Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry

Summary Background Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan–Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448–4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619–8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093–0.732) and obesity (aOR 0.105, 95%CI 0.014–0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. Funding EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan-Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448-4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619-8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093-0.732) and obesity (aOR 0.105, 95%CI 0.014-0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration.
Interpretation Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir.

Introduction
Since the coronavirus disease 2019 (COVID- 19) pandemic was declared in March 2020, 1 unprecedented efforts by all stakeholders led to effective treatment options that can ameliorate the disease. Vaccines have proved to be a most effective method preventing

Research in context
Evidence before this study Nirmatrelvir/ritonavir is a new antiviral targeting the SARS-CoV-2 3Cl protease. It is widely recommended for patients with mild symptoms to prevent severe episodes of COVID-19. A web search was performed on November 12th for articles in English, French, German, Italian, or Spanish using strings combining the terms "haemato*, "hemato*", "nirmatrelvir*", "paxlovid" with "administration", "mortality", "outcome", and "treatment". No studies focusing specifically on nirmatrelvir/ ritonavir administration in haematological patients were found. Single publications targeting the general population or immunosuppressed patients were retrieved, but provided no detailed information on patients with haematological malignancy.

Added value of this study
To the best of our knowledge, this is the first publication describing the factors associated with nirmatrelvir/ritonavir administration and investigating factors associated with mortality in patients with haematological malignancy. Our results show that nirmatrelvir/ritonavir was administered more frequently to patients with extrapulmonary symptoms and those who had received a 2nd vaccine booster dose against SARS-CoV-2. On the contrary, patients with chronic pulmonary disease or obesity were less likely to receive nirmatrelvir/ritonavir. Mortality was significantly lower than in patients with other directed treatments.

Implications of all the available evidence
Clinical management of COVID-19 patients with baseline haematological malignancies remains challenging two years after onset of the pandemic. Although vaccines prevent hospitalization and reduce mortality rates, patients with haematological malignancy may not mount protective immune response. In this vulnerable immunosuppressed patient group nirmatrelvir/ritonavir treatment results in lower mortality rates as compared to other treatment approaches. Still not all patients qualifying for nirmatrelvir/ritonavir received that treatment. Reasons for underuse remain unclear at this point. hospitalisation and mortality. 2,3 Immunocompromised patients, for instance those with haematological malignancy, have been at increased risk for severe courses of COVID-19 and fatal outcome. Because of impaired immune response to vaccination, they are still at highrisk and need other approaches than current vaccines. [4][5][6] Such approaches have been implemented with the antivirals molnupiravir, 7 nirmatrelvir/ritonavir, 8 and remdesivir, 9 and with the monoclonal antibodies targeting viral antigens. [10][11][12][13][14] The common goal of these drugs is reducing rates of hospitalisation, severe disease, and death. Approved for administration in 2022, 15,16 during the initial moments of the omicron wave, nirmatrelvir/ritonavir is an oral protease inhibitor administered in high-risk patients with mild symptoms early in the course of COVID-19. 15,16 Although the phase 3 development programme addressed high-risk patients, only few patients with cancer were enrolled. 8 Current consensus guidelines recommend nirmatrelvir/ritonavir in patients with haematological malignancy, 17 although there is a lack of available data on this patient group. 18 This EPICOVIDEHA study compares epidemiology and outcome of patients with haematological malignancy receiving nirmatrelvir/ritonavir treatment versus those who did not.

Methods
All data included in this analysis were exported from the EPICOVIDEHA registry. EPICOVIDEHA (NCT04733729) is an online registry open for patients with haematologic malignancy and SARS-CoV-2 infection. Cases from various regions of the world are documented in an electronic case report form (eCRF) accessible via www. clinicalsurveys.net (EFS Summer 2021, TIVIAN, Cologne, Germany). The eCRF comprises epidemiological data, such as baseline pre-COVID-19 conditions, previous clinical management of the haematologic malignancy, anti-SARS-CoV-2 vaccination history, COVID-19 diagnosis and management, and outcome. All patients are included in a validation process for data coherence and completeness performed by experts in haematologic malignancy and infectious diseases. 19 In this validation process, data missing completely at random were reduced as possible, contacting contributors were to solve pending queries. Exclusions from the database only happened if a patient was not fulfilling all the inclusion criteria (no haematological malignancy, not active within the last 5 years prior to COVID-19, no adult, no laboratory-based COVID-19 diagnosis).
For the present analysis, patients needed to fulfil all inclusion criteria to be eligible: active haematologic malignancy within the last five years prior to COVID-19, including patients at onset or watch and wait; age ≥18 years; SARS-CoV-2 infection confirmed by either polymerase chain reaction (PCR) or antigen test; and SARS-CoV-2 diagnosis between January 1st and September 30th, 2022.
Selected patients were grouped according to treatment specifically received for COVID-19. Thus, we formed the following categories: patients treated with nirmatrelvir/ritonavir ± other directed or non-directed treatments, patients receiving other SARS-CoV-2 directed antivirals or monoclonal antibodies ± other non-directed treatments, and finally patients receiving neither directed antivirals or monoclonal antibodies, nor corticosteroids or convalescent plasma.

