Post-pandemic recommendations for the management of COVID-19 in patients with haematological malignancies or undergoing cellular therapy, from the European Conference on Infections in Leukaemia (ECIL-10)

Abstract

In the post-pandemic years, SARS-CoV-2 morbidity and mortality declined due to less pathogenic variants, active and passive immunization, and antiviral therapies. However, patients with hematological malignancies and/or undergoing hematopoietic cell transplantation (HCT) remain at increased risk for poor outcomes. Therefore, adherence to contact and droplet precautions is essential to avoid transmission, especially during epidemic waves. Detection of viral RNA by nucleic acid testing of naso-oro-pharyngeal samples is the gold standard for diagnosis due to its high sensitivity and specificity. Direct antigen testing allows for rapid management decisions if positive, but has a low sensitivity, especially in asymptomatic patients. Active immunisation is the key to prevention and may require annual matching to circulating variants. Passive immunization with SARS-CoV-2 neutralizing anti-antibodies lost its indication due to the emergence of immune escape variants. Convalescent plasma has been proposed for passive immunization but is not readily available in most centres. For symptomatic patients, early antiviral treatment with nirmatrelvir/ritonavir or remdesivir may reduce the risk of progression to severe-critical COVID-19. Prolonged administration, repeated courses, and a combination of antivirals are considered for patients with clinical or virological failure to antiviral monotherapy. In severe-critical COVID-19, dexamethasone or drugs downregulating the inflammatory cytokine responses (anti-Il-6/anti-IL-2 agents, Janus kinase inhibitor) are recommended, together with the best supportive and intensive care, but care should be exercised in immunosuppressed patients. Deferral of intensive chemotherapy, HCT conditioning, T-cell-based immunotherapy, or T-cell engaging antibodies are considered for patients with COVID-19, whereas deferral decisions are taken on a case-by-case basis for asymptomatic patients with confirmed SARS-CoV-2 infection.

Introduction

Since 2021, the European Conference on Infectious Disease in Leukaemia (ECIL-9) issued two editions of specific recommendations for the management of SARS-CoV-2 infection and COVID-19 in patients with haematological malignancies (HM-patients) or those undergoing hematopoietic cell transplantation (HCT-patients) or other immunotherapies [1, 2]. In light of the changing epidemiology, in particular the better prognosis of the Omicron variant and subvariants compared with the pre-Omicron variants [3–8], and the availability of more effective medical interventions for COVID-19 in the last two years, the scientific board of ECIL decided to review and update the earlier recommendations. Here, we present the final recommendations for the management of COVID-19 in HM patients approved at the tenth meeting (ECIL-10), held on 19-21 September 2024 in Nice, France.

Methods

European Conference on Infections in Leukemia (ECIL) is a society cofounded by the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation (IDWP-EBMT), the International Immunocompromised Host Society (ICHS), the European Leukemia Net (ELN), and the European Organisation for Research and Treatment of Cancer (EORTC). ECIL aims to develop guidelines for the management of infections in HM and HCT patients which are freely available on the ECIL website [9].

In 2024, the ECIL scientific board appointed the expert working group for COVID-19. For this update, the literature search was limited to the period of October 2022 to September 2024 and performed on PubMed using keywords: COVID-19 and haematology, lymphoproliferative and/or myeloproliferative disease, stem cell transplant, CAR-T, SARS-CoV-2/COVID-19 diagnosis, epidemiology, therapy, vaccination. Considering the huge amount of publications on COVID-19, only the most relevant studies in the English language were considered. Preprints were considered only if accepted after peer-review by September 19th, 2024.

Grading of the quality of evidence and of the strength of recommendation was according to the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) system [10] (Table 1).

Table 1.

Evidence-based medicine grading system according to the European Society for Clinical Microbiology and Infectious Diseases (ESCMID).

STRENGTH OF RECOMMENDATION (SoR)
Grade	Definition
A	ECIL strongly supports a recommendation for use
B	ECIL moderately supports a recommendation for use
C	ECIL marginally supports a recommendation for use
D	ECIL supports a recommendation against use
QUALITY OF EVIDENCE (QoE)
Level	Definition
I	Evidence from at least 1 properly designed randomized, controlled trial (orientated on the primary endpoint of the trial)
II	Evidence from at least 1 well-designed clinical trial (including secondary endpoints), without randomization; from cohort or case-controlled analytic studies (preferably from >1 centre); from multiple time series; or from dramatic results of uncontrolled experiments
III	Evidence from opinions of respected authorities, based on clinical experience, descriptive case studies, or reports of expert committees
ADDED INDEX FOR SOURCE OF LEVEL II EVIDENCE
Index	Source
r	Meta-analysis or systematic review of RCT
t	Transferred evidence, that is, results from different patient cohorts, or similar immune-status situation
h	Comparator group: historical control
u	Uncontrolled trials
a	Published abstract presented at an international symposium or meeting

The ECIL-10 meeting was attended by 46 infectious disease, laboratory, and haematology experts from 14 European countries, and Australia, Brazil, Israel, Saudi Arabia, and the United States. The meeting was prepared in four pre-meeting sessions. The ECIL-10 meeting involved a first round in a plenary session where the update of COVID-19 guidelines was presented by the expert working group and discussed with attendees to obtain a consensus, and a second round, where the revised guideline proposals were presented again to participants and voted for approval. The final slide set with recommendations was made publicly available on the ECIL website for one month (October 2024) for comments or observations, and after that, the final approved slide set of recommendations was published on the ECIL website.

