included 15 statements covering major TN CLL patient subsets. The recommendations highlight the importance of molecular testing for key biomarkers, where available/accessible, to guide initial therapy. Due to the superior efficacy of targeted agents (Bruton's tyrosine kinase inhibitors [BTKis] and B-cell lymphoma 2 inhibitors [BCL2is]), sthese are favoured over standard chemotherapy or chemotherapy-immunotherapy, especially for patients with del(17p) or TP53 mutation, and less fit patients.

Conclusion: These consensus statements provide practical recommendations for the current management of TN CLL patients in Singapore and similar healthcare systems based on up-to-date evidence. Regular updates to treatment guidelines are important to ensure responsiveness to emerging evidence and evolving clinical practices and to improve patient outcomes and quality of life.

CLINICAL IMPACT

What is New

• This comprehensive, up-to-date clinical consensus for treatment-naïve chronic lymphocytic leukaemia in Singapore emphasises a balanced approach to therapy selection, integrating patient preferences, side-effect profile, cost, accessibility and logistics for informed decision-making.

Clinical Implications

• These recommendations offer a practical treatment algorithm that aligns with Singapore’s healthcare system.
• Treatment decision-making requires consideration of multiple factors and this should be recognised when adapting recommendations for different resource settings.

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Chronic lymphocytic leukaemia (CLL) is a lymphoid neoplasm characterised by clonal expansion of mature B-lymphocytes and has a characteristic immunophenotypic pattern. CLL prevalence varies considerably across populations. Although CLL is the most common leukaemia in adults in Western countries (25–30% of all leukaemia cases), it is much less common among individuals of Asian and Middle Eastern ancestry.^1,2  As most CLL patients are older adults, with median age of onset ranging from 65 to >70 years,^3,4 many will have coexisting conditions that increase their risk of morbidity and mortality from treatment. When selecting the optimal regimen for an individual patient, these factors and other disease and patient-related features (e.g. clinical/disease characteristics, symptoms, genetic risk factors and fitness) should be considered.^5,6

In Singapore, an estimated 20–30 new cases of CLL are diagnosed annually.⁷ Patients may receive treatment at public or private institutions, including specialised haematology centres. Singapore’s healthcare system offers a mix of insurance-paid, subsidised, co-pay and self-paying options for patients; thus, treatment decision-making involves consideration of several factors, including availability/access to approved or investigational drugs, companion diagnostics, the experience of the specific treatment centre or team, financial considerations and patient preferences. In terms of access to important diagnostic tests for CLL, this is relatively uniform across the public and private sectors. Financing of outpatient cancer treatment in Singapore is determined by a drug’s local approval status, and its inclusion in the Ministry of Health’s Cancer Drug List (CDL) based on evaluations of its clinical effectiveness and cost-effectiveness.⁸ Patients can receive subsidised access to drugs included in the CDL. With a complex and rapidly evolving treatment landscape, clinicians require practical guidance incorporating up-to-date and emerging clinical evidence. Guidelines from various sources are available but may have greater or lesser applicability to local clinical populations and health systems.^5,6,9,10 This clinical consensus from a panel of experts in Singapore seeks to offer pragmatic recommendations for the management of treatment-naïve (TN) CLL, considering factors relevant to the local clinical population and healthcare setting. Although the panel’s recommendations were developed for a primary audience of haemato-oncologists in the Singapore setting, the practice discussed here may be relevant to specialists practising in similar healthcare settings or systems.

METHOD

Two-round modified Delphi process for consensus generation

A modified Delphi process was used to generate consensus for the management of TN CLL. This consensus aims to provide guidance on contemporary treatment options for TN CLL, with consideration of specific patient subpopulations and important clinical outcomes, including but not limited to treatment efficacy. The expert panel comprised 8 haematology oncology specialists with extensive experience in CLL, practising in Singapore’s public healthcare institutions (with all 3 public healthcare administrative clusters represented) or in private specialist centres. The modified Delphi process consisted of 2 rounds. A set of provisional statements on CLL management was developed based on a targeted review of recent clinical guidelines for CLL management and available published literature. A steering committee provided guidance and input for drafting the consensus statements and revising them based on the panel’s feedback.

The evidence base for these recommendations includes pivotal studies on CLL management, as identified in recent evidence-based guidelines (European Society for Medical Oncology [ESMO], Canadian evidence-based guidelines for CLL [2022 update], and National Comprehensive Cancer Network [NCCN] Guidelines Version 3.2023).^10-13 Literature relevant to first-line CLL treatment was considered, including primary and follow-up publications for key trials. An adapted version of the evidence grading system employed for the Pan-Asian adapted ESMO clinical practice guidelines for non-small-cell lung cancer¹⁴ was used to define the level of evidence available for each statement proposed (I: at least 1 large randomised, controlled trial of good methodological quality—low potential for bias—or meta-analyses of well-conducted randomised trials without heterogeneity; II: small randomised trials or large randomised trials with a suspicion of bias—low methodological quality—or meta-analyses of such trials or of trials with demonstrated heterogeneity). Following the development of this consensus in 2023, updates to guidelines from ESMO and NCCN (2024) became available and are summarised in Supplementary Table S1.^15,16

The 17 statements covered 5 major areas: (1) general principles of management for TN CLL; (2) treatment of patients with deletion 17p [del(17p)] or tumour protein 53 (TP53) mutation; (3) treatment of fit, immunoglobulin heavy chain (IGHV) mutated patients without del(17p) or TP53 mutation, (4) Treatment of unfit, IGHV-mutated patients without del(17p) or TP53 mutation, and (5) treatment of IGHV-unmutated patients without del(17p) or TP53 mutation.

