Update of recommendations for the management of COVID-19 in patients with haematological malignancies, haematopoietic cell transplantation and CAR T therapy, from the 2022 European Conference on Infections in Leukaemia (ECIL 9)

TO THE EDITOR: In 2022, the European Conference on Infections in Leukemia, 9th edition (ECIL-9), published the guidelines for the management of severe acute respiratory syndrome infection (SARS-CoV-2) and disease (COVID-19) in hematological malignancy (HM) and haematopoietic cell transplant (HCT) patients [1]. During the year 2022, the worldwide epidemiology, morbidity, and mortality changed for the better compared to the previous two years of the pandemic due to the positive effect of public health and social measures, the mass vaccination campaigns, availability of antiviral drugs and anti-spike monoclonal antibodies (MoAbs) [2]. The achievements were partly hampered by the continuous emergence of highly contagious variants of concern, escaping the immunity acquired by infection or vaccination. Considering these significant changes, an update of the SARS-CoV-2/COVID19 recommendations was performed at ECIL-9 Conference held in Nice, France, on 14–15 September 2022 and published on the ECIL web page (https://www.ecil-leukaemia.com/en/program). Table 1 shows the updated recommendations on prevention, diagnosis, vaccination, and therapy. In the prevention part, the added recommendations highlight the importance to personalize the decision to defer chemotherapy, HCT, chimeric-antigen-receptor-T (CAR-T) therapy, and other non-cellular therapies in asymptomatic patients or in patients with prolonged viral shedding, based on the individual risk/benefit ratio assessment. The deferral of treatment to avoid the risk of progression to severe COVID-19 is no longer considered mandatory but should weigh the urgency of the patient’s treatment, the effect of postponing therapy on the risk of relapse or progression of the underlying disease, the degree of immunocompromise, the remission status against the possibility to control viral replication by antivirals and/or MoAbs. In the diagnostic part, the new recommendations highlight the need for the surveillance and external quality assurance of the performance of nucleic acid tests and rapid antigen assays on newly emerging (sub)variants. While nucleic acid tests on nasopharyngeal specimen remain the reference, the use of less invasive samples such as oropharyngeal gargle or saliva can be a reliable alternative only for the symptomatic patient. Sampling of lower respiratory tract fluids is not needed for patients testing positive for SARS-CoV-2 RNA on upper respiratory tract specimens, but is recommended in case of a differential diagnosis with other clinical etiologies, of suspicion of coinfections (together with the appropriate diagnostic workup with blood and sputum cultures, fungal serum markers, urine antigens for pneumococci and Legionella) or if upper respiratory tract sampling is negative but SARS-CoV-2 is suspected. The prognostic significance of the qualitative and quantitative detection of SARS-CoV-2 RNAemia or N-antigenemia requires further investigation [3]. Testing for SARS-CoV-2 spike antibodies, whose levels correlate with serum neutralizing activity, is not recommended for clinical decision-making regarding vaccine boosters and administration of MoAbs [4]. Despite T-cell responses having a protective role after natural infection and vaccination, the use of SARS-CoV-2 T-cell assays is not recommended for clinical decision-making [5]. In the vaccine part, the recommended mRNA vaccine schedule for the vulnerable population of HM and HCT patients is adjourned to the three-dose primary schedule followed by an additional vaccine dose. A third dose improved the rate of seroconversion in patients who had not responded to two doses of mRNA vaccine [6, 7] and a 4th dose was safe and could increase antibody titers [8]. It is highlighted that there are no safety issues in non-transplanted HM patients and that vaccination should not delay the treatment of the underlying disease. With the spread of the Omicron variant many patients with HMs and after HCT have now developed SARS-CoV-2 infections both before and after having received vaccinations. It is recommended that the interval between COVID-19 and subsequent boosters should be at least three and preferably four months. An important change in the recommendations is that also patients with expected poor or very poor responses, such as those receiving therapy with anti-CD20 antibodies or being 6–12 months after the last dose, those with profound hypogammaglobulinemia (<4 g/L), deep lymphopenia (<500/μL), receiving B-cell-maturationantigen (BCMA) targeted bispecific therapy and patients starting induction chemotherapy for acute leukemia, might still benefit from vaccination also by inducing a T-cell response. Regarding patients after allogeneic HCT, several studies have shown that additional doses of vaccine can result in seroconversion of patients not having responded to the first two or three doses [9]. At the time of the meeting, the mRNA adapted bivalent vaccines targeting original strains and Omicron subvariants BA.4/5


