Axicabtagene ciloleucel (KTE-C19), an anti-CD19 CAR T therapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin’s lymphoma

Figures & data

Figure 1 Comparative serum concentrations of chemotherapy and CAR T-cell expansion.

Notes: Traditional cytoreductive chemotherapy has the greatest impact immediately following initiation; however, it is short-lived, requiring multiple cycles for a long-term antineoplastic effect. In contrast, the pharmacokinetic profile of axi-cel leads to a slower initial decrease in tumor burden, but it is sustained after a single infusion due to potential persistence of CAR T cells in patients’ blood over time.
Abbreviations: CAR, chimeric antigen receptor; LOD, limit of detection.

Table 1 Highlights of the ZUMA-1 trial of axicabtagene ciloleucel, a CD19 CAR T-cell product, in DLBCL and variants

Highlights of the Zuma-1 clinical trial with axicabtagene ciloleucel (Yescarta) in DLBCL and variants
Product	Autologous T cells expressing a CAR:
	• Antibody fragment to target CD19
	• Intracellular domains of CD3 zeta (to activate T-cell receptor signaling) and CD28 (for co-stimulation and persistence)
Inclusion/exclusion highlights	• DLBCL, TFL and PMBCL all allowed. Richter transformation from CLL, indolent lymphoma and mantle cell lymphoma was not included
	• Chemorefractory disease: stable disease or progressive disease as the best response to the most recent regimen (second line or greater), or progression within 12 months of autologous stem cell transplant
	• No history of CNS lymphoma or current involvement
Manufacturing	• Median time from leukapheresis to delivery 17 days
	• Successful CAR T production in 99% of patients
Conditioning and dose	• Days −5 to −3: Fludarabine 30 mg/m^2 and cyclophosphamide 500 mg/m^2 daily
	• Day 0: 2×10^6 CAR T cells/kg
Bridging while awaiting cell infusion	• Chemotherapy not allowed
	• Ten of 111 patients with successful manufacturing did not proceed to CAR T-cell infusion. Seven were due to adverse events or death prior to infusion
Efficacy	• Median time to response 1 month (range 0.8–6.0 months)
	• ORR 82%, CR 54%, 6-month PFS 49%. Relapses appear to be infrequent after 6 months
	• TFL and PMBCL have a higher CR rate than de novo DLBCL (71% versus 49%)
	• Historical cohort (SCHOLAR-1) ORR 26%, median OS of 6.3 months
Deaths	Of 101 patients receiving CAR T cells:
	• 37 died of disease progression
	• 2 died of CRS-associated events (cardiac arrest, HLH)
	• 1 died of pulmonary embolus
Toxicity	• CRS grade 3 or higher: 13%
	• Neurologic events grade 3 or higher: 28%
	• Toxicity management with tocilizumab or steroids did not appear to affect CAR T-cell efficacy
Biomarkers	• CAR T-cell efficacy was not affected by classic prognostic markers in DLBCL, such as IPI, cell of origin (ABC versus GCB) or number of prior lines of therapy
	• Expansion (peak CAR T-cell levels in the blood) was correlated not only with response, but also with neurologic events
	• Cytokine release was associated with CRS and neurologic events

Abbreviations: ABC, activated B-cell subtype of DLBCL; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; CR, complete response rate; CRS, cytokine release syndrome; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell subtype of DLBCL; HLH, hemophagocytic lymphohistiocytosis; IPI, International Prognostic Index; ORR, objective response rate (includes complete and partial responses); OS, overall survival; PFS, progression-free survival; PMBCL, primary mediastinal B-cell lymphoma; TFL, transformed follicular lymphoma; CNS, central nervous system; ABC, activated B-cell subtype of DLBCL.

Table 2 Grading of CRS

Grade 1	Grade 2	Grade 3	Grade 4
Fever (≥38.3°C)	Hypotension responsive to fluids or one low-dose vasopressor	Hypotension requiring multiple or high-dose vasopressors	Requiring mechanical ventilation
Constitutional symptoms	Hypoxia responsive to <40% FiO2 Organ toxicity grade 2	Hypoxia requiring ≥40% FiO2 Organ toxicity grade 3 Grade 4 transaminitis	Organ toxicity grade 4 excluding transaminitis

Abbreviation: CRS, cytokine release syndrome.

Table 3 Grading of the common neurotoxicity symptoms

Neurotoxicity grading assessment (CTCAE 4.03)	Grade 1	Grade 2	Grade 3	Grade 4
Encephalopathy	Mild limiting of ADL	Limiting instrumental ADL	Limiting self-care ADLs	Life-threatening consequences
Confusion	Mild disorientation	Moderate disorientation; limiting instrumental ADL	Severe disorientation; limiting self-care ADL	Life-threatening consequences; urgent intervention indicated
Dysphasia	Awareness of receptive or expressive characteristics; impaired ability to communicate	Moderate receptive/expressive characteristics; impaired ability to communicate spontaneously	Severe receptive/expressive characteristics; impaired ability to read, write or communicate intelligibly	N/A
Seizure	Brief partial seizure; no loss of consciousness	Brief generalized seizure	Multiple seizures despite medical intervention	Life-threatening; prolonged repetitive seizures
Somnolence	Mild, but more than usual drowsiness or sleepiness	Moderate sedation; limiting instrumental ADL	Obtundation or stupor	Life-threatening; urgent intervention indicated

Note: Neurotoxicity grading assessment of common adverse events from CAR T-cell therapy.

Abbreviations: ADL, activities of daily living; CAR, chimeric antigen receptor; CTCAE, Common Terminology Criteria for Adverse Events; N/A, not applicable.