Data collection and consensus classification

In round 1, the statements and supporting evidence were presented to panel members for input. Responses were collected anonymously using an electronic survey form. Panel members were asked to respond within 2 weeks, with email reminders as required. For each statement, panel members rated their level of agreement on a 5-point Likert scale: “accept completely”; (2) “accept with minor changes”; (3) “accept with major changes required”; (4) “reject with major changes required”; (5) “reject completely”. If panel members selected options 2–5, they were asked to elaborate on the reasoning for their response and their suggestions for modifying the statement and could propose the addition of other relevant supporting references. A statement was deemed to have achieved consensus when ≥80% of the panel voted “1” or “2” (accept completely or with minor changes). Statements that did not achieve consensus in round 1 were modified based on panel members’ input and presented for discussion and voting in round 2.

Round 2 consisted of a moderated face-to-face meeting in Singapore on 26 October 2023. The round 1 voting results and the panel’s consolidated input on the statements were presented. This was followed by a moderated discussion to clarify the clinical reasoning for different viewpoints and provide opportunities for alignment. Statements that did not achieve consensus in round 1 were refined after the discussion and presented for a final round of voting and endorsement by the panel members.

RESULTS AND DISCUSSION

Seventeen provisional statements were presented for the panel’s input and voting in round 1. Consensus was reached on 14 out of 17 statements (82.3%) in round 1. The 3 statements that did not reach consensus were presented for discussion and refinement before the final voting process in round 2. After discussion, the panel agreed to omit 1 statement from consideration for the consensus. The remaining 2 statements were refined based on the panel’s input, and consensus was reached on both modified statements (2 out of 2, 100.0%) during round 2. Overall, consensus was achieved on 15 statements (≥80% voted “1” or “2” to accept completely or with minor changes). The final consensus statements are shown in Table 1. The corresponding algorithm for TN CLL is illustrated in Fig. 1. The following sections cover the clinical reasoning and supporting evidence for the final consensus statements.

Table 1. Final list of consensus statements.

Fig. 1. Algorithm for treatment-naïve CLL.



General principles of treatment

Early-stage and asymptomatic CLL

CLL is a heterogenous disease with a variable clinical course. A subset of CLL patients can live with their disease without needing any active treatment over the course of their life, while other patient subsets require treatment and exhibit poor overall survival (OS) and progression-free survival (PFS) even with multiple therapeutic interventions.¹⁷ Only 5% of CLL patients require treatment at diagnosis.¹⁷ Table 2 provides an overview of the suggested clinical workup for newly diagnosed CLL in routine practice settings, as per iwCLL criteria.¹⁸ For most patients, active surveillance (i.e. watchful waiting) is considered appropriate until there are signs of active disease, as defined by iwCLL criteria.¹⁸ In line with iwCLL criteria, the authors recommend initiating treatment only for symptomatic patients.¹⁸ For asymptomatic patients or those not meeting iwCLL treatment criteria, any concurrent conditions, such as autoimmune haemolytic anaemia or immune thrombocytopenia, should be investigated and addressed prior to considering CLL-specific therapy. All international guidelines support this approach of watchful waiting in asymptomatic disease.

Table 2. Overview of clinical workup for newly diagnosed chronic lymphocytic leukaemia in routine practice settings.

	Recommendations (as per iwCLL 2018 guidelines)18 and notes
Diagnosis
Blood tests	Complete blood cell count (CBC) with differential count ·       (≥5×109/L B lymphocytes in the peripheral blood for at least 3 months)
Immunophenotyping	Flow cytometry analysis of peripheral blood to confirm ·       Expression of CD19, CD20, CD23 ·       CD5 co-expression ·       Expression of kappa or lambda immunoglobulin light chains
Before treatment
Medical history and physical examination	·       Complete physical examination, including evaluation of lymph nodes, liver and spleen ·       Performance status (ECOG) ·       Comorbidities
Laboratory studies	·       CBC with differential count ·       Serum chemistry (liver and kidney function) ·       Serum immunoglobulin levels ·       Direct antiglobulin test ·       Infectious disease status (e.g., cytomegalovirus, hepatitis B virus or hepatitis C virus)
Imaging	·       Chest radiograph
Other tests
Cytogenetics and molecular genetics studies	·       Interphase FISH tests for del(13q), del(11q), del(17p), trisomy 12 in peripheral blood lymphocytes ·       TP53 mutation analysis ·       IGHV mutational status

