Dr. Diorio’s second case was that of a 13-year-old patient with chemorefractory B-ALL who received CAR T-cell therapy and had no prior history of immunotherapy (Diorio C, et al. Blood. 2024;144[13]:1387–1398). Prior to CAR T infusion, the patient had 26 percent bone marrow blasts, indicating high disease burden. The patient developed severe ICANS followed by acute flaccid paraparesis.
The patient was admitted with fever immediately after infusion and then developed grade four CRS, requiring intensive care.
The patient recovered from the CRS, and the CRS-associated delirium and encephalopathy he had developed began to wane. Sudden onset of flaccid paraparesis followed, with absent lower extremity deep tendon reflexes. A lumbar puncture found no elevation in white blood cell count and no blasts in the cerebrospinal fluid, but the protein level was very high (164 mg/dL).
The patient was treated with tocilizumab, intravenous immunoglobulin, dexamethasone, anakinra, therapeutic plasma exchange, and Sinemet without improvement in his paraparesis. Disease response was excellent; B-ALL was cured and remains in remission. But he did not recover his ability to move his lower extremities.
At the time of the development of CRS, the patient’s cytokine panel revealed a pattern similar to that of the first case: a very high interferon gamma level and elevations in IL-6 and IL-8. He was treated with tocilizumab for the severe CRS.
However, at the time of his development of paraparesis, Dr. Diorio said, the patient’s cytokine panel revealed mild elevations in his IL-6 and IL-8 that were considered clinically insignificant, and no other evidence of inflammation.
“At the time we were not able to get CSF cytokines,” Dr. Diorio said. “But we were impressed by the lack of inflammation systemically in this patient.”
ICANS can include a vast array of conditions: encephalopathy, aphasia, strength and coordination (focal weakness, paraplegia, dysmetria), seizures, cerebral edema, and executive dysfunction. “That becomes very challenging from a laboratory perspective,” Dr. Diorio said, “because this highly heterogeneous condition probably has multiple different paths of physiology specific to the neurologic issue that’s occurring.”
Dr. Diorio and colleagues studied ICANS across a cohort of more than 450 patients treated with CAR T for B-ALL and found the occurrence of movement disorders, as in the 13-year-old patient, to be exceptionally rare. “We’ve had only a handful of cases out of that almost 500 patients,” she said. “The vast majority of ICANS is either encephalopathy or seizure.”
Using CSF flow cytometry, Dr. Diorio’s group found no clear evidence of an inflammatory population that was any different from the other patients treated with CAR T who did not develop any sort of paresis (Diorio C, et al. Blood. 2024;144[13]:1387–1398).
“And then we also looked in my lab at the CSF cytokine levels using a proximity extension assay,” Dr. Diorio said. She and coauthors reported in their article in Blood that four of more than 150 patients developed quadriparesis or paraparesis post-CAR T. “And what’s notable is that the inflammatory signature is in the patients who didn’t develop paraparesis,” she said. Cytokines of interferon gamma and CCL17 were lower in the four patients who developed paresis than in those who developed any other phenomenology of ICANS (n=78).
“We also have autopsy studies on some of those patients and there’s an utter lack of inflammation, implying that the cause of at least that phenotype of ICANS does not actually appear to be inflammatory,” Dr. Diorio said. “It was very helpful in the moment to have our clinical cytokines available to help us direct our therapies away from cytokine blockade when that clearly was not the issue for that patient.”
Case No. 3 was that of an 18-year-old patient with multiply relapsed B-ALL treated with a CART22-65s. The patient developed fever, hyperferritinemia greater than the limit of detection of the assay, splenomegaly, and cytopenias on day 40 post-CAR T. The diagnosis was IEC-HS, which is an emerging toxicity. “It’s unique to IEC-HS to occur so far out,” Dr. Diorio noted.
In addition to the fever and laboratory abnormalities, the patient had significant bleeding disproportionate to the mild biochemical coagulopathy he had. “A sort of giveaway clinically for us is bleeding from the port site. Our patients live for years with ports without bleeding and then all of a sudden they start bleeding in the setting of IEC-HS.”