Table 5:

Prevention, monitoring, evaluation, and treatment of CAR T-cell toxicities: hematologic and immunologic toxicities^*

Toxicity category and references	Pre-treatment assessment	Preventative measures	Post treatment monitoring	Diagnostic evaluation if toxicity occurs	Supportive care for toxicity	Pharmacologic/immunologic management of toxicity (flat doses for adult patients only)
Hematologic toxicity/ICAHT 35,43-45,104	-Pre-treatment risk stratification with CAR-HEMATOTOX score: CBC, CRP and ferritin. Consider baseline bone marrow biopsy in high-risk patients.	-Minimize/discontinue myelosuppressive medications -Consider early growth factors and prophylactic antimicrobials for patients with a high CAR-HEMATOX score.	-CBC monitoring daily during CRS -At CRS resolution, CBC monitoring at least weekly for the first month and monthly for the first six months in all patients (author recommendation) -Monitoring may be modified based on risk.	-For grade 3-4 cytopenias with duration > 28 days: reticulocyte count, peripheral blood smear, and survey for infections. --Complete metabolic panel, ferritin, fibrinogen, triglycerides to evaluate for IEC-HS --Bone marrow aspirate and biopsy for with flow cytometry, cytogenetics +/− myeloid NGS panel --viral studies: PCR for CMV/EBV, parvovirus, HHV6	-Transfusion support with irradiated packed red cell and platelet blood products per institutional guidelines -Growth factor support is controversial; consider initiating when ANC < 500 cells/mcL. Avoid GM-CSF.	-TPO agonists +/− corticosteroids -stem cell boost (if cells available) -allogeneic stem cell transplant if feasible in truly refractory cases
IEC-HS 43-45,113	-Baseline CMP, CBC, CRP, ferritin, LDH, PT, PTT, fibrinogen, triglycerides.	-Appropriate prophylactic antimicrobial therapy as below (“Immunosuppression/infections”); consider gram negative and fungal coverage for patients receiving anti-cytokine and corticosteroids therapies. -Outpatients should arrange caretakers to assist in toxicity monitoring in the first 30 days.	-Temperature monitoring for outpatients; urgent evaluation of fevers -Inpatients with active CRS or recovering from CRS: daily CBC, PT/PTT, CMP, CRP, ferritin, fibrinogen	-Diagnostic labs include ferritin, CMP, CBC, PT, PTT, fibrinogen, triglycerides, and LDH -Consider other causes: blood cultures and other evaluation for infection -Consider bone marrow biopsy to evaluate for hemophagocytosis -Consider soluble CD25, blood lymphocyte phenotyping for NK-cell count, IL-10, IL-18 IFN-γ, CXCL9 ratio, CXCL10 to support diagnosis.	-Correct hypofibrinogenemia of < 100 mg/dL with cryoprecipitate, correct for < 150 mg/dL if bleeding -Vitamin K for INR > 1.5; FFP for INR > 2. -Transfusion and growth factor support (per above ICAHT)	-First line: anakinra +/− corticosteroids -Second line: increase dose of anakinra, then increase dose of corticosteroids -Alternative agents: ruxolitinib, low-dose etoposide, emapalumab
Tumor lysis syndrome (TLS) 45,46	-Assess for G6PD deficiency prior to treatment in patients considered high risk for TLS due to high tumor burden or aggressive malignancy histology	-Start allopurinol or rasburicase (for allopurinol intolerant patients) with LD chemotherapy in patients with high marrow or extramedullary disease burden.	-At least daily CMP (as Table 2 “CRS” row), with LDH, uric acid. For high-risk patients, more frequent lab monitoring (at least 2x per day, author recommendation).	-Monitor TLS labs q 6-12 hrs or per institutional guidelines for active TLS	-Hydration and electrolyte management per institutional guidelines	Rasburicase for patients without G6PD deficiency; febuxostat for patients with G6PD deficiency, as per institutional guidelines
Immunosuppression/infections12,44-46,124,125, except covid-19	-Pre-leukapheresis serologies for EBV, HBV, HCV, HIV, HSV, VZV, CMV -HBV PCR for viral DNA if surface antigen or core antibody positive. -Hepatitis C PCR for viral RNA if antibody positive. -Consider PCR testing for EBV, CMV, and HBV regardless of serology results. -Treatment of individuals with HIV can be made on a case-by-case basis^	-Delay lymphodepletion and/or CAR T-cell infusion if patient is febrile and has evidence of infection and give appropriate antimicrobial treatment. Resume therapy when patient is afebrile at least 48 hrs and clinical evidence infection is controlled/symptoms improved. -Delay treatment for patients with detectable HBV/HCV DNA/RNA or positive HBV surface antigen until infection is treated. -Entecavir or tenofovir prophylaxis for patients with + HBV core antibody, at least 6 months- 1 yr, consider longer for continued B-cell aplasia -All patients should receive prophylactic antimicrobials for pneumocystis and HSV/VZV x 6 months to 1 yr; consider longer if CD4 < 200 cells/mcL. -Re-vaccinate with killed/inactivated vaccines and live attenuated > 6 months and > 12 months after CAR T cells, respectively AND CD4 count > 200 cells/mcL (exceptions below).	-check immunoglobulin levels monthly -check CD4 count, B-cell count every ~3 months -HBV viral DNA monitoring in core antibody positive patients -Consider weekly CMV PCR monitoring in seropositive individuals who have received > 3 days of steroids until 1 month after last dose of corticosteroids.	-Rule out infectious causes of fever: blood cultures. Depending on symptomatology: nasal swab for covid-19 and other respiratory viruses, urine cultures, sputum cultures.	-Immunoglobulin replacement therapy for IgG < 400-600 mg/dL or recurrent infections; replacement given more routinely in children; may consider cessation of replacement in adults > 3 months after anti-CD19 CAR T-cell infusion -Consider fungal and gram-negative antibacterial prophylaxis in the following circumstances: intensive lymphodepletion regimens (e.g., containing anti-CD52), prolonged corticosteroid use, prolonged neutropenia.	- Treat identified bacterial, fungal or influenza infections per institutional guidelines for immunosuppressed individuals -Empiric antibiotics for neutropenic fever
Covid-19 infection 132,172,173	-PCR testing for SARS-CoV-2 within 2-3 days of lymphodepletion chemotherapy	-Delay lymphodepletion chemotherapy at least 14-20 days and until symptom improvement in patients with covid-19 infection -counsel masking and social distancing during periods of high community infection rate -pre-CAR-T vaccination for influenza and covid-19, if not already received - Caretakers should follow CDC guidelines for COVID-19 vaccination based on age and health status -Re-vaccination for covid-19 and influenza at ≥ 90 days after cell infusion.	-Patients and caretakers counseled to monitor for symptoms and seek care promptly	-SARS-CoV-2 PCR testing, concurrent testing for influenza and RSV in patients with respiratory symptoms -In patients with covid-19 symptoms and negative nasal PCR testing for SARS-CoV-2, consider repeat testing, chest CT imaging +/− bronchoscopy to evaluate for lower respiratory infection and other infectious causes	-Consider early hospital admission for monitoring in symptomatic patients, depending on institutional resources	- Nirmatrelvir and ritonavir or best available antiviral therapy for prevention of hospitalization and death in outpatients with covid-19 infection -Remdesivir or best available antiviral therapy for inpatients with covid-19, except in critical illness -Dexamethasone for inpatients with covid-19 requiring supplemental oxygen; anti-cytokine therapy (tocilizumab) or Jak inhibitors may be considered in worsening illness (infectious disease consultation recommended). -High titer convalescent plasma can be considered in outpatient or inpatient settings, with most benefit early in the course of illness, or in cases of protracted illness.

