Propensity Score Matching Analysis Comparing Azathioprine Plus Prednisone Vs Prednisone Alone Regimens As First-Line Treatment in Chronic Graft-Versus-Host Disease

Background: Azathioprine (AZA) has been used as a steroid sparing agent in allogeneic BMT program at the Princess Margaret Cancer Centre, Toronto, Canada for last two decades especially for cGVHD treatment. A previous clinical trial (Sullivan, Blood 1998) compared prednisone (PRD) alone vs PRD plus AZA for the treatment of extensive chronic GVHD (cGVHD) suggesting that PRD alone showed a better survival than PRD+AZA. However, the NIH consensus criteria (NCC, 2005) for cGVHD and new statistic endpoint to evaluate efficacy of cGVHD, failure free survival (FFS), have been recently introduced and increasingly used. Therefore, we conducted retrospective study attempted to evaluate the efficacy of PRD+AZA regimen compared to PRD alone regimen with respect to failure free survival (FFS) as well as overall survival (OS), non-relapse mortality (NRM)and relapse incidence. In order to adjust for the risk factors which affect the choice of treatment between different treatment options, propensity score matching (PSM) analysis was adopted in the present study.

Methods: The patients diagnosed with late onset acute GVHD was excluded. A total of 240 patients were included in the analysis, transplanted at the Princess Margret Cancer Center between 2009 and 2013, diagnosed with cGVHD by NCC, and treated with PRD+AZA (n=98) or PRD alone (n=142) as first line treatment. Failure free survival (FFS), OS, NRM and relapse were compared between the 2 groups.

A case-control study was performed with well-balanced pairs of PRD+AZA vs PRD patients. For the PSM analysis, propensity score (PS) was calculated. Clinical variables included in PS calculation were global score (GS) by NCC, subtype of cGVHD (classical vs overlapping), age, gender, duration from HCT to cGVHD initial treatment, performance status (PS), progressive type onset (PTO) of cGVHD, thrombocytopenia (TP) and each organ involvement of cGVHD per skin, gastrointestinal tract, liver, lung and musculoskeletal system. A total of 74 case-control pairs were selected within 0.1 of a difference in propensity score.

RESULTS: With a follow-up of 43. 6 months, the 2-year FFS, OS, NRM and relapse incidence was 24.7 %, 75.6 %, 16.6% and 7.7%, respectively. The median FFS was 7.9 months (95% CI, 6.1-9.6 months). PRD+AZA group showed a longer FFS duration compared to PRD group (13.2 vs 5.6 months, p<0.001). In addition, PRD+AZA showed a lower NRM rate than PRD group (10.8% vs 20.6% at 2 years, p=0.008). A trend of lower relapse risk was noted in PRD+AZA over PRD group (2.6%vs 11.0% at 2 years, p=0.074).

Within the overall population, imbalanced demographic and disease characteristics were observed between the 2 groups, including longer duration from HCT to cGVHD initial treatment (p<0.001), fewer patients with severe GS by NCC (p<0.001), fewer patients with PTO (p=0.002), fewer with TP (p=0.008) and better performance status (p=0.008) in the PRD+AZA group. After PSM procedure, all clinical variables became well balanced between the 2 groups.

The PSM analysis successfully confirmed our previous observation of superior outcomes in PRD+AZA group to those in PRD group. The median FFS duration was significantly longer in PRD+AZA (17.6 months) compared to PRD group (7.4 months, p<0.001). There was a trend of survival benefit in favor of PRD+AZA group (87.4% vs 78.2% at 2 years; p=0.074). There was no significant difference between 2 groups in NRM (p=0.289) and relapse rate at 2 years (p=0.187). Confined to the same NCC GS group, there was a trend of a longer FFS in PRD+AZA compared to PRD group. In the group with moderate grade of cGVHD, a longer FFS duration was noted in PRD+AZA than in PRD alone ( 11.1 vs 7.4 months, p=0.001).

Compared to PRD group, PRD+AZA group showed a higher success rate of PRD tapering below 0.5mg/Kg/day by first 6 months (90.5% in PRD+AZA vs 75.8% in PRD group, p=0.018).

Conclusion: The present study suggested that 1) addition of AZA in the PRD based regimen for cGVHD treatment could improve FFS in patients with cGVHD requiring systemic immunosuppression, and that 2) AZA did not increase the risk of relapse and may have a survival benefit with rapid reduction of corticosteroid or delay of switch to second line treatment. Thus AZA should be considered as a therapeutic option for steroid sparing agent in frontline cGVHD treatment, PRD based.