CBC: complete blood count; CLL: chronic lymphocytic leukaemia; ECOG: Eastern Cooperative Oncology Group; FISH: fluorescence in situ hybridisation; iwCLL: International Workshop on CLL; TP53: tumour protein p53; IGHV: Immunoglobulin heavy chain gene

Several clinical trials have sought to address whether active treatment with monotherapy or combinations offers meaningful benefit for early-stage asymptomatic patients with CLL, particularly those at a higher risk of disease progression. These include trials of fludarabine monotherapy (CLL-1),¹⁹ fludarabine, cyclophosphamide and rituximab (FCR; CLL7),¹⁹ and ibrutinib (CLL12).²⁰ However, none of these trials demonstrated OS benefit with active treatment versus active surveillance for asymptomatic early-stage CLL in patients with high-risk genetic profiles, i.e. TP53 mutation or del(17p). With the continuing development of additional novel targeted agents, there has been interest in re-evaluating the benefits of early therapeutic intervention. Several phase II/III trials comparing early intervention using newer targeted agents with watchful waiting are ongoing, including acalabrutinib-venetoclax (PreVent-ACaLL, NCT03868722),²¹ acalabrutinib with or without obinutuzumab (NCT03516617)²² and venetoclax-obinutuzumab (EVOLVE, NCT04269902)²³. Considering the available evidence, the authors favour the current standard approach of monitoring early-stage asymptomatic patients with CLL until there is evidence of disease progression and/or symptoms¹⁸ (see statement 1 in Table 1).

Pre-treatment testing

Due to the heterogeneous characteristics of CLL, pre-treatment testing of molecular biomarkers is considered valuable for guiding patient counselling, prognosticate disease and subsequent disease management.^9,18 Cytogenetic aberrations (assessed using fluorescence in situ hybridisation, or FISH) and the somatic hypermutation (SHM) status of the IGHV gene (assessed using Sanger sequencing or next-generation sequencing) are important biomarkers that provide both prognostic and predictive information in CLL.^18,24-26 Patients with del(17p) or TP53 mutation show poor responses to chemoimmunotherapy (CIT) but respond better to targeted agents.^18,27-29 In general, patients with unmutated IGHV (defined as <2% somatic hypermutation relative to the germline sequence) have a poorer prognosis than those with mutated IGHV due to faster tumour cell regrowth kinetics.^9,30 An exception is the B-cell receptor (BCR) stereotyped subset 2, representing 3% of CLL cases; although appearing IGHV-mutated in terms of SHM status, this subset is characterised by an aggressive clinical course and a poor prognosis.^31,32

The authors acknowledge the key factors of availability, accessibility and affordability in facilitating the uptake of molecular testing. A recent Asian consensus highlighted that resources for IGHV mutation testing are scarce in several Asian countries.⁹ As IGHV mutational status does not change over time, IGHV mutational testing can be done at the time of diagnosis. In contrast, cytogenetic testing should be conducted pre-treatment, as these aberrations may accumulate over the course of the disease¹⁸ (see statement 2 in Table 1).

Patient fitness

Patient fitness has been an important consideration for treatment selection, notably in the context of chemotherapy and CIT regimens. In clinical trials, the Cumulative Illness Rating Scale (CIRS) and creatine clearance (CrCl) are often used in combination to define patients’ fitness to receive CIT.^33,34 Fit patients are commonly defined as those aged <65 years with a CIRS score <6 and CrCl ≥70 mL/min.

In real-world practice, the assessment of fitness has evolved from focusing on chronological age to considering the patient’s physical condition and comorbidities. As such, comprehensive geriatric assessments and frailty indices may support a more nuanced evaluation of fitness and may be helpful in specific cases. That said, the CIRS remains practical and highly relevant in clinical settings as a well-established, standardised approach and judgements based on the CIRS and CrCl criteria are easily aligned with clinical trial data.

Treatment with novel targeted agents

Multiple studies have demonstrated the superior efficacy of novel targeted agents for TN symptomatic CLL, and these agents are now considered the standard of care in several healthcare systems.^5,6,10,11,35 Targeted agents include BTK inhibitors (BTKis such as ibrutinib, acalabrutinib and zanubrutinib) and B-cell lymphoma 2 (BCL-2i) inhibitors (i.e. BCL2is such as venetoclax).³⁶ CIT, the previous standard of care, may be a reasonable treatment option under certain circumstances, as discussed in later sections. However, CIT would not be considered for subgroups expected to show poor response to CIT, including patients with del(17p), TP53 mutations and the BCR stereotyped subset 2 (i.e. poor prognosis CLL subset characterised by IGHV3-21 gene expression with a short immunoglobulin heavy chain complementarity determining region 3, and a progressive phenotype regardless of IGHV mutational status³⁷). Pivotal randomised controlled trials (RCTs) of frontline therapies for CLL are summarised in Table 3. Most of these RCTs enrolled patients aged ≥65 years or unfit patients aged ≥18 years to <65 years, except for ALLIANCE A041202, which included only patients aged ≥65 years.³⁸

Table 3. Pivotal studies for treatment-naïve CLL.

