Routine frontline chemoimmunotherapy is out, targeted therapy is in under updated Australasian guidance for chronic lymphocytic leukaemia.
Chemoimmunotherapy should no longer be considered routine first-line treatment for chronic lymphocytic leukaemia, according to an updated Australasian consensus statement that reflects the growing dominance of targeted therapies and precision medicine in the disease.
The 2026 update, published in the Internal Medicine Journal, revises the region’s 2023 guidance following the publication of pivotal phase III trials, longer-term follow-up of established studies and wider availability of molecular diagnostics and novel agents in Australia and New Zealand.
Developed by haematologists from across both countries, the recommendations are endorsed by the Australasian Lymphoma Alliance, the Australasian Leukaemia and Lymphoma Group CLL Working Party and the Haematology Society of Australia and New Zealand and use the GRADE framework to assign levels of evidence and strength of recommendations.
The statement places greater emphasis on genomic profiling before treatment.
The panel now recommends immunoglobulin heavy chain variable region (IGHV) mutation analysis, next-generation sequencing (NGS) and FISH or microarray testing before first-line therapy, with repeat NGS and FISH or microarray before each subsequent line of treatment. Testing for TP53, BTK and BCL2 mutations at relapse is expected to play an increasingly important role in selecting therapy as resistance mechanisms emerge.
The researchers said that evidence accumulated since 2023 had shifted the balance decisively away from chemoimmunotherapy.
“There is now long-term follow-up of fixed-duration (FD) venetoclax combinations in patients with mutated IGHV (IGHV-M) disease showing excellent outcomes (five-year progression free (PFS) 82.9%) and a plethora of clinical trials showing superiority of targeted agents over CIT approaches,” the researchers wrote.
“Given the well-recognised toxicities of CIT, in particular those associated with DNA damage such as the cumulative risk of therapy-related myeloid neoplasms (tMN) (6.3% post FCR7), the risk benefit analysis now favours targeted approaches over CIT including for IGHV-M disease.
“As such, CIT should only be used in exceptional circumstances where targeted therapies are not available.”
Instead, clinicians should offer either continuous covalent Bruton tyrosine kinase inhibitor (BTKi) therapy or fixed-duration venetoclax-based combinations.
The guideline recommends venetoclax-obinutuzumab, ibrutinib-venetoclax, acalabrutinib-venetoclax and acalabrutinib-venetoclax-obinutuzumab as appropriate first-line options, with treatment individualised according to genomic risk, cardiovascular and bleeding risk, renal function, comorbidities and patient preference for fixed-duration or continuous therapy.
Among BTK inhibitors, the panel favoured the second-generation agents acalabrutinib and zanubrutinib over ibrutinib because they maintain efficacy while reducing important cardiovascular toxicities, including atrial fibrillation, and, in the case of acalabrutinib, hypertension.
Continuous BTKi therapy also appeared less affected by adverse biological features such as unmutated IGHV, TP53 abnormalities and bulky disease, although it required indefinite treatment and carries ongoing risks of bleeding, infection and cardiac adverse events.
The guideline reviewed emerging evidence for fixed-duration combination strategies. Venetoclax-obinutuzumab remains an attractive option because it achieves high rates of undetectable minimal residual disease (MRD), with around three-quarters of patients reaching undetectable MRD at the end of treatment.
The regimen also offered the possibility of successful retreatment after relapse. However, the researchers said benefits of this should be measured against the need for intravenous therapy, tumour lysis syndrome monitoring and a potentially higher infection risk than some BTKi-based combinations.
Newer BTKi-BCL2 inhibitor combinations continued to reshape the treatment landscape, the researchers said.
They noted that acalabrutinib-venetoclax demonstrated progression-free and overall survival advantages over chemoimmunotherapy in the AMPLIFY trial while avoiding some of the cardiac toxicity associated with ibrutinib-containing regimens.
Triplet therapy with acalabrutinib, venetoclax and obinutuzumab produced deeper MRD responses and may overcome the adverse prognosis associated with unmutated IGHV disease, although this came at the cost of increased serious infections.
Related
The researchers suggested that triplet therapy may be most appropriate for younger patients with high-risk disease after careful discussion of risks and benefits.
The update substantially revises management of relapsed disease by focusing on prior treatment history rather than simply line of therapy.
Clinicians are encouraged to distinguish between patients who discontinued treatment because of intolerance and those whose disease progressed on therapy, as this has important implications for subsequent treatment choice.
Patients previously treated with fixed-duration venetoclax could reasonably receive retreatment with venetoclax or switch to a BTK inhibitor, while patients progressing on continuous BTKi therapy should generally receive venetoclax-rituximab.
The researchers highlighted the growing importance of molecular resistance testing in relapsed disease.
Mutations affecting BTK, PLCG2 and BCL2 pathways may guide treatment decisions, while emerging BTK mutations such as L528W and A428D could confer resistance to both covalent and non-covalent BTK inhibitors, underscoring the need for repeat genomic assessment before treatment selection.
For patients with disease refractory to both BTK and BCL2 inhibition, treatment options remain limited. The panel recommended prioritising enrolment in clinical trials wherever possible.
Outside a trial, the non-covalent BTK inhibitor pirtobrutinib was identified as the preferred option based on evidence of meaningful response rates in heavily pretreated patients, although progression-free survival remained modest.
Cellular therapies also receive updated recommendations. The statement reiterated that allogeneic stem cell transplantation remains the only proven curative treatment for CLL and should be considered in younger, fit patients after commencing a second targeted therapy, particularly those with adverse genetic features or Richter transformation.
The researchers acknowledged the emerging role of CD19-directed CAR T-cell therapy, noting that while durable remissions have been achieved in selected patients, response rates remain modest and toxicity was greater than in several other B-cell malignancies.
Beyond treatment, the guideline expands its recommendations on supportive care, arguing that improved survival meant clinicians must increasingly manage the long-term consequences of CLL.
Infection prevention, cardiovascular disease, secondary malignancies (particularly skin cancer and therapy-related myeloid neoplasms), bone health, frailty and psychosocial wellbeing were core components of survivorship care and advocated a person-centred approach that extends beyond disease control, the researchers said.
“A survivorship model of care provides an opportunity to deliver a person-centred approach to optimise outcomes for patients with CLL,” the researchers concluded.
