Conference Coverage

Rapid CAR-T Expansion Signals Higher Delayed Neurotoxicity Risk After Cilta-cel

Edited by:
Ashton L. Stahl

Key Highlights

  • Delayed neurotoxicity occurred in 11% of patients treated with commercial ciltacabtagene autoleucel across 3 US centers.
  • Higher peak CAR T-cell expansion and higher peak absolute lymphocyte count (ALC) were associated with delayed neurotoxicity and Parkinsonism.
  • Simple ALC thresholds between days 7–21 post-infusion captured most delayed neurotoxicity events while excluding over half of patients without these toxicities.

Relapsed/refractory multiple myeloma (RRMM) remains a major therapeutic challenge, and ciltacabtagene autoleucel (cilta-cel) has shown deep and durable responses in this setting. However, broader adoption in the US has been constrained by unique toxicities, notably delayed neurotoxicity (DNT). In an abstract presented at the 67th ASH Annual Meeting and Exposition, investigators from 3 US academic centers evaluated whether early CAR T-cell expansion and absolute lymphocyte count (ALC) could stratify DNT risk after commercial cilta-cel in routine practice.

The analysis included 256 adults with RRMM treated with cilta-cel between 2022 and 2024 (ALC cohort) and a subset of 54 patients with detailed flow cytometry–based CAR T-cell expansion data (CAR expansion cohort). Investigators assessed associations between peak ALC and DNT, characterized patterns of CAR T-cell expansion, and derived clinically usable ALC thresholds during the first 3 weeks after infusion.

Study Findings

In the ALC cohort (n = 256), the median age was 64 years; 54% were male, and 38% were penta-refractory. The median follow-up was 14.7 months, and the median progression-free survival reached 28.7 months. Delayed neurotoxicity occurred in 11% of patients (n = 29), including 8% with cranial nerve palsy (n = 20) and 3% with Parkinsonism (n = 8).

Within the CAR expansion cohort (n = 54), peak CAR T-cell expansion did not significantly differ between patients who achieved at least a partial response versus those who did not at either 3 or 6 months, and it was not associated with time-to-progression. Peak expansion was also not significantly different between patients who developed cytokine release syndrome (CRS) and those who did not. By contrast, expansion was significantly higher in patients who developed immune effector cell–associated neurotoxicity syndrome or DNT.

In the broader ALC cohort, patients with DNT had a higher median peak ALC (5,780/μL) compared with those without DNT (2,200/μL). Among patients with Parkinsonism, peak ALC was markedly higher (13,335/μL) than in those without Parkinsonism (2,270/μL). The early rise in ALC from day 7 to 12 after infusion was greater in patients who later developed DNT (5,360/μL vs 1,040/μL).

Using these data, the investigators identified 2 practical ALC thresholds to stratify DNT risk: (1) peak ALC ≥ 3,000/μL between days 7–21, and/or (2) peak ALC ≥ 2,500/μL between days 8–12 with at least a twofold increase from the prior value. Together, these criteria captured 81% of DNT cases while excluding 59% of patients who did not develop DNT.

Clinical Implications

According to the authors, rapid and robust CAR T-cell expansion after cilta-cel was associated with an increased risk of delayed neurotoxicity, including Parkinsonism, in adults with RRMM treated at major US centers. They further note that ALC, a routinely available laboratory parameter, may function as a surrogate marker of CAR T-cell expansion and enable earlier recognition of patients at higher risk of DNT.

The authors suggest that the proposed ALC thresholds, ≥ 3,000/μL between days 7–21 or ≥ 2,500/μL between days 8–12 with a ≥ 2-fold rise, could guide risk stratification and inform the timing of preemptive interventions aimed at mitigating neurotoxicity in real-world cilta-cel programs.

Expert Commentary

“Rapid and robust CAR T-cell expansion was associated with an increased risk of DNT,” the researchers concluded. “Additionally, ALC may serve as a practical surrogate for early identification of high-risk patients.”

Reference

Hosoya H, Velayati A, Dima D, et al. Rapid peak CAR-T expansion is associated with delayed neurotoxicity following ciltacabtagene autoleucel in multiple myeloma. Presented at: 67th ASH Annual Meeting and Exposition in Orlando, FL. December 7, 2025. Accessed December 5, 2025. https://submit.hematology.org/program/presentation/673758.