ASH 2024 | A retrospective study of outcomes with ven-based treatment in cBTKi-treated, chemotherapy-naïve CLL

This is an area where lots of questions and limited data. So venetoclax-based treatment, very effective regimens in both first-line and relapsed-refractory settings for patients with CLL. The issue being that in the relapsed setting, the pivotal Phase III trial of the MURANO study really lacked patients with prior B cell receptor inhibitors, specifically BTK inhibitors which are now one of the main standard of care first-line options. The single prospective then-monotherapy study in a BTKI-exposed and refractory patient population reported fairly underwhelming outcomes with median progression-free survival that was lacking compared to the data in MURANO and chemotherapy-exposed patients. And subsequently multiple retrospective cohorts that looked at venetoclax-based regimens after BTKI exposure, and specifically BTKI resistance, also kind of were underwhelming in the results there. However, across all of those, the issue was that these patients were actually more heavily pretreated, and so the more common contemporary scenario of you have BTKI with no prior chemo, and then you move on and you’re getting a venetoclax-based regimen as a subsequent line of therapy, what does that look like? Do you still see these kind of worse outcomes? And so that’s the aim of this study. This was a multi-center international retrospective study, including patients from Mayo Clinic and eight centers across France. And we had a total of 80-odd patients, 39 of which were covalent BTKI resistant, meaning they had disease progression on a covalent BTK inhibitor, and the remainder were exposed, meaning they had been treated with a BTKI for some amount of time without having disease progression on this. The median time to next therapy or death, TTNTD, was around three years for the total cohort. It was actually about 6.5 years for the patients who just had BTKI exposed disease, so not refractory to that class of drugs, which is excellent. Whereas it was around two and a half years, around 30 months, I believe, in the patients who had true disease resistance to covalent BTKI inhibitors. Overall survival likewise, the median looks actually fairly good at this, maybe around 6 years, but when you look after 2 years the continued deaths make that keep kind of trending down for the patients with covalent BTKI resistant disease, and so the median OS was also underwhelming. The only thing that we saw that continued to kind of shine through from a prognostic perspective was TP53 disruption in the overall cohort but specifically in the covalent BTKI resistant cohort both for time to next therapy or death as well as overall survival, kind of still showing the importance of that prognostic marker. So these are the take-home points: even in a chemotherapy-naive patient population who have CLL that is resistant to covalent BTK inhibitor, you’re getting less mileage than I think most of us were expecting and patients are often expecting from that next line of therapy with venetoclax. I do want to caution in generalizing these more broadly because it was a retrospective study and still a relatively small cohort. They’re enriched for high-risk features and a kind of intangible high-risk feature that we may not directly think of as much as complex karyotype and TP53 and IGHV is their duration of benefit on their BTK inhibitor. So the time that the patients who had covalent BTKI resistant disease were treated, derived benefit from that BTK inhibitor was shorter than you would, than the median, the shorter than you would expect. So that’s kind of telling us some intangibles about the disease itself, in a way that isn’t as easily quantifiable with molecular testing. So I think as good as the progress has been, I think there is still a subset of high-risk patients that we need to be creative and have novel clinical trial strategies and try to address both first-line and subsequent-line targeted agent strategies.

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