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Chimeric antigen receptor-modified T cells (CAR-T) have become an effective treatment for refractory and relapsed B-cell non-Hodgkin’s lymphoma (NHL).
Under this background, it is imperative to standardize the clinical treatment of its side effects.
.
The Biotherapeutics Committee of the Chinese Research Hospital Association organized experts to compile the "Expert Consensus on the Clinical Management of CAR-T Cells Treating NHL Toxic Side Effects", which aims to provide clinicians with a more standardized identification and treatment of CAR-T treatment of NHL-related side effects The disposal principles and exploratory disposal recommendations.
The CAR-T-related toxic and side effects mainly introduced in this consensus include cytokine release syndrome (CRS), CAR-T-related encephalopathy syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), Bone marrow suppression, infection, B cell deficiency/hypogammaglobulinemia, tumor lysis syndrome, allergic reaction, abnormal proliferation of CAR-T cells, etc.
In this issue, the editor summarizes the infection part as follows for the reference of readers.
Epidemiological survey results show that within 1 to 2 years after receiving CAR-T cell treatment, the incidence of various types of infections is about 55%, of which about 33% are severe infections of grade ≥3, and invasive fungal (including mold) infections No more than 8%, and no more than 5% of deaths due to serious infections.
Among them, the incidence of infection within 1 month after CAR-T cell treatment can be as high as 40%, most of which are bacterial infections, mainly after cell infusion Within 2 weeks.
The mortality rate of co-infection during the CRS reaction period is high.
Therefore, infection prevention and control is the top priority of CAR-T cell therapy.Screening period-infection screening items before pretreatment hepatitis B, hepatitis C, syphilis, AIDS; Epstein-Barr virus, cytomegalovirus, simple-zoster virus, Toxoplasma gondii; procalcitonin, endotoxin; C-reactive protein (CRP) ; IL-6; Erythrocyte sedimentation rate; Mycobacterium tuberculosis (TB, TB SPOT, PPD test, etc.
); lung CT; respiratory-related virus (with upper respiratory symptoms); fungal D-glucan test/curve Mold galactomannan detection.
Imaging examination chest CT; bronchoscopy/ultrasound guided bronchoscopy; alveolar lavage.
Special inspection: Infectious microbial genomics testing: sample collection of peripheral blood or body fluids (sputum, urine, serous effusion, skin and soft tissue), etc.
; proteomic microbial testing.
The differential diagnosis of CRS and infection has similar clinical manifestations, but there is no specific marker to clearly distinguish the two; and CRS co-infection occurs from time to time.
Therefore, the occurrence and development of the two The anticipation of CRS and the timing of intervention are very important; CRS grades and infection levels do not show significant differences in cytokine levels; when CRS is combined with severe infections, a second increase in IL-6 levels may occur, but Predictive models are established through IL-8, IL-1β and IFN-γ and other cytokines to improve the specificity of CRS and infection identification, but there is still a lack of sufficient clinical data; if the two cannot be clearly distinguished, preventive Anti-infection combined with CRS graded treatment is the guiding principle.
Infection prevention and control strategy 01 Infection prevention and control during the pretreatment period About 10% of serious or life-threatening infections start before the CAR-T cell reinfusion (pretreatment period).
If the hepatitis B surface antigen is positive and the hepatitis B virus DNA copy number is less than 500 U/L (according to the lower limit of the normal value of the detection level in each hospital), antiviral drugs (such as entecavir 0.
5 mg/d) can be taken at the same time as appropriate at the beginning of the pretreatment, at least until the cell recovery 6 months after the infusion, follow-up regularly every month to test the copy number of hepatitis B virus DNA; general principles of preventive anti-infection. 02 When the absolute number of neutrophils (ANC) for infection prevention and control after pretreatment is less than 5×10-4/L (the following treatments can be selectively used as appropriate): give granulocyte colony stimulating factor (G-CSF) 5μg (kg ·D); levofloxacin 750mg/d, fluconazole 400mg/d; those who are positive for herpes simplex/herpes zoster virology serology, continue to take antiviral drugs (such as acyclovir 800mg, twice a day) until CAR -3 months after T cell reinfusion; compound trimethoprim 800mg, twice a day (2 days a week), recovering from agranulocytosis to 3 months after CAR-T cell reinfusion.
