Cyclophosphamide may mitigate non-immune effector cell-associated neurotoxicity syndrome (non-ICANS) neurotoxicities (NINTs), particularly movement and neurocognitive treatment-emergent adverse events (MNTs), occurring in patients following treatment with the B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapy ciltacabtagene autoleucel (cilta-cel) for relapsed or refractory multiple myeloma (R/R MM). This is according to a case series published in Blood.
“Our findings underscore the importance of distinguishing between clinically different presentations of NINTs to optimize treatment strategies,” said co-first author Viktoria Blumenberg, MD, of Massachusetts General Hospital Cancer Center and Harvard Medical School, both in Boston. “We found that cyclophosphamide was able to lead to rapid improvement of MNT symptoms in some patients.”
“Early identification of patients with MNTs, especially in the setting of a higher peak absolute lymphocyte count (ALC), could enable timely cyclophosphamide intervention, potentially improving clinical outcomes and reducing the risk of prolonged or permanent neurologic sequelae. In contrast, NINTs presenting solely with cranial nerve palsies are likely to respond to corticosteroids, suggesting a distinct underlying pathophysiology compared to other forms of NINTs,” Dr. Blumenberg said.
In the study, 42 patients with R/R MM were treated with cilta-cel between January and September 2024; of these, 13 (30.9%) developed NINTs. Six of the patients with NINTs (males = 4, age range = 60-76 years) were treated with cyclophosphamide. Their symptoms included movement disorders (n=6), neurocognitive impairments (n=4), personality changes (n=3), cranial nerve palsies (n=4), and peripheral neuropathy (n=2). One patient developed a severe Guillain-Barré-like syndrome requiring temporary mechanical ventilation. For the six patients with NINTs, treatment with corticosteroids achieved only partial symptom resolution, and five patients showed elevated peak ALC, suggesting high CAR T-cell expansion.
The six patients’ symptoms persisted despite treatment with additional immunosuppressive agents, and they received cyclophosphamide at a median of 19 days after symptom onset. Five patients showed an ALC decrease following cyclophosphamide administration. Four patients experienced neurologic improvements within a median of three days, with two of these patients achieving complete resolution at 68 and 144 days, respectively. One patient continued to show unresolved toxicities at data cutoff, and one patient did not respond and died from progressive motor dysfunction and neuropathy. One patient who initially experienced neurologic improvements died from COVID-19. Grade 3-4 infectious complications occurred in four patients within 30 days of cyclophosphamide administration, which the authors said highlights the need for “vigilant infection monitoring, prophylaxis, and treatment.”
Four patients “experienced rapid and durable symptom responses upon treatment with cyclophosphamide without diminishing anti-tumor responses, including up to 21 months after cyclophosphamide administration,” the authors noted. The two patients achieving complete resolution of toxicities had the “highest ALC peak count after CAR T-cell infusion and the highest ALC and CAR T-cell count prior to cyclophosphamide administration.”
Of the seven patients with NINTs not treated with cyclophosphamide (males = 4, age range = 63-70 years), five experienced isolated cranial nerve palsies, which resolved with corticosteroids with or without intravenous immunoglobulin. The peak ALCs before symptom onset were lower among patients not treated with cyclophosphamide versus those treated with cyclophosphamide (2.2 vs. 6.335 k/μl).
According to Dr. Blumenberg, the main takeaways for clinicians are as follows: “Patients who develop NINTs after BCMA-directed CAR T-cell therapy need to be evaluated expeditiously to develop a treatment plan; NINTs presenting solely with cranial nerve palsies are likely to respond to corticosteroids; NINTs presenting with MNTs are less likely to respond to corticosteroids alone, and some patients may benefit from early initiation of a CAR T-cell-ablating strategy such as cyclophosphamide; and high peak ALC counts early post-infusion may serve as a predictive marker for developing MNTs, guiding earlier intervention strategies.”
Limitations to the study include its retrospective design, the small sample size, and the patients’ complex treatment regimens, including other immunosuppressive therapies, which could have potentially contributed to symptom relief. Additionally, the inconsistent complete clinical responses to cyclophosphamide and the delayed full symptom recovery underscore the need for prospective studies with larger cohorts to help establish how to use cyclophosphamide to treat NINTs.
“Further studies are needed to extend these findings and establish evidence-based guidelines for managing NINTs following BCMA-targeted CAR T-cell therapy,” Dr. Blumenberg concluded.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Blumenberg V, Puliafito BR, Graham CE, et al. Cyclophosphamide mitigates non-ICANS neurotoxicities after ciltacabtagene autoleucel treatment [published online ahead of print, 2025 March 31]. Blood. doi: 10.1182/blood.2024028172.