Clinical trials of first-generation (i.e. ibrutinib) and second-generation BTKis (i.e. acalabrutinib and zanubrutinib) have demonstrated the superior efficacy of these targeted agents over standard CIT regimens for TN CLL. In the E1912 trial, the ibrutinib-rituximab combination demonstrated superior PFS (hazard ratio [HR] 0.35, 95% confidence interval [CI] 0.22–0.56) and OS (HR 0.17, 95% CI 0.05–0.54) compared with the FCR regimen in fit, young patients (<70-years-old) with TN CLL without del(17p).³⁹ In the ALLIANCE A041202 trial, ibrutinib alone (HR 0.39, 95% CI 0.26–0.58) and ibrutinib-rituximab (HR 0.38, 95% CI 0.25–0.59) both demonstrated superior PFS to bendamustine-rituximab (BR) in TN CLL patients ≥65 years; however, the OS duration was similar across the treatment arms.⁴⁰ Notably, the incidence of grade ≥3 hypertension and atrial fibrillation adverse events (AEs) was significantly higher with ibrutinib-containing regimens than with CIT (P<0.05) in ALLIANCE.⁴⁰ The ELEVATE-TN trial showed that acalabrutinib, with or without obinutuzumab, significantly prolonged PFS versus obinutuzumab-chlorambucil in elderly and generally less fit patients (CIRS score >6 or reduced creatinine clearance).³⁸ No cardiac AEs were reported with acalabrutinib-containing regimens in ELEVATE-TN.³⁸ The efficacy and safety of acalabrutinib, with or without obinutuzumab, were maintained at 6 years of follow-up. Estimated 72-month PFS rates were 78% for acalabrutinib-obinutuzumab, 62% for acalabrutinib monotherapy and 17% for obinutuzumab-chlorambucil.⁴¹ The median OS was not reached in any treatment arm and was significantly longer on acalabrutinib-obinutuzumab versus obinutuzumab-chlorambucil.⁴¹ The SEQUOIA study demonstrated superior PFS for zanubrutinib versus BR in TN CLL patients >65 years, with the rates of grade ≥3 cardiac events being similar across treatment arms.⁴² BTKis carry a possible risk for cardiac toxicity, as noted in studies on ibrutinib, although this risk is lower with second-generation agents (e.g. acalabrutinib, zanubrutinib). Clinicians should weigh the risks and benefits accordingly. Recent analyses, including a 3-year real-world study, reported a more favourable cardiovascular safety profile including lower rates of atrial flutter, hypertension and sepsis in patients treated with acalabrutinib versus ibrutinib.⁴³ Safety analyses using FDA Adverse Event Reporting System (FAERS) data highlighted that ibrutinib carries a higher incidence of severe cardiovascular events, notably atrial fibrillation, cardiac failure, pericardial effusion or haemorrhage, underscoring the need for careful patient selection and toxicity monitoring with long-term therapy.^44,45

Similarly, BCL2i-containing regimens were superior to CIT comparator regimens in TN CLL patients with coexisting conditions. In the CLL14 study, unfit patients with CIRS score >6 venetoclax-obinutuzumab for a fixed duration of 1 year demonstrated a significantly lower risk of progression than those receiving chlorambucil-obinutuzumab (HR 0.35, 95% CI 0.23–0.453).⁴⁶ The reduced risk of progression with venetoclax-obinutuzumab was maintained at 2 years after treatment cessation (HR 0.31, 95% CI 0.22–0.44).⁴⁷ Several trials, including CAPTIVATE and GLOW, have assessed the effects of combining a BCL2i with a BTKi.^48,55  In GLOW, treatment with a fixed-duration combination of venetoclax plus ibrutinib significantly reduced the risk of progression compared with chlorambucil-obinutuzumab (HR, 0.22; 95% CI, 0.13–0.36; P<0.001).⁴⁸

Targeted agents are now generally preferred over CIT because of their superior efficacy (see statement 3 in Table 1). In higher-risk TN CLL patients, i.e. unmutated or with del(17p) or TP53 mutation, CIT is generally not recommended, given the significantly inferior outcomes compared with BTKi or BCL2i-based therapy. CIT may be considered for TN CLL patients who are fit and have low-risk disease, i.e. mutated IGHV, without del(17p) or TP53 mutation, after careful consideration of side-effects associated with CIT—such as increased risk of acute haematological toxicity and infection, and a small increased risk of secondary myeloid malignancies.^49,50

Important considerations for selecting initial therapy in CLL include genetic risk, side-effect profile, clinical characteristics in a patient (overall fitness/performance, organ function, co-morbidities), patient preference (e.g. if there is a choice between continuous or time-limited therapy, or method of administration, such as intravenous injections), cost, accessibility and logistical concerns. Additionally, physician and centre experience managing treatment-related side effects may influence treatment selection. Resource availability at the system level, including access to specific drugs and diagnostic tests, may also be a relevant consideration.  Treating physicians should consider all these aspects and carefully counsel their patients to support informed decision-making as appropriate within their local context (see statement 4 in Table 1).

