Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells

Abstract

Background: Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited.

Methods: We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period.

Results: Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1-0.7; P = .010).

Conclusions: CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted.

Keywords: CAR T-cells; CNS lymphoma; chimeric antigen receptor; neurotoxicity; response.

Figure 1.

Neurotoxicity following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for central nervous system lymphoma. (A) Kinetics of immune effector cell-associated neurotoxicity syndrome (ICANS) for 30 days after each CAR T-cell transfusion for PCNSL (n = 18). Each row represents one patient, and the highest grade of ICANS recorded per day is color-coded. Median time to first fever ≥ 38°C for patients with no ICANS (yellow dotted line) and ICANS grade 1–4 is indicated (red dotted line). (B) Distribution of ICANS between patients with PCNSL and SCNSL. (C) Number of patients with each grade of cytokine release syndrome (CRS) and neurotoxicity. (D) Serum levels of the acute-phase proteins C-reactive protein (CRP; upper panel) and Ferritin (lower panel) in relationship to serum levels at CAR T-cell transfusion. Ratio is shown for patients with PCNSL (orange) and SCNSL (blue) for 20 days after CAR T-cell transfusion. Note the profound increase in CRP levels among SCNSL patients. Median ratio and SEM are given. (E) Kinetics of ICANS for 30 days after each CAR T-cell transfusion for SCNSL (n = 27). Each row represents one patient, and the highest grade of ICANS recorded per day is color-coded. Median time to first fever ≥ 38°C for patients with no ICANS (yellow dotted line) and ICANS grade 1–4 is indicated (red dotted line). (F–H) Receiver operating curve curves for the prediction of ICANS by serum levels of CRP (F), Ferritin (G), and lactate dehydrogenase (LDH; H) at CAR T-cell transfusion.

Figure 2.

Response of central nervous system (CNS) lymphoma following chimeric antigen receptor (CAR) T-cell therapy. (A) Axial brain MRI of the brain with contrast-enhanced T1−weighted (T1+; upper panel) and fluid-attenuated inversion recovery (FLAIR; lower panel) sequences before CAR T-cell transfusion and after 4 months. Complete resolution of a left periventricular lesion (arrowheads) is seen. (B) Whole-body FET-PET before and 30 days after CAR T-cell transfusion. Areas of avid metabolism (arrows) are seen at the left foramen ovale (upper panel), the right brachial plexus (middle panel), and the right S1 nerve root (lower panel); suggestive of leptomeningeal involvement by lymphoma. No abnormal metabolism is detected after CAR T-cell transfusion. (C) Response of PCNSL (left) and SCNSL (right) at staging exams 1 month, 3 months, 6 months, and 1 year following CAR T-cell therapy. Each column represents one patient, and disease response is color-coded. (D) Distribution of best response in all patients with CNS lymphoma. (E) Kaplan–Meier estimates of CNS-progression-free survival after CAR T-cell transfusion in patients with primary or secondary CNS lymphoma (n = 45). Points indicate deceased or censored patients, light shading indicates SEM. (F) Axial brain MRI of a patient with pseudoprogression before, 5 days after, and 24 days after CAR T-cell transfusion. For all timepoints, contrast-enhanced T1-weighted (left in each panel) and FLAIR sequences (right in each panel) are given. Note the interval increase in FLAIR-hyperintense edema early after CAR T-cell transfusion while contrast-enhancement is reduced.

Figure 3.

Predictors of outcome for central nervous system (CNS) disease. (A) Overview of corticosteroid use and bridging therapies at intervals around chimeric antigen receptor (CAR) T-cell transfusion. CTX, chemotherapy; IF-RT, Involved-field radiation therapy; WBRT, whole brain radiotherapy. (B) Hazard ratios for CNS progression were calculated for each individual dexamethasone dose (in mg/d) at different intervals among all CNS lymphoma patients undergoing CAR T-cell transfusion (n = 45). The binary prognostic cutoff of 8 mg/d dexamethasones during lymphodepletion calculated with step-wise log-rank tests (Figure 3C) is indicated. An exponential hazard increase can be seen for higher dexamethasone doses during lymphodepletion. (C) Univariate analysis using log-rank tests comparing patients with different amounts of daily dexamethasone doses during lymphodepletion to patients with 0–1 mg/d dexamethasone during lymphodepletion. Note that an association with worse outcomes was seen for dexamethasone doses ≥ 8 mg/d. Hazard ratio ± 95% confidence interval. (D–E) Kaplan–Meier estimates of CNS-progression-free survival after CAR T-cell transfusion for the use of ibrutinib when bridging has been provided (D; n = 36) and for different forms of CNS involvement (E; n = 45). Points indicate deceased or censored patients, light shading indicates SEM. (F) Distribution of best response patterns for various bridging therapies (upper panel) and different forms of CNS involvement (lower panel).