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Management of patients undergoing CAR T-cell therapy
Table 5A. Checklist before starting the conditioning. SPCs
EBMT recommendations
LD conditioning should only be administered following receipt of product on site
Active infections must be excluded or under control before starting LD conditioning
Administer LD conditioning to all patients regardless of WBC or ALC
Comments
Exceptional situations may necessitate the administration of LD conditioning following confirmation of successful production but prior to arrival
Patient has to be able to tolerate LD conditioning
Some investigators have suggested that patients with low ALC (<0.1x109/L) may not require LD as these patients are already “lymphodepleted”
CAR T-cell product
Clinical conditions
WBC
The availability of the CAR T-cell product must be confirmed prior to starting the LD conditioning
LD conditioning should be administered before the KymriahTM infusion unless the WBC count within 1 week of
the infusion is ≤1.0x109/L
SPC: summary of product characteristics; EBMT: European Society for Blood and Marrow Transplantation; CAR: chimeric antigen receptor; LD: lymphodepletion; WBC: white blood cell count; ALC: absolute lymphocyte count.
Table 5B. Checklist of laboratory tests prior to conditioning.
Test methods
C-reactive protein and/or fibrinogen level
Bilirubin
AST/ALT
Creatinine clearance
Cardiac function
Trials and SPC
<26-34 μmol/L
<5xULN
EBMT recommendations
Chemistry
Required to rule out ongoing infection
<34 μmol/L; higher limit acceptable (>43 μmol/L) with Gilbert syndrome
<5xULN
> 30 mL/min
Other work-up
Repeat cardiac investigations only if clinically indicated (e.g. cardiotoxic bridging chemotherapy)
Comment
LD is contraindicated in patients with active infection. Active infection must be excluded or under control before starting LD
No trial data regarding patients outside of these parameters
Attempt to identify causes e.g. active infections
Modify drugs doses according to
creatinine clearance
LVEF >40%;
assess for pericardial effusion by echocardiography; ECG
SPC:summary of product characteristics;EBMT:European Society for Blood and MarrowTransplantation;AST:aspartate aminotransferase:ALT:alanine aminotransferase;LD:lym- phodepletion; ULN: upper limit of normal; LVEF: left ventricular ejection fraction; ECG: electrocardiogram.
which may damage the CAR T-cell product; typically, paracetamol derivatives and antihistamines, such as chlor- pheniramine or diphenhydramine, are used. Individual guidelines are provided by the manufacturers.
The product is aseptically connected to the port of a central venous catheter. The line to be used for the CAR T-cell infusion must be clearly designated; as with blood and stem cell products, no concurrent medication may be given during the CAR T-cell infusion. Infusion should begin as rapidly after spiking as possible, but no later than 30 min thereafter. The small volumes and cell numbers allow for rapid (less than 30 min) drip infusion of the cell suspension. The infusion bag and set should be disposed of as a biohazard and genetically modified organism waste in compliance with institutional policies and coun- try-specific regulations. Transfusion of the low-volume CAR T-cell product is typically uneventful.
Short-term complications and management: infusion to day +28
The rapid in vivo proliferation of CAR T cells may be associated with potentially life-threatening toxicities such
as CRS and neurotoxicity, which generally occur within 14 and 28 days of the CAR T-cell infusion, respectively.11,36- 38 LD conditioning may also contribute to the cytopenias.
Hospitalization
Some centers have established policies and infrastructure that allow for the safe administration of CAR T cells on an outpatient, ambulatory care basis. However, for ambulato- ry care to work, clear protocols, staffing and training need to be in place so that patients are able to access a coordina- tor on a 24/7 basis. Centers must also be able to provide both immediate review and the emergency admission of patients under the care of experienced staff. As such arrangements are not currently available in most European centers, we recommend that patients are admitted to hos- pital during the early post-infusion period unless high-level ambulatory care and rapid re-admission pathways are already well established, as in centers already providing ambulatory hematopoietic cell transplantation (HCT). Table 7 summarizes our recommendations relating to the first 28 days following the CAR T-cell infusion. These are in line with a number of clinical trial protocols and the recom- mendations of scientific societies.21,39
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