In a breakthrough for managing serious neurological complications of advanced cancer treatment, researchers at Virginia Commonwealth University have reported that the JAK inhibitor ruxolitinib effectively resolved severe parkinsonism symptoms in two multiple myeloma patients who received ciltacabtagene autoleucel (cilta-cel) CAR T-cell therapy.
The findings, published in the Journal of Hematology by Dr. Baldeep Wirk and Dr. Jin Lim, address a critical unmet need in the expanding field of cellular immunotherapy, where movement disorders have emerged as potentially life-threatening complications.
CAR T-Cell Therapy and Neurological Complications
B-cell maturation antigen (BCMA)-targeted CAR T-cell therapies like cilta-cel have revolutionized treatment for relapsed or refractory multiple myeloma. However, the CARTITUDE-1 trial, which led to cilta-cel's approval, revealed that approximately 5% of patients developed movement and neurocognitive adverse events, including parkinsonism.
Unlike Parkinson's disease, cilta-cel-associated parkinsonism has a distinct pathogenesis, rendering standard treatments like carbidopa/levodopa ineffective. Traditional therapies for CAR T-cell adverse events, including corticosteroids and immunosuppressants, have shown minimal response in these cases.
"As CAR T-cell therapy for multiple myeloma is expanding and moving to earlier lines, the need to optimize therapy for parkinsonism, a potentially life-threatening complication, becomes more urgent," the researchers emphasized.
Case Reports Demonstrate Ruxolitinib Efficacy
The researchers documented two cases where ruxolitinib successfully treated severe parkinsonism that developed after cilta-cel therapy.
First Patient Case
A 53-year-old female with stage I kappa light chain multiple myeloma became penta-refractory after three years of conventional treatments. Following cilta-cel infusion, she developed grade 2 cytokine-release syndrome on day 6, which resolved with tocilizumab. By day 10, she developed immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome (IEC-HS).
On day 30, she presented with classic parkinsonism symptoms: hypomimia, hypophonia, cogwheel rigidity, micrographia, bradykinesia, and shuffling gait. Brain imaging showed increased T1 signaling in the bilateral basal ganglia, and FDG-PET indicated hypometabolism of the caudate and frontal lobes, confirming stage 4 cilta-cel-associated parkinsonism.
Initial treatments with intravenous immunoglobulin and methylprednisolone failed to improve her condition. Ruxolitinib at 5 mg twice daily was initiated on day 95, and remarkably, within three weeks, her parkinsonism symptoms resolved. Follow-up brain MRI showed normalization of the basal ganglia. The patient achieved stringent complete remission that was sustained one year after treatment.
Second Patient Case
A 70-year-old male with stage I IgA kappa multiple myeloma received cilta-cel after failing multiple prior therapies. He developed grade 1 cytokine-release syndrome on day 8, which resolved with tocilizumab. By day 17, he presented with parkinsonism symptoms concurrent with grade 2 IEC-HS.
Treatment with ruxolitinib, along with other therapies including intravenous immunoglobulin, methylprednisolone, and anakinra, led to resolution of IEC-HS by day 50 and significant improvement in parkinsonism symptoms by day 57. The patient achieved stringent complete remission with measurable residual disease negativity at day 100.
Mechanism of Action and Implications
The researchers noted that ruxolitinib was considered as a treatment option because it blocks signal transduction in the JAK/STAT pathway and reduces proinflammatory cytokine activity. Previous studies had shown that patients with movement disorders following cilta-cel treatment displayed elevated levels of interleukin-6 and interferon-gamma.
Interestingly, both patients had no family history of Parkinson's disease and had low tumor burden at the time of treatment—unlike many patients who developed parkinsonism in the CARTITUDE clinical trials.
"The neurological manifestations of immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome are unknown. It is intriguing to postulate that parkinsonism is a neurological manifestation of IEC-HS. Or is IEC-HS a predictive factor for cilta-cel–associated parkinsonism?" the researchers wrote.
Future Directions
These cases represent the first reported instances of patients experiencing both IEC-HS and parkinsonism concurrently after cilta-cel treatment, suggesting a possible connection between these conditions.
The researchers concluded that "ruxolitinib is a life-saving therapy for IEC-HS and cilta-cel–associated parkinsonism and should be further explored in clinical studies."
As CAR T-cell therapies continue to advance into earlier treatment lines for multiple myeloma, these findings offer a promising approach to managing one of the most serious neurological complications, potentially improving both safety and outcomes for patients receiving these innovative cellular therapies.
