Role of remdesivir for the treatment of COVID-19 in patients with hematologic malignancy-A narrative review and expert opinion.

INTRODUCTION

Starting in 2022, considerable reductions in coronavirus disease 2019 (COVID‐19)‐related hospitalisation and mortality compared to the early phase of the pandemic have been reported. 1 Wide access to vaccines, acquired immunity via SARS‐CoV‐2 infection and reinfection, availability of effective treatments, as well as lower pathogenicity of the Omicron variant, have all contributed to this achievement. 1 , 2 , 3 Nevertheless, although the World Health Organization (WHO) no longer considers COVID‐19 a public health emergency of international concern, COVID‐19 remains a potentially severe condition for immunocompromised individuals. 1

COVID‐19 management in patients with hematologic malignancy is challenging, as they are typically immunocompromised, although to a variable extent. 4 , 5 While specific treatment recommendations are available, 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 many issues remain uncertain. Direct antiviral agents including remdesivir, nirmatrelvir‐ritonavir and molnupiravir have proven effective for COVID‐19 treatment. 11 , 12 , 13 These small‐molecule drugs target SARS‐CoV‐2 components other than the spike protein, which is the primary target for vaccines and therapeutic monoclonal antibodies but is prone to amino acid substitutions that result in new virus variants. 14 , 15 Thus, antivirals have so far retained their efficacy across all virus variants, including Omicron, while therapeutic monoclonal antibodies approved in the pre‐Omicron era are no longer effective against the new virus variants. 3 , 14 , 16 , 17 , 18 , 19

Remdesivir was the first and most extensively investigated drug among the treatments initially tested for their potential against SARS‐CoV‐2. 20 It is characterised by limited off‐target toxicity, good tolerability in patients with impaired renal function, 21 , 22 and few drug–drug interactions compared to other antivirals. 21 , 23 In this narrative review, we provide an overview of the evidence supporting the use of remdesivir for the treatment of COVID‐19 in patients with haemato‐oncological malignancy, including those at highest risk for hospitalisation and progression to severe–critical disease.

METHODS

PubMed was searched with combinations of the following terms: ‘remdesivir’, ‘hematologic malignancy’, ‘blood cancer’, ‘immunosuppression’, ‘immunocompromised’, ‘COVID‐19’. The retrieved articles were screened based on their titles. Articles identified as potentially interesting were further checked by evaluating their abstract; if the content of the abstract was found to be relevant (i.e., large and well‐documented population; included number of patients with hematologic malignancy or immunocompromised; reported outcomes of these patients separately), the full text of the article was obtained. Additional articles were identified in the reference lists of the articles found via PubMed search.

EPIDEMIOLOGY OF COVID‐19 IN PATIENTS WITH HEMATOLOGIC MALIGNANCY

Due to acquired immunodeficiency and treatment‐related immunosuppression, patients with hematologic malignancy are often unable to achieve viral clearance and to develop neutralizing antibodies against SARS‐CoV‐2. 2 , 3 , 4 They are therefore at high risk of developing severe COVID‐19. 2 , 3 , 4 During the initial phase of the pandemic, elevated mortality rates ranging from 29% to 42% were reported for onco‐hematologic patients versus 2%–7% in the general population. 8

The observational study INFORM analysed the impact of COVID‐19 on immunocompromised patients during the Omicron era, based on data collected throughout 2022 in the United Kingdom. 1 The study compared rates of COVID‐19‐related hospitalization, admission to the intensive care unit (ICU), and mortality in groups of immunocompromised patients versus the general population and found that the burden of COVID‐19 on these patients continued to be substantial. 1 Despite widespread vaccination, in immunocompromised individuals the risk of COVID‐19‐related hospitalization, ICU admission, and death remained high, with crude incidence rates per 1000 patient years of, respectively, 20.2, .9 and 4.6 in stringently defined immunocompromised patients versus 1.7, .04 and .4 in the overall study population. 1 The subgroup of patients on active treatment for hematologic malignancies within the previous 6 months was among those at the highest risk, with over a 10‐fold increase in the risk of hospitalization, ICU admission and death compared with patients with less recent anti‐cancer treatment. 1

