ASH 2025 | Guidance for treating patients with CLL who have relapsed after initial therapy

So I think it depends a little bit on how exactly they relapsed, right? So did they get a BTK inhibitor as a single agent? Did they get a BTK inhibitor in combination with something else? Were they on a treatment-free interval and did they have a durable remission if they had some sort of BTK-based combination? Or are they truly refractory to the BTK inhibitor and needing to have their next course of therapy? So I’ll take a little bit of those scenarios and sort of how I’ve been managing them. So for patients who are on a single agent BTK inhibitor as monotherapy and who actually progress and become refractory while on treatment, I think the critical aspect in management is not to stop the BTK inhibitor until you absolutely have to. So if you’re going to enroll them on a clinical trial that requires a washout, you want to minimize that time as much as possible. These patients, when they do discontinue therapy, will get hyperprogression. They can often have very dramatic inflammation in their lymph nodes and spleen, significant cytopenias, and a lot of constitutional symptoms. And so you really want to try and keep them on that until you get your next course of therapy in. I typically use a venetoclax-based strategy. So the MURANO is the international Phase III that established venetoclax and rituximab. We found from CLL13 in the treatment-naive setting that venetoclax and obinutuzumab was superior to venetoclax and rituximab. And so consequently, I’ve largely been using obinutuzumab and venetoclax. And generally, I keep the BTK inhibitor going, I start the obinutuzumab, and then I do the venetoclax dose escalation. Once we’ve established some control of the CLL, then I’ll often discontinue the BTK inhibitor. In patients who may not be eligible for venetoclax, pirtobrutinib has reasonable data, and I have been using some pirtobrutinib. The challenge with pirto is if you have a patient that’s truly BTK refractory, their median PFS is only about a year and a half with single agent pirtobrutinib. So that is a little bit not acceptable to a fair number of patients, but I work in a practice where I have a number of rural patients who it’s very challenging to get them in for venetoclax. If they’ve had combination therapy and have had a durable response to combination therapy, then pretty much whatever you want to do is fair game. You can retreat them with what they had in the first place. There’s certainly retreatment data for both obinutuzumab and venetoclax as well as with BTK inhibitor doublets. And so I think it’s reasonable to offer them pretty much whatever you want. The other part of this that I think is really important is that the main governor is patient preference. So we don’t have randomized data suggesting that any of the regimens that I just discussed are superior to any of the others other than the areas where I’ve cited them. And as a consequence, if a patient has a really strong preference towards doing one thing or another, that will often sway me to pursue one approach versus another one.

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