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

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).</p

MOLNUPIRAVIR COMPARED TO NIRMATRELVIR/RITONAVIR FOR COVID-19 IN HIGH-RISK PATIENTS WITH HAEMATOLOGICAL MALIGNANCY IN EUROPE. A MATCHED-PAIRED ANALYSIS FROM THE EPICOVIDEHA REGISTRY

Introduction: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections, which reduce both hospitalization and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, while molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir, because it displays less frequent drug-drug interactions and contraindications. A caveat connected to molnupiravir derives from the mode of action inducing viral mutations. In clinical trials on patients without haematological malignancy, mortality rate reduction of molnupiravir appeared less pronounced than that of nirmatrelvir/ritonavir. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, we here assess the effectiveness of molnupiravir compared to nirmatrelvir/ritonavir in our cohort of patients with haematological malignancies. Methods: Clinical data of patients treated either with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and baseline haematological malignancy severity to controls treated with nirmatrelvir/ritonavir. Results: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (IQR 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 57% (n=66) of the patients had controlled baseline haematological malignancy, 13% (n=15) stable, and 30% (n=35) had active disease at COVID-19 onset in each of the groups. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of vaccinated patients was observed in both groups (molnupiravir n=77, 66% vs nirmatrelvir/ritonavir n=87, 75%), those treated with nirmatrelvir/ritonavir had more often received four doses (n=27, 23%) as compared to patients treated with molnupiravir (n=5, 4%, p&lt;0.001). No differences were detected in COVID-19 severity (p=0.39) or hospitalization (p=1.0). No statistically significant differences were identified in overall mortality rate (p=0.78) or in survival probability (d30 p=0.19, d60 p=0.67, d90 p=0.68, last day of follow up p=0.68). In all patients, deaths were either attributed to COVID-19 or the infection contributed to death as per treating physician's judgement. Conclusions: In high-risk patients with haematological malignancies and COVID-19, molnupiravir showed rates of hospitalization and mortality comparable to those of nirmatrelvir/ritonavir in this matched-pair analysis. Molnupiravir appears to be a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy

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

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&nbsp;=&nbsp;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)

Age, Successive Waves, Immunization, and Mortality in Elderly COVID-19 Haematological Patients: EPICOVIDEHA Findings

Introduction: elderly patients with haematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection impact in different age groups remains unstudied in detail. Methods: We analysed elderly patients (age groups: 65-70, 71-75, 76-80 and &gt;80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with haematological malignancy. results: the study included data from 3,603 elderly patients (aged 65 or older) with haematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves.tThe 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukaemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment. Conclusions: These data underscore the heterogeneity of elderly haematological patients, highlight the different impact of COVID waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts

Correction: Need for ICU and outcome of critically ill patients with COVID-19 and haematological malignancies: results from the EPICOVIDEHA survey

Peer reviewe

Decoding the historical tale: COVID-19 impact on haematological malignancy patients-EPICOVIDEHA insights from 2020 to 2022