A retrospective study in 328 patients with hematologic malignancies with mild‐to‐moderate COVID‐19 investigated the impact of early treatment of COVID‐19. 24 Early treatment involved the administration of monoclonal antibodies or antiviral agents as soon as possible following the diagnosis of SARS‐CoV‐2 infection, before the progression to respiratory failure and need for oxygen supplementation. The study found significantly higher rates of treatment failure in the pre‐Omicron period (36.8%) versus the Omicron period (7.8%). Though improved, the rate of treatment failure in the Omicron period was still higher than that reported in the general population in the same period, and ranging between 1.2% and 1.4%. 24 Independent predictors of treatment failure were older age, fewer vaccine doses, and diagnosis of acute myeloid leukaemia and myelodysplastic syndrome. 24 Although the mortality rate of patients who progressed to severe COVID‐19 substantially decreased – from 57% in the pre‐Omicron period to 26% in the Omicron period – it nonetheless remained very high. 24

A retrospective analysis of the Spanish Transplant Group registry found that only about half of the 692 patients with hematologic diseases and SARS‐CoV‐2 infection had respiratory symptoms. 25 Overall, 69% received antiviral therapy, 23% were admitted to hospital, and 18% had COVID‐19‐related pneumonia. COVID‐19‐related mortality was 3.7% in the overall cohort, but 14% in hospital‐admitted patients. Independent predictors of COVID‐19‐related pneumonia were older age, autologous haematopoietic stem cell transplant (HSCT) or chimeric antigen receptor (CAR) T cell therapy, incomplete vaccination status and use of corticosteroids at the time of SARS‐CoV‐2 infection; independent predictors of COVID‐19‐related mortality were cardiomyopathy, prior anti‐CD20 therapy and incomplete vaccination status. 25

The European EPICOVIDEHA registry established in 2020 to study the epidemiology of SARS‐CoV‐2 infection in patients with hematologic malignancy has been recently expanded to include real‐world data on other community‐acquired respiratory viral infections, and is now called EPICOVIDEHA‐EPIFLUEHA registry. 26 A recent analysis of the data of 1312 patients with community‐acquired respiratory viral infections during the 2023–2024 autumn‐winter season has reported an overall 30‐day mortality rate of 5.9%, with variability among viruses: 5.0% for SARS‐CoV‐2, 8.8% for influenza virus and 5.9% for respiratory syncytial virus. 26 Viral infection was the reason for mortality in 64% of deaths overall, and for 72%, 82% and 25% of deaths in patients with SARS‐CoV‐2, influenza virus and respiratory syncytial virus infection, respectively. 26

REMDESIVIR

Remdesivir is a prodrug that is administered by intravenous infusion and is metabolised within cells into an analogue of adenosine triphosphate (Figure 1 ). 27 The incorporation of this analogue into the growing RNA chain by viral RNA‐dependent RNA polymerases leads to the inhibition of viral RNA synthesis (Figure 1 ). 27 , 28 Remdesivir has demonstrated antiviral activity against a broad spectrum of RNA viruses, including coronaviruses such as SARS‐CoV, SARS‐CoV‐2 and Middle East respiratory syndrome coronavirus. 29

Based on the findings from clinical trials performed at the outbreak of the COVID‐19 pandemic, 31 , 32 , 33 remdesivir was granted approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of COVID‐19 in adults and paediatric patients who are hospitalized or not hospitalized with mild‐to‐moderate COVID‐19 and are at high risk for progression to severe COVID‐19. 21 Remdesivir is included among the therapeutics recommended by the living guidelines of the WHO and the Infectious Diseases Society of America for the treatment and management of patients with COVID‐19. 34 , 35

