In December 2023, professor Erlie Jiang and team from Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science published an influential study in Frontiers in Immunology, detailing the challenges of managing refractory cytomegalovirus (CMV) infections in Chinese patients after allogeneic hematopoietic cell transplantation (allo-HCT). With a focus on China’s unique position in the global context of allo-HCT and the specific difficulties faced by patients with haploidentical donors, this review underscores the urgent need for standardized care protocols. Jiang’s work, through its comprehensive analysis of existing literature, significantly advances our understanding of CMV management post-transplant, aiming to improve patient outcomes and establish effective treatment guidelines. This study marks a critical step forward in optimizing post-transplant care to enhance patient survival and quality of life amidst CMV infection challenges.
Cytomegalovirus (CMV) infection remains a daunting challenge in the post-transplantation period for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). This viral infection, often reactivated in the immunocompromised state induced by transplantation, is notorious for its contribution to increased morbidity and mortality among recipients. The prevalence of CMV in the general population underscores the risk of reactivation or infection in the transplant setting. In China, where roughly a quarter of all allo-HCTs are performed globally, the burden of CMV infection is notably higher. This heightened prevalence necessitates a tailored approach to CMV management in Chinese allo-HCT recipients, underlining the urgent need for effective antiviral therapeutic strategies specific to this demographic.
The core aim of this study is to conduct a comprehensive review of the literature surrounding refractory CMV infections following allo-HCT in the Chinese patient population. By doing so, we seek to identify unique challenges, prevalence rates, risk factors, and potential therapeutic strategies that could mitigate the impact of CMV infections in this specific setting.
To achieve our objectives, we embarked on an extensive literature review focusing on refractory CMV infections post-allo-HCT within China. Our methodology involved the utilization of established definitions of CMV infection and refractoriness as outlined by the CMV Drug Development Forum, ensuring consistency and clarity in our analysis. This approach allowed us to systematically evaluate and synthesize existing research findings, offering a detailed perspective on the current state of knowledge in this area.
A Phase 3 randomized trial showed that letermovir significantly reduced the risk of clinically significant CMV infections compared with placebo. Subsequent studies worldwide confirmed its safety and efficacy, with a high adoption rate in European centers and endorsement by relevant guidelines. In the U.S., letermovir prophylaxis was linked to a substantial reduction in refractory or resistant CMV infections. Data on other antivirals in China are limited, with no approval for maribavir and restrictions on letermovir use. While combined antiviral therapies like ganciclovir and foscarnet are considered for refractory CMV, their effectiveness in improving survival outcomes requires further investigation.
The analysis identifies several key findings:
– Haploidentical Donor Use: The prevalence of using haploidentical donors in Chinese allo-HCT procedures emerges as a significant factor contributing to the elevated incidence of refractory CMV infections. This finding suggests a complex interplay between donor selection and CMV reactivation risks, warranting further investigation.
– Risk Factor for Mortality: Refractory CMV infection is pinpointed as an independent risk factor for non-relapse mortality among Chinese allo-HCT recipients. This association highlights the severe impact of uncontrolled CMV infections on patient outcomes.
– Emerging Strategies: The concept of primary prophylaxis is identified as a promising strategy in the prevention of refractory CMV infections and subsequent CMV disease. The potential for this approach to significantly alter the management landscape for CMV in allo-HCT recipients is considerable.
Multiple Chinese studies have reported promising outcomes using CMV-specific cytotoxic T lymphocyte (CMV-CTL) therapy for refractory CMV infection, with one study showing an 89.5% clearance rate. CMV-CTL therapy is gaining traction due to its potential to reduce systemic toxicities and T-cell exhaustion compared to antiviral agents. Methodological challenges in CMV-CTL production are being addressed through advances in T-cell generation and ‘off-the-shelf’ T-cell products. Natural killer (NK) cells also show potential in CMV and tumor defense. Larger, prospective studies are needed to better understand refractory CMV and the mechanisms behind it, despite low incidence of resistance mutations. Funding for this research and publication has been provided by various sources including MSD China and national grants.
In China, the increasing use of HID allo-HCT has led to a higher incidence of refractory CMV infections, despite improved management with PET. Letermovir’s recent approval offers hope for reducing refractory CMV, necessitating further research to refine treatment approaches. CMV-specific immunotherapy emerges as a promising option to prevent resistance and toxicity seen with conventional treatments. However, to fully understand refractoriness and optimize therapies, larger and more rigorous studies are urgently required.