Statistical analysis
Consecutive data from participating institutions were summarised with frequencies and percentages for categorical variables and with median, interquartile range (IQR) and absolute range for continuous variables. Proportion comparisons were performed using Fisher's exact or Pearson's chi (X) squared tests, respectively. Logistic regression was utilised to determine which independent variables were associated with subsequent nirmatrelvir/ritonavir administration. For comparison analyses, patients were matched with a propensity score based on a logistic regression. The model included the variables sex, age (±10 years), baseline haematological malignancy, haematological malignancy status at COVID-19 onset, and origin continent (Europe). In order to determine the power and robustness of the performed propensity score, variables used for the matching were confronted with a median difference (age), Phi coefficient (sex and origin continent [Europe]), or Cramér's V (baseline haematological malignancy and haematological malignancy status at COVID-19 onset), as appropriate (Supplementary Table S1). A log-rank test was used to compare the survival probability of the patients based on the treatment received for COVID-19, which was graphically represented with a Kaplan-Meier survival plot. Additionally, Cox regression was used to analyse which factor could be associated with mortality both in every patient and in nirmatrelvir/ritonavir recipients who had data on duration of follow up. Variables with a p value < 0.1 in the univariable models were considered for the respective multivariable model. P value < 0.05 was considered statistically significant.

Ethics statement
The central ethics committee is at Fondazione Policlinico Universitario Agostino Gemelli -IRCCS, Università Cattolica del Sacro Cuore of Rome, Italy (Study ID: 3226). Additionally, each participating institution may also have a local approval for the research initiative as appropriate. The anonymized data that do not contain any personally identifiable information from any sources implies that the informed consent is not applicable.

Role of the funding source
The funders had no role in the study design, the collection, analysis, and interpretation of data, writing of the report and the decision to submit for publication. JSG, FM, LP, and OAC had access to and verified all raw data sets and made the decision to submit the manuscript.

Results
This EPICOVIDEHA data set comprises 1859 patients with haematological malignancy from 84 centres in 28 countries, who were diagnosed with COVID-19 between January and September 2022 (Fig. 1A).
Sensitivity analyses we performed to determine which factors were associated to mortality in all the matched patients. Thus, we could observe how, in the univariable analyses, administration of directed drugs other than nirmatrelvir/ritonavir was associated with an increased mortality (p = 0.046), as compared to nirmatrelvir/ritonavir. Nevertheless, the factor more greatly associated with mortality in the analysed patients, either in the univariable or in multivariable analyses was the hospital, especially to ICU (Supplementary Tables S3 and S4). Nirmatrelvir/ritonavir administration remained as a protective factor in the coupled multivariable analyses performed considering the COVID-19 treatment and the variables observed to have a p < 0.1 in the univariable models when including in couples COVID-19 treatment and age, comorbidities, neutrophils, status of the malignancy at COVID-19 onset and symptoms at COVID-19 onset, respectively (Supplementary Tables S5 and S6).

