ASH 2023 | Ibrutinib + venetoclax in treatment-naïve WM: results from a Phase II trial

So this year, we’re presenting an abstract on the study combining ibrutinib and venetoclax in patients with Waldenström’s. This is actually the first study that is looking at this combination in patients with Waldenström’s and we looked at this combination in patients who were previously untreated, so this is the first treatment that these patients received. The main reason we wanted to do this is that we wanted to offer patients a chemotherapy-free, all-oral, finite-duration therapy, and we had previous experience from our laboratory, as well as clinical experience with other conditions like CLL and mantle cell lymphoma, showing that this combination was actually safe and effective. 

So we aimed at enrolling 50 patients, and we wanted to show that we could achieve a VGPR rate of at least 45%. So when we were into 45 patient accrual, we had a couple of bad outcomes. We had a couple of patients who actually died from a ventricular arrhythmia -that’s called a grade five. And at that moment, we had to stop the study, stop the treatments but follow-up will continue on these patients. So some patients took about two years of the therapy, which was the initial plan, but some patients took only 12 months, some patients took about six months. The median time on treatment was about ten cycles and that’s what most patients received. And we were able to get to a VGPR rate of about 42%. So we’re very close to our goal. 

Obviously, this was an unexpected outcome, and kind of thinking about what the potential hypotheses are as to why something like this could have happened. You know, since we don’t really know exactly what has happened, we wanted to do autopsies on these patients and families declined, and we were not collecting serum samples from these patients so we could look back because we were not expecting this outcome. So I don’t think we’re going to have an answer, but, you know, we have a lot of theories. And one of them is maybe there was an interaction, a pharmacological interaction between ibrutinib venetoclax. Maybe there’s something underlying to the disease itself, maybe some IgM or free light chain or amyloid deposition in the heart that we were not aware of. These two patients had a high risk of cardiac disease- between obesity, hypertension, diabetes, and prior history of coronary artery disease. So maybe it’s the patient substrates, or maybe it was just a random occurrence. 

Regardless, I think obviously it is not safe to use this combination in patients with Waldenström’s at this time, and we cannot recommend it. However, the combination of a BTK inhibitor and a BCL2 antagonist is still reasonable and it’s a potent combination. So we are running a study now combining pirtobrutinib, which is a new BTK inhibitor, with venetoclax in patients with Waldenström’s. And we have already enrolled about eight out of 40 patients, so that’s going very well and hopefully, next year, I’ll be presenting some of those data.