A New Era for Waldenström’s Macroglobulinemia Treatment

In the more than 70 years since Jan G. Waldenström discovered Waldenström’s macroglobulinemia, there have been few answers about what causes the malignant B-cell lymphoma or the best way to treat it. But, after the recent discovery of a single activating somatic mutation present in most patients with the disease and encouraging survival results with a new medication, the future for patients with this rare blood cancer looks more promising than ever.

Investigators recently discovered that ibrutinib, the first and only treatment approved by the U.S. Food and Drug Administration to treat Waldenström’s macroglobulinemia, produced a two-year overall survival rate of 95.2 percent. In this prospective study, the drug was also shown to decrease median serum IgM levels, increase median hemoglobin levels, and reduce bone marrow involvement.

These results compare favorably to response and survival rates seen in previous trials of monotherapies in patients with relapsed or refractory Waldenström’s macroglobulinemia, which found response rates of 40 to 80 percent and a median progression-free survival of 8 to 20 months, the authors of the current study noted.

“These findings change the paradigm for an orphan disease that really had no established therapeutics, and I think they have moved us away from an era of ‘hand-me-down’ therapies,” Steven P. Treon, MD, PhD, the study’s first author and director of the Bing Center for Waldenström’s Macroglobulinemia at Dana-Farber Cancer Institute, told ASH Clinical News.

Waldenström’s macroglobulinemia is characterized by an abnormality in B lymphocytes in the bone marrow that causes the overproduction of the immunoglobulin protein IgM. Specific genetic mutations in MYD88 and CXCR4 have been identified as drivers of the disease; in the case of MYD88, these mutations also trigger the abnormal activity of Bruton’s tyrosine kinase (BTK).

Ibrutinib is designed to kill cancer cells by targeting a pathway involving BTK and has shown promising results for patients with Waldenström’s macroglobulinemia.

In this study published in The New England Journal of Medicine, Dr. Treon and his team prospectively studied the outcomes of 63 patients with Waldenstrom’s macroglobulinemia who had the MYD88 and CXCR4 mutations and who were taking a 420-mg daily dose of ibrutinib. Ibrutinib was administered orally until disease progression or the development of unacceptable toxic effects.

Patients taking ibrutinib saw a significant drop in median serum IgM levels, from 3520 mg/dL to 880 mg/dL (p<0.001). The median percentage of bone marrow affected by the disease also dropped (from 60 percent to 25 percent; p<0.001) during the course of the study, while median hemoglobin levels increased from 10.5 g/dL to 13.8 g/dL.

Overall response rate was 90.5 percent, with 69.1 percent of patients experiencing progression-free survival at two years.

Dr. Treon and investigators also found that presence of a genetic mutation played a role in patient outcomes: patients with MYD88L265PCXCR4WT had the greatest response rates to ibrutinib (TABLE).

The oral medication was also found to be safe: 22 percent of study participants experienced neutropenia and 14 percent had thrombocytopenia. “Ibrutinib is an extremely convenient therapy,” Dr. Treon added.

While the study’s findings have important implications for patients with Waldenström’s macroglobulinemia, Dr. Treon said it also illustrates the powerful role genomic sequencing can play in developing cancer treatments: “Whole-genome sequencing can really drive therapeutics in cancer and Waldenström’s macroglobulinemia. Ibrutinib represents one of the best examples of that happening.”


Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. N Engl J Med. 2015;372:1430-40.

TABLE. Response Rates According to Genomic Subgroup


Major response (≥50% reduction in IgM levels)

Overall response