Table 2.

Summary of candidate therapies for cytokine release syndrome (CRS) and related diseases.

Therapy	Trigger/associated diseases	Mechanism	Status for hypercytokinemia	Approved by U.S. FDA	Ref
Biologic therapy
Tocilizumab	MAS, CRS, visceral leishmaniasis-associated HLH, GvHD and sepsis	Human monoclonal anti-IL-6 receptor antibody	●Approval for CAR T cell therapy-associated CRS ●Phase 4 for SARS-CoV-2 (ChiCTR2000029765, NCT04310228, NCT04315480, NCT04317092 …) ●Phase 2 for GvHD (NCT02206035, NCT04070781, NCT03434730, NCT03699631)	Yes	[44,45,[64], [65], [66]]
Siltuximab	CRS	Anti-IL-6 antibody	●Preclinical for CRS	Yes	[67]
Anakinra	MAS, sepsis, HIV/AIDS-associated HLH and CRS	IL-1 receptor antagonist blocking IL-1α and IL-1β	●Phase 1 for MAS (NCT02780583) ●Phase 2 for MAS and sepsis (NCT03332225)	Yes	[[68], [69], [70]]
Canakinumab	MAS	Human monoclonal anti-IL-1β antibody	●Phase 3 for MAS (NCT00889863, NCT00886769, NCT00891046)	Yes	[71,72]
Rilonacep	MAS	Neutralizing IL-1α and IL-1β	●Randomized controlled trial for MAS	Yes	[73]
Rituximab	Epstein-Barr virus-induced HLH, GvHD and MAS	Human monoclonal anti-CD20 antibody to deplete B cells	●Phase 1–2 for GvHD (NCT04235036, NCT01135641, NCT00350545, NCT01001780 …)	Yes	[[74], [75], [76]]
Alemtuzumab	HLH, GvHD	Human monoclonal anti-CD52 antibody	●Phase 2 for HLH (NCT02472054, NCT02385110) ●Phase 1–2 for GvHD (NCT00410657, NCT00495755)	Yes	[77,78]
Ruxolitinib	HLH, GvHD and MAS	Inhibition of JAK/STAT signaling	●Phase 3 for HLH (NCT04120090, NCT03533790) ●Phase 4 for GvHD (ChiCTR1900024408)	Yes	[66,79]
Tofacitinib	GvHD	Selective inhibition of JAK1/JAK3	●Preclinical for GvHD	Yes	[80,81]
Tadekinig alfa	NLRC4-associated MAS	Recombinant human IL-18-binding protein (rhIL-18BP) to tightly bind IL-18	●Phase 3 for NLRC4-associated MAS (NCT03512314, NCT03113760)	No	[82]
Emapalumab	HLH	Anti-IFN γ antibody	●Approval for primary HLH	Yes	[83]
Infliximab	HLH, GvHD and sepsis	Human monoclonal anti-TNFα antibody	●Phase 1–2 for GvHD (NCT00228839, NCT00228839, NCT00201799) ●Phase 4 for GvHD in combination with daclizumab (NCT00574470)	Yes	[[84], [85], [86]]
Etanercept	MAS, GvHD and CRS	Decoy TNF receptor competitively inhibiting TNF	●Phase 2–3 for GvHD (NCT00726375, NCT00141739 NCT00141713, NCT00224874, ChiCTR1900024408)	Yes	[[87], [88], [89]]
Ponatinib	Influenza A	Inhibiting breakpoint cluster region-Abelson (BCR-ABL) kinase to regulate type I IFNs	●Preclinical for cytokine storms in influenza	Yes	[90]
Alternative therapy: corticosteroids, IVIG, chemotherapeutic agents, blood purification, NSAIDs, cell-based therapy and others
Corticosteroids	Widely used for increased levels of cytokines	Inhibition of HAT and recruitment of HDAC2 activity to the inflammatory gene transcriptional complex to downregulate inflammatory genes	Widely used for cytokine storms ●Phase 4 for SARS-CoV-2 severe pneumonia (NCT04263402, ChiCTR2000029386, ChiCTR2000029656)	Yes	[91]
IVIG	Widely used for increased levels of cytokines	Inhibition of complement activation, blockade of Fc-fragments and Fc receptors and neutralization of cytokines	Widely used for cytokine storms ●Phase 2–3 for SARS-CoV-2 (NCT04261426)	Yes	[92]
Etoposide	Widely used for primary and secondary HLH, but little evidence on HLH induced by influenza or coronavirus	Selective deletion of activated T cells and efficient suppression of inflammatory cytokine production	●Widely used for HLH in combination of corticosteroids and cyclosporine A (HLH2004) ●Preclinical for ARDS	Yes	[79,93,94]
Cyclosporine A	Widely used for primary and secondary HLH, but little evidence on HLH induced by influenza or coronavirus	Inhibition of the translocation into the nucleus of NF-AT to lower the activity of overactivated T cells	●Widely used for HLH in combination with corticosteroids and etoposide (HLH2004)	Yes	[79,93,95]
