Advertisement
Mayo Clinic Proceedings Home

A 50-Year-Long Study of Waldenström Macroglobulinemia

      Waldenström macroglobulinemia (WM) is a rare low-grade lymphoma in which lymphoplasmacytic cells infiltrate the bone marrow and produce monoclonal IgM protein.
      It has a well-defined immunophenotype, although exclusion of other low-grade lymphoproliferative disorders is required to confirm diagnosis.
      • Owen R.G.
      • Treon S.P.
      • Al-Katib A.
      • et al.
      Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.
      The clinical features of WM include a constellation of signs and symptoms related to infiltration of the bone marrow or other organs by the clonal cells, the production of the monoclonal immunoglobulin M (IgM) and its unique physicochemical and immunologic properties, as well as the production of cytokines that may cause various symptoms and complications. Recently, a somatic mutation of the MYD88 gene (L265P), found in 90% to 95% of patients with WM, shed new light on the biology of the disease.
      • Treon S.P.
      • Xu L.
      • Yang G.
      • et al.
      MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia.
      Not all patients are symptomatic at the time of WM diagnosis, and therapy is considered only for symptomatic patients, based on consensus criteria.
      • Kyle R.A.
      • Treon S.P.
      • Alexanian R.
      • et al.
      Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.
      • Leblond V.
      • Kastritis E.
      • Advani R.
      • et al.
      Treatment recommendations from the Eighth International Workshop on Waldenstrom's Macroglobulinemia.
      A significant proportion of patients diagnosed as having WM are asymptomatic and may remain so for several years, and some may never require therapy.
      • Kyle R.A.
      • Benson J.T.
      • Larson D.R.
      • et al.
      Progression in smoldering Waldenstrom macroglobulinemia: long-term results.
      The rarity of the disease makes accurate estimation of its incidence and prevalence quite challenging. Although there are cancer registry data to provide a rough estimation, there are major limitations to their use.
      • Herrinton L.J.
      • Weiss N.S.
      Incidence of Waldenstrom's macroglobulinemia.
      • Phekoo K.J.
      • Jack R.H.
      • Davies E.
      • et al.
      The incidence and survival of Waldenstrom's Macroglobulinaemia in South East England.
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2017.
      • Wang H.
      • Chen Y.
      • Li F.
      • et al.
      Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study.
      • Groves F.D.
      • Travis L.B.
      • Devesa S.S.
      • et al.
      Waldenstrom's macroglobulinemia: incidence patterns in the United States, 1988-1994.
      The most important limitation is the lack of differentiation among IgM monoclonal gammopathy of undetermined significance, asymptomatic WM, and symptomatic WM requiring therapy and actually treated.
      • Kristinsson S.Y.
      • Bjorkholm M.
      • Landgren O.
      Survival in monoclonal gammopathy of undetermined significance and Waldenstrom macroglobulinemia.
      • Kristinsson S.Y.
      • Eloranta S.
      • Dickman P.W.
      • et al.
      Patterns of survival in lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia: a population-based study of 1,555 patients diagnosed in Sweden from 1980 to 2005.
      • Castillo J.J.
      • Olszewski A.J.
      • Kanan S.
      • et al.
      Overall survival and competing risks of death in patients with Waldenstrom macroglobulinaemia: an analysis of the Surveillance, Epidemiology and End Results database.
      • Castillo J.J.
      • Olszewski A.J.
      • Cronin A.M.
      • et al.
      Survival trends in Waldenstrom macroglobulinemia: an analysis of the Surveillance, Epidemiology and End Results database.
      Another limitation is the requirement for an accurate histologic diagnosis, which in large retrospective registries may not be very strict. Furthermore, modifications in the diagnostic criteria and the methods have occurred in the past 30 years, and the differential diagnosis from other low-grade lymphomas may be difficult if, for example, a serum immunofixation to determine the presence of a monoclonal IgM is not available. Thus, it is likely that many cases of WM are not reported and are missed if the diagnosis is made in medical centers with low volumes of lymphomas and hematologic malignancies.
      In the June 2018 issue of Mayo Clinic Proceedings, Kyle et al
      • Kyle R.A.
      • Larson D.R.
      • McPhail E.D.
      • et al.
      Fifty-year incidence of Waldenström macroglobulinemia in Olmsted County, Minnesota, from 1961 through 2010: a population-based study with complete case capture and hematopathologic review.
      reported the incidence of WM in Olmsted County, Minnesota, where Mayo Clinic is located. Mayo Clinic is a referral center for hematologic malignancies and disorders associated with monoclonal gammopathies. Inhabitants of this county have been diagnosed, treated, and followed up at Mayo Clinic and associated medical centers, so the diagnosis of WM is made by experienced pathologists and the data are linked and centrally reviewed. Databases that were reviewed by Kyle et al
      • Kyle R.A.
      • Larson D.R.
