COVID-19 Induces Prolonged Immunological Exhaustion Leading To Relapse Of Hematological Malignancies Except In Hematopoietic Cell Transplant Recipients

We studied the impact of COVID-19 on relapse in patients with hematological malignancies who had achieved complete remission (CR) and were either treatment-free or maintained on uninterrupted therapy over a 24-month period. Among 144 patients fulfilling the inclusion criteria, the overall relapse rate was 30.9%, with a significantly higher incidence in COVID-19-positive patients (60.9%) compared to COVID-19-negative individuals (25.2%, HR- p = 0.0001). Stratification by disease risk index (DRI) revealed a pronounced effect of COVID-19 on relapse in the DRI-high cohort (64.3% vs. 20.1%, p = 0.0001). Hematopoietic cell transplantation (HCT) appeared protective, with relapse rates of 22% in HCT recipients and 36.9% in the non-HCT cohort (p = 0.06), with no impact of COVID-19 on relapse in patients undergoing HCT. However, the effect of COVID-19 on relapse was predominantly observed in the non-HCT group (92.3% vs. 27.8%, HR-8.9, p < 0.001). Immune exhaustion markers, including PD-1 on T cells and NKG2A on NK cells, were significantly upregulated in COVID-19-exposed patients, particularly in those who relapsed, compared to recipients of allogeneic HCT with and without exposure to SARS-CoV2. These findings suggest COVID-19-induced immune dysregulation may facilitate relapse, particularly in non-HCT patients, warranting further exploration of the immunobiological mechanisms responsible for this phenomenon and possible immune-targeted interventions in this context.