The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced.Peer reviewe

Activated lymphocytes and monocytes in myelodysplastic syndromes

De myelodysplastische syndromen (MDS) vormen een heterogene groep van klonale hematologische aandoeningen die gekenmerkt worden door perifere cytopenieën en een verhoogde intrinsieke kans om te evolueren naar acute myeloïde leukemie. Verworven afwijkingen in het genetisch materiaal van primitieve hematopoïetische stamcellen liggen aan de basis van MDS, maar de laatste jaren is duidelijk geworden dat ook immunologische processen een belangrijke rol spelen in het ontstaan van MDS-gerelateerd beenmergfalen. Het verder ontrafelen van de rol van lymfocyten en monocyten in beenmergfalen bij MDS maakte het voorwerp uit van dit doctoraatsonderzoek.De meeste patiënten met MDS hebben cytopenieën en dit vormt de belangrijkste bron van morbiditeit en mortaliteit. Voornamelijk het aantal circulerende myeloïde bloedelementen (rode bloedcellen, neutrofielen, bloedplaatjes) is gedaald bij MDS. Er is minder eensgezindheid over het aantal lymfocyten en natural killer (NK) cellen bij patiënten met MDS. De gepubliceerde resultaten zijn immers niet éénduidend, grotendeels te wijten aan de relatief kleine patiëntenreeksen. Allereerst hebben we deze immuuncellen (CD4+ en CD8+ T cellen, B cellen en NK celllen) gekwantificeerd in het bloed van een grote groep (n=101) onbehandelde patiënten en de resultaten vergeleken met gezonde vrijwilligers van dezelfde leeftijd. We toonden aan dat patiënten vergelijkbare aantallen CD4+ en CD8+ T cellen hebben; de aantallen NK cellen en B cellen daarentegen waren significant lager in patiënten.MDS wordt gekenmerkt door klonale hematopoiese en de huidige evidentie wijst aan dat de primaire maligne transformatie bij de meeste patiënten plaatsgrijpt in een primitieve maar myeloïde stamcel. Een tweede doelstelling van dit onderzoek was nagaan of bij patiënten met MDS de circulerende immuuncellen ook deel uitmaakten van de maligne kloon. Hiervoor onderzochten we gezuiverde celfracties uit het bloed van patiënten met de HUMARA-techniek (n=12) en fluorescente in situ hybridisatie (FISH, n=12). Monocyten die van myeloïde oorsprong zijn, waren zoals verwacht nagenoeg steeds van klonale origine. CD4+ en CD8+ T cellen waren daarentegen van polyklonale oorsprong. Opmerkelijk was de bevinding van klonale NK en B cellen in ongeveer de helft van de patiënten die we onderzochtten. Onze resultaten ondersteunen daarmee vroegere rapporten over klonale afwijkingen in B cellen en NK cellen, en dagen het concept dat MDS louter de myeloïde stamcellen treft uit. Uit onze resultaten konden we echter niet besluiten dat wanneer een celpopulatie deel uitmaakte van de MDS-kloon, dit automatisch resulteerde in lagere bloedwaarden.Er zijn aanwijzingen dat immuunprocessen mee verantwoordelijk zijn voor het beenmergfalen bij specifieke patiënten met MDS. Illustratief hiervoor is het feit dat immuunsuppressieve therapie bij een derde van patiënten een significante verbetering van de bloedwaarden teweegbrengt. Bij bepaalde patiënten met MDS kan men zgn. klonale T cell expansies detecteren, waarvan men heeft kunnen aantonen dat ze de groei van progenitorcellen afremmen in vitro. Bovendien brengen deze T cellen bepaalde activatie-merkers tot expressie op hun celoppervlak. Mogelijkerwijs zijn het deze patiënten, waarbij men deze groepjes T cellen kan detecteren, juist deze mensen die beantwoorden aan immuunsuppressieve therapie. Gezien de bepaling van het T cel receptor-repertoire zeer arbeidsintensief is, onderzochten we of er een groep patiënten kon gedefinieerd worden op basis van de expressie van activatiemerkers op circulerende T cellen. Daartoe bepaalden we het fenotype van T cellen in een grote groep patiënten met MDS (n=131) met flowcytometrie en correleerden onze bevindingen met klinische variabelen. MDS patiënten hebben significant meer geactiveerde T cellen (d.w.z. HLA-DR+, CD28-, CD57+, CD62L-) in vergelijking met gezonde leeftijdsgenoten, maar desondanks konden we geen subgroep onderkennen bij wie dit meer uitgesproken was. Bovendien vonden we geen verband tussen expressie van deze merkers door T cellen, en een groei-inhiberende activiteit van deze cellen in vitro.Het is vooralsnog niet geweten hoe geactiveerde T cellen bij patiënten uiteindelijk leiden tot globaal beenmergfalen. We onderzochten de mogelijkheid dat monocyten betrokken zijn in dit proces. We hebben verschillende aanwijzingen dit monocyten, meer bepaald via CD40-CD40L-interacties met T cellen, de groei van progenitorcellen bij MDS kunnen onderdrukken. Van monocyten werd vermoed de belangrijkste bron van tumor necrosis factor-alpha (TNF-&#945;) te zijn, waarvan geweten is dat het de groei van progenitorcellen onderdrukt en in patiënten met MDS ook meer geproduceerd wordt. We toonden aan dat MDS monocyten meer TNF-&#945; produceren t.g.v. stimulatie van de CD40 receptor. Bovendien toonden we aan dat deze receptor meer tot expressie wordt gebracht door monocyten van MDS patiënten. Ook het ligand van deze receptor (CD40L), wordt significant meer geëxprimeerd door CD4+ T cellen in (dezelfde) patiënten. Meer nog, inhibitie van deze CD40-CD40L interactie in vitro leidde tot een significant hogere productie van hematopoietische kolonies. Het klinisch belang van onze bevinding wordt gestaafd door de vaststelling dat patiënten waarvan de circulerende monocyten de hoogste CD40-expressie hebben, juist deze patiënten zijn die geacht worden het best te reageren op immuunsuppressieve therapie (nl. jonger dan 60j, cytogenetische afwijking trisomie 8). Anderzijds lijken onze bevindingen te suggereren dat inhibitie van CD40-CD40L-interacties tussen monocyten en T cellen een nieuwe therapeutische piste zou kunnen zijn om patiënten met beenmergfalen t.g.v. MDS te behandelen.Tenslotte evalueerden de werkzaamheid van thalidomide op geïsoleerde monocyten van MDS patiënten. Thalidomide leidt immers bij een beperkte groep patiënten tot een verbetering van de anemie, en dit wordt o.a. toegeschreven aan het feit dat thalidomide de TNF-&#945; productie door monocyten inhibeert. In het licht van onze bevinding dat activatie via de CD40-receptor een belangrijke rol speelt in vivo, stimuleerden we gezuiverde monocyten met CD40-agonisten in toenemende concentraties van thalidomide. Waar de TNF-&#945; productie van gezonde monocyten in elke concentratie van thalidomide significant werd geïnhibeerd, waren zeer hoge concentraties van dit product nodig om de productie door MDS monocyten te onderdrukken. Deze bevinding kan een verklaring bieden waarom patiënten met MDS relatief hoge dosissen thalidomide nodig hebben voor een respons, die t.g.v. de nevenwerking van dit product vaak niet te bereiken zijn.status: publishe