Efficacy and safety of remdesivir in randomised clinical trials

Early studies with remdesivir were performed in the general population of patients who were hospitalized due to COVID‐19 31 , 32 , 33 , 36 ; subsequent studies investigated the possibility of using remdesivir early in the course of COVID‐19 and were performed mostly in the outpatient setting. 11 The primary efficacy endpoints included usually clinical improvement and survival in hospitalized patients, and progression to severe COVID‐19 and/or hospitalization in outpatients. In these initial trials, patients with cancer and immunosuppression, if reported at all, were a minority. 11 Another issue potentially limiting the applicability of the findings from the initial trials is that they were mostly performed in unvaccinated patients. 31 , 32 , 33

Studies in hospitalized patients

The first stage Adaptive Covid‐19 Treatment Trial (ACTT‐1) was a double‐blind, randomized, placebo‐controlled study that evaluated remdesivir in 1062 patients who were hospitalized with COVID‐19, of whom 541 were assigned to remdesivir and 521 to placebo. 31 The primary outcome was the time to recovery, defined as the first day a patient met the criteria for categories 1–3 on an 8‐category ordinal scale of disease severity. 31 A 10‐day course of remdesivir was associated with a shorter median time to recovery (10 days) versus placebo (15 days), with a rate ratio for recovery of 1.29. 31 These benefits were greater when remdesivir was given earlier in the illness. Patients treated with remdesivir were also more likely than those who received placebo to have an improvement in their clinical status at day 15 (odds ratio for improvement 1.5). 31 Serious adverse events, including acute respiratory failure and need for endotracheal intubation, occurred in 24.6% of patients treated with remdesivir and in 31.6% of patients who received placebo. 31 The most frequent non‐serious adverse events occurring in ≥5% of patients included reductions in glomerular filtration rate, haemoglobin levels, and lymphocyte count, respiratory failure, anaemia, fever, hyperglycaemia and increases in blood creatinine and glucose levels. These adverse events occurred at comparable rates in both the remdesivir and placebo groups. 31 A subsequent randomized, open‐label, phase 3 study involving hospitalized patients with severe COVID‐19 not requiring mechanical ventilation showed that a 5‐day course of remdesivir improved the clinical status as effectively as a 10‐day course, leading to the adoption of shorter antiviral treatment regimens in clinical practice. 32 The efficacy of a 5‐day course of remdesivir on the clinical status, versus the standard of care, was demonstrated also in a randomized, open‐label, phase 3 trial that included 584 hospitalized patients with moderate COVID‐19. 33

The WHO Solidarity trial was a large, open‐label randomized study involving hospitalized patients with COVID‐19 who were assigned in equal proportions to receive one of four drugs available at that time (lopinavir, hydroxychloroquine, interferon‐β1a, remdesivir) or no study drug. 36 Overall, 14,221 patients were enrolled, of whom 8275 were assigned to remdesivir or its control. The primary endpoint was in‐hospital mortality, both overall and categorized by disease severity at entry, which was defined by respiratory support status: no supplemental oxygen, oxygen supplementation, or ventilation. 36 Overall, 602 of 4146 patients (14.5%) assigned to remdesivir died vs. 643 of 4149 (15.6%) assigned to control; the rate ratio for mortality was .91. In ventilated patients, the rate ratio for mortality was 1.13, while it was .86 in non‐ventilated patients, highlighting a benefit in the subgroup with less severe disease. The benefit associated with remdesivir in this subgroup was suggested also by a rate ratio of .84 for the non‐prespecified composite outcome of death or progression to ventilation. 36

Studies in the outpatient setting

The randomized, double‐blind, placebo‐controlled PINETREE study addressed the efficacy and safety of early remdesivir treatment in 562 non‐hospitalized patients with at least one risk factor for disease progression, including immune compromise, present in 4.1% of patients, and current cancer, affecting 5.3% of patients. 11 Patients were assigned to a 3‐day course of remdesivir or to placebo. Treatment with remdesivir was associated with a significant and >85% reduction in the risk of COVID‐19‐related hospitalization or death by day 28 compared to placebo. Adverse events were reported in 42.3% of patients who received remdesivir and in 46.3% of patients who received placebo. The most frequent non‐serious adverse events occurring in ≥5% of patients in both groups were nausea, headache, and cough. Serious adverse events were more frequent in the placebo group (6.7%) than in the remdesivir group (1.8%).

