ICML 2023 | BRAWM: bendamustine, rituximab and acalabrutinib for Waldenström’s macroglobulinemia

So we’re presenting here a poster on a Phase II trial, which we’ve organized across Canada, there’s actually nine sites, which is looking at a novel first line chemotherapy for patients with Waldenström’s macroglobulinemia. Around the world, different first line treatments are used for the management of patients with Waldenström’s. In some places, chemoimmunotherapy is used such as bendamustine and rituximab and other places, proteasome inhibitors such as bortezomib is added. And now we have the BTK inhibitors, which are also available in some geographic locations. All of these have are quite effective in that they cause patients to respond and to go into remissions, but the observation is that the percentage of complete remissions or very good, what we call very good partial remissions, is very low. It’s around 20% or 23%. So patients go into remissions, remissions last for a while, but there’s a lot of lymphoma left in the body and these patients eventually relapse. So we’ve hypothesized that what we could do is perhaps get deeper responses in patients with Waldenström’s by combining two accepted frontline therapies and the two therapies that we’ve combined are bendamustine and Rituxan, together with acalabrutinib, which is a second generation BTK inhibitor. So that’s the rationale behind it. And our objective is to look at what happens to the complete and very good partial response. Do we see more patients, a higher percentage of patients going into complete and very good partial responses? And then we’re also going to look at, of course, other conventional endpoints such as progression-free survival, overall survival. And we also have some novel endpoints which are minimal residual disease. So often patients can have significant amount of lymphoma left in their bone marrow or their peripheral blood, which can’t be detected by conventional tests. And there are some molecular tests. So we’ll be using next generation sequencing of DNA from the bone marrow and from the peripheral blood to see if we can detect very, very small frequencies of lymphoma DNA in those sites. And so that would be another test of how deep the response is with this novel combination of two different treatments for Waldenström’s. So that’s the idea behind this. We’re trying to accrue 59 patients, right now we’re presenting at this meeting the interim results with 38 patients. The interim results look very good. I think we’re achieving what we expected to achieve. So whereas I told you with one of those therapies, either bendamustine-Rituxan or ibrutinib as monotherapy first line therapies, we expect to have a complete and VGPR rate of 23%. We’re already seeing that our rate is closer to 60 or 70%. So we’re really doing quite well. No patient yet has relapsed, although the follow-up is short. We are seeing in the patients that we’ve assessed to date that we are achieving a negative MRD in the peripheral blood and most patients and in the bone marrow, we are achieving negative MRD in some patients. Further follow-up of later samples will be very interesting in those patients. The one question you might ask is what’s the toxicity profile? Now you’re combining two different types of therapy, will you get a lot more toxicity? Well, what we’re finding is that the adverse events are what we expect from both of these types of treatments. We’re not seeing synergistic or greater adverse events. The high level or grade three, grade four toxicity is relatively low. We’ve only had to dose reduce one patient out of the 38 and there’s been some serious adverse events that are treatment-related. Generally, they’re neutropenia and infection, which is something that you would expect with bendamustine chemotherapy. So those are the results in a nutshell. They’re preliminary, but they do look promising, I think we are going to achieve the endpoint that we expected to achieve.