The outcome of myelodysplastic syndrome (MDS) patients with uniformly higher-risk disease treated with azacitidine (AZA) in the 'real-world' remains largely unknown. We evaluated 1101 consecutive higher-risk MDS patients (International Prognostic Scoring System intermediate-2/high) and low-blast count acute myeloid leukaemia (AML; 21-30% blasts) patients treated in Ontario, Canada. By dosing schedule, 24·7% received AZA for seven consecutive days, 12·4% for six consecutive days and 62·9% by 5-2-2. Overall, median number of cycles was 6 (range 1-67) and 8 (range 6-14) when restricted to the 692 (63%) patients who received at least 4 cycles. The actuarial median survival was 11·6 months [95% confidence interval (CI) 10·7-12·4) for the entire cohort and 18·0 months (landmark analysis; 95% CI 16·6-19·1 months) for those receiving at least 4 cycles. There was no difference in overall survival (OS) between the 3 dosing schedules (P = 0·87). In our large 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML, we demonstrated a lower than expected OS. Reassuringly, survival did not differ by dosing schedules. The OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realised. This represents the largest 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML.
Broadly neutralizing, anti-hemagglutinin stem antibodies (Abs) are a promising universal influenza vaccine target. While anti-stem Abs are not believed to block viral attachment, we show that C1q confers attachment inhibition and boosts fusion and neuraminidase inhibition, greatly enhancing virus neutralization activity in vitro and in mice challenged with influenza virus via the respiratory route. These effects reflect increased steric interference and not increased Ab avidity. Remarkably, C1q greatly expands the anti-stem Ab viral escape repertoire to include residues throughout the hemagglutinin. Some substitutions cause antigenic alterations in the globular region or modulate HA receptor avidity. We also show that C1q enhances the neutralization activity of non-RBD anti SARS-CoV-2 Spike Abs, an effect dependent on Spike density on the virion surface. Together, our findings show that first, Ab function must be considered in a physiological context and second, inferring the exact selection pressure for Ab-driven viral evolution is risky business, at best.
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