Resistance analysis

Various in vitro studies reported that monoclonal antibodies (imdevimab‐casirivimab, tixagevimab‐cilgavimab, sotrovimab and bebtelovimab), as well as the older plasma of convalescent or vaccinated subjects, are not effective against the more recently emerged variants, such as the XBB.1.5 Omicron subvariant. 19 By contrast, antiviral drugs (remdesivir, molnupiravir, nirmatrelvir and ensitrelvir) retain in vitro levels of activity against XBB.1.5 overlapping with those observed against the ancestral strain, 19 suggesting their long‐lasting efficacy in clinical practice as well.

Sustained clinical efficacy is also supported by the high genetic barrier to resistance development, an extensively investigated feature of remdesivir. In vitro studies have reported the emergence of SARS‐CoV‐2 pools expressing amino acid substitutions in nsp12, the RNA‐dependent RNA polymerase targeted by remdesivir, only after an elevated number of passages. 15 , 37 , 38 In addition, these amino acid substitutions, including two potential escape motifs (nsp12:R467‐V493 and nsp12:L544‐Q570), were associated with an overall minor reduction in sensitivity to remdesivir. 15 , 37 , 38 , 39

The emergence of novel viral strains with resistance to antiviral drugs is an ongoing risk. Compared with other RNA viruses, however, coronaviruses present a low mutational frequency due to the proofreading activity of the viral exonuclease nsp14. 40 , 41 Also, the acute nature of COVID‐19 does not require a life‐long treatment, which limits the selection pressure for resistance development and the risk of failure due to poor patient compliance. Indeed, virological data from COVID‐19 patients involved in remdesivir clinical trials did not report any cases of drug resistance during or after treatment. 15 , 31 , 32 , 33 , 42 Genotypic and phenotypic analyses of baseline and post‐baseline virological samples from patients treated with remdesivir or placebo reported similar rates of amino acid substitutions in nsp12 (38.7% and 40.0%, respectively), not related to clinical outcome. 42 According to the phenotypic analysis, the observed amino acid substitutions in nsp12 were not expected to have a major impact on SARS‐CoV‐2 susceptibility to remdesivir. 15 , 42 This high barrier to resistance might be explained by the fact that nsp12 mutations affecting the susceptibility to remdesivir might, at the same time, impair viral replication and fitness. 15 Interestingly, case reports of patients with persistent COVID‐19, treated for extended periods with remdesivir combined with other anti‐SARS‐CoV‐2 therapies, have shown that viral isolates retained the susceptibility to remdesivir. 43 , 44

However, despite the high barrier of remdesivir to resistance, the increased transmissibility of Omicron variants and subvariants, the routine use of antivirals in monotherapy and, most importantly, their use in patients with reduced viral clearance capacity, such as patients with hematologic malignancies, provide the perfect breeding ground for the emergence of new mutations, as highlighted by few case reports. 45 , 46 For this reason, it is imperative to assess drug‐resistance in patients who seem unresponsive to treatment, as well as to monitor genomic databases for the emergence of novel SARS‐CoV‐2 variants.

REAL‐WORLD EFFECTIVENESS AND SAFETY OF REMDESIVIR IN PATIENTS WITH HEMATOLOGIC MALIGNANCY

Table 1 summarizes the results of 29 real‐world studies of remdesivir in patients with COVID‐19, which were performed predominantly during the Omicron era (22/29 studies). 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 Most studies had a retrospective design, while the source of patient data were very heterogenous and ranged from large, well‐established healthcare databases 60 , 61 , 67 , 69 , 70 , 71 and national dedicated registries 48 , 59 , 63 , 66 to single‐center patient records. Sixteen studies described patients receiving early treatment for non‐severe COVID‐19, 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 72 , 73 two studies reported on the treatment of patients requiring oxygen supplementation, 74 , 75 and eleven studies involved both patients with early disease and patients requiring supplemental oxygen. 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 In clinical practice, treatment with remdesivir was administered as recommended in the drug label 21 to both patients with early disease and patients with more advanced disease.