Preventive measures for high abdominal tumor burden: oral berberine hydrochloride 0.
9g, 3 times a day; Bacillus licheniformis capsule 0.
25g, 3 times a day; normal saline/glycerin enema 250mL or glycerin enema 110mL enema, once a night ; Benzalkonium chloride 250mL sitz bath, once a night.
03 Special site infections and treatment principles Skin and soft tissue infections: Due to the suppression of immune function caused by CAR-T cell therapy, skin and soft tissue infections are more common in the following situations: skin and soft tissue local tumor involvement with open wounds; affected site Local severe CRS causes damage to the skin and soft tissues and secondary infections.
In severe cases, it can lead to cellulitis and even life-threatening.
Prevention and treatment measures: Strengthen the dressing of the local open wounds, take care of the wounds, clean up the necrotic tissue in time, keep the wounds dry, topical use of preventive anti-infective drugs and dressings to promote wound healing; predict that severe local CRS may occur For patients at high risk of secondary infection, follow the principles of local CRS management and use drugs that reduce the risk of CRS prophylactically.
Urinary system infection: It is more common in perimenopausal or postmenopausal women.
Due to the suppression of immune function caused by CAR-T cell therapy, urinary system infection is more common than conventional anti-tumor treatment.
Specific prevention and treatment principles should be used to prevent infection , Such as daily sitz bath, routine dynamic monitoring of urine, and timely anti-infective treatment.
Catheter-related infections: ①Catheter-related bloodstream infections: Staphylococcus epidermidis on the skin of the operators and patients is the main source of pathogenic bacteria; common clinical manifestations include fever, chills, swelling, induration, or pus exudation at the catheter site, etc.
. Treatment principle: Collect blood culture + drug susceptibility, remove the catheter as soon as possible, disinfect the skin at the catheter, and change the dressing in time; before the blood culture results are reported, broad-spectrum antibiotics can be used empirically; after the pathogen is identified, drugs are used against the pathogen, and body temperature and temperature are monitored.
Blood pressure to prevent the occurrence of severe infections/septic shock.
②Catheter-related urinary tract infection: some patients may need to have a urinary catheter after CAR-T cell therapy.
During the period of severe CRS and bone marrow suppression, the risk of catheter-related urinary tract infection is high, and the following prevention and control principles need to be implemented, such as perineum Flushing (1 to 2 times a day), bladder flushing (1 time per night), regular replacement of urinary catheters, timely monitoring of urine routine and urine culture, and active anti-infection treatment when there are clear signs of infection.
③Ventilator-associated pneumonia: Patients with severe respiratory failure due to grade 4 CRS and/or co-infection require tracheal intubation and ventilator assisted breathing.
Such patients have a very high mortality rate.
It is recommended to be transferred to a respiratory care unit for active treatment.
④ Serosal cavity catheter-related infections: patients with serous cavity effusions such as chest, abdomen, and pericardial cavity, often due to pressure load leading to heart, respiratory function suppression, severe abdominal distension and obstruction of venous return, etc.
, need to be punctured in time Tube drainage eases.
Operation principle reference: Under protective isolation, place tubes in the thoracic cavity, abdominal cavity, and pericardium under bedside ultrasound guidance, replace drainage bags and joints regularly, disinfect and change the dressing at the puncture catheter site daily, and observe whether there is redness, swelling, and blood oozing on the wound.
, Exudate, keep the local wound clean and dry, and give preventive anti-infection treatment if necessary.
This article is excerpted from the Biotherapeutics Committee of Chinese Research Hospital Association.
Expert consensus on clinical management of toxic and side effects of CAR T cell treatment of NHL[J].
Journal of Translational Medicine, 2021, 10(1):1-11.
Please contact us if you encounter copyright issues delete. RECOMMEND recommended reading 1.
CAR-T cytotoxic side effects CRS | CAR-T cell treatment of NHL toxic side effects clinical management expert consensus 2.
CAR-T cytotoxic side effects of CAR-T-related encephalopathy syndrome | CAR-T cell treatment of NHL toxicity Expert consensus on clinical management of side effects 3.
HLH/MAS on toxic side effects of CAR-T cells | Expert consensus on clinical management of side effects of CAR-T cells in the treatment of NHL.
