Severe Anemia Is Associated with a Risk of Infection in Patients with Myelodysplastic Syndromes
Authors: Kasprzak Annika , Andresen Julia , Hildebrandt Barbara , Nachtkamp Kathrin , Kündgen Andrea , Kobbe Guido , Gattermann Norbert , Germing Ulrich 
Published: November 2021

Abstract
Introduction: Infections are a well-recognized complication in patients (pts) with myelodysplastic syndromes (MDS) that contribute substantially to the morbidity and mortality particularly in pts suffering from neutropenia. Neutropenia and other immune defects including impaired neutrophil function have been reported to be predisposing factors for severe infections. Furthermore, some of the therapies may worsen neutropenia and lead to an additional risk factor to develop infectious episodes. Since infectious complications are no primary endpoint in clinical trials epidemiological data on infections in large cohorts of MDS pts is sparse.
Methods: We performed a retrospective analysis of 3.787 MDS-patients from the Duesseldorf MDS Registry who were diagnosed between 1980 and 2018. Infectious complications were defined as clinical symptoms of infection associated with the need for antibiotic and/or antifungal therapy, and/or the isolation of a pathogen and/or an identifiable site of infection by physical examination. Infectious episodes were categorized as fever of unknown origin, microbiologically or clinically documented infection.
Results: Amongst our study cohort, 42% of the pts suffered from at least one infectious complication of any type during the course of their disease. Most infectious diseases were of bacterial origin (34.7%) and in 17% a pathogen was isolated. Pneumonia was the most common site of infection (64%). Pts who experienced at least one infectious episode had a significant poorer overall survival (OS) than pts without such events (21 vs 37 months, p&lt;0.001). Pts with a higher risk disease according to the IPSS-R had fewer infections during the course of the disease than pts with a lower-risk MDS (487 total infections vs 1481, p&lt;0.001). Nevertheless, the presence of any infectious episode lead to an inferior OS in lower-risk (40 vs 29 months, p&lt;0.001) as well as in higher-risk disease (38 vs 24 months, p=0.006).
In univariate analyses comparing pts who had no infections versus those who had one or more, pts with older age (&gt;65 years) tended to have a higher incidence of infectious episodes (p&lt;0.001). In addition, patients older than 65 suffering from infections had a shorter OS than patients who did not experience an infectious complication. The difference in OS was highly significant with 16 months for pts suffering from infectious complications compared to 24 months (p&lt;0.001). Likewise, an excruciating higher incidence of infections was noted in MDS pts compared to infections incidence in a non-MDS population in Germany. The risk of a 65-year-old or older MDS pt to suffer from pneumonia was 6.9 times higher compared to a non-MDS pt of the same age.
We found a highly significant negative correlation between the depth of cytopenia in all three myeloid lineages and the presence of infections (p&lt;0.001), suggesting that patients with severe cytopenia suffer from infectious episodes more frequently. However, pts with an isolated neutropenia having an absolute neutrophil count below a threshold of 0.8 × 10 9/L and suffering from infectious episodes had no inferior OS than neutropenic pts without any infection (25 vs 32 months, p=0.583). Pts with isolated severe thrombocytopenia with a platelet count &lt;50 × 10 9/L had a similar OS of 26 months for pts with infectious complications. The difference in OS between pts with and without infections was even more pronounced in this group (26 vs 48 months, p=0.002). Still, a low hemoglobin (Hb) level &lt;9g/dl appeared to be the most significant risk factor for pts with infections, resulting in the poorest OAS of only 17 months in pts with isolated anemia suffering from infections. In multivariate analyses, we found that Hb &lt;9g/dl, followed by ANC &lt;0.8 × 10 9/L, were independently associated with the risk to suffer from an infection during the disease. In addition, a Hb &lt;9g/dl was the most important blood count parameter with regard to OS when compared to platelets &lt;50 × 10 9/L, and ANC &lt;0.8 × 10 9/L.
Conclusion: The incidence of infections significantly increases in pts with advanced age. MDS-pts in general are more vulnerable for infection-related morbidity and mortality than non-MDS-pts. Low hemoglobin and platelet counts were both found to be associated with a worse prognosis compared to low neutrophil counts. The appearance of at least one infectious episode leads to an inferior

Disclosures
Nachtkamp: Jazz: Speakers Bureau; bsh medical: Speakers Bureau; Celgene: Other: Travel Support. Kobbe: Celgene: Research Funding. Gattermann: Celgene: Honoraria; Takeda: Research Funding; Novartis: Honoraria. Germing: Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria.