PMC9872508_01
Clinical course and diagnosis of diabetes insipidus. (A) Timeline depicting clinical events, therapeutic interventions (black arrows), grading of CRS/ICANS and inflammatory markers from day -5 until day +30 after CAR-T cell infusion. Tocilizumab was administered once at a dose of 8 mg/kg body weight and dexamethasone initially at 8 mg every 6 hours. Intravenous immunoglobulin was administered at 2 g/kg body weight. CRS/ICANS scores were acquired according to ASTCT consensus criteria and determined under omission of GBS-related and DI-related symptoms. (B) Onset and course of central diabetes insipidus on day +11 was assessed by urine output (mL/hour) as well as urine and serum sodium concentration (mmol/L). Increased diuresis of hyponatriuric urine was reversed by repetitive administration of desmopressin (black arrows). ASTCT, American Society for Transplantation and Cellular Therapy; CAR, chimeric antigen receptor; CRP, C reactive protein; CRS, cytokine release syndrome; DI, diabetes insipidus; GBS, Guillain-Barre-like syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.
jitc-2022-006059f01.jpg
PMC9872508_03_jitc-2022-006059f01.jpg
F1
Urine sodium concentration and osmolality were markedly decreased and, consistent with a diagnosis of cDI, the patient rapidly responded to treatment with desmopressin (figure 1B).
PMC9872508_02
Clinical course and diagnosis of diabetes insipidus. (A) Timeline depicting clinical events, therapeutic interventions (black arrows), grading of CRS/ICANS and inflammatory markers from day -5 until day +30 after CAR-T cell infusion. Tocilizumab was administered once at a dose of 8 mg/kg body weight and dexamethasone initially at 8 mg every 6 hours. Intravenous immunoglobulin was administered at 2 g/kg body weight. CRS/ICANS scores were acquired according to ASTCT consensus criteria and determined under omission of GBS-related and DI-related symptoms. (B) Onset and course of central diabetes insipidus on day +11 was assessed by urine output (mL/hour) as well as urine and serum sodium concentration (mmol/L). Increased diuresis of hyponatriuric urine was reversed by repetitive administration of desmopressin (black arrows). ASTCT, American Society for Transplantation and Cellular Therapy; CAR, chimeric antigen receptor; CRP, C reactive protein; CRS, cytokine release syndrome; DI, diabetes insipidus; GBS, Guillain-Barre-like syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.
jitc-2022-006059f01.jpg
PMC9872508_03_jitc-2022-006059f01.jpg
F1
Urine sodium concentration and osmolality were markedly decreased and, consistent with a diagnosis of cDI, the patient rapidly responded to treatment with desmopressin (figure 1B).
PMC9872508_03
Clinical course and diagnosis of diabetes insipidus. (A) Timeline depicting clinical events, therapeutic interventions (black arrows), grading of CRS/ICANS and inflammatory markers from day -5 until day +30 after CAR-T cell infusion. Tocilizumab was administered once at a dose of 8 mg/kg body weight and dexamethasone initially at 8 mg every 6 hours. Intravenous immunoglobulin was administered at 2 g/kg body weight. CRS/ICANS scores were acquired according to ASTCT consensus criteria and determined under omission of GBS-related and DI-related symptoms. (B) Onset and course of central diabetes insipidus on day +11 was assessed by urine output (mL/hour) as well as urine and serum sodium concentration (mmol/L). Increased diuresis of hyponatriuric urine was reversed by repetitive administration of desmopressin (black arrows). ASTCT, American Society for Transplantation and Cellular Therapy; CAR, chimeric antigen receptor; CRP, C reactive protein; CRS, cytokine release syndrome; DI, diabetes insipidus; GBS, Guillain-Barre-like syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.
jitc-2022-006059f01.jpg
PMC9872508_03_jitc-2022-006059f01.jpg
F1
Urine sodium concentration and osmolality were markedly decreased and, consistent with a diagnosis of cDI, the patient rapidly responded to treatment with desmopressin (figure 1B).
PMC9872508_04
Hallmarks of the Guillain-Barre-like syndrome after CAR-T cell therapy. (A) Serial motor nerve conduction studies (NCS) of the left median and the right tibial nerve on day +18, +33 and +124 after CAR-T cell infusion. On day +18, drastic reduction of distal compound muscle action potentials was observed with only a modest reduction in conduction velocity, indicating an axonal damage pattern (left panel). Intravenous immunoglobulin therapy did not have immediate effects on NCS on day +33 (middle panel). After 3 months (day+ 124), signs of improvement in the upper extremities were evident (right panel). Sensory fibers were less affected in general (not shown). (B) Tissue sections of the gastrocnemius muscle were acquired on day +52 and demonstrated predominant perivascular immune cell infiltration (panels i-iv, H&E and IHC as indicated). Chronic neurogenic muscular atrophy with fiber type grouping and increase of endomysial and perimysial connective tissue was evident as a consequence of nerve damage (panels v-viii, H&E and IHC as indicated). Panels i-vi: scale bar = 100 microm. Panels vii + viii: scale bar = 500 microm. CAR, chimeric antigen receptor; IHC, immunohistochemistry; MHC, myosin heavy chain.
jitc-2022-006059f02.jpg
PMC9872508_04_jitc-2022-006059f02.jpg
F2
NCS demonstrated marked amplitude reductions of compound muscle action potentials while motor nerve conduction velocity and distal motor latency were only discretely reduced (figure 2A), consistent with an axonal damage-pattern. T cell-dominant lymphocytic infiltrates and severe neurogenic damage of muscle fibers (figure 2B). The vector copy number of the CAR transgene was comparable in biopsy and peripheral blood (0.418% and 0.512%), indicating presence of CAR-T cells in muscle tissue. While a trial of intravenous immunoglobulin failed to produce an immediate benefit, improvement of quadriparesis was observed clinically and in NCS from 2 months onwards (figure 2A).
PMC9872508_05