^*Recommendations per one or more of the cited published guidelines. In cases of disagreement between guidelines, the recommendation incorporating the earliest intervention or most conservative monitoring strategy has been presented. Additional recommendations per authors’ opinion where indicated.

^{^}Depending on processing capabilities of the manufacturer; infectious disease consultation strongly recommended. ANC: absolute neutrophil count. CBC: complete blood count with differential. CMP: complete metabolic panel, including sodium, potassium, creatinine, aspartate aminotransferase, alanine aminotransferase, bilirubin, direct bilirubin, phosphorus, and magnesium. CMV: cytomegalovirus. CRP: C-reactive protein. CRS: cytokine release syndrome. CXCL: chemokine (C-X-C motif). EBV: Epstein-Barr virus. FFP: fresh frozen plasma. GM-CSF: granulocyte macrophage colony-stimulating factor. HBV: hepatitis B virus. HCV: hepatitis C virus. HHV: human herpes virus. HIV: human immunodeficiency virus. HSV: herpes simplex viruses. ICAHT: immune effector cell-associated hematotoxicity. IEC-HS: immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. IFN-γ: interferon gamma. IL: interleukin. INR: international normalised ratio. LDH: lactate dehydrogenase. NGS: next generation sequencing. PCR: polymerase chain reaction. PT: Prothrombin time. PTT: Partial thromboplastin time. RSV: respiratory syncytial virus. SARS-CoV-2: severe acute respiratory syndrome coronavirus 2. TPO: thrombopoietin. VZV: varicella zoster virus.