Identifying risk factors for second malignancies after non-Hodgkin lymphoma
Open AccessPurpose: To develop a better understanding of the risks of developing second malignancies after non-Hodgkin lymphoma (NHL).Methods: To examine the potential associations between NHL treatments, autoimmune conditions, and selected infections and second lung cancer, melanoma, and acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) after first primary NHL we conducted an analytic study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Hazard ratios (HR) and 95% confidence intervals (CI) for the associations between the specific risk factors and second malignancy risks were estimated using Cox proportional hazards regression models. Results: Fludarabine-containing chemotherapy with or without rituximab increased melanoma risk after chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (HR=1.86, 95% CI=1.06-3.27; N=10, HR=2.72, 95%CI=1.33-5.56, respectively), whereas melanoma risk was not associated with specific treatments among patients with other NHLs. Lung cancer risks were also significantly increased among CLL/SLL patients who received fludarabine-containing chemotherapy without rituximab (HR=2.28, 95% CI=1.48-3.52). Significantly elevated lung cancer risks were also observed among diffuse large B-cell lymphoma (DLBCL) survivors who received cyclophosphamide-containing chemotherapy without rituximab (HR=2.13, 95%CI=1.01-4.47). AML/MDS risk was significantly elevated among NHL survivors who received any fludarabine-, cyclophosphamide-, and rituximab-containing chemotherapy compared with those who did not receive any infused chemotherapy (HR=3.52, 95% 1.96-6.33). Risks were highest for survivors who received fludarabine- and rituximab-containing chemotherapy without cyclophosphamide (HR=4.72, 95% CI 2.53-8.84) as well as for those who received fludarabine-containing chemotherapy alone (HR=5.95, 95% CI 2.27-15.58).T-cell activating autoimmune diseases diagnosed prior to (HR=1.76, 95%CI=1.06-2.93) or after CLL/SLL (HR=2.32, 95%CI=1.34-4.03) increased second melanoma risks, whereas melanoma risk was not associated with T-cell/B-cell activating autoimmune diseases among patients with other NHLs. Increased second lung cancer risks were observed for B-cell activating autoimmune conditions occurring after DLBCL (HR=1.63, 95%CI=1.00-2.66), with strongest associations for rheumatoid arthritis (HR=1.89, 95%CI=0.91-3.65), and for T-cell activating autoimmune conditions diagnosed after other NHL subtypes (HR=1.56, 95%CI=1.07-2.27), with strongest associations for asthma (HR=2.00, 95%CI=1.34-2.97). In contrast, T-cell activating autoimmune conditions were significantly inversely associated after FL (HR=0.57, 95%CI=0.34-0.96), likely driven by skin autoimmune conditions, particularly localized scleroderma (HR=0.25, 95%CI=0.08-0.81). AML/MDS risks were increased 1.5- to 2.0-fold for autoimmune diseases occurring prior to NHL diagnosis for nearly all conditions we evaluated. Few associations were observed for diagnoses of autoimmune diseases occurring after NHL, with the exception of pernicious anemia (HR=2.24, 95% CI 1.46-3.42) and asthma (HR=1.98, 95% CI 1.22-3.19).After accounting for history of smoking, lower airway respiratory infections, particularly pneumonia, were associated with increased risks of second lung cancer before and after CLL/SLL (before CLL/SLL: HR=1.53, 95%CI=1.10-2.12; after CLL/SLL: HR=2.21, 95%CI=1.65-2.96), and after DLBCL (HR=1.90, 95%CI=1.26-2.87) and follicular lymphoma [FL]( HR=1.98, 95%CI=1.31-3.00). Upper airway respiratory infections were associated with increased second AML/MDS risk (before NHL HR=1.47, 95% CI 1.01-2.12, after NHL HR=1.74, 95% CI 1.10-2.76), particularly sinusitis (after NHL HR=2.18, 95% CI 1.44-3.31). Additionally, subsequent AML/MDS was also associated with pneumonia (after NHL HR=1.69, 95% CI 1.16-2.46). Other infections increased AML/MDS risks including skin infections likely driven by herpes zoster (HR=1.91, 95% CI 1.18-3.10), and urinary tract infections, particularly prostatitis (before NHL HR=1.71, 95% CI 1.05-2.76, after NHL HR=2.32, 95% CI 1.21-4.45) and cystitis/pyelonephritis (after NHL HR=1.68, 95% CI 1.07-2.62). Gastroenteritis was associated with second AML/MDS when diagnosed after NHL (HR=1.76, 95%CI=1.11-2.79). Generally, infections were not associated with melanoma risk, except for urinary tract infections among CLL/SLL survivors, and pneumonia and gastrohepatic infections among survivors of other NHLs.Conclusion: We have shown that specific chemotherapeutic agents, namely fludarabine and to a lesser extent cyclophosphamide, are associated with increased risk of second melanoma, lung cancer, and AML/MDS. We also identified numerous autoimmune conditions and infections that were associated with increased risk of second malignancies after NHL, particularly T-cell mediated diseases and melanoma, respiratory infections and lung cancer, and B-cell and T-cell mediated autoimmune conditions and various infections and AML/MDS. In addition, we were able to evaluate differences in risk by NHL subtype, especially for CLL/SLL. Our studies have provided valuable information regarding risks that can be considered when evaluating the risks and benefits of screening, particularly for melanoma and lung cancer, and can be used to better inform clinicians and their patients about treatment options and follow-up monitoring for their first cancers to improve long term health outcomes for these patients.
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