Discussion
Of 1859 patients with haematological malignancy registered in EPICOVIDEHA since the licensing of nirmatrelvir/ritonavir, 117 (6.3%) received the drug to prevent complicated courses of COVID-19. 8 Patients with extrapulmonary symptoms at COVID-19 onset and those who had received a 2nd booster dose of an mRNA vaccine were more likely to receive nirmatrelvir/ritonavir. Recipients of nirmatrelvir/ritonavir had a significantly lower mortality rate than patients with other treatment approaches. Additionally, we aimed to discover factors associated with mortality in patients receiving nirmatrelvir/ritonavir for the COVID-19 treatment, although none was observed as significant, potentially linked to the reduced sample size and overall mortality rate.
Patients with chronic pulmonary diseases and obesity were less likely to receive nirmatrelvir/ritonavir, although precisely these are patients at risk of developing more severe COVID-19, 20 and therefore being the most appropriate candidates for nirmatrelvir/ritonavir administration even in the absence of haematological malignancy. [15][16][17] This apparent underuse of nirmatrelvir/ ritonavir may have multiple reasons explaining such results: lack of stock in hospital pharmacies and clinical practices, 21 unawareness on when and how to administer it, unidentified obstacles in prescription, or already described adverse events, such us dysgeusia, diarrhoea or emboli, or drug-drug interactions. 8,22 The performance of a similar analyses once the drug has been longer available may show broader use and may provide results more in line with the drug recommendations. In parallel, the presence of only extrapulmonary symptoms at COVID-19 was associated with nirmatrelvir/ritonavir use, following the prescription recommendations regarding target patients: mild COVID-19 episodes with high-risk for SARS-CoV-2 progression. 15   directed treatment, and 74.2% in patients with directed drugs other than nirmatrelvir/ritonavir. These vaccination rates are similar to those in the general population. 24 In line with previous experiences in immunosuppressed settings, 25 the absence of vaccination in our patients was related to an ongoing haematological malignancy treatment or to patient refusal. However, in the majority of them it was unknown the rationale. Specific studies analysing the vaccination coverage in patients with an increased risk for COVID-19-associated mortality could help to understand and overcome this situation, facilitating a close-to-full vaccination in haematological malignancy patients.
With these data, one could elucidate that the variables included in the propensity score-based matching performed in our analysis (sex, age (±10 years), baseline haematological malignancy, haematological malignancy status at COVID-19 onset, and origin continent [Europe]) has made the treatment groups very homogeneous and comparable, not only in the matching variables, but also in the vaccination coverage. Additionally, the fact that all the patients were diagnosed in 2022 has facilitated a higher coverage. In order to see more detailed reasons, we may need to look patient to patient and thus, the heterogenicity of the results to be potentially obtained could have a very poor significance. Further analysis may need to focus on this aspect and we will definitely keep in mind in our prospective research. Surprisingly, the patients in our sample received nirmatrelvir/ritonavir for a median of only four days, one day less than the manufacturer recommendations, which may hint towards general shortage of the drug. 15,16 Other potential reasons may be drug-drug interactions, 26,27 adverse effects 22 or prompt recovery of symptoms. Additionally, storage and supply restrictions, 21 which can potentially end in a distribution of available doses among more patients than recommended, and difficulties in the access to the compound, 28 might have interfered with the correct number of administration days.
A retrospective study from Israel analysed factors associated with mortality in patients with high-risk of COVID-19 progression after receiving nirmatrelvir/ ritonavir. 29 Immunosuppressed patients showed increased mortality, adjusted by different comorbidities (i.e., cardiovascular disease, chronic kidney disease, chronic lung disease, diabetes mellitus, malignancy in the prior year, or neurological disease), but the authors did not differentiate haematologic malignancy from other causes of immunosuppression. Interestingly we did not identify factors associated with mortality. The high rate of vaccinated patients may have reduced death rates even in our immunosuppressed population. The 6.8% mortality rate in nirmatrelvir/ritonavir recipients, much lower than in previously reported populations without vaccination (31.2%) 5 or including pre-nirmatrelvir/ritonavir cases 4 (9.2%), jeopardises the performance of further mortality analyses.
Our study has some limitations. The retrospective design may intrinsically yield lower data quality, and the sample size is large by comparison to published studies, but still too small to allow additional subgroup comparisons. We do not capture the actual antineoplastic treatment days and doses limiting analyses of drug-drug interactions with ritonavir. 26 Finally, we have been unable to detect which factors are associated with mortality. Further analyses with a larger sample size collecting more variables, including laboratory values, might overcome these limitations.
In conclusion, patients with extrapulmonary symptoms at COVID-19 onset and a 2nd vaccine dose are more prone to receive nirmatrelvir/ritonavir as opposed to those with chronic pulmonary disease and obesity. Despite mortality in patients with nirmatrelvir/ritonavir is lower as compared to that in other treatment schemes, no statistical significance was observed. Thus, further analyses are needed to depict the factors associated to this observation.

Articles
Contributors JSG, FM, LP and OAC contributed to study design and study supervision. JSG did the statistical plan and analysis. JSG and OAC interpreted the data and wrote the paper. All the authors recruited, and documented participants, critically read, reviewed, and agreed to publish the manuscript.

Declaration of interests
The authors do not declare conflicts of interest related to the submitted manuscript. The funder of the study had no role in study design, data analysis, interpretation, or writing of the report. All authors had full access to the data and had final responsibility for the decision to submit for publication.