Stamp "Read the original text" and we will make progress together
Under this background, it is imperative to standardize the clinical treatment of its side effects.
.
The Biotherapeutics Committee of the Chinese Research Hospital Association organized experts to compile the "Expert Consensus on the Clinical Management of CAR-T Cells Treating NHL Toxic Side Effects", which aims to provide clinicians with a more standardized identification and treatment of CAR-T treatment of NHL-related side effects The disposal principles and exploratory disposal recommendations.
The CAR-T-related toxic and side effects mainly introduced in this consensus include cytokine release syndrome (CRS), CAR-T-related encephalopathy syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), Bone marrow suppression, infection, B cell deficiency/hypogammaglobulinemia, tumor lysis syndrome, allergic reaction, abnormal proliferation of CAR-T cells, etc.
In this issue, the editor summarizes the infection part as follows for the reference of readers.
Epidemiological survey results show that within 1 to 2 years after receiving CAR-T cell treatment, the incidence of various types of infections is about 55%, of which about 33% are severe infections of grade ≥3, and invasive fungal (including mold) infections No more than 8%, and no more than 5% of deaths due to serious infections.
Among them, the incidence of infection within 1 month after CAR-T cell treatment can be as high as 40%, most of which are bacterial infections, mainly after cell infusion Within 2 weeks.
The mortality rate of co-infection during the CRS reaction period is high.
Therefore, infection prevention and control is the top priority of CAR-T cell therapy.Screening period-infection screening items before pretreatment hepatitis B, hepatitis C, syphilis, AIDS; Epstein-Barr virus, cytomegalovirus, simple-zoster virus, Toxoplasma gondii; procalcitonin, endotoxin; C-reactive protein (CRP) ; IL-6; Erythrocyte sedimentation rate; Mycobacterium tuberculosis (TB, TB SPOT, PPD test, etc.
); lung CT; respiratory-related virus (with upper respiratory symptoms); fungal D-glucan test/curve Mold galactomannan detection.
Imaging examination chest CT; bronchoscopy/ultrasound guided bronchoscopy; alveolar lavage.
Special inspection: Infectious microbial genomics testing: sample collection of peripheral blood or body fluids (sputum, urine, serous effusion, skin and soft tissue), etc.
; proteomic microbial testing.
The differential diagnosis of CRS and infection has similar clinical manifestations, but there is no specific marker to clearly distinguish the two; and CRS co-infection occurs from time to time.
Therefore, the occurrence and development of the two The anticipation of CRS and the timing of intervention are very important; CRS grades and infection levels do not show significant differences in cytokine levels; when CRS is combined with severe infections, a second increase in IL-6 levels may occur, but Predictive models are established through IL-8, IL-1β and IFN-γ and other cytokines to improve the specificity of CRS and infection identification, but there is still a lack of sufficient clinical data; if the two cannot be clearly distinguished, preventive Anti-infection combined with CRS graded treatment is the guiding principle.
Infection prevention and control strategy 01 Infection prevention and control during the pretreatment period About 10% of serious or life-threatening infections start before the CAR-T cell reinfusion (pretreatment period).
If the hepatitis B surface antigen is positive and the hepatitis B virus DNA copy number is less than 500 U/L (according to the lower limit of the normal value of the detection level in each hospital), antiviral drugs (such as entecavir 0.
5 mg/d) can be taken at the same time as appropriate at the beginning of the pretreatment, at least until the cell recovery 6 months after the infusion, follow-up regularly every month to test the copy number of hepatitis B virus DNA; general principles of preventive anti-infection. 02 When the absolute number of neutrophils (ANC) for infection prevention and control after pretreatment is less than 5×10-4/L (the following treatments can be selectively used as appropriate): give granulocyte colony stimulating factor (G-CSF) 5μg (kg ·D); levofloxacin 750mg/d, fluconazole 400mg/d; those who are positive for herpes simplex/herpes zoster virology serology, continue to take antiviral drugs (such as acyclovir 800mg, twice a day) until CAR -3 months after T cell reinfusion; compound trimethoprim 800mg, twice a day (2 days a week), recovering from agranulocytosis to 3 months after CAR-T cell reinfusion.
