Table 6.

Recommendations before starting LD for CART cells (adapted from EBMT/EHA recommendations: Hayden et al., 2022,³⁹ Rejeski/Subklewe et al., 2023)⁴⁰ and before infusion of other CTs (MSC, Tregs).

Criterion	EBMT/EHA recommendationsa39,40	AD-specific recommendations
Lymphodepletion before CART	Fludarabine- cyclophosphamide Dose-reduced LD as per local approved label of fludarabine (i.e. 50%) in case of renal impairment	LD generally consists of cyclophosphamide and fludarabine.b Use of standard supportive care (such as Mesna) is highly recommended
CART product	LD should be administered following receipt of CART product on site Exceptional situations may necessitate the administration of LD following confirmation of successful CART manufacture, but before receipt	LD should be administered in AD following the receipt of CART product on site.
Clinical conditions	Active infections should be ruled out before starting LD Active or chronic infection is a contraindication Patient should be medically fit to proceed to LD	Referral should be made to a center with appropriate on site inter-disciplinary interaction using combined haematological and AD specialist experience to select and manage AD patients. If patient develops fever in presence of active infection after LD but before CART infusion, the latter must be postponed until 48 h without fever.
Cardiac function	Repeat TTE, ECG and cardiac biomarkers (troponin and NT-proBNP)	Detailed cardiopulmonary assessment is required at time of patent selection for CT in AD including ECG and echocardiography for all AD patients. MRI and MUGA can be necessary depending on the underlying AD and on patient comorbidities.
Lung function/Blood oxygen saturation	92% on ambient air Chest X ray	Lung function (i.e. FVC, DLCO) and chest CT scan should have been carefully assessed at time of patent selection for CT in ADs; detailed cardiopulmonary assessment from less than 3 months is required before CTs (CART, MSC, Treg).
WBC	Administer LD to all patients irrespective of WBC or ALC The SPC for tisagenlecleucel (Kymriah) state that patients with low WBC (<1 × 109/l) 1 week before CART infusion may not require LD. use LD with caution when unexplained neutropenia pre-dates CART admission. LD is important to CART activity and proceeding with CART without LD is not generally recommended	Acquired neutropenia, usually mild and often intermittent, lymphopenia and thrombocytopenia may accompany ADs (SLE, SS, SSc, RA, IBD). LD should be considered for all patients regardless of blood cells counts. In severe cytopenia, LD dose may be reduced based on an individual patient risk assessment.
Infections markers (C-reactive protein, ferritin, LDH, metabolic profiling, fibrinogen level)	Required to rule out ongoing infection Baseline assessments of risk for CRS and ICANS	Inflammatory/ADs may account for abnormalities in routine laboratory studies (i.e. serum proteins, produced in response to inflammation and referred as inflammatory markers). In AD patients, a complete metabolic profile (e.g. protein electrophoresis, pre-albumin, HbA1c) is recommended.
Liver function (Bilirubin/AST/ALT)	Bilirubin <34 mmol/l; higher limit acceptable (>43 mmol/l) with Gilbert's syndrome criteria AST/ALT ≤4 × ULN or trial-specific criteria should be met Identify cause of liver derangement, e.g. infection, drug toxicity including antifungals, etc.	Clear identification of the cause of liver derangement is mandatory before starting the CT program in ADs. MDT evaluation is recommended to assess the risk benefit of CT in case of AD specific liver function abnormalities. An increase in muscle enzymes (creatinine kinase and AST, while ALT are normal) can be seen in autoimmune inflammatory myopathies; In SLE, lupoid hepatitis is frequent (3–4 ULN liver enzymes, in presence of anti-nuclear, anti-ASMA antibodies, and rheumatoid factor). Primary cholangitis can be associated with SSc in case of Reynolds syndrome, with Goujerot-Sjogren or be observed in other mixed connective tissue diseases. Drug-induced hepatotoxicity related to azathioprine can account for high liver enzymes (3–4 ULN).
Renal function (Crcl)	Crcl >30 ml/min Physicians should consider appropriate dose reductions in cyclophosphamide and fludarabine when Crcl is <60 ml/min and potentially an increased interval between LD and CART return to permit clearance of fludarabine metabolites	Comprehensive urine analysis, including culture, is recommended before LD to assess renal injury (glomerulonephritis, interstitial nephritis) and may show proteinuria, hematuria or active urinary sediment. Patients with severe renal insufficiency should be carefully evaluated by MDT to assess risk/benefit ratio, adapting LD dose (see above) and medications/dialysis.
CNS involvement	EBMT recommendations consider risk/benefit ratio. Anticonvulsant prophylaxis is mandatory in CNS involvement for CART.	There is no evidence suggesting substantially increased ICANS risk in AD patients, however CNS involvement and peripheral neuropathy should be assessed before treatment and individual patient risk has to be considered.

LD refers only to CART.

Abbreviations: AD autoimmune diseases; ALC absolute lymphocyte count; ALT alanine aminotransferase; AST aspartate aminotransferase; ASMA anti-smooth muscle antibody; CART chimeric antigen receptors T cells; CNS central nervous system; Crcl creatinine clearance; CRS cytokine release syndrome; CT cellular therapy; CT scan computerized tomography scan; DLCO diffusing capacity for carbon monoxide; EBMT European Society for Blood and Marrow Transplantation; ECG electrocardiogram; EHA European Hematology Association; FVC forced vital capacity; HbA1c hemoglobin A1C; IBD inflammatory bowel diseases; ICANS immune effector cell-associated neurotoxicity syndrome; LD lymphodepleting conditioning; LDH lactate dehydrogenase; MSC mesenchymal stromal cells; MUGA multigated acquisition scan; NT-proBNP N-terminal pro-brain natriuretic peptide; RA rheumatoid arthritis; SLE systemic lupus erythematosus; SPC summary of product characteristics; SS Sjögren syndrome; SSc systemic sclerosis; TTE transthoracic echocardiogram; Tregs regulatory T cells; ULN upper limits of normal; WBC white blood cells.

^aThese EBMT recommendations were made for CART in hematologic malignancies and may differ to ADs.

^bRNA-based CART did not use LD at all.³⁷