Treatment in patients with del(17p) or TP53 mutation

The presence of TP53 aberrations or del(17p) has historically been associated with poor prognosis,^27,29 with a median PFS of 11.3 months on FCR therapy.⁵¹ The introduction of small-molecule inhibitors (BTKis and BCL2is) significantly improved PFS among previously untreated patients with del(17p) or TP53 mutation,^38,40,46 and these targeted agents are now considered the standard of care for this patient subset.

A pooled analysis of 4 trials (PCYC-1122e, RESONATE-2, iLLUMINATE and E1912) included 89 patients with del(17p) or TP53 mutation receiving single-agent ibrutinib (n=45) or ibrutinib in combination with an anti-CD20 antibody (n=44). In this analysis, median PFS was not reached at 4 years of follow-up, and the estimated 4-year PFS and OS rates were 79% and 88%, respectively.⁵² Direct comparisons between continuous BTKi therapy versus (vs) time-limited targeted agent-based combinations are not available as the head-to-head trials are ongoing (e.g. CLL17/NCT04608318). However, there are indications that continuous BTKi therapy may confer longer PFS than time-limited regimens. While exercising caution in drawing inferences from cross-trial comparisons, at 76.4 months of follow-up in the CLL14 study for 10% of patients with del(17p) or TP53 mutation,⁴⁶ patients treated with fixed-duration venetoclax-obinutuzumab had a median PFS of 51.9 months.⁵³ The 5-year PFS for del(17p) or TP53 mutated patients was 40.6%, and the approximate 4-year estimated PFS was 52%.⁵⁴ Other highly-anticipated readouts include longer-term follow-up data for ibrutinib-venetoclax time-limited treatment regimens. Several factors are relevant when choosing between continuous BTKi-based therapy and time-limited therapy with venetoclax combinations. Time-limited therapy can potentially produce complete responses⁴² and allows for treatment-free intervals, which some patients may prefer. With finite treatment duration, there may be reduced risk of toxicity and potentially lower drug-related costs. However, these potential advantages must be weighed against additional requirements for safety monitoring (risk of tumour lysis syndrome) and dose ramp-up, which have logistical implications.

Available evidence indicates that second-generation BTKis are as effective as ibrutinib for the del(17p) or TP53-mutated patient subset. ELEVATE-TN randomised patients to receive acalabrutinib monotherapy, acalabrutinib-obinutuzumab, or obinutuzumab-chlorambucil.³⁸ A pre-specified subgroup analysis of ELEVATE-TN showed that the PFS benefit with acalabrutinib therapy was consistent across subgroups, including patients with del(17p) and TP53 mutation (14% of patients).³⁸ As for zanubrutinib, Arm C of the SEQUOIA trial includes patients with del(17p13.1) receiving zanubrutinib monotherapy.⁴² At the 24-month follow-up, the PFS and OS rates for Arm C were 88.9% and 93.6%, respectively.⁴² Given the accruing evidence for both first- and second-generation BTKis, continuous BTKi therapy is preferred over time-limited regimens for patients with del(17p) or TP53 mutation^{42, 52} (see statement 6 in Table 1).

Although continuous therapy is preferred in TP53 patient group, a BTKi + BCL2i time-limited regimen could be considered in the case of cardiac or bleeding concerns. Evidence supporting the use of venetoclax-BTKi combinations for patients with del(17p) or TP53 mutation has been limited, as trials have included few of these patients. However, the ongoing CAPTIVATE trial includes patients with del(17p) or TP53 mutation (17% of patients with known mutational status).⁵⁵ A follow-up analysis of CAPTIVATE data estimated the 4-year PFS and OS rates in this patient population at 63% and 96%, respectively.⁵⁶ In the venetoclax-obinutuzumab arm of CLL14, the grade ≥3 AE rates were 78.8% for all AEs, 52.8% for neutropenia and 6.6% for vascular AEs (i.e. hypertension and hypotension).⁴⁶ Of note, the incidence of grade ≥3 tumour lysis syndrome was lower with venetoclax-obinutuzumab than with chlorambucil-obinutuzumab (1% vs 3%).⁴⁶  In view of the available evidence, a BTKi-BCL2i combination is preferred over a combination of BCL2i plus an anti-CD20 monoclonal antibody for patients with del(17p) or TP53 mutation who prefer time-limited treatment (see statements 7 and 8 in Table 1). However, it should be noted that the follow-up of trials using BTKi and BCL2i combination regimens are relatively short.

