ASCO 2021 | Zanubrutinib versus rituximab-based chemoimmunotherapy in Waldenström’s macroglobulinemia

We wanted to investigate what are the potential differences in terms of treating somebody with a BTK inhibitor and treating somebody with Waldenström’s with rituximab-based chemoimmunotherapy regimen? Truth of the matter is all of these are very reasonable treatment options for a patient with Waldenström’s. However, there is not a formal randomized study comparing BTK inhibitors versus chemoimmunotherapy in Waldenström’s.

Short from doing a randomized study, which I think is unlikely that is going to be done, looking for indirect comparisons is one way of approaching this, and there are many different methodologies for this. We decided to do a matching adjusting indirect comparison study. For that, we actually use data from the ASPEN study, which is a randomized study that compared zanubrutinib versus ibrutinib. So, we collected the data from 102 patients with Waldenström’s, who were treated in the ASPEN study with zanubrutinib specifically, of which 83 patients were relapsed/refractory and about 19 were treatment naïve.

Then we perform a systematic review of the literature looking for potential studies in patients with Waldenström’s using chemoimmunotherapy, studies that will provide us with information that we can match. Right? So, the idea is we don’t have the individual data from each patient, but as long as the study provides enough information in terms of the characteristics of the patients and the outcomes, then we can potentially try to match these using different computational algorithms.

So, we came up with two studies. One of them it’s a study in which patients were relapsed/refractory and had received bendamustine and rituximab. This was an Italian study. 71 patients that were previously treated were included. For the frontline approach, we actually selected the frontline study from the Greeks that basically use cyclophosphamide-dexamethasone-rituximab. There were 72 patients included there.

When we tried to match the features with bendamustine, we included age, prior lines of therapy, IgM concentration, IPSSWM score, and extramedullary disease. For comparisons with cyclophosphamide regimen, we included age, platelet counts, hemoglobin levels, and extramedullary disease. So, based on all these features, we kind of match those data and we rerun the analysis and we kind of doing a mimicking a randomized study, even though there is no direct comparison, per se. So, we were interested in looking at progression-free survival, overall survival and some toxicities of interest.

So, when we looked into comparing against cyclophosphamide-based regimens really zanubrutinib had a longer progression-free survival and a longer overall survival and this was before matching and after the matching as well. In terms of side-effects, there was slightly more neutropenia with zanubrutinib, but this was not statistically significant. When we compare it with bendamustine, the zanubrutinib was also associated with a longer progression-free survival, and also overall survival. This was pre- and post-matching, and lower incidences of neutropenia and this was also statistically significant. There were also lower rate of pneumonia, but this was not statistically significant.

So, based on this, and again, in the absence of a randomized study, I think this data can help, kind of, understand that zanubrutinib does have, appears to have a benefit of progression-free survival and overall survival over the two most commonly used chemoimmunotherapy regimens in patients with Waldenström’s. There are some benefits and side effects versus these agents as well, although most of these differences are not precisely statistically significant. For all these reasons, I think these data supports BTK inhibitors and specifically zanubrutinib in this setting as a standard of care for patients with Waldenström’s macroglobulinemia.