Clinical Case of the Month – SARS-CoV2 Infection after allogeneic stem cell transplantation

February 2022 Clinical Case of the Month

Title: SARS-CoV2 Infection after allogeneic stem cell transplantation
Submitted by: Syed Ali Abutalib and Nicolaus Kröger
Physicians expert perspective: Malgorzata Mikulska

A 53-year-old male patient received an allogeneic hematopoietic stem cell transplantation 8 days ago from HLA-MUD for high-risk AML in first complete remission (CR1). He had received a short visit from his wife on day 7.  After the visit the wife became febrile and PCR for SARS-CoV-2 was positive. Their 8-year-old son was also tested positive for SARS-CoV-2. The patient was tested routinely at the ward 3 times a week (institutional guidelines may vary; but not less than once a week) and the last PCR test 2 days ago was negative. A new PCR on day 10 showed positivity but patient is completely asymptomatic from the viral infection. The virus copy number per ml was 50,000.000 and sequencing showed Omicron variant. Patient has had SARS-CoV-2 immunization with a booster 4 weeks prior to transplant without detectable antibodies.

What would be your recommendation?

A. Provide treatment with a single dose of casirivimab/imdevimab
B. Provide treatment with a single dose of sotrovimab
C. Start remdesivir and steroids
D. Start nirmatrelvir/ritonavir
E. Provide treatment with a single dose of bamlanivimab/etesevimab
F. Provide treatment with a single dose of tixagevimab/cilgavimab
G. Wait till he becomes symptomatic to treat with monoclonal antibody active against Omicron variant

Expert Perspective by Professor Mikulska Malgorzata

It is challenging to argue that there is only one correct answer on how to manage the patient presented in this clinical vignette. Thus, we will discuss all the options provided in this challenging case.

Asymptomatic PCR positive patient such as in this case was not included in the studies and hence not contemplated in the guidelines. We have data on post-exposure prophylaxis, as opposed to asymptomatic PCR positivity, and in patients with very early (~3 to 5 days) mild symptomatic infection (Table 1).

Our patient is asymptomatic with the infection, but some symptoms might be difficult to definitely attribute to SARS-COV-2 infection in the setting of recent HSCT (e.g. asthenia, fever). It makes sense to treat the infection as early as possible, even before the onset of symptoms given high risk of rapid progression to severe COVID-19 due to underlying cancerous disease and transplant related severe immunosuppression. The knowledge of the comorbidities and past immunization might help us to better evaluate the risk. Since this patient has absence of humoral response to vaccination and the booster, it is tempting to intervene with monoclonal antibodies as soon as possible. Waiting for the development of symptoms, hoping they will never appear, might be easier in patients who responded to vaccination and received the booster dose, particularly in case of the Omicron variant. Indeed, the infection with the Omicron variant might result in milder infection compared to other variants (e.g. delta), but still the risk of severe COVID-19 is present, particularly in a non-immunized or anergic persons with severe immunosuppression.

The regulatory authorities approved the anti-spike monoclonal antibodies, oral antivirals, and 3-day intravenous remdesivir for those with mild to moderate symptoms of COVID-19. For instance, in the formal request for these treatments in Italy you should provide the patient’s symptoms in order to obtain the approval.

With this background, let’s review and briefly discuss the choices available to us,

• The choices A (casirivimab/imdevimab) and E (bamlanivimab/etesevimab) are incorrect since these monoclonal antibodies are not active against the Omicron variant. They could be a reasonable choice of therapy in non-omicron variant in a symptomatic patient with SARS-CoV-2 infection and risk factors for severe COVID-19, or in case of post-exposure prophylaxis if most of the circulating variants are susceptible (Table 2).
• The choice F (tixagevimab/cilgavimab) is also incorrect since this combination of long-lasting antibodies is approved for pre-exposure prophylaxis. It could be an option before transplant when the lack of serological response was documented. Of note, CDC warns that although Omicron variant remains susceptible to this combination, more data are needed to fully assess the activity and efficacy of this regimen in situations where the Omicron variant is circulating at high levels.
• The choice C (remdesivir and steroids) is another incorrect answer since the use of steroids in this asymptomatic phase, and in mild to moderate infection which does not require oxygen therapy, increases the risk of a negative clinical outcome.
• Choices B (sotrovimab in asymptomatic immunocompromised host) and D (nirmatrelvir/ritonavir) might protect this patient against severe COVID-19, as could also be true for 3-days of intravenous remdesivir or 5 days of oral molnupiravir (not included in choices; of note, molnupiravir had lower efficacy in the pivotal study than the other options), but formally, SARS-CoV-2 infection with mild to moderate symptoms should be present, unlike the asymptomatic situation of our patient.

