Second Primary Malignancy in Waldenström Macroglobulinemia: Insights from a Population-Based Analysis

INTRODUCTION: Waldenström Macroglobulinemia (WM), is a hyper-viscosity syndrome characterized by unrestricted proliferation of lymphoplasmacytic precursors in the bone marrow and monoclonal IgM gammopathy. The development of secondary primary malignancy (SPMs) in WM is a multifactorial phenomenon; the indolent nature of the disease, associated immune dysregulation, environmental factors and therapeutic measures, are responsible for high incidence of SPM in WM. This study was conducted to analyse the site-specific incidence of SPM in WM using data from the US Surveillance, Epidemiology and End Results (SEER) cancer registries.

METHODS:

A retrospective study was conducted using the SEER-18 dataset. WM patients who were diagnosed between 2000 and 2018, according to the ICD-O-3 = 9761/3 were included. Patients diagnosed on autopsy or through death certificates, and patients with incomplete follow-up data were excluded. SPM was defined as other malignancy appearing at least 1 year after WM diagnosis. Latency was defined as interval between WM and SPM diagnosis. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated using SEER*Stat software (version 8.3.9). P-values and 95% confidence intervals (CI) were generated assuming Poisson distribution of observed incidence of SPM.

RESULTS:

A total of 4112 WM patients were identified. SPM was reported in 699 (17.0%) patients. The overall risk of developing SPM was significantly higher in WM patients as compared to the general population (SIR= 1.53, 95% CI=1.42-1.65, p <0.05) with an AER of 102.69 per 10,000 population. The risk of developing second primary solid tumors was significantly greater compared to the general population (SIR = 1.12, 95% CI= 1.02-1.23, p >0.05), but significantly increased risks were reported for secondary tumours of the lung and bronchus (SIR = 1.44), skin melanoma (SIR = 1.88), mouth (SIR 3.28), brain (SIR 2.73) and non-melanotic skin tumors (SIR = 4.09). The overall risk of developing secondary hematological malignancies was significantly increased (SIR = 4.95, 95% CI 4.31-5.66, p <0.05). Significantly increased risks were reported for nodal non-Hodgkin lymphoma (NHL) (SIR = 6.62), extranodal NHL (SIR = 11.3), acute lymphocytic leukemia (ALL) (SIR 8.04), acute non-lymphocytic leukemia (ANLL) (SIR = 4.2) and acute myeloid leukemia (AML) (SIR 4.22).

Increased risk of SPMs was noted for patients with age 50-74 years (SIR= 1.65, 95%CI=1.44-1.89, p value <0.05) or > 75 years (SIR= 1.3, 95% CI= 1.13-1.49, p value <0.05), but not for patients younger than 50 years. Patients aged 50-74 years had a significantly increased risk of developing SPMs of lungs and bronchus (SIR 2.23), skin (SIR 3.09), vulva (SIR 8.5), thyroid (SIR 3.59), nodal NHL (SIR 6.06), extranodal NHL (SIR 11.87), ANLL (SIR 5.77) and AML (SIR 6.37). Patients aged >75 years had a significantly increased risk of developing SPMs of cecum (SIR 2.50), colon (SIR 1.62), soft tissues (SIR 5.25), nodal NHL (SIR 2.38), extranodal NHL (SIR 7.51), ANLL (SIR 3.69) and AML (SIR 3.63).

Risk of SPM was significantly increased in both males (SIR 1.39) and females (SIR 1.59). On subsite evaluation, males had a significantly greater risk of SPMs involving lung and bronchus (SIR 1.71), soft tissues (SIR 4.52), skin (SIR 1.88), nodal NHL (SIR 3.85), extra-nodal NHL (SIR 6.9), ANLL (SIR 5.4) and AML (SIR 5.55). Females reported a significantly increased risk of SPM involving cecum (SIR 3.88), skin (SIR 2.87), vagina (SIR 11.51) nodal NHL (SIR 3.86) and extranodal NHL (SIR 13.57).

The risk of SPM was significantly greater in Caucasians (SIR 1.46) but not African Americans or other races. The risk of SPM was significantly greater in patients at all latencies. The risk of SPM of cecum (SIR 2.76) and non-melanotic skin cancer (SIR 5.52) was significantly greater in patients with latency of 12-59 months, but not at subsequent latencies. The risk of melanotic skin cancer (SIR 2.61) was significantly greater in patients with latency of 60-119 months but not other latencies. The risk of thyroid cancer (SIR 6.43) was significantly increased for patients with latency 120+ months only.

CONCLUSION:

This study showed that 17% of WM patients developed SPM. WM patients were at a 53% greater risk of developing SPM compared to the general population. Caucasians and patients aged greater than 50 years were at particularly high risk of developing SPM.

Anwer:BMS: Consultancy, Research Funding, Speakers Bureau; Allogene Therapeutics: Research Funding; Janssen: Consultancy.