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Waldenstrom Macroglobulinemia: Risk Factors

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, Mar 22, 2019



Transcript: 

Meletios A. Dimopoulos, MD:
Waldenström macroglobulinemia is a rare, low-grade lymphoma. We believe that the incidence is about one-tenth that of myeloma, meaning approximately 1 new case per 1 million every year. There is no clear correlation with known risk factors, including environmental factors regarding Waldenström macroglobulinemia. However, we know that there is a slight familial predisposition, meaning that relatives of patients with Waldenström macroglobulinemia may have a slightly higher probability of developing the disease.

Patients with Waldenström macroglobulinemia usually present to their physician with weakness, and initial blood tests may show a decreased hemoglobinemia. In the majority of patients, the white blood cell count and the platelet count are preserved. Another presentation of this disease is if there are large lymph nodes that the patient can palpate, then this may trigger further work-up and help establish a diagnosis. Sometimes patients develop symptoms and signs of peripheral neuropathy, and this is something that should trigger the suspicion that for each patient who presents with peripheral neuropathy, one should think about Waldenström and monoclonal IgM. A minority of patients will present with symptoms and signs of hyperviscosity, meaning headaches, nose bleeding, dizziness due to the very elevated levels of IgM monoclonal protein and the subsequent elevated serum viscosity. Finally, some patients may present with low-grade fever, weight loss, and pruritus.

Today it should be part of the standard initial diagnostic work-up of the patient to see whether the patient is expressing the MYD88 mutation, which is seen in 85% to 90% of the patients with Waldenström macroglobulinemia. Furthermore, we want to see what the status of CXCR4 is because they can be wild type in approximately 70% of the patients but mutated in about 30% of the patients.

Steven P. Treon, MD, PhD: The CXCR4 mutation is a mutation that occurs in the C-terminal domain of the receptor CXCR4. CXCR4 actually signals for stromal cell-derived factor 1. It’s produced by the bone marrow stroma. And that access of stromal cell–derived factor 1 [SDF-1] interaction with CXCR4 also is –important in explaining why cells traffic to the bone marrow. In addition, because of the signaling that’s induced when you have the mutation in CXCR4, you get enhanced survival signaling. ERK [extracellular signal-regulated kinase] and Akt, in particular, are activated by the induction of the CXCR4-mutated receptor by SDF-1. And this is important because it can affect the way these cells respond to various drugs, including BTK [Bruton tyrosine kinase] inhibitors.

When you look at a patient who has a CXCR4 mutation, particularly the ones who have the nonsense mutations, this is when the mutation has caused a lobbing off of part of that C-terminal domain. These are individuals who are going to present with very high IgM levels and symptomatic hyperviscosity. So these are patients who are going to be far more acute in their care. And that’s why being able to get the MYD88 and CXCR4 mutation status at time of presentation is important. It helps you understand really the needs of the patient and the disease presentation and perhaps also helps you in terms of navigating their therapeutic options.


Transcript Edited for Clarity
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Transcript: 

Meletios A. Dimopoulos, MD:
Waldenström macroglobulinemia is a rare, low-grade lymphoma. We believe that the incidence is about one-tenth that of myeloma, meaning approximately 1 new case per 1 million every year. There is no clear correlation with known risk factors, including environmental factors regarding Waldenström macroglobulinemia. However, we know that there is a slight familial predisposition, meaning that relatives of patients with Waldenström macroglobulinemia may have a slightly higher probability of developing the disease.

Patients with Waldenström macroglobulinemia usually present to their physician with weakness, and initial blood tests may show a decreased hemoglobinemia. In the majority of patients, the white blood cell count and the platelet count are preserved. Another presentation of this disease is if there are large lymph nodes that the patient can palpate, then this may trigger further work-up and help establish a diagnosis. Sometimes patients develop symptoms and signs of peripheral neuropathy, and this is something that should trigger the suspicion that for each patient who presents with peripheral neuropathy, one should think about Waldenström and monoclonal IgM. A minority of patients will present with symptoms and signs of hyperviscosity, meaning headaches, nose bleeding, dizziness due to the very elevated levels of IgM monoclonal protein and the subsequent elevated serum viscosity. Finally, some patients may present with low-grade fever, weight loss, and pruritus.

Today it should be part of the standard initial diagnostic work-up of the patient to see whether the patient is expressing the MYD88 mutation, which is seen in 85% to 90% of the patients with Waldenström macroglobulinemia. Furthermore, we want to see what the status of CXCR4 is because they can be wild type in approximately 70% of the patients but mutated in about 30% of the patients.

Steven P. Treon, MD, PhD: The CXCR4 mutation is a mutation that occurs in the C-terminal domain of the receptor CXCR4. CXCR4 actually signals for stromal cell-derived factor 1. It’s produced by the bone marrow stroma. And that access of stromal cell–derived factor 1 [SDF-1] interaction with CXCR4 also is –important in explaining why cells traffic to the bone marrow. In addition, because of the signaling that’s induced when you have the mutation in CXCR4, you get enhanced survival signaling. ERK [extracellular signal-regulated kinase] and Akt, in particular, are activated by the induction of the CXCR4-mutated receptor by SDF-1. And this is important because it can affect the way these cells respond to various drugs, including BTK [Bruton tyrosine kinase] inhibitors.

When you look at a patient who has a CXCR4 mutation, particularly the ones who have the nonsense mutations, this is when the mutation has caused a lobbing off of part of that C-terminal domain. These are individuals who are going to present with very high IgM levels and symptomatic hyperviscosity. So these are patients who are going to be far more acute in their care. And that’s why being able to get the MYD88 and CXCR4 mutation status at time of presentation is important. It helps you understand really the needs of the patient and the disease presentation and perhaps also helps you in terms of navigating their therapeutic options.


Transcript Edited for Clarity
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