The current evidence-based correct answer is choice G, single dose of Omicron-active antibody (such as sotrovimab, and very recently, also bebtelovimab) as soon as symptoms declare themselves although the rationale to wait for the symptoms and not treat the viral phase as early as possible is weak especially in this patient as explained earlier. Given good tolerability of sotrovimab, the case of a severely immunocompromised patient with transplant treatment that can potentially cure his leukemia, and with high risk of early mortality from COVID-19 infection, the early treatment of asymptomatic patient should be considered and weighted against remote possibility of remaining asymptomatic with SARS-CoV-2 infection and cost of sotrovimab. Additional motive to provide early treatment while the patient remains asymptomatic is the reduction of viral load and the length of shedding which would reduce the risk of a nosocomial outbreak in transplant unit or ward.

In my personal opinion, I would treat with sotrovimab (if approved by the institution) as soon as possible while he is asymptomatic. Otherwise, will resort to choose G as mentioned earlier.  

Correct Answer: G (with B being a very reasonable choice in this case)

Table 1: Prophylactic and Treatment authorization for use against SARS-CoV-2 infection

1. Tixagevimab/cilgavimab¹: Pre-exposure prophylaxis (prevention) of COVID-19 in certain adults and pediatric individuals (12 years of age and older weighing at least 40 kilograms [about 88 pounds]). The product is only authorized for those individuals who are not currently infected with the SARS-CoV-2 virus and who have not recently been exposed to an individual infected with SARS-CoV-2. The authorization also requires that individuals either have: 

a. Moderate to severely compromised immune systems due to a medical condition or due to taking immunosuppressive medications or treatments and may not mount an adequate immune response to COVID-19 vaccination or,

b. History of severe adverse reactions to a COVID-19 vaccine and/or component(s) of those vaccines, therefore vaccination with an available COVID-19 vaccine, according to the approved or authorized schedule, is not recommended.

Neutralizing activity of tixagevimab/cilgavimab against Omicron variant has been reported, but possibly diminished compared to other variants. More data are needed, as stated by CDC.

2. Bamlanivimab/etesevimab^2,3: Post-exposure prophylaxis (prevention) and treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization.
3. Casirivimab/imdevimab^4,5: Post-exposure prophylaxis (prevention) and treatment of mild/moderate COVID-19 in adults and pediatric individuals (12 years of age and older weighing at least 40 kg) who are at high risk for progression to severe COVID-19, including hospitalization or death.
4. Sotrovimab⁶: Treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization.
5. Nirmatrelvir/ritonavir⁷: Treatment of mild to moderate coronavirus disease (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kilograms or about 88 pounds) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. 
6. Molnupiravir⁸: Treatment of mild to moderate coronavirus disease (COVID-19) in adults with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate.

Remdesivir^9,10: Treatment in adults and adolescents (from 12 years of age and weighing at least 40 kilograms) with pneumonia requiring supplemental oxygen (low- or high-flow oxygen or other non-invasive ventilation at the start of treatment), and treatment of mild to moderate COVID-19 in adults who do not require supplemental oxygen and who are at increased risk of developing severe COVID-19.

