Table 4.
Summary of current and investigational strategies for CRS and ICANS management after CAR T-cell therapy for ALL
| Reference | Study design | CRS | ICANS | |
|---|---|---|---|---|
| Current management according to the Kymriah REMS | ||||
| Prophylaxis | Maude SL et al. NEJM 2018 (ELIANA) | Phase 2 | Not recommended | Not recommended |
| Mild symptoms | Supportive care only | Supportive care only | ||
| Moderate to severe symptoms | Tocilizumab Corticosteroids in the absence of clinical improvement after the first dose of tocilizumab |
Corticosteroids1 | ||
| Investigational strategies | ||||
| Prophylaxis | ||||
| Tumor burden-based CAR T-cell dose reduction | Turtle CJ et al, JCI 2016 | Retrospective analysis of Phase I/II data after ad hoc amendments | Lower rates of ICU admission in high tumor burden patients | Lower rates of severe ICANS in high tumor burden patients |
| Split-dosing (day 1, 10%; day 2, 30%; day 3, 60%) | Frey NV et al JCO 2020 | Lower rates of severe CRS | Not specifically reported per cohort | |
| Early intervention | ||||
| Tocilizumab for mild2 CRS | Gardner RA et al. Blood 2019 | Retrospective analysis of Phase I/II data after ad hoc amendments | Comparable rates of any grade
CRS Lower rates of severe CRS |
Comparable rates of severe ICANS |
| Tocilizumab for fever if high tumor burden (≥40% marrow blasts) | Kadauke S et al. Cytotherapy 2019 | Prospective, non-randomized, two cohort (high and low tumor burden) | Low rates of severe CRS Met primary endpoint (grade ≥ 4 CRS <30%) |
Not reported |
| Steroid for grade ≥2 ICANS | Shah BD et al ASCO 2019 (ZUMA-3) | Retrospective analysis of
Phase I/II data after ad hoc amendments |
Comparable rates of CRS (any grade and severe) | Lower rates of severe ICANS Shorter duration of ICANS |
| HLH-type manifestations 3 | ||||
| Anakinra (5-8mg/kg/day subcutaneously) +/− corticosteroids | Shah NN, JCO 2020 | Retrospective analysis of
Phase I/II data after ad hoc amendments |
Resolution of HLH-like manifestations in all patients | Not specifically reported Overall mild ICANS severity |
| Refractory ICANS or HLH | ||||
| Anakinra (1mg/kg/day subcutaneously) +/− corticosteroids | Strati P et al, Blood Advances, 2020 | Retrospective analysis of case series (n=8) after axicatagene ciloleucel treatment for LBCL | Not specifically reported All patients had presented with grade ≥3 CRS prior to severe ICANS or HLH |
Response in 4 of 8 patients Recurrence of ICANS in 1 or 4 responders |
Per the Kymriah Risk Evaluation and Mitigation Strategy (REMS) only supportive care is recommended for ICANS but most institutions would recommend corticosteroids.
Mild CRS symptoms were defined as follows: persistent fever for 10 hours unresponsive to acetaminophen, recurrent hypotension unresponsive to fluid bolus, hypoxia requiring oxygen supplementation
Defined by peak ferritin >100,000μg/L and at least two of the following criteria: hepatic aminotransferases or bilirubin grade ≥3; creatinine increase grade ≥3; pulmonary edema grade ≥3; evidence of hemophagocytosis on bone marrow aspirate/biopsy. Abbreviations: ASCO, American Society of Clinical Oncology; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; HLH, hemophagocytic lymphohistocytosis; ICANS, immune effector cell-associated neurotoxicity syndrome; JCI, Journal of Clinical Investigation; JCO, Journal of Clinical Oncology; LBCL, large B cell lymphoma; NEJM, New England Journal of Medicine.