Immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy for lymphoma: predictive biomarkers and clinical outcomes

Abstract

Background: CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR-T) has emerged as effective for relapsed/refractory large B-cell lymphoma (R/R LBCL). The neurologic toxicity seen with CAR-T, referred to as immune effector cell-associated neurotoxicity syndrome (ICANS), is poorly understood. To better elucidate the clinical characteristics, treatment outcomes, and correlative biomarkers of ICANS, we review here a single-center analysis of ICANS after CAR T-cell therapy in R/R LBCL.

Methods: Patients (n = 45) with R/R LBCL treated with axicabtagene ciloleucel (axi-cel) were identified. Data regarding treatment course, clinical outcomes, and correlative studies were collected. Patients were monitored and graded for ICANS via CARTOX-10 scoring and Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria, respectively.

Results: Twenty-five (56%) patients developed ICANS, 18 (72%) of whom had severe (CTCAE grades 3-4) ICANS. Median time to development of ICANS was 5 days (range, 3-11). Elevated pre-infusion (day 0 [D0]) fibrinogen (517 vs 403 mg/dL, upper limit of normal [ULN] 438 mg/dL, P = 0.01) and D0 lactate dehydrogenase (618 vs 506 units/L, ULN 618 units/L, P = 0.04) were associated with ICANS. A larger drop in fibrinogen was associated with ICANS (393 vs 200, P < 0.01). Development of ICANS of any grade had no effect on complete remission (CR), progression-free survival (PFS), or overall survival (OS). Duration and total dose of steroid treatment administered for ICANS did not influence CR, PFS, or OS.

Conclusions: ICANS after CAR-T with axi-cel for R/R LBCL was seen in about half of patients, the majority of which were high grade. Contrary to previous reports, neither development of ICANS nor its treatment were associated with inferior CR, PFS, or OS. The novel finding of high D0 fibrinogen level can identify patients at higher risk for ICANS.

Keywords: chimeric antigen receptor T cells; fibrinogen; immunotherapy; lymphoma; neurotoxicity.

Fig. 1

PFS (A) and OS (B) of whole patient cohort: not reached and 15 months, respectively. Kaplan–Meier estimate of PFS (C) and OS (D) for patients with (broken line/light gray) and without (solid line/dark gray) severe (grade 3–4) ICANS; PFS (E) and OS (F) with (broken line/light gray) and without (solid line/dark gray) any grade ICANS.

Fig. 2

ROC curve (AUC 0.724, 95% CI: 0.5642–0.88438). The high area under the ROC curve (AUROC) suggests the discriminative ability of fibrinogen to predict ICANS.

Fig. 3

Median values for select correlative biomarker values and trends post CAR-T infusion: (A) fibrinogen (days 0–10), (B) ferritin (days 0–10), (C) CRP (days 0–5), (D) LDH (days 0–10). Per legend: triangle markers (black line) represent patients with no ICANS; square markers (dark gray line) represent patients with grade 1–2 ICANS; circle markers (light gray line) represent patients with severe, or grade 3–4 ICANS.

Fig. 4

Radiologic findings in ICANS. Brain MRI showing: (A) cerebral late subacute infarcts on axial fluid attenuated inversion recovery (FLAIR); (B) nonspecific white matter lesion on axial FLAIR; (C) nonocclusive thrombosis of the left sigmoid and distal transverse sinuses on coronal T1 multiplanar reformation gadolinium (MPR gad); (D) a new focus of presumed petechial hemorrhage within the inferior left cerebellar hemisphere on axial FLAIR MR; (E) left cerebellar likely embolic acute/subacute infarct on axial FLAIR MR; (F) pretreatment transcalvarial mass, with thrombus within the superior sagittal sinus; (G) new subocclusive thrombus within left transverse sinus on sagittal T1 MPR gad; (H) with posttreatment pseudoprogression within the sagittal sinus with effacement of the sulci on sagittal T1 MPR gad; (F) an acute left pontine infarct with associated tiny petechial hemorrhage on axial diffusion weighted imaging (DWI) MR, which led to led to neurogenic bladder; neurogenic bladder seen on CT abdomen/pelvis demonstrating (I) urinary overflow incontinence (J) causing hydronephrosis.