Blood cancers

Updated CLL guidelines mark a ‘paradigm shift’ in treatment strategy


Updated guidelines on the treatment of chronic lymphocytic leukaemia (CLL), incorporate new strategies that the UK authors say amount to a paradigm shift in treatment approach.

Published in the British Journal of Haematology, the guidelines recommend acalabrutinib-obinutuzumab and ibrutinib monotherapy as first-line treatment options for all CLL patients with or without TP53 disruption.

Other recommendations include venetoclax-obinutuzumab (VenO) or acalabrutinib as initial therapy in patients unsuitable for chemoimmunotherapy, irrespective of TP53 status.

Options for fit patients with TP53 disruption and a contra-indication to a B-cell receptor inhibitor include acalabrutinib, ibrutinib, or venetoclax monotherapy.

For fit patients with intact TP53, VenO can be used, and for those with mutated IGHV, chemoimmunotherapy with FCR (fludarabine, cyclophosphamide and rituximab) remains “an acceptable initial therapy”, but bendamustine-rituximab or chlorambucil with obinutuzumab are no longer recommended.

Targeted inhibitors (BTKi or BCL2i alone or in combination with rituximab) “are the treatment of choice for relapsed CLL”, the guidelines state, while allogeneic stem cell transplantation remains an option for suitable patients with high-risk CLL, but CAR-T therapy is still only an option in clinical trials.

The guidelines also make a comprehensive set of recommendations on infection prevention and COVID, including offering all patients vaccinations at diagnosis, prophylactic antibiotics to those with recurrent or serious infections, and monoclonal antibody therapy for CLL patients who develop COVID-19 infection and are within five days of symptom onset.

Speaking to the limbic, Professor Adrian Bloor, Consultant Haematologist at The Christie NHS Foundation Trust, Manchester, said one of the biggest changes within the new guidelines “is the move away from immunochemotherapy to more targeted treatment, particularly in the frontline setting”.

This, he noted, has been driven by the emergence of evidence showing that targeted therapy with BTK or BCL2 inhibitors works better first-line than further back in the treatment pathway, which in turn, has driven a “paradigm shift” away from use of immunochemotherapy.

As per the new guidelines, “a lot of people with CLL will no longer be exposed to chemotherapy and are going to be getting generally better tolerated treatment without the long-term/short-term side effects,” he said.

Newer, targeted therapies have also changed the treatment algorithm in that they have been shown to be more effective at improving progression-free survival in a much wider range of patients, including those deemed “less fit”.

“There will clearly still be some patients who are not suitable for anything beyond supportive therapy, but they’ve actually now become a small minority, which has been a really positive development”.

However, Professor Bloor also noted that treatment decisions are less clear as the distinction between which CLL patients are “fit” and “less fit” becomes less relevant with targeted therapies. Sequencing decisions will also become more challenging given the wider choice of treatments available. As such, physicians are now faced with making choices on whether to give shorter duration or continuous treatments, and which of the newer therapies (ibrutinib and acalabrutinib) to use first.

Click here to view the guideline in full.      

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