Risk‐adapted therapy for the management of cytokine release syndrome in children undergoing unmanipulated haploidentical stem cell transplantation

Abstract

Background:We aimed to describe an algorithm for the management of cytokine release syndrome (CRS) associated with haploidentical hematopoietic stem cell transplantation (haploSCT). Patients and methods:We performed a prospective study where children up to 18 years of age undergoing haploSCT with post-transplant cyclophosphamide from September 2014 to March 2020 were included. Supportive care included low-dose adrenaline, high-flow nasal cannula, and N-acetylcysteine (NAC). Methylprednisolone and tocilizumab were administered in the peri-engraftment phase for grade 2 CRS or one-log increase and grade 3 CRS or a two-log increase in ferritin, respectively.Results: Data were analyzed in 135/148 children as 13 children died before engraftment due to sepsis. CRS was noted in 97% transplants (grade 1-74.1%, grade 2-15.6%, grade 3-6.7%, grade 4-1.4%). Grade 2 and above CRS was higher in nonmalignant conditions (33% vs 13%, P-value .009). The percentage median rise in ferritin was 129%-grade 1, 171%-grade 2, and 344%-grade 3. Seven children received tocilizumab, and two of whom had ferritin values greater than 100 000 ng/mL with no mortality in this group. Low-dose adrenaline, high-flow nasal cannula, and ventilator support were needed in 13%, 10%, and 4%, respectively. Mortality in our cohort was 3/135 (2.2%), with two deaths due to sepsis and one due to grade 4 CRS. Conclusions:A risk-stratified approach using steroids in grade 2 and tocilizumab in grade 3/4 in the setting of haploSCT with NAC infusion and early use of low-dose adrenaline and HFNC can help provide adequate control of CRS, thereby ensuring optimal outcomes and survival.

Clinical Significance of Haplo-Fever and Cytokine Profiling After Graft Infusion in Allogeneic Stem Cell Transplantation From Haplo-Identical Donors

“…In the current study, haplo-fever was defined as fever early after PBSC infusion, specifically from day 0 to day +6, because fever together with most cytokines decreased to baseline level right after PTCy. Notably, however, other studies have included patients with CRS-associated symptoms until the peri-engraftment period ( 10 , 13 ), in which case patients with engraftment syndrome or early-onset aGvHD may not be able to be ruled out. Third, cytokine elevation was not associated with aGvHD in the present study.…”

“…Interleukin (IL) 6 is one of the key cytokines involved in CRS after chimeric antigen receptor (CAR) T cell treatment, and the use of the monoclonal anti-IL6 antibody tocilizumab was effective in treating such CRS ( 11 , 12 ). With respect to CLSs in haplo-HSCT, several studies have demonstrated that IL6 was increased and the CLSs could be treated with methylprednisolone or tocilizumab ( 9 , 10 , 13 ). In phase I/II study, cyclosporine and mycophenolate mofetil given from day -1 instead of from day +5 in the PTCy model successfully diminished the incidence of early fever after graft infusion, further supporting an immune-based mechanism of fever and/or CLSs ( 14 ).…”