Movement and neurocognitive disorders are emerging as CAR T “toxicities of concern” and could become more apparent as Australia increases access to therapy, specialists at an international conference have heard.

Speaking at the MASCC/ISOO Annual Meeting in Melbourne last week, Professor Robert Weinkove, who leads the CAR T program at the Malaghan Institute of Medical Research in New Zealand, highlighted the toxicities could present much later and were being picked up by global cellular therapy registries.

He said Australian specialists were likely to see more neurotoxicities in their patients in the future as these events appeared linked to anti-BCMA products specifically, like ciltacabtagene autoleucel (cilta-cel, Carvykti), which had been recently subsidised.

The haematologist also shared some of the latest strategies for earlier detection of common and acute toxicities like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), including scoring systems predicting risk in patients using characteristics like creatinine, LDH, platelets and ferritin.

Emerging late CAR T-cell toxicities

Neurological conditions

Professor Weinkove said immune effector cell-associated Parkinsonism was one of the late neurotoxicities that had been associated with anti-BCMA products.

“No one knows exactly why it’s happening, but there appear to be CAR T-cells turning up in the basal ganglia and contributing to this toxicity,” he said.

Professor Robert Weinkove.

“It tends to be associated with more prior lines of therapy, more myeloma burden, and more robust early CAR T-cell expansion. Some of the ways of managing it are to try and offset this very early robust CAR T-cell expansion, try and spot it early and try and damp down the CAR T-cells early if that’s occurring.”

However, spotting it early could be difficult.

Professor Weinkove said patients could present with a triad of movement, cognitive and personality change but a normal ICE score. The median onset was week 6, with an estimated 5% of patients affected.

Another neurological toxicity related to anti-BCMA products was cranial neuropathies. Professor Weinkove said these occurred earlier (median onset week 3 from infusion), were often low grade and responded well to corticosteroids.

There was also an “important signal” for late-emerging cognitive dysfunction at one year, he said, particularly among older adults receiving CAR T who had early neurologic inflammation, but how it developed and its severity were not yet known.

Secondary malignancies

Professor Weinkove said most of the malignancies that occurred after CAR T-cell treatment were “the ones you’d expect to see after cytotoxic chemotherapy and radiotherapy”, which refractory patients had already received as treatment.

These included myelodysplasia, acute myeloid leukaemia, and some solid cancers, but he also pointed out the rare signal of T-cell lymphoma that was likely to do with the CAR T cells themselves, occurring at a rate of about 1 in 1000.

Enterocolitis was another late toxicity with a 1-3% incidence after ciltacabtagene autoleucel that emerged about three months post CAR T infusion and carried a risk of perforation.

Detection of common and early toxicities

CRS

Professor Weinkove said CRS was one of the first toxicities recognised and also one of the most common, affecting 40-95% of patients, depending on the CAR T product and indication.

Attention was now turning to better identification of the complication to improve patient outcomes and reduce the hospital burden, with continuous temperature readings via wearable monitors increasingly used, he added.

He showed data of a patient treated during the COVID pandemic as an outpatient, who had his fever detected remotely by a temperature tracking device. After an early alert, the patient was evaluated in ED and hospitalised with grade 1 CRS.

“The continuous monitor gave much more granular information about what was happening with his temperature in real time. And some other studies… do indicate that these devices have the potential to detect fevers earlier than intermittent monitoring as you might expect,” Professor Weinkove said.

ICANS

Professor Weinkove said ICANS was harder to detect because the early features, such as mild tremor or dysgraphia, were not always obvious unless clinicians were looking for them specifically. The syndrome usually presented within the first two weeks of CAR T, often concurrent with or after CRS, but could present beyond three weeks.

“[Early detection is] important because it can progress and become very serious indeed, with loss of consciousness, cerebral oedema, or seizures,” Professor Weinkove said.

Patients at his centre were monitored twice daily using the simple 10-point ICE score for ICANS assessment, usually administered by a nurse and a support person in the morning and by the patient’s support person in the evening.

Changes, such as difficulty with writing, could be subtle, Professor Weinkove said.

“I would say often the patient’s support person is the first person to notice that they’re just not quite right, and in the past, we’ve admitted patients because they’re not quite right and then ICANS has been diagnosed subsequently,” he said.

“So really listen to the support person, they will often pick this up before any of the tests do, and before the patient notices it themselves.”

Cytopenias

Professor Weinkove said while cytopenias often occurred early from lymphodepleting chemotherapy, they could also occur later as CAR T-cells entered the bone marrow and released cytokines that suppress haematopoietic stem cells.

Typically management involved excluding other causes like infections or underlying myelodysplasia from prior chemotherapies, giving granulocyte colony-stimulating factor (G-CSF) or other growth factors like thrombopoietin and transfusion support.

Infections

Professor Weinkove said infection was both an early and late side effect, and was “absolutely critical” to identify as it was the primary cause of non-relapse death after CAR T treatment.

“…with CAR T-cells as we’re currently using (them), we’re actually not specifically eradicating the lymphoma or myeloma cells, we’re basically eradicating all the patient’s B-cells or plasma cells. And that means a patient receiving these CAR T-cell treatments cannot make their own antibodies,” he said.

“We’ve completely removed an entire arm of the immune system.”

While a lot of the management focused on the early risk phase and was undertaken at the CAR T-cell treating centre, Professor Weinkove said it was important to recognise the risk of infection beyond the patient’s neutropenic period.

“There’s an ongoing risk of infection that lasts for a couple of years after treatment. It’s really important we have guidelines that help to steer us in how to prevent this risk, because it doesn’t just take place in the treating centre, patients can present to any clinicians,” Professor Weinkove said.

He also shared scoring systems that could help predict risk. These included the pre-infusion EASIX-F score for CRS risk, a modified EASIX-FC version for ICANS risk and the CAR-HEMATOTOX score for cytopenia and infection risk.