Of the 29 real‐world studies in Table 1 , nine were specifically focused on patients with hematologic malignancy, 47 , 50 , 51 , 62 , 65 , 66 , 68 , 73 , 75 and two on patients with different immunocompromising conditions including cancer and hematologic malignancy. 61 , 67 In the remaining studies, the proportions of patients with hematologic malignancy were usually reported and were included between 5.2% 74 and 48.8%. 58 In the two studies by Mozaffari et al. on large cohorts of hospitalized immunocompromised patients from the PINC AI Healthcare Database, including patients with hematologic malignancies, the prompt treatment with remdesivir was associated with significant improvements in survival at 14 days ranging from 25% to 30%. 61 , 67 When treating COVID‐19 in onco‐hematologic patients with aggressive malignancies, achieving rapid SARS‐CoV‐2 PCR negativity and avoiding delays or interruptions in oncologic therapy is crucial. The benefits of early treatment with remdesivir have emerged from several real‐world studies in patients with hematologic malignancy, 47 , 51 , 65 , 73 especially in the outpatient setting of COVID‐19 treatment. 65

Rapti et al. investigated the burden of COVID‐19 and COVID‐19 treatment patterns in 60 hospital‐admitted patients with hematologic malignancy and found that the duration of the treatment with remdesivir was determined not only by COVID‐19 severity but also by the type of underlying blood cancer. 62 An extended course of remdesivir for up to 10 days was observed predominantly in patients with cancers of lymphocytic origin, including non‐Hodgkin lymphoma, Hodgkin lymphoma and chronic lymphocytic leukaemia. 62 This practice probably reflects the fact that patients with hematologic malignancies, especially those with lymphoma, hypogammaglobulinemia or prior intensive chemotherapy, may be characterized by a persistent viral load beyond the 5‐day standard course of treatment with remdesivir. 62 Prolonged SARS‐CoV‐2 shedding is indeed common among patients with hematologic malignancy, as highlighted by the study by Piñana et al., showing that in 52% of onco‐hematologic patients from the Spanish registry on HSCT and cell therapy, viral shedding lasted for >25 days. 66 These authors also reported that early antiviral therapy with nirmatrelvir‐ritonavir for mild cases or with remdesivir for moderate–severe cases was associated with a shorter duration of viral shedding. 66

Gras et al. retrospectively evaluated a cohort of patients with hematologic malignancies treated with remdesivir for more than 10 days. 68 Extended treatment with remdesivir was administered mainly to patients who were severely B cell‐depleted due to the oncologic treatments received. In terms of COVID‐19 severity, the cohort was heterogeneous: most patients were symptomatic at diagnosis (16/18, 89%) and a minority required oxygen therapy (2/18, 11%). Two patients were asymptomatic and received a prolonged course of remdesivir after having been previously treated for the same COVID‐19 episode without achieving virus clearance. In the overall cohort, the median duration of remdesivir course was 19 days, and viral clearance was achieved in a median time of 3.5 weeks. 68 Notably, remdesivir was combined with convalescent plasma in most patients, as well as with other antiviral therapies, 68 highlighting the importance of combination therapy in high‐risk patients.

COVID‐19 TREATMENT WITH REMDESIVIR IN PATIENTS WITH HEMATOLOGIC MALIGNANCY

As pointed out in the previous sections, all patients with hematologic malignancy are at increased risk for developing severe‐critical and persistent COVID‐19 compared to the general population. There is however a great variability in their outcomes following infection with SARS‐CoV‐2, depending on the type of malignancy and ongoing and previously received anti‐cancer treatment. 1 , 2 , 5 , 10 , 25 , 54 , 62 , 76 , 77 Based on our clinical experience and on published evidence, we recognize two categories of risk, namely ‘standard risk’ and ‘high risk’. Included in the high‐risk category are patients with B‐cell depletion and recipients of allogeneic HSCT, CAR T cell therapy or bispecific antibodies, as summarized in Table 2 ; demographic and clinical characteristics like older age, chronic lung disease, cardiac disease and no recent immunization are also important to correctly evaluate the risk and the need for intensive treatment. 1 , 2 , 10 , 25 , 54 Patients with hematologic malignancies treated with therapies not included in Table 2 generally belong to the standard‐risk category.

