Neurologic toxicity has been observed with anti-CD19 chimeric antigen receptor (CAR) T cells and the anti-CD19 BiTE blinatumomab. Both focal (e.g., cranial nerve palsy) and global (e.g., generalized seizures) abnormalities have been reported, often associated with systemic cytokine release syndrome (CRS) but also observed after recovery from or in absence of CRS. CART-BCMA consists of expanded autologous T cells transduced with a 4-1BB:CD3-zeta-based CAR specific for B Cell Maturation Antigen. Here, we report clinical features and management of a severe neurotoxicity observed on a phase 1 trial of CART-BCMA for multiple myeloma (MM) (NCT02546167).
The subject is a 55-year-old female with high-risk IgA lambda MM. At time of CART-BCMA infusion, her MM manifestations included cytopenias and plasmacytomas of the pleura and paravertebral muscles. Bone marrow (BM) was >95% BCMA+ plasma cells. Pre-treatment brain MRI showed pachymeningeal thickening and enhancement over the left cerebral convexity, possibly due to extension of calvarial MM lesions. There was no evidence of CNS MM on a neurologist's exam or by CSF cytology.
The subject received 2x108 CART-BCMA cells, 40% of the planned dose, over two consecutive days, without lymphodepleting chemotherapy; a third planned infusion was held due to fevers. Over the next 4 days, fevers persisted, hypoxia and delirium developed, and cytopenias worsened. Brain MRI and lumbar puncture on day 4 showed no new abnormalities. Evaluation for infection was negative. These symptoms coincided with rise in serum IL-6 (nl range <5 pg/ml) and other CRS biomarkers. On day 6, tocilizumab was administered, which led to resolution of fevers and hypoxia; IL-6 transiently rose and then declined but remained above normal (Figure, orange & black lines).
On day 8, the subject became obtunded. She was intubated, and methylprednisolone 1000mg was administered followed by hydrocortisone 100mg q8h. By day 11, she was more alert, permitting extubation and cessation of steroids, but remained slow to respond. On day 12 she developed a generalized seizure, was re-intubated for airway protection, and received antiepileptic drugs (AED). She again improved and was extubated but, on day 15, developed status epilepticus that required five AEDs to control. Repeat MRI showed new diffuse sulcal, cortical, and subcortical T2/FLAIR signal abnormalities involving the bilateral frontal, parietal, occipital, posterior temporal, and cerebellar hemispheres, with sulcal effacement concerning for cerebral edema. This deterioration was not associated with fevers, other features of systemic CRS, or hypertension, but it coincided with rise in circulating CAR T cell frequency to one of the highest levels observed on our CAR trials (Figure, red line). CRS-related cytokines continued to decrease in serum, but CSF on day 16 showed marked elevation in IL-6, IL-8, and other CRS-related cytokines compared to day-16 serum and day-4 CSF (Figure, green line). CART-BCMA cells were detected in CSF. High-dose methylprednisolone was restarted without improvement. On day 17, cyclophosphamide 1.5 g/m2 was administered to reduce CART-BCMA cells. Beginning on day 18, mental status improved substantially, and she was extubated on day 20. Steroids were gradually tapered. MRI on day 23 showed near-resolution of signal abnormalities, which were completely resolved on MRI 4 weeks later. Neurologic signs and symptoms resolved; the last symptom to recover was mild difficulty processing visual information. Despite cyclophosphamide and a prolonged steroid course, CART-BCMA cells remained detectable in both blood and BM at last evaluation, 164 days after infusion, and the subject achieved a five-month VGPR.
Conclusions: Given the rapid reversibility and MRI appearance, this neurologic syndrome was felt to be most consistent with posterior reversible encephalopathy syndrome (PRES), possibly due to high CSF levels of CRS-related cytokines, as opposed to encephalitis from direct CART-BCMA cytotoxicity against neuronal tissue. PRES developed amidst improvement of systemic CRS, suggesting a CNS-localized CRS, possibly due to occult CNS MM encountered by expanding CART-BCMA cells and/or failure of tocilizumab to block IL-6 receptor in the CNS. Cyclophosphamide may effectively reverse life-threatening, steroid-refractory CAR T cell neurotoxicity while retaining some CAR T cell efficacy and long-term persistence.
Garfall:Medimmune: Consultancy; Bioinvent: Research Funding; Novartis: Consultancy, Research Funding. Lancaster:Grifols, Inc.: Other: Teaching courses; Medimmune, Inc.: Consultancy; Janssen: Consultancy. Stadtmauer:Teva: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Takada: Consultancy; Celgene: Consultancy. Lacey:Novartis: Research Funding. Ambrose:Novartis: Research Funding. Chen:Novartis: Research Funding. Kulikovskaya:Novartis: Research Funding. Vogl:Acetylon: Research Funding; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Celgene: Consultancy; Constellation: Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy. Plesa:Novartis: Patents & Royalties, Research Funding. Weiss:Novartis: Consultancy. Richardson:Novartis: Employment, Patents & Royalties, Research Funding. Melenhorst:Novartis: Patents & Royalties: Novartis, Research Funding. Levine:Novartis: Patents & Royalties, Research Funding; GE Healthcare Bio-Sciences: Consultancy. June:Novartis: Honoraria, Patents & Royalties, Research Funding; Celldex: Consultancy, Equity Ownership; Immune Design: Consultancy, Equity Ownership; Tmunity Therapeutics: Equity Ownership; Johnson & Johnson: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Pfizer: Honoraria. Milone:Novartis: Patents & Royalties, Research Funding. Cohen:Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy, Research Funding.
Asterisk with author names denotes non-ASH members.