Table 5.

SARS-CoV-2 variants in patients with haematological malignancies: summary of received treatments and hypothesis for haematological malignancies

Types of vaccines or drugs	SARS-CoV-2 variants	Haematological malignancies	Description (advantage, disadvantage, function, or target)	Ref
Drugs
AZD7442 (tixagevimab–cilgavimab)	Omicron	NHL B-cell malignancies	• AZD7442 did not successfully neutralize Omicron-RBD in patients with haematological malignancies who received a single dose of 150 mg • Neutralization increased above the positive threshold after a 300 mg dose, although it was still variable • AZD7442 counteracts weak performance against contemporary Omicron SARS-CoV-2 strains	[251–254]
Dexamethasone	Omicron	Myeloma	• Administration of dexamethasone resulted in a reduction in 28-day mortality in subjects randomized to receive oxygen therapy or invasive mechanical ventilation. No significant reduction in mortality was observed in patients who received no respiratory support	[8, 255, 256]
Plitidepsin	SARS-CoV-2 B.1.1.7	Haematological malignancies	• It inhibits the translation of ORFs, ORF1A and ORF1B, leading to reduced synthesis of pp, pp1a and pp1ab, and through eEF1A drive, reduces the amount of repetitive nonstructural proteins such as RNA-dependent RNA polymerase • Inhibits the translation of various sub-genomic mRNAs, resulting in insufficient production of structural and auxiliary viral proteins • The absence of essential viral proteins such as RdRp and structural proteins simultaneously prevents the production of virus copies	[257–259]
Remdesivir and plasma therapy and free remdesivir	SARS-CoV-2 variants and Omicron	Acute B Lymphoblastic leukemia, AML, ALL, NHL, myeloma/plasmacytoma, myelodysplastic syndrome, CLL, active neoplasia	• Accelerate resolution of infection and safe initiation of immunosuppressive therapy • It is a nucleoside-like compound that inhibits the RdRp of coronaviruses	[260, 261]
Bamlanivimab D etesevimab	Alpha variant	B-cell malignancies	• Causes SARS-CoV-2 immune escape mutations and secondary clinical deterioration in COVID-19 patients with B-cell malignancies	[262]
Obatoclax*	Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617)	N.A	• Block endocytosis and membrane fusion	[263]
Olverembatinib	Omicron	CML	• Inhibits the release of cytokines	[264]
Abemaciclib, Dasatinib and Spiperone*	Omicron	N.A	• Block the interaction between the omicron spike protein and the host cell receptor ACE2	[265]
Azacytidine*	Delta	N.A	• As a potent inhibitor of DNA methylation, both in preclinical models and in cancer patients	[266]
Atovaquone*	SARS-CoV-2 and other variants of concern including the alpha, beta, and delta variants	N.A	• Inhibits replication • Its ability is partly related to the expression of TMPRSS2, and the drug can prevent the spike protein from binding to the viral receptor, ACE2 • Spike-mediated membrane fusion was also reduced in the presence of atovaquone	[267]
Venetoclax (BTK inhibitors)	Delta	AML, CLL, SLL, B-cell malignancies, and MCL	• Reduction of mortality • Antitumor agents	[268, 269]
Vaccines
BNT162b2*	Alpha and Delta	MM	BNT162b2 induced a specific T cell response in healthy individuals. Conversely, in MM patents, T cell responses are weaker and more heterogeneous than healthy controls.	[270, 271]
3 doses of mRNA vaccine	SARS-CoV-2 variants expect Omicron	CLL	• Robust hybrid immunity in serum, saliva, and T-cell compartments in patients	[272]
mRNA-1273	Omicron	MM	• MM patients who received mRNA-1273 vaccination developed severe infections 10 weeks after vaccination, despite the production of protective antibodies • After administration of two mRNA vaccines to people with NSCLC and healthy participants, it was observed that NSCLC patients showed less neutralizing activity against live viruses compared to their healthy counterparts	[273]
Moderna (second vaccine) Pfizer (second vaccine) Janssen (1 vaccine)	Omicron	AML	• Boosted immunity	[274]
Monoclonal antibodies
Anti-CD38 therapy	Alpha and delta	MM	• It is approved in the first line in combination with other agents (immunomodulatory drugs—IMID or PI) and high-dose steroids • Anti-CD38 therapy was even less associated with NAbs response among MM patients • Anti-CD38 antibodies also cause a relative depletion of NK cells, which could contribute to immunodeficiency in MM receiving these immunosuppressive regimens	[275]
Anti-CD20	SARS-CoV-2 (delta)	B-cell malignancies	• Disrupts humoral responses after two or three vaccinations • Patients who received anti-CD20 antibodies showed limited efficacy of a BNT162b2 booster dose	[276–279]