Treatment in fit, IGHV-mutated patients without del(17p), TP53

The choice of treatment for TN CLL patients with mutated IGHV depends on their age, physiological fitness, presence of comorbidities, and FCR eligibility. As discussed above, younger patients (<65 years) with a CIRS score of <6 and CrCl ≥70 mL/min are considered fit to receive a more intensive CIT regimen in clinical trials.^33,34 In clinical practice, physicians may consider older patients (≥65 years) with good functional capacity or without comorbidities fit for treatment. Notably, the clinical trials discussed in this section included a substantial proportion of fit older patients, including 41% of patients in the E1912 trial,³⁹ 84% of those in ELEVATE-TN,³⁸ and 34% of patients enrolled in GAIA (CLL13).⁵⁷

For several years, fixed-duration CIT or chemotherapy was the standard treatment for previously untreated fit patients. FCR therapy in TN CLL was associated with significant PFS benefit over FC across several prognostic subgroups, including patients with mutated IGHV.⁵¹ A 5.9-year follow-up analysis of the CLL8 trial confirmed significant OS and PFS benefit with FCR over FC across several prognostic subgroups, including patients with mutated IGHV (HR [progression] 0.47, 95% CI 0.33–0.68; HR [death] 0.62, 95% CI 0.34–1.11).⁵¹ Median PFS and OS were not reached among IGHV-mutated patients who received FCR.⁵¹ In CLL10, frontline FCR therapy was associated with a higher PFS rate than BR at 31.7 months of follow-up. Although patients aged ≤65 years derived significant PFS benefit from FCR in CLL10, there was no significant PFS difference between FCR and fludarabine-cyclophosphamide (FC) for physically fit older patients aged >65 years (median PFS not reached versus 48.5 months; P=0.172).

Some studies have demonstrated the superiority of ibrutinib-based therapy over FCR in unselected CLL patient populations, including E1912 and FLAIR. Approximately 29% of patients in E1912 and 33.1% of those in FLAIR had mutated IGHV.^39,58 Although the planned interim analysis for E1912 (ibrutinib-rituximab versus FCR) showed a similar 3-year PFS rate in both treatment arms for patients with mutated IGHV (87.7% versus 88.0%; HR 0.44, 95% CI 0.14–1.36),³⁹ a long-term follow-up analysis (median follow up of 70 months) showed a significantly better 5-year PFS rate with ibrutinib-rituximab versus FCR (83% vs 68%; HR 0.27, 95% CI 0.11–0.62).⁵⁹ In FLAIR, a randomised trial (minimal residual disease-guided therapy comparing ibrutinib monotherapy with ibrutinib-venetoclax for up to 6 years versus FCR), ibrutinib-venetoclax therapy showed significantly higher efficacy than standard FCR.⁵⁸ After a median follow-up of 44 months, the 3-year PFS rate was 97.2% for ibrutinib-venetoclax versus 76.8% for FCR (HR [progression] 0.13, 95% CI 0.07–0.24), with OS benefit (HR 0.31, 95% CI 0.15–0.67), in the overall trial population.⁵⁸ However, the PFS results in the IGHV-mutated subgroup did not favour ibrutinib-venetoclax over FCR at the time of the analysis (HR 0.54, 95% CI 0.21-1.38). The OS results favoured ibrutinib-venetoclax in IGHV-unmutated patients (HR 0.23, 95% CI 0.06–0.81) but not in IGHV-mutated patients (HR 0.61, 95% CI 0.20–1.82).⁵⁸ It remains to be seen how and whether longer follow-up will impact these results as in the E1912 trial.

The GAIA trial showed that venetoclax-based combinations (venetoclax-rituximab vs venetoclax-obinutuzumab vs venetoclax-obinutuzumab-ibrutinib) were superior to CIT (FCR or BR) in physically fit patients with TN CLL. At 38.8 months of follow-up, among patients with unmutated IGHV, PFS rates were 86.6% in the venetoclax-obinutuzumab-ibrutinib group, 82.9% in the venetoclax-obinutuzumab group, 76.4% in the venetoclax-rituximab group and 65.5% in the CIT group, as compared with 96.0%, 93.6%, 87.0% and 89.9%, respectively, in patients with mutated IGHV. In the prespecified subgroup analysis, this benefit of venetoclax-obinutuzumab therapy with or without ibrutinib was observed in all groups except for those with mutated IGHV, trisomy 12, normal karyotype and intermediate CLL-IPI scores. OS rates at 3 years were comparable across all treatment arms.⁵⁷ Overall grade ≥3 SAEs were numerically higher in the venetoclax-obinutuzumab-ibrutinib arm compared with CIT or other venetoclax arms.⁵⁷

Based on available evidence, first-generation BTKi-based or venetoclax-based regimens or FCR are reasonable options for fit patients with mutated IGHV. Expected toxicity profiles, medical comorbidities, patient preference, cost, accessibility and logistical concerns all play an important role in guiding treatment decisions (see statements 9 and 10 in Table 1). As for FCR, the availability of data on long-term outcomes of BTKi-based and venetoclax-based therapy trials will help clarify their comparative “curative” potential in this patient subset.

