Rafael Fonseca, MD

Question

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

Answer

Staging is not as important for WM as it is for other malignancies. Most people have focused more on the various prognostic models to determine outcomes for patients. These models all include factors directly associated with the disease complications (eg, anemia or thrombocytopenia) or directly related to the tumor bulk.

The Second International Workshop on Waldenström Macroglobulinemia, and our group have proposed criteria to define the disease.^1,2 The Mayo classification requires that patients have at least a 105 involvement of their bone marrow by clonal cells to avoid treatment of patients with IgM, though some patients with lower levels of involvement could well be symptomatic.

However, there are important stages to recognize with regards to therapy initiation. There is some disagreement in these staging models, but they all recognize the presence of a premalignant condition, IgM MGUS [monoclonal gammopathy of undetermined significance], the smoldering variant of WM, and the active disease. Perhaps additional understanding of disease biology and further epidemiologic studies will clarify this attempts at classification of the various stages.

Question

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

Answer

It has been reported that the vast majority of patients with WM harbor mutations of the gene called MYD88^L265P.3 This gene is central to the Bruton tyrosine kinase pathway that is central in B cell development. The mutation described results in super activation of signaling and accordingly inhibitors of this pathway were tested in the clinic.

Various clinical trials have shown the ability of ibrutinib to exert antitumor effects on WM cells. As such the medication was granted FDA [US Food and Drug Administration] approval for the treatment of this disease. A subset of patients also harbor mutations of the CXCR4^WHIM gene, a mutation that is believed to be secondary, although it has been associated with longer time to response in those treated with ibrutinib and perhaps a lower response rate. While MYD mutations are seen in nearly all cases of WM, they are not specific and can be observed in other B-cell neoplasia.

In the past, we did studies on the clonal cells of WM and found them to be unlike cells from multiple myeloma, and more resembling of CLL [chronic lymphocytic leukemia] at the gene expression profile level. Also, we reported that WM cells lack translocations of chromosome 14 and that they do not have the common chromosome abnormalities seen in MM [multiple myeloma]. The only cytogenetic aberration seen in a substantial number of patients is a deletion of the long arm of chromosome 6, which is observed in about 50% of cases.

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

Treatment can be started using a number of agents or combinations. One such approach is mentioned above, and is ibrutinib, which is taken orally daily. Patients with borderline symptoms can be treated also with single agent rituximab, and in more symptomatic situations one can combine rituximab with bendamustine (or other agents). Many other therapeutic options exist but these are the most common regimens used for the management of this disease. Just today I was discussing with a patient the various options available, although we did not yet make a decision.

Ibrutinib has the advantage of being an all-oral medication regimen, but needs to be administered long term. While it is generally well-tolerated it can have side effects including bleeding propensity (in up to 50% of cases, one must be careful in patients receiving anticoagulation or antiplatelet agents), myelosuppression, atrial fibrillation, and infection. It is also suspected of being teratogenic.

The combination of rituximab and bendamustine can also be used effectively for the treatment of WM. Its main advantage is the shorter duration of therapy and good outcomes. It does not result in alopecia (only about 3% of cases) and overall is well-tolerated. Bendamustine can also result in myelosuppression, headaches, infection, and gastrointestinal abnormalities. Severe allergic reaction with skin desquamation have also been reported. Some patients can have severe infusional reactions to the rituximab. Bendamustine, an alkylator, should not be used in pregnant patients.

Lastly, any patient who is treated with rituximab as a single agent must be monitored for a flare reaction. There is a paradoxical increase in the serum IgM seen after the initial infusions of rituximab. It is important to know of its existence for 2 reasons: it does not indicate disease progression and it should be monitored in those at risk for hyperviscosity (ie, those with IgM values of 4000 mg/dl or higher). In some cases, plasmapheresis will be indicated prior to or during treatment initiation.

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

It is pretty straightforward. Once we start treatment the decision is as follows: if the disease is responding and the patient can tolerate, and has access to the medication, then we continue with the treatment.

It is important to remark that some of these drugs that interfere with cell signaling will not have prolonged “after effects” on these cancer cells, much like other chemotherapies can. If one stops therapy there is a possibility of regrowth of the clone and recurrence of symptoms. But all of this assumes one has a good response and that the patient is tolerating therapy.

Two other important findings were reported in that study: one that the rate of responses was quite high, and two, that patients with CXCR4^WHIM mutations can take longer to achieve response.

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

Determination of the need for therapy is one of the most important aspects to consider when caring for patients with WM. Patients who have no evidence of end-organ damage can be safely observed at regular intervals. However, individuals who present with progressive anemia, constitutional symptoms, weight loss, progressive hepatomegaly or splenomegaly, or hyperviscosity should be offered treatment.

While international guidelines have been developed to address criteria for treatment initiation there is still significant variation in clinical practice. I use the word “bother” when discussion treatment need with my patients, and ask them if they are bothered by symptoms that we could assign to the disease. If so then we will usually initiate therapy.

With the exception of hyperviscosity, most of the time treatment is not urgent and if needed a second opinion could be sought. Unlike myeloma, where progression can lead to negative life-long consequences such as a painful vertebral compression fracture or irreversible renal failure, that is rarely the case for WM.