Second-Line Treatment In Steroid Refractory Acute Graft Versus Host Disease During a 10-Year Period: A Single Centre Experience Comparing 4 Strategies

Steroid-refractory acute graft versus host disease (SR-aGVHD) is a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (alloHSCT). Long-term mortality rate remains around 80% (Robin et al. Transplantation 2009: 88:1131) whatever the treatment is and there is no consensus concerning the optimal second-line treatment for SR-aGVHD. In our centre, the policy to treat SR-aGVHD has changed over time: tacrolimus (FK) or cyclosporine (CsA) plus mycophenolate mofetil (MMF) from 2000 to 2004, etanercept or inolimomab after this period with a preference for etanercept in patients with gut or liver involvement.

An observational study was conducted to compare survival of patients who received the 4 different strategies.

All consecutive patients with SR-aGVHD were included. Ninety-four patients met the criteria and were included in this study. The main end-point was overall survival. Survival curves were estimated by Kaplan-Meier estimator and compared using log-rank test. The proportional hazards assumption was checked by examination of Schoenfeld residuals and Grambsch and Therneau's lack-of-fit test. SR-aGVHD was defined as progressive disease after 3 days, stable disease at 7 days or partial response at 14 days.

Median age was 37 years (range: 5 to 64). Sixty-two (66%) patients had received a myelo-ablative conditioning regimen and 64 (68%) were transplanted from an unrelated donor. Stem cell source was peripheral blood stem cell (PBSC) in 41 patients (44%), bone marrow in 40 (43%) and cord blood in 13 (14%). Most patients received CsA as part of the GVHD prophylaxis regimen, either with methotrexate or MMF (except for MMF second-line treatment patients). GVHD occurred at a median of 15 days after transplant (range: 4 to 105). All patients received steroids as first-line treatment of acute GVHD. Second-line treatment was CsA/MMF in 15 patients (16%), FK/MMF in 38 (40%), inolimomab in 20 (21%) and etanercept in 21 (22%), and was initiated a median of 12 days (range: 1 to 218) after GVHD diagnosis. Grade III-IV acute GVHD was more frequent in patients treated by etanercept (72%) compared to inolimomab (35%), FK/MMF (40%) or CsA/MMF (40%). Overall, 36 (39%) patients responded to the second-line treatment (complete response (CR): 27%, partial response (PR): 12%). Overall response (CR+PR) was 30%, 15%, 53% and 47% with inolimomab, etanercept, FK/MMF and CsA/MMF, respectively. With 74 (range: 3 to 103) months median follow-up from the date of initiation of second-line treatment, 2-year survival was 29% (95%CI: 21–41). Risk factors for overall survival in univariate analysis were age (HR: 1.17, 95%CI: 1.01–1.36), disease status at transplant (HR: 3.09, 95%CI: 1.84–5.2), PBSC as graft source (HR: 1.86, 95%CI: 1.08–3.19), recipient CMV positive status (HR: 1.78, 95%CI: 1.07–2.96), grade 3–4 GVHD (HR: 2.92, 95%CI: 1.77–4.82), liver involvement (HR: 4, 95%CI: 2.39–6.69) and etanercept as second-line treatment (HR: 2.04, 95%CI: 1.09–3.82). In multivariate analysis, only disease status at transplant, grade 3–4 GVHD and liver involvement were significantly associated with survival.

Four strategies of treatment including 2 anti-cytokines treatment over a 10-year period give similar survival in patients with steroid refractory acute GVHD.

No relevant conflicts of interest to declare.