Table 2 summarizes the updated recommendations for prevention, diagnosis, vaccination, and treatment approved at the ECIL-10 meeting. In the following paragraphs, the recommendations are commented and discussed with the supporting literature.

Table 2.

Recommendations for the management of SARS-CoV-2 infection and COVID-19 issued by ECIL-10.

Prevention
1	Hand hygiene and face mask (surgical mask or high-filtering capacity maske), are recommended measures for HM patients to prevent SARS-CoV-2 and other respiratory virus infection, while distancing, and ventilation of rooms are recommended in case of high circulation of SARS-CoV-2 virus	AII
2	Caring for a SARS-CoV-2 positive HM patient requires the use of personal protective equipment (high-filtering capacity mask,a mask, gloves, gown, glasses) by health personnel and isolation in single room	AII
3	Placing a SARS-CoV-2 positive HM patient into positive pressure rooms is not recommended	DIII
4	In HM patient with SARS-CoV-2 infection, ensure the best possible treatment of underlying HM disease weighing individual patient related risks and benefits	AIIu
5	Depending on severity of COVID-19 and vaccination status, after assessment of the clinical risk/benefit ratio, deferral until clinical and virological recovery is appropriate before proceeding with hematological treatment	No grading
6	Therapy with JAK2-inhibitors and TKI/BTKi should be continued in HM patients with SARS-CoV-2 infection	AIIu
7	In case of high circulation of SARS-CoV-2 virus, aim to reduce the risk of SARS-CoV-2 exposure by avoiding hospital visits, where feasible, and promoting use of telemedicine and of home care, when clinically appropriate	BIIu
Diagnosis
8	Molecular assays are recommended for the diagnosis of SARS-CoV-2 infection	AII
9	SARS-CoV-2 molecular assays should target at least two distinct viral gene sequences	AIIt
10	The performance of SARS-CoV-2 molecular assays should be evaluated for newly emerging variants	AIIt
11	Rapid antigen testing should be used for rapid point-of-care diagnosis	AII
12	Testing for SARS-CoV-2 RNA in saliva or oropharyngeal gargle may be considered for symptomatic HM and HCT patients	BIIt
13	Testing for SARS-CoV-2 RNA in saliva or oropharyngeal gargle may have a lower sensitivity in asymptomatic HM and HCT patients, but may be considered for serial (repeated) screening	BIII
14	Clinical virology laboratories need to document proficiency in external SARS-CoV-2 quality accredited programs	AII
15	A negative rapid antigen testing should be confirmed by molecular assays to rule out infection	AII
16	Nasopharyngeal or combined naso-oropharyngeal swab (with nostrils and throat with one swab) are recommended to diagnose SARS-CoV-2 upper respiratory tract infections	AII
17	Bronchoalveolar lavage should be performed if COVID-19 LRTI is suspected and nasopharyngeal molecular swab is negative for SARS-CoV-2	AII
18	Testing lower respiratory tract fluid (tracheal aspirate, bronchoalveolar lavage) is recommended if a lung coinfection is suspected despite a positive SARS-CoV-2 nasopharyngeal swab	AII
19	Screening the patient before hospitalization for chemotherapy, HCT, CAR T is recommended, especially during the period of high viral circulation, to inform decisions regarding infection control or deferral of therapy, HCT, or CAR T	BIII
20	The detection of SARS-CoV-2-RNA or N-protein in blood correlates with a more severe course of COVID-19, but harnessing this information for clinical management requires further study	No grading
21	Patients having consecutive SARS-CoV-2 PCR Ct-values of 30-35 and negative antigen test are unlikely to transmit infection, provided adequate sampling	No grading
22	SARS-CoV-2 antibody assays are not recommended to diagnose a new-onset acute SARS-CoV-2 infection	AII
23	Immunocompromised persons such as HM and HCT patients have a mitigated antibody response	No grading
24	The role of quantitative antibody assays, calibrated to the 1st WHO-approved SARS-CoV-2 antibody standard, is not defined for routine clinical-decision making regarding administration of booster vaccine doses or monoclonal antibody therapies	CIII
25	Antibodies assay targeting N-protein can be considered to ascertain previous SARS-CoV-2 exposure	AII
26	Antibodies assay targeting S-protein can be considered to ascertain vaccine response or previous exposure to SARS-CoV-2	AII
27	Antibody assay targeting to N-protein can be considered in patients with suspected multi-inflammatory syndrome in children	AII
28	The use of “in house” or commercially-available T-cell assays for the diagnosis or the management of SARS-CoV-2 infection requires further study	No grading
Vaccination
General recommendations for all HM patients including HCT or CAR-T cell recipients
29	HM patients, who were never vaccinated or have had a verified COVID-19 infection should receive a primary vaccination program according to recommendations by international and national authorities and authorized age range, preferably starting before initiation of treatment for the underlying disease (2-4 weeks), during maintenance, or when off-therapy	AIIu
30	HM patients, vaccinated with a full program including those having had SARS-CoV-2 infection should receive at least yearly booster doses with an updated vaccine according to country recommendations	AIIu
31	In preparation of the winter season the co-administration at the same day of COVID-19 vaccine booster dose with influenza vaccine, according to the age-appropriate doses for children, adolescents, and adults is recommended	BIIt
32	The data regarding use of protein subunit vaccines in patients with hematological malignancies is limited	No grading
33	In the absence of well-established criteria for protection, it is not recommended to assess anti-SARS-CoV-2 antibody titers nor T-cell response with the aim to determine the need for booster doses	DIIt