Table 2:  The confirmed utility of currently available anti-COVID-19 agents

Underlined if active against Omicron variant

*Important drug-drug interactions; **reported lower efficacy than for other options

References

1. Tixagevimab and Cilgavimab (Evusheld) for Pre-Exposure Prophylaxis of COVID-19. JAMA. 2022 Jan 25;327(4):384-385. doi: 10.1001/jama.2021.24931. PMID: 35076671.
2. Cohen, M.S.; Nirula, A.; Mulligan, M.J.; Novak, R.M.; Marovich, M.; Yen, C.; Stemer, A.; Mayer, S.M.; Wohl, D.; Brengle, B.; et al. Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial. Jama 2021, 326, 46-55, doi:10.1001/jama.2021.8828.
3. Dougan M, Nirula A, Azizad M, Mocherla B, Gottlieb RL, Chen P, Hebert C, Perry R, Boscia J, Heller B, Morris J, Crystal C, Igbinadolor A, Huhn G, Cardona J, Shawa I, Kumar P, Adams AC, Van Naarden J, Custer KL, Durante M, Oakley G, Schade AE, Holzer TR, Ebert PJ, Higgs RE, Kallewaard NL, Sabo J, Patel DR, Dabora MC, Klekotka P, Shen L, Skovronsky DM; BLAZE-1 Investigators. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N Engl J Med. 2021 Oct 7;385(15):1382-1392. doi: 10.1056/NEJMoa2102685. Epub 2021 Jul 14. PMID: 34260849; PMCID: PMC8314785.
4. O'Brien, M.P.; Forleo-Neto, E.; Musser, B.J.; Isa, F.; Chan, K.C.; Sarkar, N.; Bar, K.J.; Barnabas, R.V.; Barouch, D.H.; Cohen, M.S.; et al. Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19. The New England journal of medicine 2021, 385, 1184-1195, doi:10.1056/NEJMoa2109682.
5. Weinreich, D.M.; Sivapalasingam, S.; Norton, T.; Ali, S.; Gao, H.; Bhore, R.; Xiao, J.; Hooper, A.T.; Hamilton, J.D.; Musser, B.J.; et al. REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19. The New England journal of medicine 2021, doi:10.1056/NEJMoa2108163.
6. Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Moya J, Falci DR, Sarkis E, Solis J, Zheng H, Scott N, Cathcart AL, Hebner CM, Sager J, Mogalian E, Tipple C, Peppercorn A, Alexander E, Pang PS, Free A, Brinson C, Aldinger M, Shapiro AE; COMET-ICE Investigators. Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N Engl J Med. 2021 Nov 18;385(21):1941-1950. doi: 10.1056/NEJMoa2107934. Epub 2021 Oct 27. PMID: 34706189.
7. McDonald EG, Lee TC. Nirmatrelvir-ritonavir for COVID-19. CMAJ. 2022 Feb 3:cmaj.220081. doi: 10.1503/cmaj.220081. Epub ahead of print. PMID: 35115376.
8. Jayk Bernal, A.; Gomes da Silva, M.M.; Musungaie, D.B.; Kovalchuk, E.; Gonzalez, A.; Delos Reyes, V.; Martín-Quirós, A.; Caraco, Y.; Williams-Diaz, A.; Brown, M.L.; et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. NEJM 2021, doi:10.1056/NEJMoa2116044.
9. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. doi: 10.1056/NEJMoa2007764. Epub 2020 Oct 8. PMID: 32445440; PMCID: PMC7262788.
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Contacts

Syed Ali Abutalib, MD
Co-Director, Hematology and Cellular Therapy Program
Director, NMDP and CTCA Apheresis Programs
Cancer Treatment Centers of America, an Affiliate of City of Hope, Zion, Illinois
Associate Professor, Rosalind Franklin University of Medicine and Science
Email: abutalib110@gmail.com

Nicolaus Kröger, MD
Professor and Medical Director of the Department of Stem Cell
Transplantation at the University Hospital Hamburg-Eppendorf, Germany
University Hospital Hamburg, Hamburg, Germany

Correspondence: Nicolaus Kröger, MD
Email: nkroeger@uke.uni-hamburg.de

Expert Perspective

Malgorzata Mikulska MD
Associated Professor of Infectious Diseases
Division of Infectious Diseases, Ospedale Policlinico San Martino and University of Genova, Genova, Italy
Email: m.mikulska@unige.it

Future Clinical Case of the Month

If you have a suggestion for future clinical case to feature, please contact Nicolaus Kröger.