Anti-BCMA MAbs	Omicron, WA1, and delta	MM	• After the third time, no significant increase in anti-spike Ab levels was observed in patients treated with anti-BCMA MAbs	[280]
ACE2-blocking antibody	Omicron BA.1 and BA.2 and other SARS-CoV-2 variants	Haematological malignancies	• Maintain potent neutralization and protection against Omicron and other SARS-CoV-2 variants	[281, 282]
Antibody-containing plasma	Omicron variant	Haematological malignancies	• Control virus replication	[283]
CAR-T cells	SARS-CoV-2 variants (Omicron variant)	CLL B-cell-depleted lymphoma	• Vaccine-induced T-cell response against SARS-CoV-2 and its Omicron variant in patients • CD19-CAR-T therapy selectively depleted all CD191/CD201 B-cells from the blood of our patients, thus eradicating the immune cell compartment secreting anti-SARS-CoV-2 antibodies	[280, 284]
Cellular therapies	SARS-CoV-2 variants	Haematological malignancies	• Cell therapy used by adoption to prevent or treat viral infections in cases of natural or transplant immune errors is safe and effective against herpes viruses, polyomaviruses, and certain respiratory pathogens such as adenovirus • Adoptive T-cell therapy has been investigated as a prophylactic or curative adjuvant therapy against SARS-CoV-2	[285–287]
GSK3326595*	Omicron, delta, and beta variants	N.A	• By inhibiting ACE2-R671 dimethylation • Able to significantly reduce ACE2 binding to RBD • Strongly reduces the interaction of ACE2 with Spike1	[288]
T-cell or B-cell immunotherapy	Omicron	Haematological malignancy (MM, lymphoma, CLL, and etc.)	• Low levels of nAb after two or three doses of vaccination • SARS-CoV-2 variants showed partial vaccine escape, especially the Omicron variant (BA.1) compared to the Delta variant (B.1.617.2) • Resistance to anti-SARS-CoV-2 mAb	[289]
ALVR109*	Alpha, Beta, Gamma, Delta, Epsilon, and Kappa	N.A	• On day 10 after the second injection of ALVR109, the patient`s nasopharyngeal SARS-CoV-2 viral load became persistently untraceable • After the second infusion, the patient was discharged on minimal oxygen support and received a second negative result of quantitative nasopharyngeal PCR	[290]
CAR-NK cell therapy*	SARS-CoV-2 variant	Leukemia and MM	• CAR-NK cells target SARS-CoV-2 spike protein with CR3022 scFv domain, a potent neutralizing antibody targeting SARS-CoV-2 S protein • The results showed that CR3022-CAR-NK cells can kill SARS-CoV-2 infected cells in vitro	[291]
Inhibitors
PAD-4 inhibitors	SARS-CoV-2 variants	MM	• Offers broad therapeutic potential in a wide range of inflammatory diseases such as COVID-19 through the formation of NETs • In reducing thrombotic complications in various inflammatory disorders such as COVID-19 and suggests that these inhibitors may be valuable in the treatment of immunothrombotic origin of SARS-CoV-2	[292]
FLT3 inhibitors	SARS-CoV-2 variant	AML	• Decreased autophagy can reduce the risk of chemotherapy resistance and mortality	[293]
SMYD2*	Delta variant	N.A	• Inhibition downregulates TMPRSS2 • Reduces SARS-CoV-2 infection	[294]
Other treatment
Convalescent plasma	Alpha	B-cell lymphoid malignancy AML	• Reduction of mortality	[295, 296]
Nanobodies*	Emerging mutant variants like Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P.1)	N.A	• Exclusive neutralization efficiency	[297]
CRISPR-Cas*	SARS-CoV-2 variant	T cell ALL	• Development of global T cells against COVID-19 • Enormous potential for the advancement of CAR-NK cell therapy through the use of CAR-NK cells derived from induced pluripotent stem cells. This is due to their ability to manipulate genes and cell surface receptors that have already been studied in the development of CAR-T cells or genetic mutations that cause disease	[291]

Abbreviations: ALL Acute lymphoid leukemia, AML Acute myeloid leukemia, BTK Bruton’s tyrosine kinase, CAR Chimeric antigen receptor, CLL Chronic lymphocytic leukemia, CRISPR Clustered regularly interspaced short palindromic repeats, CML Chronic myeloid leukemia, MCL Mantle cell lymphoma, MM Multiple myeloma, NK Natural killer, NETs Neutrophil extracellular traps, nAb Neutralizing antibodies, NHL Non-hodgkin’s lymphoma, NSCLC non-small cell lung cancer, ORFs Open reading frames, PCR Polymerase chain reaction, pp Polyproteins, PI Proteasome inhibitors, RBD Receptor‐binding domain, RdRp RNA-dependent RNA polymerase, SLL Small lymphocytic lymphoma

^*Hypotheses about the use of vaccines and other treatments, as well as the possibility of finding new treatment methods in people with blood diseases exposed to this virus, have been proposed with further studies