Evolution of the Evidence for the Management of COVID-19 in Hematologic Malignancies: A Systematic Literature Review of Remdesivir

Background: Patients with immunocompromising conditions, including those affected by hematologic malignancies, have a disproportionately high burden of morbidity and mortality related to COVID-19 compared to individuals without such conditions.Clinical practice guidelines (CPGs) recommend the use of remdesivir, a broad-spectrum antiviral, for treatment of mild to severeCOVID-19 in immunocompetent patients not requiring invasive mechanical ventilation. While the CPGs issued by the World Health Organization (WHO, 2023), National Institutes of Health (NIH, 2023) and the Infectious Diseases Society of America (IDSA, 2022) also recommended the use of remdesivir in patients with immunocompromising conditions at high risk for severe disease, there was limited evidence available at the time the recommendations were communicated, more than two years after the start of the pandemic. The European Conference on Infections in Leukemia (ECIL, 2022) guidelines include remdesivir among the treatment options for mild to moderate COVID-19 patients with hematologic malignancies. The lack of evidence for treatment efficacy and safety in patients with immunocompromising conditions, a population underrepresented or excluded from clinical trials, was mentioned in CPGs as a knowledge gap and as need for further research. In this research, we summarize the evidence for remdesivir efficacy and safety for treatment of COVID-19 in hospitalized patients with hematologic malignancies accumulated since the start of the pandemic.

Methods: We systematically searched MEDLINE, Embase and Cochrane Library databases from January 2019 through December 2023 for interventional and observational studies examining remdesivir efficacy and safety. Case reports and case studies were excluded. A dual-reviewer approach was used for screening and data extraction.

Results: Of the 7,654 references retrieved through the implementation of the extensive search strategy 59 (0.8%) reporting on patients with hematologic malignancies, unspecified cancers, or immunodeficiencies were identified and reviewed in full text. Only eight unique studies (8 of 59) were conducted in patients with hematologic malignancies, of which two reported remdesivir use in a minority of participants (n<5) and were excluded from further analyses. The remaining six studies, of which four were peer-reviewed original articles, one was a letter to editor and the last was a conference abstract, used a retrospective cohort design and reported efficacy outcomes for a combined total of 1,579 individuals across the studies. Three of the six studies were conducted during the pre-Omicron variant era (November 2021) while the remaining three started data collection in December 2021. There were four studies reporting number of deaths or the mortality rate, while a fifth study based on medical chart reviews of 313 patients in Israel found a significantly reduced risk of mortality among remdesivir recipients compared to patients not receiving remdesivir (OR: 0.297; 95% CI: 0.105, 0.834). In addition, a study including 466 patients from the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Registry reported mortality among remdesivir treated group related to baseline disease progression, use of corticosteroids for COVID-19 therapy and the presence of coinfections while B-cell malignancy as underlying disease, severe COVID-19, late antiviral initiation (≥5 days after first positive PCR) and longer treatment duration (≥5 days) were factors significantly associated with prolonged viral shedding. The same Spanish study reported safety outcomes indicating that adverse events of grade 3 or above were rare, occurring in 0.5% of remdesivir treated patients.

Conclusion: Despite the call for research to fill the knowledge gap signaled by the CPGs, our comprehensive systematic literature review identified only a few publications conducted since the start of the pandemic in patients with hematological malignancies. In the current endemic era, these patients are among the most at risk for severe outcomes and COVID-19 related hospitalizations. While the limited evidence suggests that remdesivir use can reduce mortality in patients with hematologic malignancies, additional research will be instrumental to inform development and updating of evidence-based recommendations to support and guide clinical management of oncology patients.

Mozaffari:Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Bartoletti:Gilead Sciences, Inc.: Consultancy, Honoraria; Advan Pharma: Consultancy, Honoraria; Biomerieux: Honoraria; Infectopharma: Consultancy; Merck Sharp & Dohme: Consultancy, Honoraria; Pfizer: Honoraria. Malin:Gilead Sciences, Inc.: Consultancy, Honoraria; Astrazeneca: Consultancy; Merck Sharp & Dohme: Consultancy. Doi:MeijiSeika Pharma: Consultancy; GlaxoSmithKline Pharmaceuticals: Consultancy; Fujifilm: Consultancy; Gilead Sciences, Inc.: Consultancy; Biomerieux: Other: Lecture fees; Entasis: Research Funding; Moderna: Other: Lecture fees; Merck Sharp & Dohme: Other: Lecture fees; Pfizer: Consultancy; Shionogi&Co., Ltd.: Other: Lecture fees, Research Funding. Loubet:Gilead Sciences, Inc.: Consultancy; Astrazeneca: Consultancy; Moderna: Consultancy; Pfizer: Consultancy. Rivera:Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees. Poulakou:Gilead Sciences, Inc.: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Merck Sharp & Dohme: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; GlaxoSmithKline Pharmaceuticals: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Bausch: Research Funding; Xenothera: Research Funding; FabNTech: Research Funding; PharmaMar: Research Funding. Oppelt:Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Chiang:Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Carlo-Stella:AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi, ADC Therapeutics: Consultancy; Humanitas University, Milano (Italy): Current Employment; ADC Therapeutics, Roche, Sanofi: Research Funding; AstraZeneca, Celgene/Bristol-Myers Squibb, Incyte, Janssen Oncology, Takeda, Novartis, ADC Therapeutics, Roche, Gilead, SOBI, Merck Sharp & Dohme: Honoraria; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Scenic Biotech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi, ADC Therapeutics, Celgene/Bristol-Myers Squibb, Karyopharm Therapeutics, Roche, Novartis, Scenic Biotech, Janssen Oncology, Merck Sharp & Dohme, SOBI, AbbVie, Genmab, AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.