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Waldenstrom Macroglobulinemia: BTK Inhibitor Monotherapy

Insights From: Meletios A. Dimopoulos, MD, the National and Kapodistrian University of Athens School of Medicine; Steven P. Treon, MD, PhD, Dana-Farber Cancer Institute
Published: Friday, Apr 05, 2019



Transcript: 

Steven P. Treon, MD, PhD:
The initial approval of ibrutinib really had a very important impact. First of all, it was the first drug ever specifically approved for Waldenström macroglobulinemia—this by the FDA here in the United States, but also by the EMA [European Medicines Agency] and many, many countries across the world. It gave patients a targeted approach to treatment. And I think also it gave patients a treatment approach that represented an advance in terms of safety over many other options that we had at our disposal. Looking at both short-term as well as long-term toxicities, BTK [Bruton tyrosine kinase] inhibitors like ibrutinib have really changed the landscape, not only from an efficacy point but also giving us a safer targeted approach in treating patients with Waldenström.

Meletios A. Dimopoulos, MD: When ibrutinib is being administered in a newly diagnosed patient as a single agent it is usually associated with at least a partial response or major responses in the overwhelming majority of the patients. More than 90%, 85% of the patients will respond with a significant decrease of monoclonal protein, with improvement of anemia, with a decrease of lymphadenopathy, and also with a decrease of bone marrow infiltration. This drug is very effective across all patients with Waldenström. It may be less effective in patients who do not have the MYD88 mutation, who are MYD88 wild type, and also in the patients with CXCR4 mutations. However, it is a very effective treatment. As I mentioned, the problem with ibrutinib is that it has to be given continuously. And for some patients who may have a life expectancy of 10 or 20 years, this may be a problem.

Steven P. Treon, MD, PhD: The use of ibrutinib monotherapy can be considered in patients who have the MYD88 mutation. This represents about 95% of all patients. It’s important to keep in mind that in the 5% of patients who are considered wild type or have no MYD88 mutation, there may be some patients who have non-L265P mutations. Usually we use Sanger sequencing or next-generation sequencing to help understand if a non-L265P mutation is present. And I think this is really important to keep in mind because those patients do respond to ibrutinib. We published very nicely in the New England Journal of Medicine that these patients can also benefit. So when you’re working somebody up for the MYD88 mutation, keep this in mind and keep in mind that these patients might also be appropriate for ibrutinib or other BTK inhibitors.

Meletios A. Dimopoulos, MD: Ibrutinib is a relatively safe drug. Sometimes it may cause gastrointestinal abnormalities that can be dealt with. Occasionally, there is a skin rash. And in some patients, we may see new episodes of atrial fibrillation. So these patients should be aware of this. If they develop an arrhythmia, they should have an electrocardiogram to make sure they are not developing this complication. Furthermore, there is some increased risk of bleeding, so patients are advised that if they need to have surgical procedure that is either major or minor, to discontinue, to hold ibrutinib for several days before the surgery.

Steven P. Treon, MD, PhD: I’ve been involved in ibrutinib research for quite a while. I think the important thing to say when one comments on one’s own experiences: How fast we see responses, and the durability of responses, and more important, how we’ve moved away from any adverse effects that used to plague our patients. You know we’ve moved away from seeing bad neuropathy associated with proteasome inhibitors. I think we’re going to be moving away from a lot of secondary cancers and problems we’ve seen in the past with nucleoside analogues and possibly also alkylator agents. So I think it represents a novel way of treating patients without really being dogged by many of the adverse effects that we used to see with a lot of our therapies.

And also, the reliance on more drastic therapeutic options like autotransplants as an example, or allogeneic transplants. These were options that we often went to for patients with multiple relapses or refractory disease. And each of these carries its own profile of adverse effects, morbidity as well as mortality. And seeing that and BTK inhibitors can work in these patients and produce long-lasting responses, where in the past we would have gone to an autotransplant or an allogeneic transplant, is really 1 of the most gratifying experiences for me personally.


Transcript Edited for Clarity 
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Transcript: 

Steven P. Treon, MD, PhD:
The initial approval of ibrutinib really had a very important impact. First of all, it was the first drug ever specifically approved for Waldenström macroglobulinemia—this by the FDA here in the United States, but also by the EMA [European Medicines Agency] and many, many countries across the world. It gave patients a targeted approach to treatment. And I think also it gave patients a treatment approach that represented an advance in terms of safety over many other options that we had at our disposal. Looking at both short-term as well as long-term toxicities, BTK [Bruton tyrosine kinase] inhibitors like ibrutinib have really changed the landscape, not only from an efficacy point but also giving us a safer targeted approach in treating patients with Waldenström.

Meletios A. Dimopoulos, MD: When ibrutinib is being administered in a newly diagnosed patient as a single agent it is usually associated with at least a partial response or major responses in the overwhelming majority of the patients. More than 90%, 85% of the patients will respond with a significant decrease of monoclonal protein, with improvement of anemia, with a decrease of lymphadenopathy, and also with a decrease of bone marrow infiltration. This drug is very effective across all patients with Waldenström. It may be less effective in patients who do not have the MYD88 mutation, who are MYD88 wild type, and also in the patients with CXCR4 mutations. However, it is a very effective treatment. As I mentioned, the problem with ibrutinib is that it has to be given continuously. And for some patients who may have a life expectancy of 10 or 20 years, this may be a problem.

Steven P. Treon, MD, PhD: The use of ibrutinib monotherapy can be considered in patients who have the MYD88 mutation. This represents about 95% of all patients. It’s important to keep in mind that in the 5% of patients who are considered wild type or have no MYD88 mutation, there may be some patients who have non-L265P mutations. Usually we use Sanger sequencing or next-generation sequencing to help understand if a non-L265P mutation is present. And I think this is really important to keep in mind because those patients do respond to ibrutinib. We published very nicely in the New England Journal of Medicine that these patients can also benefit. So when you’re working somebody up for the MYD88 mutation, keep this in mind and keep in mind that these patients might also be appropriate for ibrutinib or other BTK inhibitors.

Meletios A. Dimopoulos, MD: Ibrutinib is a relatively safe drug. Sometimes it may cause gastrointestinal abnormalities that can be dealt with. Occasionally, there is a skin rash. And in some patients, we may see new episodes of atrial fibrillation. So these patients should be aware of this. If they develop an arrhythmia, they should have an electrocardiogram to make sure they are not developing this complication. Furthermore, there is some increased risk of bleeding, so patients are advised that if they need to have surgical procedure that is either major or minor, to discontinue, to hold ibrutinib for several days before the surgery.

Steven P. Treon, MD, PhD: I’ve been involved in ibrutinib research for quite a while. I think the important thing to say when one comments on one’s own experiences: How fast we see responses, and the durability of responses, and more important, how we’ve moved away from any adverse effects that used to plague our patients. You know we’ve moved away from seeing bad neuropathy associated with proteasome inhibitors. I think we’re going to be moving away from a lot of secondary cancers and problems we’ve seen in the past with nucleoside analogues and possibly also alkylator agents. So I think it represents a novel way of treating patients without really being dogged by many of the adverse effects that we used to see with a lot of our therapies.

And also, the reliance on more drastic therapeutic options like autotransplants as an example, or allogeneic transplants. These were options that we often went to for patients with multiple relapses or refractory disease. And each of these carries its own profile of adverse effects, morbidity as well as mortality. And seeing that and BTK inhibitors can work in these patients and produce long-lasting responses, where in the past we would have gone to an autotransplant or an allogeneic transplant, is really 1 of the most gratifying experiences for me personally.


Transcript Edited for Clarity 
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