Patients with chronic lymphocytic leukaemia (CLL) are at an increased risk of infections, which is believed to result primarily from various immune defects induced by the malignant cells. The same mechanisms presumably also explain why infection susceptibility increases as CLL diagnosis approaches. Accordingly, the CLL clone or precursors hereof emerge several years before leukemia diagnosis, and a gradually deteriorating immune function owing to CLL cell accumulation could explain the infections.
Previous investigations leave room for an additional component in the association between infections and CLL, namely that infection susceptibility predates CLL initiation. We explored this possibility by taking advantage of independent nationwide registrations of cancers, antimicrobial prescriptions and family relations, respectively.
We first assessed the temporal variation in use of antimicrobials – used to approximate infection risk – before CLL diagnosis. We found that use of antimicrobials increased continuously in the last 6-7 years before diagnosis, but intriguingly we also observed an elevated use of macrolides, antivirals and antimycotics more than 20 years in advance of CLL diagnosis.
The long-term increased risk of infection predating CLL diagnosis could point to a constitutional origin. In genome-wide association studies of CLL, multiple loci annotating genes central for B-cell development have been identified, raising the possibility that CLL and infection risk share common risk factors. To investigate this possibility, we studied use of antimicrobials among children and grandchildren of patients with CLL. Similar to individuals who later developed CLL, we observed increased use of macrolides, antivirals and antimycotics in first- and second-degree relatives of CLL patients.
Infections may contribute to CLL development through antigenic stimulation, inducing somatic mutations, or epigenetic modifications analogous to the antigenic drive in lymphoid malignancies. Our study is compatible with such a causal role, but it also illustrates the shortcomings of the definition of cancer latency, as Robert Peter Gale recently wrote. Infections are not the only cause of CLL and CLL may develop in the absence of many infections as randomness plays a role in its pathogenesis. Still, Casabonne and colleagues observed that persons vaccinated for influenzae and/or pneumococci had lower prevalence of monoclonal lymphocytosis - suggesting primary prevention may be feasible. Going forward, the increased risk of infections should be recognized, and future studies will hopefully bring more insight into the underlying biology such that we one day can prevent either development or progression of CLL.
Abecasis M, Cross NCP, Brito M, Ferreira I, Sakamoto KM, Hijiya N, et al. Is cancer latency an outdated concept? Lessons from chronic myeloid leukemia. Leukemia. 2020; doi: https://doi.org/10.1038/s41375-020-0957-z
Casabonne D, Almeida J, Nieto WG, Romero A, Fernández-Navarro P, Rodriguez-Caballero A, et al. Common Infectious Agents and Monoclonal B-Cell Lymphocytosis: A Cross-Sectional Epidemiological Study among Healthy Adults. PLoS One. 2012;7(12):1–8.