Jorge J. Castillo, MD

Question

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

Answer

All patients with WM are by definition stage IV, as over 95% of WM patients present with bone marrow involvement. Prognostic factors associated with worse survival are age of 65 years or older, hemoglobin lower than 11.5 g/dl, platelet count lower than 100 K/uL, beta-2-microlgobulin lower than 3 mg/l, and serum IgM of 7,000 mg/dl or higher.

However, these factors were identified in a cohort of patients treated with chemotherapy only, and might not apply to patients treated with rituximab, proteasome inhibitors, or BTK [Bruton’s tyrosine kinase] inhibitors.

Question

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

Answer

A recurrent mutation in MYD88 L265P has been detected in over 90% of patients with WM, which is now endorsed by the WHO [World Health Organization] to support a diagnosis of WM. Retrospective data have shown than WM patients without MYD88 mutations have a worse prognosis. Also, patients without MYD88 mutations have lower response rates to the BTK inhibitor ibrutinib, which is the only FDA [US Food and Drug Administration]-approved treatment for WM patients.

Mutations in CXCR4 have been identified in about 40% of WM patients, and have been associated with slower, more superficial, and shorter responses to ibrutinib therapy. There are data showing that responses can also be slower in WM patients with CXCR4 mutations treated with the proteasome inhibitor ixazomib.

Overall, about 55% to 60% of WM patients will have the MYD88 mutation without CXCR4 mutations. In these patients, ibrutinib is associated with a response rate of virtually 100% and a median progression-free survival (PFS) that has not been reached at 5 years.

About 35% to 40% of WM patients will have MYD88 and CXCR4 mutations. In these patients, ibrutinib, bendamustine-rituximab, and bortezomib-dexamethasone-rituximab (BDR) are all effective options with response rates of 80% to 90% and median PFS of 4 to 5 years.

For the 5% to 10% of patients without MYD88 or CXCR4 mutations, ibrutinib is not an effective option, and bendamustine-rituximab or BDR are probably more effective regimens.

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

The side effect profile differs depending on the regimen used. For bendamustine-rituximab, most common adverse events include cytopenias, nausea, constipation, rash, and infusion reactions. Infusion reactions are common with rituximab. Of importance is a 0.5% risk of developing secondary myelodysplasia or myeloid leukemia due to exposure to bendamustine.

For BDR, the most common adverse events are neuropathy, thrombocytopenia, herpes zoster, and infusion reactions. All patients on BDR should be on acyclovir or valacyclovir to minimize the risk of herpes zoster. No secondary cancers have been described with BDR.

Finally, for ibrutinib, adverse events can be divided in short-term and long-term events. Common short-term events include rash, nausea, diarrhea, and joint pains. However, these symptoms resolve within 2 to 3 months of therapy in the majority of patients. Long-term events include bleeding (common) and atrial fibrillation (rare). Bleeding can be minimized by holding ibrutinib for a few days prior and after invasive procedure such as surgeries, endoscopies or biopsies.

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

That has been our experience at the Bing Center for Waldenstrom Macroglobulinemia Clinic. Ibrutinib induces fast and deep responses in a substantial proportion of patients with WM. However, even if these responses are deep, upon ibrutinib discontinuation, more than 75% of patients will experience an increase in his serum IgM levels as an indicator of disease progression.

In addition, research from our center indicates that ibrutinib dose intensity also plays a role in response duration, with a dose intensity lower than 97% associated with shorter duration of response.

At the moment, we have no evidence that ibrutinib therapy can be discontinued in patients with WM. Can we stop ibrutinib therapy at some point? This question would likely be answered by the next generation of studies in WM, in which ibrutinib will be used in combination with other highly effective agents.

Question

Given that WM is generally an indolent disease, are there conditions when it’s best not to treat the disease, and rather to treat symptoms only?

Answer

WM is an incurable disease, but patient can enjoy prolonged survival times measured in some cases in decades. Therefore, our treatments are never aimed at curing the disease and in a few cases to prolong survival. We treat patient mostly to improve their symptoms focusing on quality of life.

There are several criteria we used to recommend therapy. In most cases, we recommend therapy when patients are tired and short of breath from anemia, or have neuropathic symptoms affecting their activities of the daily living, or their serum IgM level is so high that the patients are having symptoms of hyperviscosity. Having said all that, an asymptomatic WM patient is almost always better left untreated on close monitoring.