Table 3 summarizes the current indications for treatment with remdesivir. Patients with non‐severe COVID‐19 34 are usually treated in the out‐patient setting, unless they are hospitalized due to their hematologic disease. These patients should receive remdesivir as soon as possible after diagnosis of SARS‐CoV‐2‐infection and within 7 days from symptom onset. 21 A 3‐day treatment duration is recommended 21 , 34 , 35 and supported also by the evidence from real‐world studies (Table 1 ). However, as stated also in the EMA label, a 3‐day duration might not be sufficient to achieve adequate viral clearance in severely immunocompromised patients. 21 , 58 In these patients, who are at highest risk of developing severe COVID‐19, treatment prolongation may be considered, as well as the combination of remdesivir with other COVID‐19 drugs (Table 3 ), for example monoclonal antibodies, if active against the circulating SARS‐CoV‐2. 68 , 78 Indeed, a growing body of evidence has suggested that combination therapy is beneficial for the early treatment of high‐risk patients. 78 , 79 , 80 , 81 , 82 , 83 For example, a retrospective analysis of 144 immunocompromised patients at high risk of progressing to severe COVID‐19 found that the prompt treatment with combinations including an antiviral plus a monoclonal antibody, two antivirals, two antivirals plus a monoclonal antibody was able to prevent prolonged viral shedding in 85.4% of patients, with an acceptable toxicity profile. 78 An observational prospective study in 52 immunocompromised outpatients evaluated the dual combination sotrovimab plus an antiviral (remdesivir or nirmatrelvir‐ritonavir); the primary outcome was hospitalization within 30 days. 83 The early treatment with the dual combination effectively prevented hospitalization, progression to severe COVID‐19 and development of persistent SARS‐CoV‐2 infection. 83

In the setting of early COVID‐19 treatment, another recommended first‐line antiviral option is nirmatrelvir‐ritonavir. 5 , 34 Nirmatrelvir inhibits the SARS‐CoV‐2 main polyprotein protease; it is administered with ritonavir, a potent CYP3A4 inhibitor that decreases nirmatrelvir metabolism. This antiviral was shown to significantly reduce the risk of disease progression in high‐risk, symptomatic outpatients in a randomized, placebo‐controlled, phase 2/3 study. 12 Nirmatrelvir‐ritonavir is the preferred option for the treatment of non‐severe disease, recommended by the WHO living guideline on COVID‐19 therapeutics. 34 This antiviral has the advantage over remdesivir of being administered orally. However, the limitation of the intravenous administration may be soon overcome as an oral formulation of remdesivir (mindeudesivir), currently under evaluation, has yielded promising results in terms of sustained symptom resolutions and safety in a placebo‐controlled, phase 3 trial in patients with mild‐to‐moderate COVID‐19. 85 In onco‐hematologic patients, the use of nirmatrelvir‐ritonavir may be limited by relevant drug–drug interactions involving immunosuppresants or drugs used for the treatment of hematologic malignancies, like for example venetoclax or ibrutininb. 2 , 35 Furthermore, nirmatrelvir‐ritonavir is not recommended for patients with severe renal dysfunction, while remdesivir can be used in these patients, including those on dialysis, without dose adjustments. 2 , 21 , 22 , 35 With regard to other safety issues related to antiviral use, bradycardia has been reported in the post‐marketing pharmacovigilance of remdesivir and increased transaminase were the most common adverse event in healthy individuals within the clinical development program of remdesivir. 21