TO THE EDITOR:
In 2022, the European Conference on Infections in Leukemia, 9th edition (ECIL-9), published the guidelines for the management of severe acute respiratory syndrome infection (SARS-CoV-2) and disease  in hematological malignancy (HM) and haematopoietic cell transplant (HCT) patients [1]. During the year 2022, the worldwide epidemiology, morbidity, and mortality changed for the better compared to the previous two years of the pandemic due to the positive effect of public health and social measures, the mass vaccination campaigns, availability of antiviral drugs and anti-spike monoclonal antibodies (MoAbs) [2]. The achievements were partly hampered by the continuous emergence of highly contagious variants of concern, escaping the immunity acquired by infection or vaccination. Considering these significant changes, an update of the SARS-CoV-2/COVID-19 recommendations was performed at ECIL-9 Conference held in Nice, France, on 14-15 September 2022 and published on the ECIL web page (https://www.ecil-leukaemia.com/en/program). Table 1 shows the updated recommendations on prevention, diagnosis, vaccination, and therapy.
In the prevention part, the added recommendations highlight the importance to personalize the decision to defer chemotherapy, HCT, chimeric-antigen-receptor-T (CAR-T) therapy, and other non-cellular therapies in asymptomatic patients or in patients with prolonged viral shedding, based on the individual risk/benefit ratio assessment. The deferral of treatment to avoid the risk of progression to severe COVID-19 is no longer considered mandatory but should weigh the urgency of the patient's treatment, the effect of postponing therapy on the risk of relapse or progression of the underlying disease, the degree of immunocompromise, the remission status against the possibility to control viral replication by antivirals and/or MoAbs.
In the diagnostic part, the new recommendations highlight the need for the surveillance and external quality assurance of the performance of nucleic acid tests and rapid antigen assays on newly emerging (sub)variants. While nucleic acid tests on nasopharyngeal specimen remain the reference, the use of less invasive samples such as oropharyngeal gargle or saliva can be a reliable alternative only for the symptomatic patient. Sampling of lower respiratory tract fluids is not needed for patients testing positive for SARS-CoV-2 RNA on upper respiratory tract specimens, but is recommended in case of a differential diagnosis with other clinical etiologies, of suspicion of coinfections (together with the appropriate diagnostic workup with blood and sputum cultures, fungal serum markers, urine antigens for pneumococci and Legionella) or if upper respiratory tract sampling is negative but SARS-CoV-2 is suspected. The prognostic significance of the qualitative and quantitative detection of SARS-CoV-2 RNAemia or N-antigenemia requires further investigation [3]. Testing for SARS-CoV-2 spike antibodies, whose levels correlate with serum neutralizing activity, is not recommended for clinical decision-making regarding vaccine boosters and administration of MoAbs [4]. Despite T-cell responses having a protective role after natural infection and vaccination, the use of SARS-CoV-2 T-cell assays is not recommended for clinical decision-making [5].
In the vaccine part, the recommended mRNA vaccine schedule for the vulnerable population of HM and HCT patients is adjourned to the three-dose primary schedule followed by an additional vaccine dose.
A third dose improved the rate of seroconversion in patients who had not responded to two doses of mRNA vaccine [6,7] and a 4th dose was safe and could increase antibody titers [8]. It is highlighted that there are no safety issues in non-transplanted HM patients and that vaccination should not delay the treatment of the underlying disease. With the spread of the Omicron variant many patients with HMs and after HCT have now developed SARS-CoV-2 infections both before and after having received vaccinations. It is recommended that the interval between COVID-19 and subsequent boosters should be at least three and preferably four months. An important change in the recommendations is that also patients with expected poor or very poor responses, such as those receiving therapy with anti-CD20 antibodies or being 6-12 months after the last dose, those with profound hypogammaglobulinemia (<4 g/L), deep lymphopenia (<500/μL), receiving B-cell-maturationantigen (BCMA) targeted bispecific therapy and patients starting induction chemotherapy for acute leukemia, might still benefit from vaccination also by inducing a T-cell response.
Regarding patients after allogeneic HCT, several studies have shown that additional doses of vaccine can result in seroconversion of patients not having responded to the first two or three doses [9]. At the time of the meeting, the mRNA adapted bivalent vaccines targeting original strains and Omicron subvariants BA.4/5 Testing for SARS-CoV-2 RNA in saliva or oropharyngeal gargle may be considered for symptomatic HM and HCT patients. BIIt

New
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.

20
Clinical virology laboratories need to document proficiency in external SARS-CoV-2 quality accredited programs. AII 21 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 22
Low respiratory tract fluid sampling (tracheal aspirate, bronchoalveolar lavage) for SARS-CoV-2 is not recommended in HM and HCT patients with positive nasopharyngeal or naso-oropharyngeal swab molecular test, unless there are clinical indications for viral, bacterial, fungal, or parasitic infections in the lower respiratory tract.