34	For mRNA vaccines, the interval between the first two doses should be at least 3 weeks and the interval between the 2nd and 3rd dose should preferably be 3 months	AIItu
35	Additional (booster) dose(s) of SARS-CoV-2 vaccine should be given after at least 3 months from the 3rd dose according to the country recommendations	AIItu
36	For patients having verified SARS-CoV-2 infection, booster dose(s) should be delayed at a minimum of 3 - 4 months after the resolution of the episode	AIItu
37	HM patients should be informed of the ongoing risk of SARS-CoV-2 infection despite vaccination and follow the hygiene and social distancing recommendations of their community or country	BIIt
General recommendations for all HM patients including HCT or CAR-T cell recipients
38	Vaccination of health care personnel and of house-hold contacts of HM patients, including children, in accordance with regulatory authority approval and national recommendations for specific age groups, is recommended	BIIt
39	Primary COVID-19 vaccination and booster administration is recommended in children affected by hematological malignancy, starting from 6 months of age with product and dosage approved for age	AIItu
40	Prophylaxis with MoAbs directed to SARS-CoV-2 should not prevent vaccination against COVID-19 in situations where such are indicated	BIII
	Vaccination in HM non-transplanted patients
41	There is until now no specific safety issue of COVID-19 vaccination with either mRNA or protein-subunit vaccines in non-transplanted HM patients	AIIu
42	COVID-19 vaccination should not delay the treatment of the underlying disease	AII
43	Patients with an expected low or very low antibody response rate to vaccine (eg. anti-CD20 MoAb therapy ongoing or within the 6-12 months from the last dose, CAR T cell or bispecific antibody treatment targeting BCMA or CD19, induction chemotherapy for AL, profound hypogammaglobulinemia, deep lymphopenia), can still benefit from vaccination	BII
Vaccination in transplanted patients
44	HCT recipients should receive a primary schedule of COVID-19 vaccine	AIIu
45	Timing of vaccination should be based on individual consideration of the immune status of the patient and the prevalence of SARS-CoV-2 in the community but no earlier than 3 months after cell infusion	BIIu
46	There might be a risk for worsening/eliciting GVHD in allogeneic HCT recipients receiving primary schedule with mRNA vaccines although data is conflicting. This risk might be considered when deciding about the appropriate timing of vaccination	CII
47	Based on data from other vaccines, it is possible that immunity obtained from either pre-transplant SARS-CoV-2 infection or vaccination will be significantly affected by the transplant procedure. It seems logical from a risk/benefit assessment that allogeneic HCT patients should receive a full primary vaccine schedule after transplantation irrespectively of pre-transplant SARS-CoV-2 infection or vaccination	BIII
Vaccination in CAR T patients
48	Patients with B-cell aplasia after treatment with CD19 + CAR T cells are unlikely to mount good antibody responses. After vaccination, T cell responses can be elicited in a majority of patients, but the importance for protection is unclear	No grading
49	Timing of vaccination should be based on individual consideration taking into consideration the immune status of the patient and the prevalence of SARS-CoV-2 in the community but no earlier than 3 months after cell infusion	BII
Therapy
50	In severely immunocompromised HM patients, particularly with B-cell depletion or inadequately vaccinated, pre-exposure prophylaxis is recommended with long-acting anti-SARS-CoV-2 MoAbs if active against circulating variants, irrespective of previous vaccination	BIIt
51	In HM patients at high risk for COVID-19 progression,b post-exposure prophylaxis can be recommended with anti-SARS-CoV-2 MoAbs, if active against the circulating variants.	CIIt
52	In moderately or severely immunocompromised HM patient with mild-moderate COVID-19, early treatment is recommended, with:	AI
	1) nirmatrelvir/ritonavir	AIIu
	2) remdesivir	BIIu
	3) molnupiravir c	CIIu
	In selected very severely immunocompromised patients or in patients with imminent necessary chemotherapy or cellular therapy, a combination of two antivirals or combination of antiviral and MoAbs/convalescent plasma or prolonged antiviral treatment can be used	CIIu
	Steroids should not be used in early treatment of mild-moderate COVID-19	DIIt
53	In HM patients with COVID-19 requiring oxygen support, the following treatments are recommended:
	Antiviral therapy with Remdesivir or	AIIu
	Combination of two antivirals or an antiviral and MoAbs/ convalescent plasma	BIIu
	Anti-inflammatory treatment with short–term steroid coursef is recommended only if COVID-19 related inflammation is presente and no presence of co-infections likely to progress with steroid treatmentg	BIIt
54	In patients with critical COVID-19 (invasive/non-invasive ventilation and/or vasopressor therapy) the following treatments are recommendedd:
	1) Remdesivir	AIIt
	2) Combination of two antivirals or an antiviral + MoAbs	BIItu
	3) Anti-inflammatory treatment with short–term steroid coursef is recommended only if COVID-19 related inflammation is presente and no presence of co-infections likely to progress with steroid treatmentg	BIIu
	4) Add a 2nd immunosuppressant, if COVID-19-related inflammation is present and worsening despite steroids: anti-IL-6 (tocilizumab, sarilumab) or Janus kinase inhibitor (baricitinib)	BIIt
	5) High-titre convalescent plasma can be useful in critical ventilated patients, preferably within the first 48 h after ventilation initiation, in addition to standard of care	BIItu

HM hematological malignancy, HCT hematopoietic cell transplantation, CAR T chimeric antigen receptor T, LTRI low tract respiratory infection, Ct cycle threshold, WHO world health organization, MoAbs monoclonal antibodies, BCMA B cell maturation antigen, GVHD graft versus host disease.