Treatment in unfit, IGHV-mutated patients without del(17p) or TP53 mutation

Several targeted agents have been investigated for the treatment of unfit patients with mutated IGHV. In the ALLIANCE study, ibrutinib with or without rituximab was superior to BR with respect to PFS in unfit older patients (note that IGHV mutation status was not reported).⁴⁰ Both RESONATE-2 and iLLUMINATE assessed the efficacy of ibrutinib-containing regimens in FCR-ineligible older patients. Up to 44% of the patients in RESONATE-2 had mutated IGHV; in this study, ibrutinib therapy was associated with significantly longer PFS (HR 0.16, 95% CI 0.09–0.28) and OS (HR 0.16, 95% CI 0.05–0.56) compared with chlorambucil. The PFS benefit with ibrutinib was consistently demonstrated across prespecified subgroups, including patients with mutated IGHV (HR 0.15, 95% CI 0.05–0.43).⁶⁰ Similarly, iLLUMINATE demonstrated PFS benefit with ibrutinib-obinutuzumab over chlorambucil-obinutuzumab (HR 0.25, 95% CI 0.16–0.39) at 45 months of follow-up. PFS benefit with ibrutinib-obinutuzumab was also observed in patients with mutated IGHV (HR 0.20, 95% CI 0.07–0.59).⁶¹

Clinical trials of second-generation BTKis (ELEVATE-TN and SEQUOIA) have enrolled FCR-ineligible older patients aged ≥65 years or unfit younger patients aged ≥18 years. Of 535 patients in ELEVATE-TN randomised to acalabrutinib or acalabrutinib-obinutuzumab or obinutuzumab-chlorambucil, there were 338 patients (63.1%) with unmutated IGHV and 191 (35.7%) patients with mutated IGHV.³⁸ Acalabrutinib-obinutuzumab significantly improved PFS versus obinutuzumab-chlorambucil in both IGHV-mutated patients (HR 0.15, 95% CI 0.04–0.52) and IGHV-unmutated patients (HR 0.08, 95% CI 0.04–0.16).³⁸ In SEQUOIA, PFS in IGHV-mutated patients who received zanubrutinib-rituximab was not significantly different from that in BR-treated patients (HR 0.67, 95% CI 0.36–1.22).⁴²

The results of CLL14 support a role for BCL2i-containing regimens in treating older or unfit younger patients with mutated IGHV. In CLL14, 39% of patients with known mutation status had mutated IGHV.⁶² In this IGHV-mutated subset, fixed-duration venetoclax-obinutuzumab significantly improved PFS relative to chlorambucil-obinutuzumab (HR 0.36, 95% CI 0.19–0.68) at 4 years of follow-up.⁶² In GLOW (26% with mutated IGHV), PFS was significantly longer with fixed-duration ibrutinib-venetoclax than with chlorambucil-obinutuzumab (HR 0.233, 95% CI 0.065–0.839) at 27.7 months, although with higher rates of cardiac toxicity related to ibrutinib.⁴⁸

Less intensive chemotherapy or CIT regimens for treatment-naïve unfit patients include bendamustine-rituximab,⁶³ chlorambucil-obinutuzumab,⁶⁴ single-agent rituximab,⁶⁵ obinutuzumab, or chlorambucil.⁶⁶ As for fit IGHV-mutated patients, treatment selection for unfit patients should also consider expected toxicity profiles, presence of comorbidities, patient preference, cost, availability, and logistical concerns (see statements 11–13 in Table 1).

Treatment in IGHV-unmutated patients without del(17p)

The presence of unmutated IGHV is consistently associated with poor prognosis in CLL, and it is one of the biomarkers included in the CLL-IPI.^30,67,68 As for other patient subsets, including those with mutated IGHV, targeted therapies have shown notable efficacy for unfit patients with unmutated IGHV, and are thus recommended (see statements 14 and 15 in Table 1). Across trials of targeted agents, the proportions of patients with unmutated IGHV (known mutational status) were 44% in RESONATE-2, 58% in iLLUMINATE, 63% in ELEVATE-TN, and 51% in SEQUOIA.^38,42,60,61 In RESONATE-2, single-agent ibrutinib therapy significantly improved PFS versus chlorambucil (HR 0.13, 95% CI 0.06–0.31) at 18.4 months follow-up in older patients with unmutated IGHV.⁶⁰ Similarly, among patients with unmutated IGHV in E1912, ibrutinib-rituximab showed superior 3-year PFS compared with FCR  (90.7% vs 62.5%; HR 0.26, 95% CI 0.14–0.50).³⁹ In a 48-month analysis of iLLUMINATE data, PFS outcomes in unfit patients with unmutated IGHV favoured ibrutinib-obinutuzumab over chlorambucil-obinutuzumab (HR 0.17, 95% CI 0.10–0.29). Similar trends have been noted with second-generation BTKi therapy in unfit patients with unmutated IGHV. In ELEVATE-TN, the 24-month PFS rate was higher in patients receiving acalabrutinib-obinutuzumab than those receiving obinutuzumab-chlorambucil (91% vs 31%; HR 0.08, 95% CI 0.04–0.16).³⁸ This was maintained at 6 years of follow-up, with the PFS rates in the IGHV-unmutated subgroup being 75% (acalabrutinib-obinutuzumab), 60% (acalabrutinib monotherapy) and 5% (obinutuzumab-chlorambucil).⁴¹ In the SEQUOIA study, zanubrutinib treatment was associated with improved PFS versus BR (HR, 0.24; 95% CI, 0.13–0.43) at 26.2 months follow-up.⁴²