To the best of our knowledge, no prospective randomized trials directly comparing remdesivir and nirmatrelvir‐ritonavir are available. However, several real‐world observations have attempted a comparison. 51 , 53 , 56 , 57 , 66 For example, Aiello and coworkers describing the early treatment of 83 onco‐hematologic patients found that nirmatrelvir‐ritonavir was significantly more effective than remdesivir in reducing the viral load at 5 days and the duration of viral shedding. 51 In an observational study involving 562 patients with COVID‐19, early treatment with nirmatrelvir‐ritonavir was associated with lower mortality or hospitalization rates compared with remdesivir and molnupiravir. 53 Nirmatrelvir‐ritonavir was, however, associated with more frequent adverse events. Rajme‐Lopez and colleagues confirmed that nirmatrelvir‐ritonavir was more effective than remdesivir in preventing hospitalization or death in over 1500 high‐risk patients, 57 while other studies did not find significant differences in the effectiveness of antivirals. 56 , 86 Finally, Piñana and colleagues in a retrospective analysis of 466 patients with hematologic malignancy found that nirmatrelvir‐ritonavir was preferentially used in patients with mild COVID‐19, while remdesivir was used more frequently in hospitalized patients with severe disase. 66 The study did not report any differences in the safety profile of the two antivirals.

Patients with severe COVID‐19 requiring supplemental oxygen are usually hospitalized. These patients should receive remdesivir as soon as possible in the course of the disease (Table 3 ). The recommended treatment duration is 5–10 days, 21 although optimal treatment duration has not been defined. 87 Based on our clinical experience, we prefer a 10‐day duration, unless a negative swab is obtained earlier. In patients at high risk, remdesivir may be combined with other COVID‐19 therapeutics. In case of relapse or persisting symptoms, cycles of treatment can be prolonged and/or repeated. 68

Although current guidelines do not recommend the use of remdesivir in patients with COVID‐19 on extracorporeal membrane oxygenation/invasive mechanical ventilation, 34 , 35 a growing body of evidence, especially from large real‐world studies, suggests that remdesivir is associated with improved survival also in these patients. 70 , 71 , 88 In fact, in severely immunocompromised patients, due to their prolonged viral shedding, critical disease might still be related to the ongoing viral replication. Therefore, in patients with hematologic malignancy, antiviral treatment may be an option also in the setting of critical COVID‐19. 88

Several approaches combining remdesivir with other therapies for the management of severe COVID‐19, with persistent symptoms and viral shedding, have been described. 7 , 68 , 75 , 82 , 89 , 90 , 91 , 92 A 5‐day course of dual antiviral treatment with remdesivir and nirmatrelvir‐ritonavir achieved high rates of clinical and virological response among 15 patients with haematologic malignancies and persistent COVID‐19. 91 Full clinical and virological remission was sustained at 3 months in 60% of patients. 91 Triple combination protocols have also been investigated. In a retrospective observational study in 22 patients, combination therapy including two antivirals and monoclonal antibodies active against the infecting strain was associated with high rates of virological and clinical response in immunocompromised patients with persistent or relapsed symptomatic COVID‐19. 89 Commercial preparations of intravenous immunoglobulins are an alternative to COVID‐19 convalescent plasma and have been investigated in few studies. 7 , 93 , 94 A randomized study in 59 patients with moderate–severe COVID‐19 needing ventilatory support found that the addition of high‐dose intravenous immunoglobulins to the standard of care, including steroids, enoxaparin and remdesivir, was well tolerated and led to clinical improvements compared to the standard of care alone. 94