^aCertified mask with high filtering capacity of 94–95% are FFP2, N95, KN95.

^bNot vaccinated, vaccine non-responders or not expected to respond to vaccine, recent B-cell depleting treatments.

^cLower efficacy and EMA not authorized.

^dVilobelimab, an anti-C5a monoclonal antibody, is authorized in COVID-19 patients on mechanical ventilation (within the first 48 hours after intubation) or extracorporeal membrane oxygenation (ECMO).

^eClinically significant increase in inflammatory markers compared to pre-COVID19, and compatible computed tomografy scan pattern.

^fDexamethasone 6 mg/day for 10 days or methylprednisolone 0.5–1 mg/kg/day for 3–7 days.

^gInvasive mould infection, other viral pneumonia than COVID-19.

Definition

SARS-CoV-2 infection may be asymptomatic or range from a mild-moderate respiratory illness to a severe life-threatening condition, depending on patient risk factors, comorbidities, and immunization status, which mandates the choice of different medical interventions. Accordingly, SARS-CoV-2 infection is defined by a test demonstrating viral replication, whereas COVID-19 requires a positive test and the presence of compatible clinical signs and/or symptoms.

Prevention (recommendations 1-7)

SARS-CoV-2 is transmitted by respiratory secretions from an infected subject, mostly through droplets or aerosol particles while coughing, sneezing, speaking, singing or breathing, as well as through contaminated hands and surfaces.

Therefore, the prevention of SARS-CoV-2 infection in HM patients requires recommended measures for reducing aerosol-droplet-contact transmission, i.e. hand hygiene, surgical or FFP2 face mask, isolation in single rooms, avoiding, instead, placing the patient in positive pressure room for the risk of diffusion of infection inside the ward [11, 12]. To obtain compliance of the patients with the personal protective measures, it is important to provide educational programs by healthcare personnel. Physical distancing, ventilation of rooms, and reducing hospital visits by implementing telemedicine, highly recommended during the pre-Omicron wave, are indicated in case of resurgence of epidemic [13, 14]. The use of protective equipment by health care workers (gloves, gowns, face shield) and practice of careful disinfection of hands remain key hygienic measures to prevent SARS-CoV-2 spread inside the hospital, among infected patients, health personnel, and other patients or workers [12].

The practice of deferral of intensive chemotherapy or any type of cellular therapy for at least 14 days, or until COVID-19 symptoms are significantly improved, is reasonable for patients with moderate-severe COVID-19 due to high propensity to progress to lower respiratory tract infection and, in turn, increase mortality. Conversely, the decision to postpone or withdraw an oncology treatment, in patients with SARS-CoV-2 infection or mild COVID-19 is less supported nowadays due the possible measures that can be implemented to prevent infection progression, such as post-exposure prophylaxis, early treatment interventions, or in case of prolonged viral shedding, even retreatment with antiviral or combination of antivirals [6, 15–17]. For these clinical situations, the recommendation is to personalize the medical decision on a case by case according to the type of underlying HM, remission status, type of chemotherapy or biological agents to administer, the intensity of planned treatment, the expected toxicity profile of the treatment, and the possibility to modify the chemotherapy regimen, for example, avoiding anti-CD 20 monoclonal antibody in lymphoma patients. However, treatment with non-chemotherapy target drugs such as JAK-inhibitors and TKI/BTKi can be maintained [18].

Diagnosis (recommendations 8-28)

Nucleic acid amplification tests (NAAT) continue to be the primary choice for the diagnosis of SARS-CoV-2 infection [19, 20]. Among NAAT, real-time transcription PCR assays (RT-PCR), most commonly targeting two viral genes (ORFs), are the mainstay of diagnosis. Primers and probes used in RT-PCRs are regularly checked in silico and in vitro testing for their ability to bind complementary sequences in newly circulating SARS-CoV-2 (sub)variants. RT-PCR assays can provide a quantitative readout, the cycle threshold (C_T), which is a surrogate of the original number of SARS-CoV-2 genome targets present in the specimen (viral load-VL is inversely related to the C_T value); but importantly, C_T values returned by different RT-PCR platforms may differ (usually +/- 3 units) for a given VL. A relationship exists between VL and viral culture results. Roughly, a threshold of 10⁴ genome copies/ml discriminates between culture-positive and culture-negative specimens. A large number of isothermal PCR assays based on loop-mediated amplification (LMP) have been commercialized; these provide results within 1 hour and are particularly suited for point-of-care (POC) testing. Alternatively, rapid antigen detection assays (RATs) detecting the virus nucleocapsid protein can be used for rapid diagnosis; RATs are highly specific but display lower sensitivity than NAAT, especially when VL is low (usually C_T > 30). Thus, molecular testing is recommendable in suspected cases when RAT returns negative results [21–23]. On the other hand, the positivity of RAT is strongly associated with recovery of live virus in culture. Importantly, RAT assays may underperform in the detection of emerging SARS-CoV-2 (sub)variants, compared to the ancestral variant. In terms of sample sites, nasopharyngeal swabs (NPS) are the standard of care for NAAT and RAT testing. Nasal swabs, mid-turbinate swabs, throat swabs, and saliva, all amenable to self-collection are acceptable alternatives. Considering that patients with severe or critical COVID-19 are at risk of bacterial superinfections, like pneumococci, or pulmonary aspergillosis, the clinical vigilance and the active screening for secondary infections are advised to avoid patient’s underdiagnosis and undertreatment. In patients with severe or critical COVID-19 and the clinical suspicion of bacterial, viral, and fungal co-infections or in patients with clinical and radiological pneumonia but testing negative for SARS-CoV-2 on NPS sample patients, lower respiratory tract sampling by tracheal aspirate or bronchoalveolar lavage is recommended [24–26].

