Why NGS testing is a must for people with Waldenström Macroglobulinemia

Waldenström Macroglobulinemia (WM) is a rare blood cancer. Swedish physician Jan Waldenstrom coined the name of this rare, unpronounceable blood cancer in 1944 when he reported the cases of three WM patients. The disease is characterized by an overproduction of the large (macro) immunoglobulin IgM (Immunoglobulin M).

The NGS (next-generation sequencing) test has recently become a standard recommendation for patients with WM or suspected WM in hospitals. However, many patients wonder if it is really necessary. That is because NGS testing is classified as a selective-benefit treatment, and the patient's out-of-pocket expense reaches 700,000 won ($523).

So, why do hospitals recommend NGS testing to patients with WM or suspected WM? On the Korea Blood Disease and Cancer Association's YouTube channel “KBDCA,” Professor Choi Yoon-seok of the Department of Hematology at Korea University Anam Hospital pointed out that NGS testing helps to diagnose accurately WM, a rare blood cancer challenging to diagnose due to its many intersections with more than 90 other lymphomas, determine treatment, and predict the patient's treatment prognosis.

There are three gene mutations currently identified by NGS in WM patients or suspected WM patients -- MYD88, CXCR4, and TP53.

“The International Workshop on Waldenstrom Macroglobulinemia (IWWM) recommends that the MYD88 gene be mutated if possible at diagnosis,” Professor Choi said, noting that NGS testing can help differentiate WM from other low-grade or delayed-onset lymphomas.

WM overlaps so much with lymphoma that it is often considered one of more than 90 subtypes and treated accordingly.

“There are many cases where we think it's lymphoma A and treat it. However, when we look at it years later, it smells like Waldenstrom Macroglobulinemia,” Choi said. “It's not a misdiagnosis but an inherent limitation of lymphoma.

NGS testing is one way to overcome the inherent limitations of WM, which has many overlaps with other lymphomas.

“NGS testing of targeted genes can help further differentiate the cases where there is ambiguity,” Professor Choi said. “Mutations in MYD88 are observed in more than 90 percent of WM patients.”

However, NGS testing is not a definitive test for WM. Even if an NGS test identifies a mutation in MYD88 in a patient, it does not necessarily confirm that the patient has WM.

“The test is not perfect, as mutations in this gene (MYD88) are observed in 10-20 percent of marginal zone B-cell lymphomas, and mutations in this gene are also observed in chronic lymphocytic leukemia,” Choi said, emphasizing the need for NGS testing. “Still, the more data we have, the more definitive the diagnosis can be.”

There is another reason why NGS testing for mutations in the MYD88, CXCR4, and TP53 genes is necessary for WM patients.

“MYD88 is highly associated with response to BTK inhibitor treatment, as a tool to prescreen patients who may be more responsive to BTK inhibitors, Professor Choi said. “MYD88 and CXCR4 are associated with poorer treatment outcomes and poorer prognosis in patients without mutations. TP53 is associated with a worse prognosis in almost all tumors when mutated.”

Choi added that NGS testing can also help determine treatment and predict outcomes.