Prognostication and Risk Stratification in WM


Jorge J. Castillo, MD:There are data showing genomic abnormalities in patients with Waldenström macroglobulinemia, and there are 2 that have become more popular. One of them is theMYD88[myeloid differentiation primary response 88] mutation. We have known about this mutation at our center since 2012. The WHO [World Health Organization] just included that finding in lymphoplasmacytic lymphoma in 2016, so it took about 4 years to be able to make this a mainstream issue. We also described a second mutation seen in about 40% of patients with Waldenström macroglobulinemia in a gene calledCXCR4. It’s a gene that has to do with homing of cells into the bone marrow, and we described that in 2015. More and more, we’re actually learning about this second mutation.

TheMYD88mutation helps us diagnose Waldenström macroglobulinemia. I think if somebody in the right context has anMYD88mutation, the diagnosis of Waldenström macroglobulinemia is fairly certain. It can also help us decide which treatments to use. There are some treatments that would not work as well if the patient does not have anMYD88mutation, ibrutinib being one of those examples.CXCR4mutations—so far, there have been few studies on this—are showing that clinical aspects might be a little bit different. These patients tend to have a higher burden of disease in the bone marrow. They tend to have higher levels of IgM [immunoglobulin M] and can actually be associated with higher risk of hyperviscosity. This is what we think is important.

In terms of treating with ibrutinib,CXCR4mutations seem to adversely affect the outcomes of these patients. Specifically, the time to reach a response is a little bit longer in these patients. The depth of response is not as good as in other patients withoutCXCR4mutations. We have data now showing that the duration of response may actually be shorter as well. Regarding the treatment of patients withCXCR4mutations with BTK [Bruton tyrosine kinase] inhibitors like ibrutinib, we need to be very careful about that and sometimes consider other options in that setting.

There have been a number of studies trying to evaluate risk factors for the survival of patients with Waldenström macroglobulinemia, and it’s really difficult to ascertain. Most studies use the classic index, the IPSSWM, or International Prognostic Scoring System for Waldenström Macroglobulinemia. That study was done several years ago, where more than 95% of the patients got treated with just chemotherapy and without the new agents that we have. In that study, we used 5 factors—age, hemoglobin, platelet counts, beta-2 microglobulin, and serum IgM levels—to decide which patient is going to do better or worse down the road in terms of survival. The downside is that that is taken specifically when the patients start treatment. Most of our patients have a few to several years between diagnosis and starting treatment.

At diagnosis, we really don’t have good prognostic factors. I think the most important factor, in my experience, is age. Patients diagnosed at a younger age tend to have a longer survival, and patients diagnosed at an older age have a shorter survival. But that’s life, to some degree. The IPSSWM is helpful once we start the first treatment. When we’re measuring IPSSWM, it’s not really overall survival, it’s actually survival after first treatment initiation. That is very important to understand. It is different than the other factors that we tend to use in patients with lymphomas.

It’s also important to realize the prognostic value that mutations can have in Waldenström macroglobulinemia. For example, patients withoutMYD88mutations, about 10% of our patients, do have a worse outcome and tend to have a higher risk of transforming to more aggressive lymphomas. On the other hand,CXCR4mutation does not seem to affect the overall survival of patients but does seem to affect how they respond to some treatments, and one of them is ibrutinib. As we described previously, these patients have shorter responses and take more time to actually get to a response. There is some value in actually identifying these mutations.

I know that it’s difficult for a community oncologist to get access toCXCR4mutation testing. We do it in our center because we have the resources and we can do it. My sense is if we think a patient is a candidate for a BTK inhibitor, then we probably do have the time to actually look for aCXCR4mutation. However, the patient is going to be treated with rituximab; we’ll continue the regimen. Some chemotherapies or other agents are not affected by these mutations, and it might not be the right thing to test.

Upon reviewing this case, the IPSSWM scoring is about 2 out of 5, which puts this patient into an intermediate-risk category. I want to remind everybody that this study, the IPSSWM, was done years ago in which patients were treated with chemotherapy. There was a more recent study that validated that same scoring system in patients treated with cetuximab-containing regimens. We don’t have any data to really suggest that the IPSSWM score is predictive in patients getting treated with BTK inhibitors. These are data that we’re not really done collecting. In our database, we have about 300 patients in my clinic on BTK inhibitors, so we want to evaluate these very shortly when we have more follow-up.

Transcript edited for clarity.

Case: A 65-Year-Old Female With Newly Diagnosed Waldenström Macroglobulinemia

September 2016

  • A 65-year old female presented to her PCP with slowly progressing anemia for the last couple of years
  • Several months prior to that, she began experiencing drenching night sweats, distended abdomen, and 15 lb weight loss
  • SH: Married, exercises regularly, social drinker, non-smoker, no illicit drug use
  • FH: Maternal aunt — breast cancer age 51
  • Laboratory results:
    • Hemoglobin; 7 g/dL (11-13 g/dL), platelets; 55,000/mm3(155,000-410,000/mm3), and leukocyte count 1,700/mm3(3,800-9,200/mm3).
    • M-protein; 2991.3 mg/dL; IgM 4710 mg/dL (45—281 mg/dL)
    • Serum viscosity; 3.7 centipoise (cP) (1.6—1.9 cP)
    • Beta-2; 3 mg/L (0-2.7 mg/L)
    • IPSSWM: 2 Intermediate
  • Bone marrow aspiration and biopsy; 40—50% B cells
  • Flow cytometry; Lambda-restricted B cells that expressed CD19 and CD20
  • B cells were negative for CD5, CD10, CD43, bcl-1, and bcl-6
  • Allele-specific PCR; MYD88L265Pmutation
  • Diagnosis; Waldenström’s macroglobulinemia (WM)


  • Patient was started on ibrutinib (420 mg) daily with monthly follow-up visits
  • After three months, her IgM was 1500 mg/dL and her serum viscosity was 1.5 cP
  • Her CBC showed improvements: WBC, 5000/mm3, Hgb 15.5g/dL; platelets 180,000/mm3
  • The patient was last seen on follow-up last month and she continues on ibrutinib 2 years after her initial presentation
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