The utility of VL quantification is debated. In studies performed before Omicron variant predominance, VL obtained at diagnosis by NPS in non-hospitalized subjects was not predictive of the severity of COVID-19; while in hospitalized COVID-19 patients, the risk of extrapulmonary complications, and in turn 90-day mortality, increased by rising baseline plasma and respiratory VL [27–29]. In the Omicron variant predominance phase, the viral shedding in immunocompromised patients is observed for a median of 9 days (range 3–27) in non-B cell hematological malignancy or solid tumors, 11 days (range 3-44) for B-cell malignancies, and 16 days (range 4-99) for HCT patients [30], but in 25% of patients the viral shedding can last up to 21 days or more especially in B-cell depleted diseases. This highlights the importance of antibody response in clearing infection. The persistence of RT-PCR positivity for 3 weeks or more or alternating positive and negative RT-PCR tests after clinical recovery from COVID-19 is associated with either low viral loads, variability in sampling, persistence of viral debris, or emergence of new Spike-protein mutations. Such RT-PCR positivity is considered an indicator of poor viral replication, viral shedding, and, in turn, a surrogate of infectivity [31]. In terms of infection control, the implications of an RT-PCR positive test may vary according to VL of the sample because infectious SARS-CoV-2 virus has been cultured in only 4% of RT-PCR samples with Ct threshold >32 [30]. Neither detection of SARS-CoV-2-specific antibodies nor that of SARS-CoV-2 T-cells by interferon-gamma release assays (IGRA) are useful for the diagnosis of acute infection.

Vaccination (recommendations 29-49)

Vaccines contributed significantly to reducing morbidity, hospitalization, need for intensive care, and mortality by COVID-19 in the whole population as well as in HM and HCT patients [3, 5, 32–34]. Although several types of vaccines, prepared with different technologies have been approved since the start of the pandemic, currently only three vaccines are recommended for HM and HCT patients: mRNA vaccines (BNT162b2 and MRNA-1273) and recombinant protein vaccine (Table 3) [35]. The mRNA vaccines, although only few prospective studies were performed in immunocompromised patients, combine a moderate-good vaccine efficacy depending on underlying patient disease and phase of treatment, with a good safety profile. However, limited data exists for the use of protein subunit vaccine as primary immunization in immunocompromised host [36].

Table 3.

Vaccines approved by European Medicine Agency (EMA).

Vaccine	Type (date of authorization)	Dose(s)	Indications
Bimervax (Hipra)	Recombinant S protein, adjuvanted	40 μg	➢Age ≥ 16 years in subject who previously received mRNA vaccine ➢Interval of 6 months between doses
Comirnaty (Pfizer/BioNtech)	mRNA JN.1 (adapted) (3Jul24) Omicron XBB.1.5 (31Aug23) Original/OmicronBA.4-5 (12Sept22) Original/Omicron BA.1 (1Sept22)	3 μg, 10 μg, 30 μg	➢Primary immunization and booster
Spikevax (Moderna)	mRNA JN.1 (adapted) (10Sept24) Omicron XBB.1.5 (15Sept23) Original/OmicronBA.4-5 (20Oct22) Original/Omicron BA.1 (1Sept22)	25 μg, 50 μg, 100 μg	➢Primary immunization and booster
Nuvaxovid (Novavax)	Recombinant S protein, adjuvanted Omicron XBB.1.5 Original	5 μg	➢Age ≥ 12 years ➢Primary immunization

Overall, the Spike-protein antibody response rate in HM patients ranged from 21% to 87% after dose 2, 14% to 96% after dose 3, and from 87% to 100% after dose 4; from 78% to 94% after dose 2 and from 58% to 90% after dose 3 in HCT patients; and from 28% to 36% after dose 2 and from 25% to 40% after dose 3 in CAR T patients [37–40]. The lower response to vaccination has been observed in HM patients receiving high-dose of steroids or up to 28 days-6 months from moderate-intensive chemotherapy in patients with B-cell lymphoproliferative diseases, especially those with aggressive or advanced non-Hodgkin lymphoma, chronic lymphocytic leukaemia, and multiple myeloma; up to 6 months from receiving target monoclonal antibody directed against CD20, CD19, CD 22, BCMA cell antigens, or treatment with Bruton tyrosine-kinase inhibitor, and in HCT and CAR T patients early after the procedure [37, 38, 41–44]. Therefore, timing of vaccination is crucial to increase vaccine efficacy, the ideal option being 2–4 weeks before starting any oncological treatment, during maintenance with low-dose chemotherapy, at least 3 months after HCT or CAR T procedure, and 6 months after therapy with anti-CD20 monoclonal antibodies and 3-6 months after the last dose of a T cell engaging antibody.

