Role of BTK Inhibitors as Second-Line Therapy for Patients With CLL


Andrew Lipsky, MD, considers the role of BTK inhibitors as second-line therapy in patients with relapsed/refractory chronic lymphocytic leukemia.


Andrew H. Lipsky, MD: BTKIs [Bruton tyrosine kinase inhibitors] absolutely have a role in treating relapse and refractory disease, a very important role. But when thinking about the best therapy for a patient with relapse disease, really the most important factor is what the patient has previously received in terms of lines of therapy. It’s worth pointing out that the NCCN [National Comprehensive Cancer Network] treatment guidelines don’t offer in-depth tailoring for which targeted treatment to pick. But I can highlight the way that I think about it.

It’s helpful to separate patients into groups based on previous exposure. Did they have frontline chemo-immunotherapy? Did they [receive] a frontline BTK inhibitor, or did they have a frontline BCL2 [B-cell lymphoma 2] inhibitor? So first, for patients who have received only chemo-immunotherapy, [therapy is] either a covalent BTK inhibitor, or a venetoclax-based strategy like venetoclax-rituximab. Those are good options. I think there’s no definitive randomized data to support one strategy over another. And it’s there that, when choosing between BTKIs or venetoclax, I focus exactly on those disease specific factors and patient specific factors like I would in the case of treating a frontline patient. Do they have a deletion 17p, etc.? How might this impact their life? What are their comorbidities? What’s their risk of TLS [tumor lysis syndrome]? How’s their renal function? Do they have significant cardiac disease, etc.? Looking at the medications they’re currently on and looking for drug interactions.

In patients who have received a prior venetoclax therapy in the frontline, [like] the patient in this case, if they progressed while on therapy it’s necessary to switch to a covalent BTK inhibitor. If they progressed after completing the venetoclax therapy, it’s acceptable to either re-treat with venetoclax or to switch to a covalent BTK inhibitor. And the duration of response to venetoclax may bias me in one direction or the other. For example, the updated 5-year data from the MURANO study [NCT02005471] showed a 72% overall response rate to venetoclax re-treatment, and real-world data shows a similar result. Thus in a patient who had a particularly longer remission with venetoclax therapy, this might be a reasonable approach. Otherwise I would definitely go with a BTK inhibitor.

For patients who have received prior BTK inhibitors, I think current guidelines recommend switching to a venetoclax-based regimen. The real-world, pooled data from multiple centers suggests this has a really high response rate of over 85%. And it’s worth pointing out that that may change with the introduction of pirtobrutinib, which is now approved in mantle cell [lymphoma]. We saw data from the BRUIN study [NCT03740529] with CLL [chronic lymphocytic leukemia] patients suggesting that this may also be an excellent option utilizing a noncovalent BTK inhibitor to overcome resistance. But for the moment that’s not an approved indication in CLL.

Transcript edited for clarity.

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