The JAK (Janus kinase) inhibitor ruxolitinib may prove to be an effective treatment of parkinsonism arising from immunotherapy for patients with multiple myeloma, according to the results of two case reports by Baldeep Wirk, MD, and Jin Lim, MD, PhD, both of Virginia Commonwealth University, Richmond. The two patients had multiple myeloma and were treated with the autologous cellular therapy ciltacabtagene autoleucel; they developed immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome (IEC-HS) and parkinsonism, which was effectively treated with ruxolitinib. Their findings were published in the Journal of Hematology.1
Background
Treatment with B-cell maturation antigen (BCMA)-targeted CAR (chimeric antigen receptor) T-cell therapy may lead to movement and neurocognitive treatment-emergent adverse events, including parkinsonism. In the CARTITUDE-1 trial, which led to the approval of the CAR T-cell therapy ciltacabtagene autoleucel for patients with relapsed or refractory multiple myeloma, 5% of patients experienced such adverse events.2 As a distinct pathogenesis has been found between ciltacabtagene autoleucel–associated parkinsonism and Parkinson’s disease, standard Parkinson’s treatments such as carbidopa/levodopa have not been effective in these patients.3
Baldeep Wirk, MD
Jin Lim, MD, PhD
“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 study authors wrote.
Both patients treated with ruxolitinib had no family history of Parkinson’s disease and had a low tumor burden at the time of treatment—unlike many of the patients who developed ciltacabtagene autoleucel–associated parkinsonism in the CARTITUDE clinical trials.
The study authors noted that ruxolitinib was considered as a possible treatment for these patients, as it blocks signal transduction in the JAK/STAT pathway and reduces the activity of proinflammatory cytokines. Patients with movement and neurocognitive treatment-emergent events following treatment with ciltacabtagene autoleucel displayed high levels of interleukin 6 and interferon-gamma.2
Case 1
The first patient was a 53-year-old female with stage I kappa light chain multiple myeloma with del(17p13) and a DNMT3A mutation. She was treated with lenalidomide, bortezomib, carfilzomib, pomalidomide, and daratumumab over 3 years and became penta-refractory. She was then treated with ciltacabtagene autoleucel with standard lymphodepleting chemotherapy.
At day 6 after infusion, she developed grade 2 cytokine-release syndrome. It resolved with two doses of tocilizumab, and on day 10, she developed immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome. She was treated with anakinra, dexamethasone, and cryoprecipitate, and the transaminitis resolved, but the hypofibrinogenemia, hyperferritinemia, and pancytopenia did not.
At day 30, she developed hypomimia, hypophonia, cogwheel rigidity, micrographia, bradykinesia, inability to stand without assistance, and shuffling gait. A brain MRI showed increased T1 signaling of the bilateral basal ganglia, which was not evident prior to ciltacabtagene autoleucel treatment. FDG (fluorodeoxyglucose)-PET indicated hypometabolism of the caudate and frontal lobes. She was diagnosed with stage 4 ciltacabtagene autoleucel–associated parkinsonism.
Intravenous gammaglobulin and methylprednisolone were tried, without any improvement of the parkinsonism. Ruxolitinib at 5 mg twice daily was initiated on day 95, and within 3 weeks, the micrographia, cogwheel rigidity, bradykinesia, hypomimia, and hypophonia resolved. Another brain MRI at day 157 showed resolution of the T1 signaling in the basal ganglia. The ruxolitinib dose was increased to 10 mg twice daily, and the patient did not develop any infections. The patient resumed normal activities and achieved a stringent complete remission with measurable residual disease (MRD) at day 100, which was sustained 1 year after CAR T-cell infusion.
Case 2
The second patient was a 70-year-old male with stage I IgA kappa multiple myeloma with del(17p13), del(1p36), and del(14q32). He was treated with daratumumab, lenalidomide, bortezomib, dexamethasone, salvage pomalidomide, and ixazomib. He then received standard lymphodepleting chemotherapy prior to ciltacabtagene autoleucel.
At day 8, the patient developed grade 1 cytokine-release syndrome, which resolved with two doses of tocilizumab. On day 17, he presented with hypomimia, hypophonia, bradykinesia, cogwheel rigidity, shuffling gait, and micrographia, associated with grade 2 immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome. A brain FDG-PET scan showed hypometabolism of the bilateral frontal lobes; brain MRI was normal. He was diagnosed with stage 4 ciltacabtagene autoleucel–associated parkinsonism.
His physicians tried treating him with intravenous gammaglobulin, methylprednisolone through day 67, anakinra for 7 days, and ruxolitinib twice daily. By day 50, the immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome resolved, and the bradykinesia, cogwheel rigidity, shuffling gait, micrographia, and hypophonia improved by day 57. At day 165, the ruxolitinib dose was lowered to 5 mg once daily without recurrence of the parkinsonism, and the patient resumed normal activities. He achieved a stringent complete remission, including MRD negativity at day 100, which was sustained through 6 months.
“The neurological manifestations of immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome [IEC-HS] are unknown. It is intriguing to postulate that parkinsonism is a neurological manifestation of IEC-HS. Or is IEC-HS a predictive factor for ciltacabtagene autoleucel–associated parkinsonism? These are the first two patients reported who had IEC-HS concomitantly with parkinsonism from ciltacabtagene autoleucel,” Drs. Wirk and Lim wrote in their case report. “In conclusion, ruxolitinib is a life-saving therapy for IEC-HS and [ciltacabtagene autoleucel]–associated parkinsonism and should be further explored in clinical studies.”
DISCLOSURE: For full disclosures of the study authors, visit jh.elmerpub.com.
REFERENCES
1. Wirk B, Lim J: J Hematol. April 22, 2025 (early release online).
2. Cohen AD, Parekh S, Santomasso BD, et al: Blood Cancer J 12:32, 2022.
3. Van Oekelen O, Aleman A, Upadhyaya B, et al: Nat Med 27:2099-2103, 2021.
