Can New Drug Combinations Bring More Effective Treatment Options? New combination drug regimens are being studied for the treatment of Waldenstrom macroglobulinemia (WM). In this segment, Dr. Jorge Castillo, MD, of Dana-Farber Cancer Institute updates patients on the information presented at the recent American Society of Hematology (ASH) conference and suggests that Waldenstrom patients pay attention to the combination of ibrutinib and rituximab (INNOVATE Study), that have shown faster and deeper responses over time versus rituximab alone.

Dr. Castillo also introduces LOXO-305, a BTK inhibitor and oral drug that was first presented for use in mantle cell lymphoma. He believes this could be a key area of study for Waldenstrom researchers in 2021.



Dr. Castillo: Hi, my name is Jorge Castillo and I'm the Clinical Director of the Waldenstrom's program at the Dana-Farber Cancer Institute. I think it's very important to look into clinical trials. I think clinical trials remain the most important source of reliable data. And there were two prospective clinical trials reported specifically on patients with Waldenstrom's during this meeting.

What is the Data Showing from the INNOVATE Study Combining Ibrutinib and Rituximab?
I think the first one was the long-term data follow-up from the INNOVATE study. Just to refresh our memories, this is a study in which ibrutinib (Imbruvica) and rituximab (Rituxan) were compared versus rituximab and placebo, 75 patients per arm, and those patients were followed. This was initially presented up to publish in 2018, and it showed that the combination of ibrutinib and rituximab induced faster and deeper responses than rituximab alone. And this study, actually, was a kind of a four-and-a-half year follow-up out, which is substantially two more years of follow-up. And it was interesting to see a couple of things.

Number one, the benefit and the time that it takes for the disease to progress remains much lower in patients who received the ibrutinib in combination with rituximab. Interestingly enough, over time, the response of the patients who remained on ibrutinib and rituximab actually continue deepening over time. So deeper responses can be seen over time. And we knew that from the ibrutinib single-agent study that we did, but now we also can see that with a combination of ibrutinib and rituximab as well.

What Treatment Options Are Available for Waldenstrom’s?
And now we do have already some data into the time to next treatment. Not only the time to progression, which is just the [inaudible] levels are increasing, but also the time until the patient actually needs to be treated just because of the longer follow-up. And we saw that about 80% of patients who were on ibrutinib and rituximab did not need to be treated yet until the end of the study, versus about 25% of patients on rituximab who needed to... who had not needed to be treated yet. So not only it delays the time to progression, but also there seems to be a significant delay into the time to next treatment.

The other study of importance is the study coming from the European consortium, in which they took a chemotherapy-based regimen, cyclophosphamide (Cytoxan), rituximab, and dexamethasone (Decadron), which is very commonly used in Europe and as well as in the United States. And the other arm had the same backbone, but they added bortezomib (Velcade) to the treatment and bortezomib was given weekly, subcutaneously. I think in terms of the time to response may be a little bit faster with the additional bortezomib to chemotherapy in patients with Waldenstrom's, but the depth of the response and the duration of the response, specifically the progression-free survival up to the two-and-a-half years, I think, of follow-up that they had, there were no major differences, and obviously bortezomib was associated with an increase…minor but increase in the risk of neuropathy.

So, it looks like the additional bortezomib to chemotherapy, at least the first couple of years of follow-up, did not seem to impact the response or the time to progression in patients with Waldenstrom's. I think those are the most important aspects.

Is LOXO-305 Effective in Treating Waldenstrom Macroglobulinemia?
A different agent that we have been looking into is this medication called LOXO-305. It's a BTK inhibitor of next-generation that seems to have some efficacy, even in patients who have been exposed to the more classic BTK inhibitors, and they progress on these agents because they develop a mutation in BTK. These new BTK inhibitors kind of bind to BTK in a different way, in which they avoid the interaction with the mutation, the mutated part, and that can still exert some benefit. There was nothing on Waldenstrom's, but there's some data on mantle cell lymphoma, which also uses similar... these BTK inhibitors are very effective in that condition as well.

And we saw that with relatively long follow-up some very high efficacy rates with these new agents, which is also oral, taken twice a day. But so far it seemed to be that the risk of arrhythmias and the risk of bleeding is actually lower than with the classic BTK inhibitors. So I think a study dedicated to Waldenstrom's with these agents would be very, very important and is going to be a goal of the Bing Center for Waldenstrom's for a study next year.