Monocytes from patients with myelodysplastic syndromes are more resistant to inhibition by thalidomide

The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias and marrow dysplasia. Immune mechanisms are in part responsible for the marrow failure observed in MDS patients [1]. We have recently provided evidence for the involvement of CD40-CD40L interactions between monocytes with T helper cells in the pathogenesis of this marrow failure [2]. More specifically, we have shown that monocytes from MDS patients produce more TNF-α in response to stimulation of the CD40-receptor than control monocytes. Thalidomide is a potent immune-modulating agent with a broad spectrum of immunologic effects and has been used in MDS patients as single-agent therapy [3-5] or in combination with other agents [6-9]. Inhibition of TNF-α production is believed to be the primordial mechanism by which thalidomide acts in MDS. However, in vitro data on the effect of thalidomide on TNF-α production in MDS currently lack. With this study, we provide the first data of the effect of increasing doses of thalidomide on the production of TNF-α by monocytes from MDS patients in response to lipopolysaccharide (LPS) or CD40-agonists. We show that only a high concentration of thalidomide is able to inhibit the TNF-α production of MDS monocytes stimulated by CD40-agonists.status: publishe

The clinical significance of activated lymphocytes in patients with myelodysplastic syndromes: A single centre study of 131 patients

We studied the immune compartment in patients with myelodysplastic syndromes. We show increased surface expression of activation markers (HLA-DR(+), CD57(+), CD28(-), CD62L(-)) on T lymphocytes in blood and bone marrow (n=131). T cell activation was not restricted to any relevant clinical subgroup (FAB, IPSS, cytogenetics) and did not correlate with blood counts or need for treatment. In vitro clonogenic growth of marrow mononuclear cells (n=18) was not influenced by T cells expressing these markers. In addition, using X-chromosome inactivation analysis (n=12) we demonstrate clonal involvement of NK and B cells in half of these patients. We conclude that although activated T lymphocytes can be found in MDS, their role in disease pathogenesis remains unclear in the majority of patients.status: publishe

Combined results of two cross-sectional surveys on the participation in clinical trials and the e-consent procedure in the landscape of haematology

Abstract: Despite the motivation of oncology patients to take part in clinical trials, only a minority of them are enrolled in clinical trials. Implementation of new practical procedures can become a barrier that withholds patients from participating in clinical trials. Treating physicians are crucial in augmenting trial accrual. The drivers that promote physicians to allocate patients for clinical trials need further assessment. We conducted two separate cross-sectional surveys, addressing patients with a haematological disease in one survey and haematologists in another survey. The patient survey was filled out by 420 patients. Significant relationships between the willingness to participate in a trial and trial knowledge (p < 0.001) and between doctor-patient relationship and participation willingness (p = 0.007) were noted. Patients above 60 years were less willing to use an electronic consent procedure vs. patients younger than 60 (p < 0.001). The physician questionnaire was completed by 42 participants of whom most (83%) were active in and (94%) motivated for clinical trials. Apart from the patient benefit and scientific interest, prestige was an equal motivator closely followed by financial remunerations. First goal was not to harm the patient. Our study confirms the high willingness of patients for trial participation and the need to rethink the structure of trial organisation. The e-consent procedure is not the method preferred by most patients above 60 years old