Preventive measures for high abdominal tumor burden: oral berberine hydrochloride 0.
9g, 3 times a day; Bacillus licheniformis capsule 0.
25g, 3 times a day; normal saline/glycerin enema 250mL or glycerin enema 110mL enema, once a night ; Benzalkonium chloride 250mL sitz bath, once a night.
03 Special site infections and treatment principles Skin and soft tissue infections: Due to the suppression of immune function caused by CAR-T cell therapy, skin and soft tissue infections are more common in the following situations: skin and soft tissue local tumor involvement with open wounds; affected site Local severe CRS causes damage to the skin and soft tissues and secondary infections.
In severe cases, it can lead to cellulitis and even life-threatening.
Prevention and treatment measures: Strengthen the dressing of the local open wounds, take care of the wounds, clean up the necrotic tissue in time, keep the wounds dry, topical use of preventive anti-infective drugs and dressings to promote wound healing; predict that severe local CRS may occur For patients at high risk of secondary infection, follow the principles of local CRS management and use drugs that reduce the risk of CRS prophylactically.
Urinary system infection: It is more common in perimenopausal or postmenopausal women.
Due to the suppression of immune function caused by CAR-T cell therapy, urinary system infection is more common than conventional anti-tumor treatment.
Specific prevention and treatment principles should be used to prevent infection , Such as daily sitz bath, routine dynamic monitoring of urine, and timely anti-infective treatment.
Catheter-related infections: ①Catheter-related bloodstream infections: Staphylococcus epidermidis on the skin of the operators and patients is the main source of pathogenic bacteria; common clinical manifestations include fever, chills, swelling, induration, or pus exudation at the catheter site, etc.
. Treatment principle: Collect blood culture + drug susceptibility, remove the catheter as soon as possible, disinfect the skin at the catheter, and change the dressing in time; before the blood culture results are reported, broad-spectrum antibiotics can be used empirically; after the pathogen is identified, drugs are used against the pathogen, and body temperature and temperature are monitored.
Blood pressure to prevent the occurrence of severe infections/septic shock.
②Catheter-related urinary tract infection: some patients may need to have a urinary catheter after CAR-T cell therapy.
During the period of severe CRS and bone marrow suppression, the risk of catheter-related urinary tract infection is high, and the following prevention and control principles need to be implemented, such as perineum Flushing (1 to 2 times a day), bladder flushing (1 time per night), regular replacement of urinary catheters, timely monitoring of urine routine and urine culture, and active anti-infection treatment when there are clear signs of infection.
③Ventilator-associated pneumonia: Patients with severe respiratory failure due to grade 4 CRS and/or co-infection require tracheal intubation and ventilator assisted breathing.
Such patients have a very high mortality rate.
It is recommended to be transferred to a respiratory care unit for active treatment.
④ Serosal cavity catheter-related infections: patients with serous cavity effusions such as chest, abdomen, and pericardial cavity, often due to pressure load leading to heart, respiratory function suppression, severe abdominal distension and obstruction of venous return, etc.
, need to be punctured in time Tube drainage eases.
Operation principle reference: Under protective isolation, place tubes in the thoracic cavity, abdominal cavity, and pericardium under bedside ultrasound guidance, replace drainage bags and joints regularly, disinfect and change the dressing at the puncture catheter site daily, and observe whether there is redness, swelling, and blood oozing on the wound.
, Exudate, keep the local wound clean and dry, and give preventive anti-infection treatment if necessary.
This article is excerpted from the Biotherapeutics Committee of Chinese Research Hospital Association.
Expert consensus on clinical management of toxic and side effects of CAR T cell treatment of NHL[J].
Journal of Translational Medicine, 2021, 10(1):1-11.
Please contact us if you encounter copyright issues delete. RECOMMEND recommended reading 1.
CAR-T cytotoxic side effects CRS | CAR-T cell treatment of NHL toxic side effects clinical management expert consensus 2.
CAR-T cytotoxic side effects of CAR-T-related encephalopathy syndrome | CAR-T cell treatment of NHL toxicity Expert consensus on clinical management of side effects 3.
HLH/MAS on toxic side effects of CAR-T cells | Expert consensus on clinical management of side effects of CAR-T cells in the treatment of NHL.
Stamp "Read the original text" and we will make progress together