AII 23 ChW
Lower respiratory tract fluid (tracheal aspirate, bronchoalveolar lavage) is recommended to diagnose SARS-CoV2 LRTI in HM and HCT patients with negative nasopharyngeal-naso-oropharyngeal molecular test.

AII 24
In symptomatic HM and HCT patients with symptoms/signs of LRTI and negative SARS-CoV-2 molecular tests, diagnostic testing should be expanded to other pathogens.

AI 27 ChW
Testing for SARS-CoV-2 RNA or antigens in blood is not recommended for diagnosis or management of COVID-19. AI

ChW
Performing serial (semi-quantitative) NAT is recommended to inform decisions regarding infection control or deferral of therapy or HCT.

BIII 29 New
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.
Not graded

New
The role of qualitative SARS-CoV-2 E-gene sgRNA for monitoring the viral response of HM or HCT patients treated with antivirals requires further study. The role of quantitative antibody assays calibrated to the 1 st WHO-approved SARS-CoV-2 antibody standard is not defined for routine clinicaldecision making regarding administration of booster vaccine doses or monoclonal antibody therapies.

35
Antibodies assay targeting N-protein can be considered to ascertain previous SARS-CoV-2 exposure. AII

36
Antibodies assay targeting S-protein can be considered to ascertain vaccine response or previous exposure to SARS-CoV-2. AII

New
Antibody assay targeting to N-protein can be considered in patients with suspected multi-inflammatory syndrome in children (MIS-C). AII

New
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. Except in specific conditions where the expected response rate is very low, HM patients should receive a three-dose program of mRNA vaccines or a two-dose program with protein subunit vaccine according to recommendations by international and national authorities and authorized age range, starting preferably before treatment of the underlying disease or HCT, or during maintenance or off-therapy phase.

New
The interval between the first two doses should be at least 3 weeks and the interval between the 2nd and 3rd dose mRNA vaccine should be one, but preferably 3 months. Patients with an expected low or very low response rate to vaccine (eg. anti-CD20 MoAb therapy ongoing or within the 6-12 months from the last dose, BCMA targeted bispecific monoclonal antibody (Belantamab-mafodotin) therapy, induction chemotherapy for AL, profound hypogammaglobulinemia (<4 g/L), deep lymphopenia (<500/μL), do still benefit from vaccination.

New
However, these patients should undergo testing for anti-S antibodies one month after each vaccine dose (from dose 2) in order to assess their response, and discuss the use of pre-exposure MoAbs or other preventative measures. Earlier vaccination should be considered if there is high prevalence of SARS-CoV-2 in the community. However, early vaccination is associated with a lower likelihood for an immune response.

56
There is a risk for worsening/eliciting GVHD in allogeneic HCT recipients. This risk needs to be considered when deciding about time for vaccination.

AIIu 57 New
It is possible that the risk for GVHD using the protein-subunit vaccine might be lower and could be considered in individual patients after careful risk assessment.
Not graded

New
Additional doses are able to improve the immune response both by allowing an increased proportion of patients to seroconvert and to increase the antibody levels. It is therefore recommended that patients should: a) receive booster doses, b) preferably with the new updated bivalent vaccines (according to authorizations for age).

59
Based on data from other vaccines, it is likely that immunity obtained from either pre-transplant SARS-CoV-2 infection or vaccination will be wiped out by the transplant procedure. However, no data currently exists regarding this issue. However, it seems logical from a risk/benefit assessment that such patients should have a full dose new vaccine schedule after transplantation.

BIII 60 New
Such repetition of a complete vaccine schedule will over time result in a large number of vaccine doses and the safety profile of such an approach is currently unknown.

ChW
HCT patients with previous COVID-19 should be vaccinated with a full program. AIItu

Specific recommendations for HCT donors 62
There is no specific recommendation for vaccinating stem cell donors for any other purpose than protecting the donor. However, previous vaccination of the donor might reduce the risk to jeopardize the donation.

Not graded 63 New
There have been reports of transfer of donor immunity to allogeneic HCT recipients. However, whether this can result in protection against SARS-CoV-2 infection or disease in the recipient is unknown.

Specific recommendations for patients treated with CAR-T cells 64 New
Patients with B-cell aplasia after treatment with CD19+ CAR T cells are very unlikely to mount antibody responses but repeated vaccine doses might show some benefit.
After vaccination, T cell responses can be elicited in a majority of patients, but the importance for protection in patients is currently unknown.