      • McPhail E.D.
      • et al.
      Fifty-year incidence of Waldenström macroglobulinemia in Olmsted County, Minnesota, from 1961 through 2010: a population-based study with complete case capture and hematopathologic review.
      included the Mayo Clinic Dysproteinemia Database and the Rochester Epidemiology Project (which includes the medical records of the Olmsted Medical Group). This allows for the collection of high-quality data over several decades. Kyle et al
      • Kyle R.A.
      • Larson D.R.
      • McPhail E.D.
      • et al.
      Fifty-year incidence of Waldenström macroglobulinemia in Olmsted County, Minnesota, from 1961 through 2010: a population-based study with complete case capture and hematopathologic review.
      reported the 50-year incidence of WM in Olmsted County, achieving a complete case capture based on the central reporting and data linkage, and a central hematopathologic review affirmed the diagnosis of WM.
      During these 50 years (from 1961 through 2010), 22 residents of Olmsted County were diagnosed as having WM, certainly a small number. Note, however, that WM is a rare disease, and the population under evaluation is not large. As expected, WM is a disease of the elderly, and the median age at the time of diagnosis was approximately 71 years, and most of the patients were males (68%) and white race (95%). Patients with asymptomatic WM were excluded from this study, but the presentation of the disease was typical, with anemia in most patients and less often with other symptoms, such as organomegaly; data on hyperviscosity, neuropathy, or other symptoms are not reported.
      Despite the small numbers, the most important information derived from this study is that from evaluation of the incidence and temporal trends of WM. Thus, the age-adjusted incidence rate for males was 0.92 of 100,000 and for females was 0.30 of 100,000 in a predominantly white population so that the age- and sex-adjusted annual incidence rate for WM was 0.57 of 100,000, not very different from other calculations,
      • Phekoo K.J.
      • Jack R.H.
      • Davies E.
      • et al.
      The incidence and survival of Waldenstrom's Macroglobulinaemia in South East England.
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2017.
      • Wang H.
      • Chen Y.
      • Li F.
      • et al.
      Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study.
      but probably more accurate. These results may be extrapolated to other white populations with similar origins, as in Europe, thus providing a significant tool for evaluation of the real WM incidence and prevalence. Such estimations are crucial for rare disease to allocate resources and support research.
      As with other low-grade lymphomas, the incidence of WM increased with age, more than doubling after age 70 years. Importantly, this study indicates that the incidence rate did not change during these 50 years; thus, it is probably the aging population that will drive an increased prevalence of WM in the coming years rather than other etiologies.
      Kyle et al
      • Kyle R.A.
      • Larson D.R.
      • McPhail E.D.
      • et al.
      Fifty-year incidence of Waldenström macroglobulinemia in Olmsted County, Minnesota, from 1961 through 2010: a population-based study with complete case capture and hematopathologic review.
      captured the causes of mortality in these patients, although one has to be careful because the treatment of WM (and of other lymphomas), as well as the supportive care, have changed substantially in 50 years. Infections were the most common cause of death, but whether this was directly or indirectly associated with WM or its treatment is not clearly reported. Myelodysplasia was reported as a cause of death in 3 patients (17% of deaths), indicating that the long-term toxicity of WM therapy is an important factor to consider when choosing therapy and that such risks should be weighed carefully over efficacy in the era of modern therapies. It is notable that patients with WM had a 5-fold excess mortality over the remaining population in Olmsted County, but after 2000 this has been significantly reduced; whether this reduction is due to the advances in the treatment of WM (such as monoclonal antibodies and chemoimmunotherapy combinations) or due to the small numbers not allowing an accurate estimation needs to be reevaluated.
      The median survival of the 22 patients in this study is approximately 5.5 years, which is not typical of the survival that we see in more recent cohorts
      • Castillo J.J.
      • Olszewski A.J.
      • Kanan S.
      • et al.
      Overall survival and competing risks of death in patients with Waldenstrom macroglobulinaemia: an analysis of the Surveillance, Epidemiology and End Results database.
      • Castillo J.J.
      • Olszewski A.J.
      • Cronin A.M.
      • et al.
      Survival trends in Waldenstrom macroglobulinemia: an analysis of the Surveillance, Epidemiology and End Results database.
      ; this is probably due to the poorer outcomes of patients with symptomatic disease in the 1960s and 1970s, when treatment options were limited to a few alkylating agents. Patients with asymptomatic WM were excluded from this study; however, such patients are included in other registry-based reports,
      • Kristinsson S.Y.
      • Eloranta S.
      • Dickman P.W.
      • et al.
      Patterns of survival in lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia: a population-based study of 1,555 patients diagnosed in Sweden from 1980 to 2005.
      • Castillo J.J.
      • Olszewski A.J.
      • Kanan S.
      • et al.