Currently, it is likely that almost all individuals, before the diagnosis and start of treatment of their HM, have developed some immunity against SARS-CoV-2 by experiencing COVID-19 at least once and/or being vaccinated. Importantly, the development of the so-called hybrid immunity, that is the immunity resulting from vaccination preceded hybrid immunity or followed by natural SARS-CoV-2 infection, might confer a higher and prolonged protection from SARS-CoV-2 reinfection [45–47].

To reduce healthcare visits and extend prevention to other seasonal respiratory virus infections, if the annual COVID-19 booster vaccine falls in the autumn period, it can be administered simultaneously with the Influenza vaccine to improve vaccination compliance and uptake [45, 46].

A new primary vaccination series is indicated in patients having been undergone HCT, even though they have been previously naturally immunized by a documented SARS-CoV-2 infection or COVID-19 episode or have been vaccinated before HCT. The recommended vaccination schedule with mRNA vaccines for patients with HM or HCT includes a three-dose primary schedule with a 3-week interval between the first two doses and the third dose after at least 4 or 8 weeks from the second one, followed by an additional vaccine dose [35, 48]. Similar recommendations now also for patients who have undergone CAR T cell therapy or treatment with bispecific antibodies [49]. The administration of a fourth vaccine dose at a distance of 2-6 months from the third one is safe and effective in increasing further antibody titers. This schedule applies to all age groups, including children from 6 months of age. In allogeneic HCT, the robustness of response depends on previous immunization status (vaccination and/or infection), older age, use of B-depleting therapy before or after HCT and CAR T, grade of ongoing immunosuppression and immune reconstitution (CD4 + < 0.2 × 109/L) [50]. Importantly, the waning of vaccine immunity, which occurs usually after 6 months from vaccination, develops quicker in immunocompromised than in otherwise healthy populations, and the continuous emergence of new variants requires the use of vaccines updated with the antigen characteristics of circulating variants, to confer the broader protection, as well as the annual administration of one or more vaccine boosters in immunocompromised patients at risk of severe COVID-19 [51].

In allogeneic HCT patients, reactivation of graft versus host disease (GVHD) has been reported in some studies, possibly related to inflammatory response following COVID-19 vaccine administration, although several other studies did not find this association. The recent ASCO guidelines interpreted the data as inconclusive [52]. On the other hand, active acute or chronic GVHD is also a risk factor for lower or non-response to vaccination [50, 53, 54].

Local vaccination policies must consider vaccinating health care personnel and family members, including children, according to the approved country schedule and age groups, to optimize the interventions for the immunocompromised patient. Lastly, patients must be informed and counseled that vaccination does not replace the need to adopt other mitigation measures against contagion and spread of infection such as hand hygiene, masking, and social distancing [55, 56].

Table 4 shows the recommended schedule of vaccination for vaccines approved by the European Medicine Agency for European countries.

Table 4.

Recommended vaccine schedule according to type of vaccine, age, and immunization status.

Vaccination status	Age 6 months-4 years	5-11 years	12 years and older
Unvaccinated	Pfizer BNT 3 × 3 μg dose or Moderna 3 × 25 μg dose	Pfizer BNT 3 × 10 μg dose or Moderna 3 × 25 μg dose	Pfizer BNT 3 × 30 μg dose or Moderna 3 × 50 μg dose or Novavax 2 × 5 μg dose
Patient received 1st dose PfizerBNT Moderna Novavax	Pfizer BNT 2 × 3 μg dose Moderna 2 × 25 μg dose Not approved	Pfizer BNT 2 × 10 μg dose Moderna 2 × 25 μg dose Not approved	Pfizer BNT 2 × 30 μg dose Moderna 2 × 50 μg dose Novavax 1 × 5 μg dose (in specific cases)
Patient received 2nd dose Pfizer BNT Moderna Novavax	Pfizer BNT 1 × 3 μg dose Moderna 1 × 25 μg dose Not approved	Pfizer BNT 1 × 10 μ g dose Moderna 1 × 25 μg dose Not approved	Pfizer BNT 1 × 30 μg dose Moderna 1 × 50 μg dose /
Patient received ≥3 doses Pfizer BNT Moderna	Pfizer BNT 1 × 3 μg dose or Moderna 1 × 25 μg dose	Pfizer BNT 1 × 10 μg dose or Moderna 1 × 25 μg dose	Pfizer BNT 1 × 10 μg dose or Moderna 1 × 25 μg dose or Novavax 1 × 5 μg dose
Interval dose 1st-2nd	Pfizer BNT 3 weeks Moderna 4 weeks	Pfizer BNT 3 weeks Moderna 4 weeks	Pfizer BNT & Novavax 3 weeks Moderna 4 weeks
Interval dose 2nd-3rd	Pfizer BNT ≥ 8 weeks Moderna ≥ 4 weeks	Pfizer BNT & Moderna ≥4 weeks	Pfizer BNT & Moderna ≥4 weeks
Interval dose 3rd (dose 2nd for Novavax) - booster	≥8 weeks	≥8 weeks	≥8 weeks
Interval booster-additional dose	≥8 weeks optional a second dose after ≥8 weeks	≥8 weeks, optional a second dose after ≥8 weeks	≥8 weeks, optional a 2° dose ≥8weeks Recommended a second dose after ≥8 weeks for patients aged ≥65 yrs

Therapy (recommendations 50-54)

Even in the Omicron era, HM patients with SARS-CoV-2 infection are at increased risk of progression to severe COVID-19, need for hospitalization and intensive care, and mortality by all causes [8]. In the post-pandemic period, the diffusion of the hybrid immunity and the less pathogenic circulating variants have reduced the need for interventions to control the hyperinflammation phase of COVID-19, and most interventions are to prevent the infection (pre-exposure prophylaxis), or, after infection onset, to prevent progression, and finally to control the challenging situation of prolonged or relapsing infection [57]. A summary of current available treatments is shown in Table 5.

