Incidence and Survival Outcomes of Secondary Malignancies Among Survivors of Waldenström Macroglobulinemia
Authors: Castillo Jorge J. , Olszewski Adam J. , Kanan Sandra , Meid Kirsten , Hunter Zachary , Treon Steven P 
Published: October 2019

Abstract
Background: Waldenstrom macroglobulinemia (WM) is an indolent malignancy characterized by extended survival, and affects predominantly older individuals, who are at risk for secondary malignancies (SM). The objectives of our study were to characterize incidence and outcomes of SM after WM diagnosis using the Surveillance, Epidemiology and End Results (SEER) database.
Methods: Using the SEER-13 data from 1992-2011, we calculated standardized incidence ratios (SIR) with 95% confidence intervals (CI) for rates of solid and hematologic SM in WM patients compared with matched general population, excluding synchronous tumors. We compared SIR in groups defined by attained age, calendar year, sex and race. SIRs from SM with less than 10 cases are not reported. Also, overall survival (OS) after a malignancy diagnosis was compared between patients with or without antecedent WM in Cox proportional-hazard regression models adjusting for attained age, sex, race and tumor stage using SEER-18 data from 2000-2011. The outcome of interest for survival was hazard ratio (HR) with 95% CI.
Results: Among the 4,676 WM patients in the SEER-13 database, 681 SM were recorded (Table). The overall SIR was 1.49 (95% CI 1.38-1.61) and the median time to SM was 3.7 years (95% CI 3.2-4.2 years). The cumulative incidence of SM was 9.5% (95% CI 8.6-10.5%) at 5 years, and 16.1% (95% CI 14.8-17.3%) at 10 years. The cumulative incidence at 10 years was 12.2% (95% CI 11.1-13.3%) for solid tumors and 4.2% (95% CI 3.5-4.9%) for hematologic SM. The excess risk of solid tumors peaked between 5-10 years from WM diagnosis (SIR 1.1, 1.4 and 1.1 for latency of 0-5, 5-10 and more than 10 years, respectively), while for hematologic malignancies it grew continuously with time (SIR 3.8, 4.4 and 6.7, respectively). The risk of solid tumors was significantly increased for cancers of the lung, urinary tract, thyroid gland and melanoma, but not for breast, prostate or colorectal cancer. Among lymphomas, diffuse large B-cell (DLBCL) was the most frequent subtype. Patients younger than 65 had a significantly higher SIR for any SM (SIR 2.2, 95% CI 1.9-2.6) than those 65 years or older (SIR 1.4, 95% CI 1.3-1.5). The SIR for SM was similar in the 1990s (SIR 1.3, 95% CI 1.1-1.6) and 2000s (SIR 1.5, 95% CI 1.4-1.7). The SIR for solid tumors was the same (SIR 1.2) among men and women, but for hematologic malignancies the excess risk was significantly higher in women (SIR 5.8, 95% CI 4.6-7.2) than men (SIR 3.4, 95% CI 2.8-4.2). There was no difference for white and non-white patients, either for aggregate SM or for the solid/hematologic categories. Compared with age- and sex-matched population and adjusting for race and stage, OS was worse with antecedent WM for colon cancer (HR, 2.0, 95% CI 1.4-2.7), melanoma (HR, 2.6, 95% CI 1.8-4.0) and DLBCL (HR, 1.9, 95% CI 1.2-3.0). It was not significantly different for acute leukemia (HR 0.9, 95% CI 0.5-1.4), prostate (HR 1.2, 95% CI 0.9-1.6), breast (HR 1.1, 95% CI 0.7-1.9), bladder (HR 1.2, 95% CI 0.8-1.7), thyroid (HR 0.9, 95% CI 0.1-6.0) or lung cancer (HR 1.2, 95% CI 1.0-1.4).
Conclusions: Patients with WM have a 49% higher risk of a SM than the general population. Further research is needed to elucidate the increased incidence of leukemia and DLBCL possibly resulting from therapy and transformation, respectively, and melanoma, lung, bladder and thyroid cancers, possibly associated with defective immune surveillance. Comparatively poor survival in WM patients with colon cancer underscores the need for guideline-adherent screening and therapy.
Table Incidencea SIR 95% CI Excess casesa All malignancies 681 1.5 1.4-1.6 95 Solid tumors 484 1.2 1.1-1.3 35 Lung 101 1.5 1.2-1.8 14 Prostate 95 1.0 0.8-1.3 1 Urinary tract 62 1.4 1.1-1.8 8 Colorectal 48 0.9 0.7-1.2 -2 Other gastrointestinal 43 1.0 0.7-1.4 0 Breast 43 1.0 0.8-1.4 1 Melanoma 35 1.9 1.3-2.7 7 Other gynecologic 21 1.3 0.8-2.0 2 Head and neck 13 0.9 0.5-1.6 0 Thyroid 10 2.7 1.3-4.9 3 Hematologic malignancies 174 4.2 3.6-4.9 56 All lymphomas 120 4.4 3.6-5.2 39 Diffuse large B-cell 31 4.3 2.9-6.1 10 Extranodal marginal zone 16 14.8 8.5-24.1 6 Other indolent B-cell 19 3.7 2.2-5.8 6 Myeloma 31 4.7 3.2-6.6 10 Acute leukemia 15 3.2 1.8-5.3 4 a per 10,000 person-years

Disclosures
No relevant conflicts of interest to declare.