Venetoclax-based regimens should be the first-line treatment for chronic lymphocytic leukaemia (CLL) without TP53 mutations, according to new European guidance presented at EHA 2026.
The guidelines also recommend acalabrutinib and zanubrutinib over ibrutinib for continuous therapy, with chemoimmunotherapy no longer recommended in any setting.
“The new guidelines support approaching the management of CLL in a more holistic fashion, from the initial diagnosis (including active surveillance) to treatment need, with particular emphasis on the interplay between disease- and patient-specific criteria for decision-making, to the latest stage of possible Richter transformation,” wrote the authors, including Professor Anna Schuh, honorary consultant haematologist at Oxford University Hospitals NHS Foundation Trust.
The guidelines, which are also published in HemaSphere [link here], were developed on behalf of EHA for the first time, having previously been produced by the European Society for Medical Oncology (ESMO).
They place a renewed focus on Richter transformation, which is now explicitly included in the guidelines’ title, and patient advocacy representatives have contributed for the first time.
The authors also note that the guidelines will now be updated annually, due to the fast pace of developments and the “continuous flurry of novel diagnostic/prognostic procedures, as well as new drug approvals.”
Regarding diagnostics, the guidelines note that all patients should be tested for IGHV mutational status before first-line treatment, and for TP53 aberrations before each line of therapy.
Complex karyotype testing is not recommended due to a lack of reproducibility.
The guidelines note that the International Workshop on CLL criteria should be used to determine if treatment should start, but that high-risk biological features alone are not an indication to treat asymptomatic patients.
Vaccinations in patients on active surveillance are recommended, but not live vaccines or antimicrobial prophylaxis, with immunoglobulin replacement therapy only advised in recurrent or active infections causing hospitalisation.
They also recommend that patients are encouraged to take part in cancer prevention screenings, while vitamin D and other supplements do not have to be prescribed routinely.
Chemoimmunotherapy is no longer recommended as a first-line treatment, as these drugs are either inferior to targeted agents or more toxic.
Time-limited therapies are preferred to continuous therapy in patients without TP53 mutations, or those with mutated IGHV status.
Acalabrutinib plus venetoclax, with or without obinutuzumab, is now recommended as a first-line treatment option for patients without IGHV aberrations, while venetoclax and obinutuzumab is the preferred option for those with mutated IGHV.
For continuous therapy, acalabrutinib and zanubrutinib are recommended over ibrutinib for all new patients due to their superior cardiac safety, although patients who are well controlled on ibrutinib should not be switched.
Recommended treatment for relapsed/refractory CLL is dependent on prior treatment, with venetoclax-based regimens advised if not used in the previous line, and retreatment with venetoclax also an option.
For Richter transformation, the guidelines recommend that patients with diffuse large B-cell lymphoma (DLBCL) should be evaluated for the clonal relationship with CLL.
Patients with Richter transformation DLBCL are strongly encouraged to enrol in clinical trials, with chemoimmunotherapy recommended otherwise.