Table 5.

Summary of treatments authorized for the use in COVID-19 by regulatory authorities.

Class	Agent	Indication	Age limit
Antivirals	Remdesivir, IV Nirmatrelvir/ritonavir, oral Molnupirvir, oral	Treatment hospitalized/not hospitalized with mild-moderate COVID-19 Treatment mild-moderate COVID-19 Treatment mild-moderate COVID-19, (not authorized by EMA)	Age 28 days (>3 kg) and older Adult (for FDA, from ≥12 years and >/= 40 kg of body weight) Adult
Monoclonals	Pemivibart, IV Sipavibart, IM	Pre-exposure prophylaxis, approved FDA Pre-exposure prophylaxis, approved EMA	Age > 12 years and  >/= 40 kg Age > 12 years and  >/= 40 kg
Immunomodulators	Baricitinb, oral Tocilizumab, IV, sc Anakinra, IV Vilobelimab, IV	Treatment of hospitalized patients with oxygen support, NMV, MV, ECMO Treatment of hospitalized patients on steroids, with oxygen support, NMV, MV, ECMO Treatment of hospitalized patients requiring oxygen, with pneumonia and elevated soluble urokinase plasminogen activator receptor (suPAR) Treatment of patients on mechanical ventilation or ECMO	Adult ≥2 years, adult ≥8 months and ≥10 kg, and adult Adult
Blood products	Convalescent plasma, high titre	Treatment of COVID 19 in immuncompromised patients (FDA)

IV intravenous, IM intramuscolar, sc subcutaneous, EMA European Medicine Agency, EU European Union, FDA Food and Drug Administration, NMV non mechanical ventilation, MC mechanical ventilation, ECMO extracoporeal membrane oxygenation.

Antivirals

Nirmatrelvir/ritonavir is an oral antiviral indicated for the treatment of patients with mild-to-moderate COVID-19 infection at high risk of progression to severe COVID-19 [58, 59]. Importantly, surveillance data showed that the emergence of resistance to nirmatrelvir/ritonavir is infrequent (<0.3%–1.1%) [60]. Concurrent patients’ medications must be carefully assessed because ritonavir is a potent P4503A4 inhibitor that can cause clinically significant drug–drug interactions [61].

Remdesivir is an intravenous antiviral agent used for COVID-19, which is indicated both for mild and moderate/severe settings. In the mild/moderate setting, remdesivir is administered within seven days from symptom onset and for 3 days. Being available only as intravenous formulation makes remdesivir less convenient for outpatient use compared with nirmatrelvir/ritonavir. The second indication is COVID-19-related pneumonia, administered for 5-10 days [62, 63]. In a recent retrospective analysis of all-cause mortality in HM, HCT, or SOT patients, the administration of remdesivir within two days from hospitalization was associated with lower 14-day and 28-day mortality both in patients with and without oxygen dependence [64]. A high barrier to resistance has been reported in vitro and in vivo [65, 66]. Advantages of remdesivir include lack of major drug-drug interactions, and the possibility of use in patients with renal failure including those receiving dialysis.

Molnupiravir is another oral antiviral with the advantage of lack of drug-drug interactions and the possibility of use in patients with renal failure (ClCr < 30 ml/mn) [61]. However, molnupiravir is no longer recommended in EU countries because it showed no clear advantage compared with standard of care and the risk of emergence of immune escape variants, particularly in immunocompromised patients [67, 68]. In countries where molnupiravir is available, it can be considered if other therapeutic options are contraindicated or unavailable.

There are clinical situations where viral replication persists for weeks, or the patients presents repeated infection relapses, or COVID-19 worsens despite antiviral monotherapy, particularly in patients after B-cell depletion. While the best management strategy is unknown, a combination of antivirals, usually remdesivir and nirmatrevir/ritonavir(sometimes prolonged to 10 days or more), or antivirals and anti-Spike monoclonal antibodies has been successfully used as rescue treatment [69, 70]. Combination or prolonged therapy has been also successfully used in patients with severe COVID-19 or even in particularly immunocompromised patients with an early SARS-CoV-2 infection [16, 62, 70].

Monoclonals

At present, none of the monoclonal antibodies developed during the pandemic period are approved, because they progressively lost neutralizing efficacy with the emergence of Omicron variant and subvariants [71]. Nevertheless, passive immunization remains a valuable option to quickly protect vulnerable patients who are not eligible for vaccination or with inadequate immune response to vaccination. In general, there is a concern about durable effectiveness of any new monoclonal antibody therapies, considering the rapid emergence of mutated variants escaping the neutralizing capacity of monoclonals [72].

Currently, there are two new anti-Spike monoclonal antibody products approved for primary prevention of COVID-19. Pemivibart, at the dose of 4500 mg intravenously (IV) every 3 months, received emergency use authorization from the FDA as pre-exposure prophylaxis in adult and pediatric patients (>12 years) who are moderate-to-severe immunocompromised [73]. In the EU, sipavibart, at the dose of 300 mg intramuscularly (IM) every 6 months, has been approved by EMA for pre-exposure prophylaxis [74, 75]. The monoclonal antibody SC27, which is a variant with superior neutralization potency and breadth, is under investigation and may represent a future option [76].

