Comorbidity burden is a major independent prognostic factor in Waldenström Macroglobulinemia: A national cancer database retrospective study.

BACKGROUND: Waldenström macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma (LPL), is a rare indolent Non-Hodgkin B-cell lymphoma, with an estimated incidence of approximately 1500 new cases diagnosed annually in the United States. Existing prognostic models: IPSS-WM, revised IPSS-WM, and MSS-WM focus primarily on age and disease-specific factors, including albumin, hemoglobin, platelet count, β2-microglobulin, LDH, and monoclonal IgM at diagnosis, and were derived from small cohorts. However, comorbidity burden is not included in these models, despite data showing that mortality is frequently attributed to comorbidities unrelated to lymphoma. We conducted this analysis to identify prognostic factors with emphasis on the impact of comorbidity burden on overall survival in WM.

METHODS: In this IRB-approved retrospective study, we analyzed 17130 patients with histologically confirmed WM (ICD-O-3 9761/3) from the NCDB (2004-2023). Univariable and multivariable Cox regression identified independent prognostic factors for overall survival. An Age-stratified sub-analysis assessed the prognostic impact of comorbidity within each age group. Kaplan-Meier curves compared survival outcomes based on comorbidity burden. Analyses were performed using SAS 9.4.

ETHICAL CONSIDERATIONS: This study was approved by the Institutional Review Board (IRB) of the Cleveland Clinic Foundation. The use of the NCDB data complied with all relevant ethical regulations, ensuring patient data privacy and data integrity.

RESULTS: On multivariable Cox regression with backward elimination, Charlson comorbidity score (CC) ≥ 1 was found to be a significant independent predictor of mortality (HR 1.67, 95% CI 1.58-1.75, p < 0.0001). Age-stratified analysis confirmed CC ≥ 1 significance in all age groups (HR 1.52-2.07, p < 0.0001). Seven additional prognostic factors were identified: advanced age was associated with progressively worse survival (55 ≤age<65: HR 1.68; 65 ≤age<75: HR 2.40; age≥75: HR 5.55; all p < 0.0001), while female sex was protective (HR 0.86; p < 0.0001). Lower median household income was associated with worse outcomes (<$40,227: HR 1.38; $40,227-$50,353: HR 1.25; $50,354-$63,332: HR 1.14; all p < 0.0001). Private insurance was associated with better OS compared with uninsured (HR 1.67; p < 0.0001) and governmental insurance (HR 1.34; p < 0.0001). Treatment at non-academic facilities (HR 1.13; p < 0.0001) and multiple primary malignancies (HR 1.19; p < 0.0001) were associated with inferior survival. No difference was observed between multi- and single-agent chemotherapy (HR 1.0; p = 0.96), while patients not requiring chemotherapy had superior survival (HR 0.80; p < 0.0001) CONCLUSION: In the largest WM cohort to date, we identified several prognostic factors that affect the survival of WM patients in the US. Among these factors, CC ≥ 1 was a strong independent predictor of mortality. Given that half of deaths in WM patients are due to comorbidities, comorbidity assessment is key for accurate prognostication and individualized treatment planning. Managing comorbidities may be as important as treating the disease itself. CC or equivalent should be integrated into future prognostic models to improve clinical decision-making in WM.

MICROABSTRACT: Current prognostic models for Waldenström macroglobulinemia (WM) do not incorporate comorbidity burden. In this National Cancer Database analysis of 17,130 WM patients, the largest cohort to date, Charlson comorbidity score ≥ 1 was a strong independent predictor of mortality (HR 1.67, p < 0.0001), persisting across all age groups. Patients with comorbidities had markedly shorter median overall survival (66 vs. 126 months). Comorbidity assessment should be integrated into prognostic evaluation and treatment planning in WM.