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Pre-Engraftment Syndrome: Why it Happens and How to Treat It

An 8 year-long study has revealed the pathogenesis of pre-engraftment syndrome and a therapeutic strategy to control clinical symptoms and reduce mortality.

Researchers from the University of Science and Technology of China have collaborated with the First Affiliated Hospital of the university to reveal the pathological mechanism of severe pre-engraftment syndrome after umbilical cord blood transplantation. Their novel work, published in Nature Communications, has provided a treatment strategy for patients with the condition and is expected to significantly improve the curative effect of unrelated cord blood transplantation.

Unrelated cord blood transplantation refers to a type of treatment that is often used to cure haematological malignancies, hematopoietic disorders, congenital immunodeficiency, and some genetic metabolic diseases. Since its first successful clinical application to treat malignant haematological diseases in children in 2000, this technique has earned itself a good reputation as an effective and attractive therapeutic approach. To date, the First Affiliated Hospital of the University of Science and Technology of China has completed 1519 cases of unrelated cord blood transplantation, earning international recognition as an umbilical cord blood transplantation centre.

The reason for its success is largely because the incidences of chronic graft-versus-host disease, which is a condition that might occur after an allogeneic transplant, is low and mild. As such, patients can still achieve a high quality of life even after the transplantation.

But where there are strengths, there are weaknesses. Like all medications and therapeutics, unrelated cord blood transplantation comes with its own fair share of limitations and challenges. One of the greatest obstacles of performing unrelated cord blood transplantation is tackling the post-surgery side effects.

In the early stages after unrelated cord blood transplantation, 70 to 80 per cent of recipients have been reported to suffer from pre-engraftment syndrome. Pre-engraftment syndrome is characterised by high fever, rash, and diarrhoea, among other symptoms, that occur during or prior to neutrophil recovery. Severe cases of pre-engraftments syndrome are associated with high mortality and morbidity. Unfortunately, the exact mechanisms behind this syndrome have remained elusive to clinicians and scientists alike, until now.

After nearly eight years of research, Professors Wei Haiming, Tian Zhigang, Sun Zimin, and colleagues have finally uncovered the pathogenesis of the pre-engraftment syndrome. They have also reported successful results of a clinical trial that tested a potent drug to control the pathology of the syndrome.

Early on in the investigation, the team first analysed the peripheral blood of patients who underwent unrelated cord blood transplantation. It was then that they noticed that patients with the pre-engraftment syndrome displayed higher amounts of inflammatory monocytes. Upon closer inspection, it was revealed that these monocytes came from cord blood and were the main source of proinflammatory cytokines like GM-CSF and IL-6, which drive the pathology of pre-engraftment syndrome.

Their conclusion was that after a patient receives unrelated cord blood transplantation, inflammatory monocytes derived from the cord blood rapidly expand in the body of the recipient, thereby increasing the levels of cytokines GM-CSF and IL-6 in their blood, which leads to the manifestation of pre-engraftment syndrome.

Having uncovered the pathogenesis of pre-engraftment syndrome, the team proceeded to conduct a clinical trial using tocilizumab, an inhibitor of the IL-6 receptor, among patients with severe cases of the syndrome. The results of the clinical trials were successful and the team reported that tocilizumab was not only capable of significantly controlling the clinical symptoms of pre-engraftment syndrome, but also reducing the mortality of patients. A 100-day follow up after the treatment showed that none of the patients experienced non-relapse mortality.

Given the promising results of tocilizumab’s anti-inflammatory effects, the study is expected to serve as a practical guide for the university to propose and implement treatment plants using tocilizumab for patients with not only pre-engraftment syndrome but also COVID-19 and pneumonia. Currently, the treatment plan has been approved by the U.S. Food and Drug Administration and the National Health Service to be used in clinical applications. [APBN]

Source: Jin et al. (2021). Inflammatory monocytes promote pre-engraftment syndrome and tocilizumab can therapeutically limit pathology in patients. Nature Communications, 12, 4317.