SOHO 2025 | Planning frontline therapy in CLL: continuous vs fixed-duration treatment, sequencing, & more

Our session was focused on how we are treating frontline CLL patients and three of us presented on our different treatment paradigms that exist right now for frontline treatment for chronic lymphocytic leukemia, continuous BTK inhibitor therapy with either acalabrutinib or zanubrutinib with or without obinutuzumab with acalabrutinib, fixed-duration therapy with venetoclax obinutuzumab, and now fixed-duration therapy with BCL2 inhibitors and BTK inhibitors such as acalabrutinib and venetoclax with or without obinutuzumab and ibrutinib and venetoclax. The key takeaway I would say from all three of the talks was that there’s more information that we need in order to be able to truly say that one therapy is better than the other. We have no comparative trials that say one particular treatment strategy is more effective and will make patients live longer and as such we really do bring our patients into the discussion about what is the best treatment option for them whether it’s continuous BTK inhibition or a fixed duration therapy with a BCL2 inhibitor backbone. One of the challenges I think that we talked about particularly in the discussion was well how should we be sequencing therapies and what do we do with this idea of clonal evolution and how do we best target that particularly for patients with higher risk genomic features such as unmutated IGHV status and deletion 17p and TP53 mutations. None of us actually have the answers, but all of us have our own intrinsic biases, with some ideas being maybe we should continuously suppress a clone, even though we know that down the line we may develop a resistance mutation to our current therapies, or should we do fixed-duration therapy knowing that that limits a number of side effects and the potential for resistance mutations developing, but then may allow the CLL clone to evolve on its own? And I think that that’s a really important question that none of us have the answer to and probably would be very important when we think about the lifespan of a CLL patient is continuing to increase and how can we better understand what our drugs do and what those implications are for treatment down the line.

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