With regard to the use of corticosteroids for the treatment of COVID‐19, it should be noted that while dexamethasone decreases the mortality in the general population of patients with severe‐critical disease, 34 , 35 , 95 its role in patients with hematologic malignancy is less clear. In this population, treatment with corticosteroids at the time of SARS‐CoV‐2 infection was shown to be independently associated with an increased risk of COVID‐19 pneumonia and hospitalization, while corticosteroid treatment for COVID‐19 was found to be associated with higher mortality. 25 Moreover, among hospital‐admitted patients with haematologic malignancy, mortality was higher in those treated with corticosteroids alone, compared to corticosteroids plus antivirals or antivirals alone. 96 Of note, this association was not present in the subgroup of ICU‐admitted patients. 96 Although biases cannot be entirely excluded—given that most available evidence derives from retrospective analyses and that patients receiving corticosteroids for COVID‐19 often present with more severe pneumonia—the potential detrimental effects of corticosteroids in patients with hematologic malignancy should be carefully considered. These patients frequently undergo immunosuppressive therapy and may have concomitant infections that contribute to a highly inflammatory state. Therefore, short‐term treatment with corticosteroids and, in selected cases, with a second immunosuppressant is currently recommended only when COVID‐19‐related inflammation is evident, as supported by a clinically significant rise in inflammatory markers vs. pre‐COVID‐19 levels and compatible findings on computed tomography, and in the absence of concomitant infections that could worsen with corticosteroid use, such as invasive mould infections and non‐COVID‐19 viral pneumonia. 84

CONCLUSIONS

Despite major advances in the management of COVID‐19, SARS‐CoV‐2 infection in patients with hematologic malignancy continues to be associated with an elevated risk of progression to severe‐critical disease and death. Antiviral treatment with remdesivir is a valid option for high‐risk patients, like patients with hematologic malignancy, across a wide spectrum of COVID‐19 severity. Evidence from clinical trials and real‐world studies suggests that remdesivir effectively prevents disease progression and is associated with a decreased mortality risk. Furthermore, remdesivir appears to be well tolerated, has so far demonstrated activity against emerging SARS‐CoV‐2 variants, and has a relatively favourable profile of drug–drug interactions. A drawback of remdesivir is the administration by intravenous infusion. However, an oral formulation of remdesivir – mindeudesivir – is currently under evaluation and may be soon available. In this article, we have discussed a set of practical indications to guide clinicians in the use of remdesivir, alone or combined with other COVID‐19 drugs, for the treatment of SARS‐CoV‐2 infection in patients with hematologic malignancy.

AUTHOR CONTRIBUTIONS

Malgorzata Mikulska: Conceptualization, methodology, investigation, resources, data curation, writing—original draft, writing—review and editing, visualization, supervision. Matteo Bassetti: Resources, writing—review and editing. Alessandro Busca: Resources, writing—original draft, writing—review and editing, visualization. Valeria Cento: Resources, writing—review and editing. Maddalena Giannella: Resources, writing—review and editing. Michele Bartoletti: Conceptualization, methodology, resources, data curation, writing—original draft, writing—review and editing, visualization.

FUNDING INFORMATION

This work was supported by Gilead Sciences S.r.l. Italy through unconditional support.

CONFLICT OF INTEREST STATEMENT

MM reports fees for lectures or advisory board meetings from Allovir, Astra‐Zeneca, Gilead, Janssen, Moderna, Mundipharma and Pfizer. AB has received lecture honoraria from Gilead Sciences, Merck, Pfizer Pharmaceuticals, Basilea, Biotest and Jazz Pharmaceuticals; he was a Board member of Gilead Science, Merck and Takeda. MaB has received funding for scientific advisory boards, travel, and speaker honoraria from Cidara, Gilead, Menarini, MSD, Mundipharma, Pfizer, and Shionogi. All other authors declare that they have no competing interests.

ACKNOWLEDGEMENTS

Editorial assistance was provided by Lorenza Lanini, PhD, and Alessia Doria on behalf of Health Publishing and Services S.r.l. This assistance was supported by an unrestricted support by Gilead Sciences S.r.l. Italy.

Mikulska M, Bassetti M, Busca A, Cento V, Giannella M, Bartoletti M. Role of remdesivir for the treatment of COVID‐19 in patients with hematologic malignancy—A narrative review and expert opinion. Eur J Clin Invest. 2025;55:e70108. doi: 10.1111/eci.70108

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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Associated Data

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.