Convalescent plasma (CP)

The use of CP with a high titer of polyclonal neutralizing antibodies showed benefits in different experimental settings: early treatment of outpatients with mild-moderate COVID-19; treatment of hospitalized patients with moderate-severe COVID-19; and the treatment of protracted viral shedding when this hinders the resumption of high-dose chemotherapy or cellular therapies [77–82]. The collection of CP from people who have been previously vaccinated also allows us to obtain units with very high titers of neutralizing antibodies (vaccine-boosted convalescent plasma or vax-plasma). The outpatient administration of vax-plasma to vaccinated immunocompromised patients, mainly within 5 days from COVID-19 diagnosis, together with standard of care including antivirals, was associated with a 65% reduction of the relative risk of hospitalization [83]. Nevertheless, the use of CP is not part of the routine practice in EU countries because of the general difficulties in organizing and maintaining a network of CP collection, storage, quality control, and release, while it was issued in the USA by an emergency use authorization in immunocompromised patients with COVID-19 [84].

Steroids

In the general population, the use of steroids (dexamethasone 6 mg/day for 10 days or methylprednisolone 0.5-1 mg/kg/day for 3-7 days) was shown to decrease mortality in hospitalized patients requiring supplemental oxygen for their capacity to decrease systemic inflammation [85–87]. However, steroids were associated with higher mortality in hospitalized patients not requiring oxygen support and had no effect in those requiring only nasal cannula oxygen supplementation [88]. The negative impact of systemic steroids has been confirmed in retrospective multicenter studies on HM patients who were recruited also during the Omicron era where the use of dexamethasone resulted in a risk factor for mortality especially when the patients did not receive concomitantly the treatment with antivirals for SARS-CoV-2 [63, 89].

Immunomodulatory agents

Immunomodulatory drugs are indicated in cases where dexamethasone is not readily available or in addition to steroids in patients with worsening systemic inflammation signs [90, 91]. In this context, tocilizumab and baricitinib have been the most used, although their use decreased in the Omicron variant period [92]. Noteworthy, the evidence supporting the use of immunomodulator drugs in HM patients is mainly transferred from the studies in immunocompetent hosts performed in the pre-Omicron period, while the hyperinflammatory phase is rare in immunocompromised patients in the Omicron era because they are usually vaccinated. In a recent retrospective study recruiting 112 immunocompromised oxygen-dependent hospitalized patients, the addition of tocilizumab or baricitinib to the standard of care did not reduce mortality [93]. In this perspective, considering the concerns for an increased risk of other opportunistic infections, the use of immunomodulators in an already immunocompromised population must be assessed carefully

Hyperactivation of the complement system, measured as the level of C5a protein, is associated with COVID-19 severity and mortality. Vilobelimab is an anti-C5a monoclonal antibody which has been approved by FDA and EMA for the treatment of adult patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) who are receiving systemic corticosteroids as part of the standard of care and on invasive mechanical ventilation (IMV) (with or without extracorporeal membrane oxygenation (ECMO)) [94, 95]. The approval was based on the results of a multicenter, randomized, double-blind, placebo-controlled trial where vilobelimab showed a mortality risk reduction of 11% [96]. Considering that this study was performed during Delta variant circulation in patients who were not vaccinated for COVID-19 and that the benefit of vilomelimab was not confirmed at site-stratified analysis, further clinical research is needed to confirm its efficacy.

Conclusions

Since the appearance of the SARS-CoV-2 virus in 2019, the prognosis of HM and HCT patients improved due to a bundle of measures consisting of infection control, personal protection, vaccines, prompt diagnosis and early intervention, antivirals, and the best supportive care. Thereby, progression to severe-critical COVID-19 disease can be reduced. In these years, we learned that the epidemiology of SARS-CoV-2 infection is continuously evolving and that new vaccines and therapies could be quickly released and available. The update of recommendations and the continuous clinical research in this setting are important tools to mitigate the risks related the COVID-19 and improve the outcome of the HM and HCT patient population.

The European Conference on Infections in Leukemia (ECIL) is a society cofounded by the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation (https://www.ebmt.org/working-parties/infectious-diseases-working-party-idwp), the International Immunocompromised Host Society (ICHS) (https://www.ichs.org/), the European Leukemia Net (ELN) (https://www.leukemia-net.org/), and the European Organisation for Research and Treatment of Cancer (EORTC).

Author contributions

SC, PL, MM, and HHH conceptualized and designed the project; SC, PL, MM, HHH, DN, CC, VM, JS, FM, JLP, GB, HH, JM, and RdlC performed the literature search and wrote the initial draft of the paper; SC, PL, MM, HHH, DN, CC, VM, JS, FM, JLP, GB, HE, JM, and RdlC, read and approved the final version of the manuscript; VM revised the English style of the manuscript; SC supervised the project and performed the final editing of the manuscript.

Funding

The ECIL 10 meeting (Sept 19-21, 2024) was supported by unrestricted grants from MSD, Pfizer, Takeda, Gilead, Basilea, F2G, Moderna, Mundipharma, Shionogi, OLM, Astrazeneca, and Scynexis. None of these pharmaceutical companies had any role in selecting experts, determining the scope and purpose of the guidelines, collecting, analyzing, and interpreting the data, or preparing the guidelines’ edition. We also thank the staff of GL Events (Lyon, France) for organizing the meeting.

Competing interests

The authors declare no competing interests.