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BTK Inhibitors in Waldenstrom Macroglobulinemia

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: Tuesday, Apr 09, 2019



Transcript: 

Meletios A. Dimopoulos, MD:
Waldenström macroglobulinemia is an indolent disease. First of all, a treating physician has to be very careful not to initiate, prematurely, treatment to a patient. Just the levels of monoclonal protein are not an indication for treatment. We need to document the decrease of hemoglobin, symptoms, enlarging lymph nodes, and other reasons for the patient to be treated. The second point is that these are elderly patients. They have comorbidities. So we need to take into consideration these aspects. The third point is that this is an indolent disease. It may respond to a variety of regimens. We know that with rituximab-based combinations that are administered for a certain period of time, we can achieve progression-free survivals for several months or years. It is important, especially in elderly patients, to give them treatment-free intervals.

On the other hand, we have 3 BTK [Bruton tyrosine kinase] inhibitors that appear to be active in the treatment of this disease. One of them has been approved by regulatory authorities. They are also very active even in patients who have failed multiple other regimens. Whether a patient should be treated in the frontline setting with 1 of these BTK inhibitors is questionable because, as I mentioned, you have to continue this therapy forever. Otherwise, the disease will come back.

Steven P. Treon, MD, PhD: My advice to community oncologists is that this is a very exciting new beginning for Waldenström. The fact that we now understand the genomic basis of the disease really is giving us opportunities to leverage many new therapeutics, as well as the developed therapeutics that target MYD88 as well as CXCR4 signaling. Being able to optimize BTK inhibitors is a very important area for us to engage in, in active research, particularly in dealing with some of the issues around CXCR4-mutated patients. Being able to develop CXCR4 antagonists in combination with BTK inhibitors represents an exciting new way forward.

The combination of venetoclax that targets BCL2, along with ibrutinib represents also a very exciting new area of us to engage in active research. And we’re also very interested in exploring other drugs like daratumumab, which targets CD38. The potential to utilize daratumumab with rituximab to be able to overlap the entire lymphoplasmacytic lymphoma clone is of great interest to us as well.

One of the challenging group of patients is the MYD88 wild-type patients. This is a small percentage of all Waldenström patients. And we now know, because of the work that we just published in Blood Advances, what the underlying genomic landscape is for these patients. We know that many of the mutations that we see are underneath BTK in terms of their signaling of the growth and survival pathways of Waldenström, and also, many of these mutations are shared with diffuse large B-cell lymphomas and other aggressive lymphomas. Being able to develop targeted therapeutics for this population of patients is extremely important to us.

Meletios A. Dimopoulos, MD: Waldenström disease is a rare but very interesting lymphoproliferative disorder. There have been significant advances in the biology and diagnosis of the disease with MYD88 detection, CXCR4 detection, and also with new agents such as BTK inhibitors, venetoclax, and monoclonal antibodies that provide an even brighter future for these patients with this disease, which already has a good prognosis and usually an indolent course.


Transcript Edited for Clarity
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Transcript: 

Meletios A. Dimopoulos, MD:
Waldenström macroglobulinemia is an indolent disease. First of all, a treating physician has to be very careful not to initiate, prematurely, treatment to a patient. Just the levels of monoclonal protein are not an indication for treatment. We need to document the decrease of hemoglobin, symptoms, enlarging lymph nodes, and other reasons for the patient to be treated. The second point is that these are elderly patients. They have comorbidities. So we need to take into consideration these aspects. The third point is that this is an indolent disease. It may respond to a variety of regimens. We know that with rituximab-based combinations that are administered for a certain period of time, we can achieve progression-free survivals for several months or years. It is important, especially in elderly patients, to give them treatment-free intervals.

On the other hand, we have 3 BTK [Bruton tyrosine kinase] inhibitors that appear to be active in the treatment of this disease. One of them has been approved by regulatory authorities. They are also very active even in patients who have failed multiple other regimens. Whether a patient should be treated in the frontline setting with 1 of these BTK inhibitors is questionable because, as I mentioned, you have to continue this therapy forever. Otherwise, the disease will come back.

Steven P. Treon, MD, PhD: My advice to community oncologists is that this is a very exciting new beginning for Waldenström. The fact that we now understand the genomic basis of the disease really is giving us opportunities to leverage many new therapeutics, as well as the developed therapeutics that target MYD88 as well as CXCR4 signaling. Being able to optimize BTK inhibitors is a very important area for us to engage in, in active research, particularly in dealing with some of the issues around CXCR4-mutated patients. Being able to develop CXCR4 antagonists in combination with BTK inhibitors represents an exciting new way forward.

The combination of venetoclax that targets BCL2, along with ibrutinib represents also a very exciting new area of us to engage in active research. And we’re also very interested in exploring other drugs like daratumumab, which targets CD38. The potential to utilize daratumumab with rituximab to be able to overlap the entire lymphoplasmacytic lymphoma clone is of great interest to us as well.

One of the challenging group of patients is the MYD88 wild-type patients. This is a small percentage of all Waldenström patients. And we now know, because of the work that we just published in Blood Advances, what the underlying genomic landscape is for these patients. We know that many of the mutations that we see are underneath BTK in terms of their signaling of the growth and survival pathways of Waldenström, and also, many of these mutations are shared with diffuse large B-cell lymphomas and other aggressive lymphomas. Being able to develop targeted therapeutics for this population of patients is extremely important to us.

Meletios A. Dimopoulos, MD: Waldenström disease is a rare but very interesting lymphoproliferative disorder. There have been significant advances in the biology and diagnosis of the disease with MYD88 detection, CXCR4 detection, and also with new agents such as BTK inhibitors, venetoclax, and monoclonal antibodies that provide an even brighter future for these patients with this disease, which already has a good prognosis and usually an indolent course.


Transcript Edited for Clarity
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