James R. Berenson, MD

Question

Can you describe the factors that influence how a patient with Waldenstrom macroglobulinemia (WM) is staged?

Answer

There is really no staging system for WM. The IPSS [International Prognostic Scoring System] is not generally used. It is really restricted to use in research studies, and has no real use in the clinical community as it does not define therapeutic options.

Question

Are there particular genetic abnormalities that are associated with WM? How can identification of those influence treatment?

Answer

Yes, two specific genetic abnormalities occur in WM patients. Nearly all patients have the MYD88 mutation involving L265P. About one-third have CXCR4 mutations.

The presence of the MYD88 portends a better response to ibrutinib whereas the CXCR4 alteration predicts less likelihood to respond to this drug.

Less commonly, patients may have mutations in ARIDIA or CD79A.CD79B. Mutations in the gene that targets ibrutinib, a Bruton tyrosine kinase (BTK), may occur and the recent approval of acalabrutinib, another BTK inhibitor, may provide another option for these ibrutinib-resistant patients.

These abnormalities are present in the tumor cells and are not inherited per se.

Question

Are there particular side effects that you look out for after initiating treatment for WM? What are your strategies for monitoring patients and addressing side effects?

Answer

Basically, side effects are related to the specific drug being used. For example, bortezomib may cause peripheral neuropathy and is associated with a higher risk of herpes zoster. Prophylactic use of antiviral agents reduces the risk of this infection.

Ibrutinib has several know side effects including bleeding problems, atrial fibrillation, and gastrointestinal problems. Rituximab as a single agent is often associated with infusion reactions that can limit its use. The combination of fludarabine, cyclophosphamide, and rituximab may be accompanied by low blood counts and lead to the development of myelodysplasia and in some cases acute leukemia.

Lenalidomide can cause thrombotic events so WM patients receiving this drug are given antithrombotic prophylaxis, usually with baby aspirin.

Question

One study presented at the 2017 American Society of Hematology annual meeting suggested that patients with WM being treated with ibrutinib should not discontinue therapy. Are there circumstances when patients should discontinue therapy, and are any emerging treatments likely to make ibrutinib discontinuation more feasible?

Answer

Ibrutinib is continued indefinitely in our patients. There is now a new BTK inhibitor, acalabrutinib, that was recently FDA [US Food and Drug Administration]-approved for treating patients resistant to ibrutinib but not as a treatment after patients discontinue its use while doing well on it.