Cyclophosphamide	MAS	A bioprecursor of a nitrogen mustard alkylation agent to disturb DNA and inhibit cell proliferation	●Phase 3 for HLH in combination with chemotherapies followed by stem cell transplant (NCT00334672) ●Phase 2 for non-Hodgkin's lymphoma with HLH in combination with rituximab and other chemotherapies (NCT01818908)	Yes	[96]
Mycophenolate mofetil	MAS and HLH	Inhibition of inosine monophosphate dehydrogenase to prevent lymphocyte proliferation	●Phase 3 for HLH in combination with other chemotherapies followed by stem cell transplant (NCT00334672)	Yes	[96]
Plasmapheresis	Widely used for increased levels of cytokines	Extracorporeal removal of cytokines, endotoxins, and immunocomplexes	●Randomized single-blind trial for sepsis（NCT01249222）	Yes	[97,98]
Hemofiltration			●Randomized open-label trial for sepsis (NCT03426943)	Yes	[18,98]
Dialysis/hemodialysis			●Randomized open-label trial for sepsis (NCT00537693)	Yes	[99,100]
Hemadsorption			●Trial for sepsis (NCT00559130, NCT02588794 NCT02288975, NCT04226430) ●Randomized open-label trial for transplant-associated hypercytokinemia (NCT03145441, NCT04203004） ●Randomized single-blind trial for CAR T cell-associated CRS (NCT04048434）	Yes	[101]
Aspirin	Acute lung injury and ARDS	Antiplatelet effects to reduce neutrophil recruitment by platelet activation	●Phase 2 for ARDS (NCT01659307)	Yes	[102]
Selective COX-2 inhibitors	Influenza A	Downregulation of COX-2 to decrease proinflammatory cytokine levels	●Phase 3 of celecoxib in combination with oseltamivir for influenza A (NCT02108366)	Yes	[103]
Mesenchymal stem/stromal cells (MSCs)	ARDS, sepsis and GvHD	Alteration of the behavior of both adaptive and innate immune cells	●Approval for GvHD in Canada ●Phase 1–2 for SARS-CoV-2 (NCT04269525, NCT04252118, ChiCTR2000029817, ChiCTR2000029816) ●Phase 1–2 for ARDS (NCT 01775774, NCT 02097641, NCT03818854, NCT 01902082) ●Phase 1–2 for sepsis (NCT03369275, NCT01849237)	Yes	[104,105]
Hematopoietic stem cell transplantation	Primary HLH and refractory HLH	Replacement with a genetically normal bone marrow	●Widely used for familial HLH in children	Yes	[93]
Anti-thymocyte globulin	Primary HLH, MAS and GvHD	Selective ablation of T cells	●Widely used to treat GvHD	Yes	[106]
Statin	Sepsis	Inhibition of hydroxymethylglutaryl-CoA reductase to reduce proinflammatory cytokine levels	●Phase 2–3 for sepsis (NCT00676897, NCT00452608)	Yes	[107]
Chloroquine/hydroxychloroquine	Sepsis and MAS	Inhibition of Toll-like receptors and high mobility group box 1 (HMBG1) to reduce proinflammatory cytokine levels	●Preclinical for sepsis ●Approval for rheumatic diseases and may reduce SLE-induced MAS ●Phase 3–4 for SARS-CoV-2 (NCT04261517, ChiCTR2000029898 …)	Yes	[108,109]
S1P1 agonist (CYM-5442)	Influenza A	S1P1 receptor agonist downregulating inflammatory mediators, possibly by NF-κB signaling	●Preclinical for cytokine storms in influenza A and GvHD	No	[110,111]

Abbreviations: MAS: macrophage activation syndrome, CRS: cytokine release syndrome, HLH: hemophagocytic lymphohistiocytosis, IVIG: intravenous immunoglobulin, CAR: chimeric antigen receptor, SARS-CoV-2: severe acute respiratory syndrome coronavirus 2, IL-1: interleukin-1, IL-6: interleukin-6, IL-18: interleukin-18, IFN: interferon. TNF: tumor necrosis factor, JAK/STAT: the Janus kinase/signal transducer and activator of transcription, GvHD: graft-versus-host disease, ARDS: acute respiratory distress syndrome, NSAIDS: nonsteroidal anti-inflammatory drugs, COX-2: cyclo-oxygenase 2; S1P1: sphingosine-1-phosphate receptor 1, NF-κB: nuclear factor kappa-B.