Effective Prevention of Steroid-Requiring Chronic Gvhd with B Cell Depletion: A Randomized, Placebo-Controlled Trial

Strategies that eliminate or inhibit B cells can be therapeutic in steroid refractory cGVHD, and two phase II trials have demonstrated effective prevention of cGVHD using post-transplant rituximab. Obinutuzumab (Obin, Genentech) is a 2nd generation monoclonal anti-CD20 antibody with enhanced B cell depletion activity over rituximab. We performed a randomized double-blind, placebo-controlled trial of 4 doses of Obin/placebo (1000 mg iv at 3, 6, 9, 12 months) to determine if steroid-requiring cGVHD (SR-cGVHD) could be prevented 12 months after HCT (NCT# 02867384). SR-cGVHD was felt to be a more objective measurement of cGVHD severity than NIH cGVHD stage alone. We present clinical trial results and compelling biologic correlates here. Results 181 subjects were enrolled (92 Obin, 89 placebo). 167 subjects followed for >1 year from HSCT (84 Obin, 83 placebo) are presented here. The primary endpoint, the cumulative incidence (CI) of SR-cGVHD at 12 months from HSCT, was significantly reduced with Obin in comparison with placebo: 11% vs 38%, p=0.008, Fig 1. The corresponding rates of NIH Mod-Severe cGVHD at 12 months were 20% vs 35% (p=0.069). The CI SR-cGVHD by 2 years remained lower in the Obin arm (28% vs 44%). In multivariable analysis, only study arm (Obin vs placebo) was associated with SR-cGVHD (p=0.01). Obin was safe and well tolerated with only 5 Gr 3-4 infusion reactions (placebo: 0) and more Gr 3-4 neutropenia (32.1% vs 4.8%). There was no difference in the 2-year CI of relapse (20% vs 28%, p=NS) and the SR-cGVHD-free, relapse-free survival in the Obin arm was superior (43% vs 30%, p=0.009). CD19+ B cell depletion was complete in the Obin arm through 1 year (median cell count 0) and B cells were lower at 24 and 36 months (36 month median 55.5 vs 484.4 cells/mL, p=0.02) while B cell recovery was normal in the placebo arm (p<0.0001 at 3, 6, 9, 12 months). In a subset of 65 male subjects, we measured allogeneic antibody (Ab) development against H-Y minor antigens at 3, 12 and 24 months (Miklos, 2005). Before randomization, the prevalence of H-Y Ab responses was the same in both arms (35% vs 40%, p=0.79). At 12 months, the incidence of H-Y Abs was markedly lower in the Obin arm (12.5% vs 36.7%, p=0.038), with no new subject in the Obin arm developing H-Y Abs in the interval. Among Obin subjects with no or low H-Y Abs at baseline, the incidence of SR-cGVHD was significantly lower than all other subjects: 13% vs 57%, p=0.026, Fig 2.B cell depletion with 4 doses of Obin significantly reduces the requirement for steroids for the treatment of cGVHD and significantly increases CRFS in well-matched, tacrolimus based PBSC. Obin is well tolerated and is associated only with transient neutropenia. Effective prevention of SR-cGVHD can be achieved in subjects without ongoing antibody responses against known mHA. This double-blind, placebo-controlled randomized trial supports practice changing cGVHD prophylaxis in tacrolimus-based HSCT.