Not graded
Correspondence had just been licensed, initially as booster dose and also for primary immunization in the following months. The of use of updated bivalent vaccines was supported in the guidelines even though it was recognized that there was no information regarding their efficacy in severely immunocompromised patients Although it is not a new recommendation, increasing evidence exists regarding the risk for the development or worsening of graft-versus-host disease after mRNA vaccination and this risk should be considered when planning vaccination schedule. It was noted that the transfer of donor-specific SARS-CoV-2 immunity has been documented but it is unknown if such transfer can be protective early after HCT or improve the vaccine response of the recipient.
A new section of the recommendations deals specifically with patients having received CAR-T cell therapy. Various studies have

New
Timing of vaccination should be based on individual consideration taking into consideration the immune status of the patient. BIII

New
Patients with B-cell aplasia after treatment with CD19+ CAR T cells should receive pre-exposure monoclonal antibody prophylaxis. AIIt

Therapy 67 ChW
In moderately or severely immunocompromised HM patients, pre-exposure prophylaxis is recommended with long-acting anti-SARS-CoV-2 monoclonal antibodies if active against circulating variants, irrespective of previous vaccination.

BIIt 68 ChW
In HM patients at high risk for COVID-19 progression (not vaccinated, vaccine non-responders or not expected to respond to vaccine) post-exposure prophylaxis is recommended with anti-SARS-CoV-2 monoclonal antibodies if active against the circulating variants. Patients with a plasma soluble urokinase plasminogen activator receptor (suPAR) level ≥ 6 ng/mL or identified in a scoring system as likely to have high suPAR levels.

Correspondence
shown that patients with B-cell aplasia are very unlikely to have an antibody response but T-cell responses can be seen in a majority of them [10]. As in other populations, the protective value of these responses remains, however, unknown. Also in CAR-T recipients additional doses resulted in improved vaccine responses.
In the therapy part, the main changes concerned the loss or significant reduction of activity of all authorized MoAbs against the new VOCs, and the increased availability of three antivirals for early treatment of mild/moderate COVID-19 [11]. MoAbs had been previously shown effective in the prevention and treatment of mild/moderate COVID-19, and, in seronegative patients, of severe COVID-19. Their limitations included the need for intravenous administration and the risk of developing in-vivo resistance in immunocompromised patients due to prolonged viral shedding and ineffective viral clearance resulting from the lack of T-cell immunity. For pre-exposure prophylaxis with long-lasting antibodies, the increase of dose has been proposed to counteract the loss of efficacy against the BA.1 Omicron variant in February 2022, but even higher doses are currently not expected to be effective. Therefore, the recommendation is to use (probably new ones) MoAbs for prophylaxis and treatment in the HM population only if they are active against circulating VOCs.
Antivirals are the cornerstone of therapy since their activity is not influenced by VOCs, and randomized trials demonstrated that, when administered within 5 or 7 days from symptom onset, they were effective in reducing the rate of hospitalization or death in unvaccinated outpatients with mild/moderate COVID-19 who had risk factors for severe COVID-19 [12][13][14]. Although few HM patients were included, this population is expected to gain maximum benefit from anti-viral treatment, as demonstrated in observational studies [15].
Oral nirmatrelvir/ritonavir or intravenous remdesivir are the first choices based on efficacy data. Drug-drug interactions limit the use of nirmatrelvir/ritonavir, but the careful reduction of immunosuppression or targeted therapy agents can allow its use in most HM patients. Molnupiravir use is limited by the lower efficacy in the randomized trial (relative risk reduction of 30%, compared to 87% of nirmatrelvir/ritonavir or remdesivir), the lack of European Medicine Agency (but not FDA) authorization and, therefore, the unavailability in some countries. The advantages of molnupiravir include absence of drug-drug interactions and the possibility to use in case of renal failure (ClCr <30 ml/min).
The data available for high titer of convalescent plasma (CVP) does not support its role in the routine treatment of mild/ moderate COVID-19. Considering the polyclonal protection given by CVP, less influenced by protein-S mutations which led to the loss of activity of MoAbs, CVP might be useful in immunocompromised patients, in addition to antivirals.
In severe or critical COVID-19 in HM, remdesivir treatment is recommended together with steroid treatment and a second immunosuppressant (mainly an anti-IL-6 agent), if required. In the HM patients, when choosing the second immunomodulator, the recent hematological treatment should be also considered, especially if patients are already on ruxolitinib, which should not be discontinued in case of SARS-CoV-2 infection. No data suggest the need for different treatment in HM children compared to HM adults, although children have a much lower risk of severe COVID-19 and the data are more limited. The reason for providing early treatment to children could be hastening the cure from SARS-CoV-2 infection to allow continuing HM treatment program.
In conclusion, the ECIL9 2022 provided the updated set of recommendations for the management of COVID-19 in HM and HCT patients. The advancements in knowledge on SARS-CoV-2/ COVID-19 and massive economical investments in immunization and treatment led to improvement of morbidity and mortality figures although the pandemic is not declared over. Many areas of research are still open and include the role of a combination of antivirals and MoAbs, the evaluation of prolonged courses of