BCL2i-containing regimens have shown superior PFS to standard CIT in patients with unmutated IGHV. In CLL14 (60% IGHV-unmutated patients), PFS outcomes at 24 months strongly favoured venetoclax-obinutuzumab over chlorambucil-obinutuzumab in patients with unmutated IGHV (HR 0.22, 95% CI 0.12–0.38).⁴⁶ In GLOW (52% IGHV-unmutated patients), PFS was also significantly longer with ibrutinib-venetoclax compared with chlorambucil-obinutuzumab (HR 0.269, 95% CI 0.148–0.488) at 27.7 months follow-up.⁴⁸

CONCLUSION

The clinical consensus developed through this modified Delphi process offers practical guidance for clinicians managing TN CLL patients in Singapore and similar healthcare systems. The recommendations made for different patient subsets are based on a range of factors, from biomarker profiles to comorbidities, fitness, and treatment preferences. For early-stage asymptomatic CLL patients, active surveillance is recommended, along with pre-treatment molecular biomarker testing to guide treatment selection. In general, targeted agents are prioritised over chemotherapy/CIT, especially for unfit patients, while chemotherapy/CIT may remain relevant for selected patients, e.g. young/fit and without del(17p) or TP53 mutations. Although the use of targeted agents has improved outcomes in patients with del(17p) or TP53 mutation, more effective regimens are needed to extend survival and preserve quality of life. Emerging strategies such as minimal residual disease (MRD)-guided adaptive approaches offer a promising way to tailor treatment duration to improve outcomes.⁵⁸ Although discussed in recent guideline updates,^15,16 MRD-guided approaches are not considered sufficiently mature for routine adoption; moreover, these assessments require specialised flow cytometry capabilities and expertise that may not be widely available—an important practical consideration.¹¹ However, once adequately validated in clinical trials, MRD-guided approaches could help rationalize treatment choices and duration.

While this clinical consensus focuses primarily on guiding front-line management, it is relevant to consider the potential implications of initial treatment selection for subsequent therapy in the relapsed/refractory setting. Patients who relapse after treatment with a novel agent (BTKi or BCL2i) may show a response to an agent of the other class. Patients achieving remission on time-limited regimens (BCL2i combinations) can be re-treated if their remission lasted 3–5 years, whilst treatment with a BTKi remains an option irrespective of the duration of remission.^10,11 On the other hand, patients relapsing after treatment with covalent BTKis (e.g. ibrutinib, acalabrutinib, zanubrutinib) are unlikely to respond to another covalent BTKi, and require alternatives such as BCL2i-based therapy. As more patients receive targeted agents earlier in the disease course, options to overcome resistance or intolerance will be increasingly important. Emerging options include non-covalent BTK inhibitors, such as pirtobrutinib, which have demonstrated promise in re-establishing BTK inhibition and clinical responses.^69,70,71 Of note, ongoing pirtobrutinib trials have recruited Asian participants; these include head-to-head studies with covalent BTKis (NCT05254743, BRUIN-CLL-314).⁷² Such studies should provide valuable Asian-specific CLL outcome data, which has hitherto been very limited. Other agents like nemtabrutinib and vecabrutinib are being studied in ongoing trials, although resistance to non-covalent BTKis is also emerging.^73,74 BTK protein degraders may represent another emerging option in cases of BTKi resistance.⁷⁵

The main motivation of this consensus is to promote clinical practice improvement and standardisation, based on the best available evidence. As an additional benefit, the exercise of regularly updating clinical guidelines facilitates consultation and dialogue among funders, regulatory bodies, local experts and national societies. These interactions are important to guide selection and implementation of appropriate interventions, which may include tiered pricing or expanded access programmes, depending on the characteristics of the health system. Effective collaboration among all stakeholders is critical for securing appropriate access to effective therapies, and achieving sustainable improvement in outcomes for patients and healthcare systems. Moving forward, regular updates will ensure these clinical recommendations remain responsive to emerging evidence and clinical practice.

Supplementary Material

Acknowledgements
The authors gratefully acknowledge the support of the Asia-Pacific Leukaemia Consortium for this project. Medical writing and editorial support during the modified Delphi process and for manuscript preparation was provided by Tech Observer Asia Pacific (Singapore).

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Ethics statement

These consensus guidelines did not involve the collection or analysis of patient data. As such, ethics review and patient informed consent were not applicable.

Declaration

CN received clinical trial research funding from Janssen and speaker honoraria/Advisory Boards from AAstraZeneca, Abbvie, DKSH and Janssen. VSS received honoraria from Roche, Amgen, Johnson and Johnson, Sanofi, Antengene, DKSH, Abbvie, AstraZeneca and Novartis. YTG served as consultant for Amgen, Antengene, Astellas, AstraZeneca, GlaxoSmithkline, Janssen, Novartis, Pfizer and Roche and received honoraria from AbbVie, DKSH and Recordati. The other authors have no conflict of interest to declare. This project was supported by the Asia-Pacific Leukaemia Consortium with a grant from AstraZeneca Singapore. AstraZeneca Singapore was not involved in the consensus generation process and did not influence the decisions or outcomes of the consensus.

Correspondence

Professor Yeow Tee Goh, Singapore General Hospital, Outram Road, Singapore 169608. Email: [email protected]