      Overall survival and competing risks of death in patients with Waldenstrom macroglobulinaemia: an analysis of the Surveillance, Epidemiology and End Results database.
      • Castillo J.J.
      • Olszewski A.J.
      • Cronin A.M.
      • et al.
      Survival trends in Waldenstrom macroglobulinemia: an analysis of the Surveillance, Epidemiology and End Results database.
      thereby making it difficult to prognosticate about the outcomes of patients with WM. This is because asymptomatic WM may actually have a survival not significantly different from the rest of the age-adjusted population.
      The report by Kyle et al
      • Kyle R.A.
      • Larson D.R.
      • McPhail E.D.
      • et al.
      Fifty-year incidence of Waldenström macroglobulinemia in Olmsted County, Minnesota, from 1961 through 2010: a population-based study with complete case capture and hematopathologic review.
      provides us with a long-term view of the disease and probably the most accurate evaluation of the real incidence of WM. However, there is still more that we need to learn. A similar study in another population would be most valuable because the currently available studies are not as accurate in the identification and review of the cases and the reference population. Kyle et al
      • Kyle R.A.
      • Larson D.R.
      • McPhail E.D.
      • et al.
      Fifty-year incidence of Waldenström macroglobulinemia in Olmsted County, Minnesota, from 1961 through 2010: a population-based study with complete case capture and hematopathologic review.
      have long been leading the field and providing insights into this disease. The present study is another one of their important contributions, spanning more than 50 years of care of patients with monoclonal gammopathies.

      References

      1. Swerdlow S.H. Campo E. Harris N.L. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. WHO Press, Geneva, Switzerland2017
        • Owen R.G.
        • Treon S.P.
        • Al-Katib A.
        • et al.
        Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.
        Semin Oncol. 2003; 30: 110-115
        • Treon S.P.
        • Xu L.
        • Yang G.
        • et al.
        MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia.
        N Engl J Med. 2012; 367: 826-833
        • Kyle R.A.
        • Treon S.P.
        • Alexanian R.
        • et al.
        Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.
        Semin Oncol. 2003; 30: 116-120
        • Leblond V.
        • Kastritis E.
        • Advani R.
        • et al.
        Treatment recommendations from the Eighth International Workshop on Waldenstrom's Macroglobulinemia.
        Blood. 2016; 128: 1321-1328
        • Kyle R.A.
        • Benson J.T.
        • Larson D.R.
        • et al.
        Progression in smoldering Waldenstrom macroglobulinemia: long-term results.
        Blood. 2012; 119: 4462-4466
        • Herrinton L.J.
        • Weiss N.S.
        Incidence of Waldenstrom's macroglobulinemia.
        Blood. 1993; 82: 3148-3150
        • Phekoo K.J.
        • Jack R.H.
        • Davies E.
        • et al.
        The incidence and survival of Waldenstrom's Macroglobulinaemia in South East England.
        Leuk Res. 2008; 32: 55-59
        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2017.
        CA Cancer J Clin. 2017; 67: 7-30
        • Wang H.
        • Chen Y.
        • Li F.
        • et al.
        Temporal and geographic variations of Waldenstrom macroglobulinemia incidence: a large population-based study.
        Cancer. 2012; 118: 3793-3800
        • Groves F.D.
        • Travis L.B.
        • Devesa S.S.
        • et al.
        Waldenstrom's macroglobulinemia: incidence patterns in the United States, 1988-1994.
        Cancer. 1998; 82: 1078-1081
        • Kristinsson S.Y.
        • Bjorkholm M.
        • Landgren O.
        Survival in monoclonal gammopathy of undetermined significance and Waldenstrom macroglobulinemia.
        Clin Lymphoma Myeloma Leuk. 2013; 13: 187-190
        • Kristinsson S.Y.
        • Eloranta S.
        • Dickman P.W.
        • et al.
        Patterns of survival in lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia: a population-based study of 1,555 patients diagnosed in Sweden from 1980 to 2005.
        Am J Hematol. 2013; 88: 60-65
        • Castillo J.J.
        • Olszewski A.J.
        • Kanan S.
        • et al.
        Overall survival and competing risks of death in patients with Waldenstrom macroglobulinaemia: an analysis of the Surveillance, Epidemiology and End Results database.
        Br J Haematol. 2015; 169: 81-89
        • Castillo J.J.
        • Olszewski A.J.
        • Cronin A.M.
        • et al.
        Survival trends in Waldenstrom macroglobulinemia: an analysis of the Surveillance, Epidemiology and End Results database.
        Blood. 2014; 123: 3999-4000
        • Kyle R.A.
        • Larson D.R.
        • McPhail E.D.
        • et al.
        Fifty-year incidence of Waldenström macroglobulinemia in Olmsted County, Minnesota, from 1961 through 2010: a population-based study with complete case capture and hematopathologic review.
        Mayo Clin Proc. 2018; 93: 739-746