Beyond CRS: Redefining CAR-T Toxicity in 2026

Following the 2026 Tandem Meeting, Yan Leyfman, MD, a fellow at NewYork-Presbyterian Hospital and a hematologic malignancies board member for the journal ONCOLOGY^®, discussed critical developments from the meeting. Based on this year’s data, he noted that toxicity associated with CAR T-cell therapy is a time-evolving sequence of biologically distinct syndromes.

Leyfman highlighted the following key domains when it comes to mitigating CAR-associated adverse effects:

1. Cytokine Release Syndrome (CRS) is a Risk Model
   1. CRS events are influenced by factors including product design, tumor context, target antigens, and host immune reserves.
   2. The incidence of CRS may differ between CAR-T products such as obecabtagene autoleucel (obe-cel; Aucatzyl) and brexucabtagene autoleucel (brexu-cel; Tecartus).¹
   3. Selection of CAR T-cell therapies is based on toxicity management rather than efficacy alone.
2. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) is Not a Single Entity
   1. A session from Caroline DiOrio, MD, MSTR, FRCPC, FAAP, of Children's Hospital of Philadelphia, outlined ICANS as an umbrella phenotype rather than a single mechanism.²
   2. Different mechanisms indicate that blanket steroid escalation may not be optimal for every phenotype.
   3. Phenotype-based classification, biomarker guidance, and personalized anti-inflammatory strategies may be necessary to optimize ICANS management.
3. Immune Effector Cell–Associated Hemophagocytic Lymphohistiocytosis–like Syndrome (IEC-HS) is an Underrecognized Threat
   1. Incidence of IEC-HS in multiple myeloma and chronic lymphocytic leukemia may challenge tocilizumab (Actemra)-based algorithms.
   2. Mitigation strategies involving anakinra (Kineret) and ruxolitinib (Jakafi) may be more rational than IL-6 inhibition alone.
4. Long-Term Risks of Cytopenia and Infection
   1. CAR-HEMATOTOX criteria may help predict prolonged severe neutropenia before cellular therapy.
   2. Phase 3 trial (NCT03073967) data for pritelivir in refractory herpes simplex virus infection suggest a shift from inpatient to outpatient care and a reduction in toxicity and disruption to cellular therapy plans.³

Leyfman concluded that toxicity management during the use of CAR T-cell therapy is shifting from a “one-size-fits-all” approach to phenotype- and mechanism-based intervention.

References

1. Valtis YK, Sandhu K, Faramand R, et al. Patient characteristics, toxicity, and response after real world administration of obecabtagene autoleucel and brexucabtagene autoleucel for R/R ALL: A ROCCA analysis. Presented at: 2026 Tandem Meetings; February 4-7, 2026; Salt Lake City, UT. Presentation 32.
2. DiOrio C. CRS & ICANS. Presented at: 2026 Tandem Meetings; February 4-7, 2026; Salt Lake City, UT.
3. Papanicolaou G, Avery R, Workowski K, et al. Pritelivir demonstrated superior efficacy compared to investigator’s choice treatment for refractory herpes simplex virus infections in immunocompromised patients: PRIOH-1, phase 3 safety and efficacy. Presented at: 2026 Tandem Meetings; February 4-7, 2026; Salt Lake City, UT. Presentation LBA-3.