To the editor:

Waldenström macroglobulinemia (WM) is a chronic lymphoproliferative disorder (LP) characterized by an immunoglobulin M monoclonal gammopathy in the presence of lymphoplasmacytic lymphoma (LPL) in the bone marrow.1  We have previously shown in a large population-based study that first-degree relatives of LPL/WM patients had an increased risk of developing LPs.2 

An earlier single-center study on 257 WM patients showed that patients with a family history of WM or other B-cell disorders had a higher bone marrow involvement and were diagnosed at a younger age.3  Furthermore, WM patients with a family history of a B-cell malignancy (n = 135) had worse response and shorter progression-free survival when treated with rituximab, compared with patients with sporadic WM. However, patients with familial WM had better response to bortezomib-containing therapy.4 

Through nationwide Swedish registries and a national hematology/oncology network, we identified 2185 LPL/WM patients diagnosed between 1958 and 2007 and their 6460 first-degree relatives. Our nationwide study is the first, to our knowledge, to estimate the impact of having a family history of B-cell malignancy on overall survival in LPL/WM patients. Family history of any LP was defined as having a first-degree relative with LPL/WM, Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, chronic lymphocytic leukemia, and/or monoclonal gammopathy of undetermined significance. Overall survival was fitted with the Cox proportional hazard model to obtain hazard ratios (HRs) and 95% confidence intervals (95% CIs), adjusting for sex, age at diagnosis, and year of diagnosis (Table 1).

Table 1

Risk of death in LPL/WM patients in relation to family history of LPs

No. of patientsHR*95% CI
Family history of    
 Any LP 93 1.34 1.03-1.75 
  Per increasing number of relatives  1.22 0.99-1.50 
 Multiple myeloma 13 1.47 0.76-2.85 
 Non-Hodgkin lymphoma 44 1.43 1.00-2.06 
 Hodgkin lymphoma 0.51 0.13-2.03 
 Chronic lymphocytic leukemia 17 1.43 0.71-2.88 
 LPL/WM 16 1.28 0.69-2.39 
 Monoclonal gammopathy of undetermined significance 11 1.12 0.53-2.37 
 Any LP (age scale)  1.32 1.02-172 
 Any LP (year-of-diagnosis scale)  1.31 1.01-1.71 
Age at diagnosis (per 1-year increase)  1.06 1.05-1.07 
Female gender  0.72 0.65-0.79 
Year of diagnosis (per 1-year increase)  0.99 0.98-1.00 
No. of patientsHR*95% CI
Family history of    
 Any LP 93 1.34 1.03-1.75 
  Per increasing number of relatives  1.22 0.99-1.50 
 Multiple myeloma 13 1.47 0.76-2.85 
 Non-Hodgkin lymphoma 44 1.43 1.00-2.06 
 Hodgkin lymphoma 0.51 0.13-2.03 
 Chronic lymphocytic leukemia 17 1.43 0.71-2.88 
 LPL/WM 16 1.28 0.69-2.39 
 Monoclonal gammopathy of undetermined significance 11 1.12 0.53-2.37 
 Any LP (age scale)  1.32 1.02-172 
 Any LP (year-of-diagnosis scale)  1.31 1.01-1.71 
Age at diagnosis (per 1-year increase)  1.06 1.05-1.07 
Female gender  0.72 0.65-0.79 
Year of diagnosis (per 1-year increase)  0.99 0.98-1.00 
*

Cox model adjusted for age at diagnosis, gender, and year of diagnosis.

The additive risk of each first-degree family member diagnosed with an LP.

Family members with non-Hodgkin lymphoma, excluding those with LPL/WM.

Overall, LPL/WM patients with a family history of any LP had an increased risk of death compared with sporadic LPL/WM patients (HR = 1.34; 95% CI, 1.03-1.75). The HR for each additive relative diagnosed with any LP was 1.22 (95% CI, 0.99-1.50). Survival differences have not been reported before in familial vs sporadic WM, but these findings are consistent with the earlier single-center study on WM showing worse outcome in familial WM when treated with rituximab.4  They are, however, in contrast to studies on Hodgkin lymphoma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia in which familiality was not associated with a poorer outcome.5-7 

Of individual diseases, with the exception of Hodgkin lymphoma (with only 4 patients), family history of the other LPs showed a nonsignificant trend to increased risk. Female gender was associated with improved survival, which is consistent with earlier findings8  and might be attributable to different clinical staging at diagnosis, comorbidity, and different distribution of prognostic factors. We performed several sensitivity analyses such as running the model on age and year-of-diagnosis scales to obtain HR for family history of any LP (HR = 1.32; 95% CI, 1.02-1.72 and HR = 1.31; 95% CI, 1.01-1.71, respectively). Furthermore, we matched each LPL/WM patient with family history and 4 sporadic patients, matched by age, gender, and year of diagnosis, and then did the same analysis with 10 matched sporadic patients. In addition, we performed cause-specific analyses, using WM death as outcome. The results from these analyses were similar to the main results (data not shown).

Our study has several strengths, for example, the generalizability of nationwide Swedish data and a hard end point (overall survival). Thorough sensitivity analyses were performed to rule out bias attributable to age and calendar period of diagnosis with essentially the same results as in the main analysis. Limitations include that as the follow-up time is through 2007, most patients did not receive novel agents, such as bortezomib, which might alleviate the negative prognostic value of familial disease.4  Additionally, because of the design of the study, we did not have detailed clinical information such as bone marrow results, laboratory data, and treatment.

In summary, we have shown in this large population-based study on LPL/WM patients that family history of any LP was associated with a significantly poorer survival. These results support the theory that genetic susceptibility predisposes patients to a more severe form of LPL/WM. We recommend that family history of LPL/WM should be incorporated in the clinical workup of LPL/WM patients; however, until we gain more insight regarding the potential differences in genetic background, response to therapy, and rate of complications, clinical management should not differ between familial and sporadic LPL/WM patients.

Contribution: V.S., S.H.L., and S.Y.K. designed the study. S.Y.K., O.L., and I.T. obtained data. V.S. and S.H.L. performed the analyses. V.S. and S.Y.K. wrote the report. All the authors were involved in the analyses and the interpretation of the results. All authors read, gave comments, and approved the final version of the manuscript. All the authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Sigurdur Y. Kristinsson, Faculty of Medicine, University of Iceland, Stapi v/Hringbraut, 101 Reykjavik, Iceland; e-mail: sigyngvi@hi.is.

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