DISCUSSION
The common and severe toxicities related to CAR T-cell therapy for patients with B-ALL are CRS and neurotoxicity. After CAR-T cells are reinfused to the body, they could bind to target antigen and then mediate the destruction of tumor cells. After the tumor cell is destroyed, cytokines could be released, including INF-γ, TNF-α, IL-2, IL-6, and IL-10(13), which all mediate CRS. IL-6 contributes to the key symptoms of CRS, leading to vascular leakage, DIC, myocardial dysfunction. These AEs are reversible and treatable with appropriate strategies, but they could become severe or life threatening(14).
The guidelines show IL-6 receptor antibody and corticosteroids are effective strategies for sCRS. Corticosteroids could be administered, especially in situations in which tocilizumab is not fully effective. Rebecca reported that the preemptive use of tocilizumab and steroids could reduce the sCRS rate, with no effect on MRD-negative rate or severe neurotoxicity(15). Thus, in the present case, several doses of IL-6 receptor antibody and dexamethasone were used preemptively, but the patient’s condiction still deteriorated rapidly, followed by neurotoxic manifestations and resistance to high-dose methylprednisolone.
NCCN demonstrated that plasma exchange may be useful for CRS combined with HLH(16). However, for conventionally therapeutic-resistant fetal CRS and ICANS, no clear guidelines about blood purification could be found. Prior case reports showed that plasma exchange or hemofiltration may be the alternative therapies for sCRS(17, 18). For sCRS, Heng recommended that TPE may be useful to eliminate cytokines, such as IL-6, IL-10, and TNF-γ(19). However, in CRS caused by sepsis and septic shock, CRRT seems more common. Aygun preferred hemofiltration, not only for AKI but also for reducing cytokine storms in a model of continuous venovenous hemofiltration(20). Ning showed that in sepsis, IL-6, IL-10, and TNF-α could be eliminated rapidly in high-volume hemofiltration compared with CRRT. The rates of replacement fluid at 60 mL/kg/h were more beneficial than at 30 mL/kg/h(21). In the present study, CRRT not only kept the fluid balance but also decreased the level of interleukins. For severe cytokine storm, TPE and high-dose CVVH are recommended in COVID-19. TPE could clear factors, including all cytokines, antibodies, complement components, immune complexes, and endotoxin. However, it could not fully remove cytokines in the immune system. High-dose CVVH (> 35 mL/kg/min) are recommended at the interval time. CVVH may have extra-renal benefits in increasing the clearance of middle-sized molecular inflammatory factors, and it may be suitable for hemodynamically unstable patients with cytokine storm. These findings showed that combination therapy could remove most toxic substances; however, disadvantages could not be warranted in single treatment for CRS(22). In addition, CRRT did not influence the expansion of CAR T-cell, indicating the effectiveness and safety of continuous blood purification in sCRS.
For patients refractory to steroids and developing life-threatening consequences, RUX may be useful for numerous pro-inflammatory cytokines to promote signaling via intracellular pathways involving Janus kinases. However, whether RUX could control CRS without toxicity against therapeutic T cells remains unclear. Jing reported that JAK-state inhibitor RUX could rapidly resolve CRS in a small-scale cohort(23). Similar with prior studies, the present study showed that RUX is useful in reducing CRS, with no influence in CAR T-cell amplification.
The mechanism underlying the development of ICANS remains unclear, and massive release of inflammatory cytokines and alterations in blood–brain barrier exacerbate the development of ICANS. Serum cytokine levels, including those of IL-6, IL-10, IFN-γ, TNF-α, and Ang-2, continuously increased in ICANS(24). For severe ICANS with grades 2, 3, or 4, corticosteroids are recommended to decrease systemic and CNS inflammation. However, no consensus guidelines are available with regard to the exact dose, timing, and duration of steroids(9). For the patient in the present study, high doses of methylprednisolone seemed to show no reaction. As tocilizumab could not cross the blood-brain barrier, levetiracetam was administered to control epileptic seizure. Plasma exchange was administered to reduce the IL-6 level, and continuously administering it two times seemed useful, followed by RUX and a low dose of methylprednisolone. The brain function of the patient rapidly recovered without neurologic symptoms and/or signs.
The incidence of AKI in adults accounts for 30%, mostly in patients with previous autologous or allogeneic stem cell transplantation. Though the incidence of grade 3 AKI was 8.7%, most patients could recover kidney function within 30 days(25). The patient in the present study had severe AKI due to sCRS but no recovery to baseline was observed, mainly because of insufficient administration of CRRT.
For sCRS, MOF, and ICANS in patients refractory under steroids, continuous blood purification seemed useful. This case demonstrated that at least two times of plasma exchange combined with CRRT could be administered at intermission. RUX also may be useful in reducing the toxic effects. As ICANS and AKI are reversible, active interventional strategies should be conducted.
Acknowledgements This work was supported by the Foundation of 2018 Beijing Key clinical Specialty Construction Project-Pediatrics(2199000726).
Conflict of Interest statement The author declare that they have no conflict of interest.