Combination Therapy with Inolimomab and Etanercept for Severe Steroid-Refractory Acute Graft-versus-Host Disease

Abstract

Steroid-refractory acute graft-versus-host disease (aGVHD) remains an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). A protocol on the management of aGVHD was introduced in our center that incorporated a prospective study on combination therapy with inolimomab (anti-IL-2Rα) and etanercept (anti-tumor necrosis factor-α) for steroid-refractory aGVHD. We evaluated the efficacy and safety in 21 consecutively treated patients. The patients had developed refractory aGVHD after SCT (n = 16) or donor lymphocyte infusion (n = 5), and aGVHD was classified as severe in all patients, mostly due to gastrointestinal involvement stages 2 to 4. No drug-related side effects were observed apart from the infections expected to occur in these severely immunocompromised patients. Overall response at day 28 of second-line therapy was 48% (10/21), with 6 and 4 patients achieving a complete and partial response, respectively. Eventually, 19 patients died (90%), with early mortality (<6 months) predominantly resulting from refractory aGVHD and secondary infections and late mortality resulting from relapse of the underlying disease. With a median follow-up of 55 days, the estimated rates of 6-month and 2-year overall survival were dismal, 29% and 10%, respectively. In conclusion, the combination of inolimomab and etanercept for steroid-refractory aGVHD failed to improve the dismal prognosis of severe steroid-refractory aGVHD.

Phase I/II Trial of a Combination of Anti-CD3/CD7 Immunotoxins for Steroid-Refractory Acute Graft-versus-Host Disease

“…As expected in the clinical setting of this study, infections were relatively common; however, the incidence of infection did not differ substantially from that in previous reports or in our institutional controls [21,39,40]. The multifaceted immune defects due to the presence-and treatment-of GVHD itself, the disruption in the mucosal barrier due to GI GVHD, and/or dysbiosis can explain the majority of these infections, particularly the C difficile infections and enterococcal bacteremia [41].…”

“…Two patients developed a Clostridium difficile infection, and 1 of them died due to pseudomembranous colitis. Moreover, although 5 patients developed bacteremia (with infection by enterococci in 2 patients, staphylococci in 2 patients, and Klebsiella oxytoca in 1 patient), the incidence rate (25%) was not higher than that reported in historical controls [21].…”

“…Kaplan-Meier curves were used to analyze OS. The chisquare test was used to compare the ORR and the rates of CR and PR on day 28 after initiation of CD3/CD7-IT therapy, with the corresponding results obtained from institutional historical controls who received either inolimomab-etanercept (n = 21) or infliximab (n = 21) [21]. The 6-month OS rate was compared using the log-rank test.…”

“…The secondary endpoints were the day 28 CR rate, 6-month overall survival (OS), and the incidence of cGVHD. ORR, CR on day 28, and 6-month OS were compared with data recorded for our institutions' historical controls who received either inolimomab-etanercept (n = 21) or infliximab (n = 21) (S4; Table 1) [21]. CR was defined as the resolution of all signs and symptoms associated with aGVHD.…”

Combining therapeutic antibodies using basiliximab and etanercept for severe steroid-refractory acute graft-versus-host disease: A multi-center prospective study

“…They concluded that the combination of inolimomab and etanercept failed to improve the dismal prognosis of severe SR-aGVHD. 33 Two factors may be related to our superior outcomes of the combination treatment by basiliximab and etanercept. First, as TNF inhibitors, etanercept, and infliximab have different structures and modes of action.…”