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.