Prophylactic Rituximab After Allogeneic Stem Cell Transplantation Prevents Steroid-Requiring Chronic Graft-Vs.Host Disease
Authors: Cutler Corey , Sun Lixian , Kim Haesook , Sarantopoulos Stefanie , Bindra Bhavjot , Chen Yi-Bin , Rosenblatt Jacalyn , Armand Philippe , Koreth John , Ho Vincent T. , Alyea Edwin P. , Soiffer Robert J. , Ritz Jerome , Antin Joseph H. 
Published: October 2019

Abstract
Abstract 214
There are no standard methods for the pharmacologic prevention of chronic GVHD (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Based on compelling biology implicating B cells in the pathophysiology of cGVHD and the utility of rituximab as therapy for established cGVHD, we performed a phase II trial of rituximab for the prevention of cGVHD after HSCT.

Methods:
64 patients in remission without active GVHD received rituximab (375 mg/m2) at 3, 6, 9 and 12 months after HSCT. Related and unrelated donor recipients of 5/6 or 6/6 HLA-matched PBSCs were eligible. Prophylactic IVIG infusions were permitted at investigator discretion. Chronic GVHD severity was assessed by the requirement for systemic corticosteroids, with a historical rate of steroid-requiring cGVHD within 1 year of transplantation of approximately 60% at our institution.

Results:
56 patients have been followed for at least 12 months from HSCT. One patient had a hypersensitivity reaction requiring treatment discontinuation and one patient was lost to follow-up, leaving 54 evaluable patients. The median patient age was 55 years (range 19 – 74); 25 were MRD recipients and 31 were URD recipients. 21 underwent myeloablative and 35 underwent reduced-intensity HSCT. Prior grade II-IV acute GVHD occurred in 6 patients (10.7%). Primary GVHD prophylaxis was sirolimus+tacrolimus (67.9%) or calcineurin inhibitor+methotrexate (32.1%), both without ATG. Overall, in the first year after HSCT there were 18 episodes of grade 3 toxicity and 8 episodes of grade IV toxicity without clear relationships to rituximab. There were 15 documented bacterial infections. Transient grade 3–4 neutropenia occurred in 11 subjects. 12 patients relapsed during the year after HSCT and 2 subjects died of non-relapse causes (pneumonitis and sepsis). The cumulative incidence of any cGVHD at 1 year from HSCT was 44.6%, however, the cumulative incidence of cGVHD requiring initiation of systemic corticosteroids was only 31.2%. When stratified by donor type, the incidence of all cGVHD and steroid-requiring cGVHD was 33.6 and 22.9% (MRD) and 52.3 and 37.0% (URD). Donor type, age, conditioning intensity, GVHD prophylaxis, donor gender or malignancy did not impact the incidence of cGVHD in a multivariable model. 8 additional patients required corticosteroids during the first post-transplant year for treatment of anorexia, pneumocystis pneumonia, pneumonitis or late acute GVHD. At 12 months, 50% of all patients had successfully discontinued all immunosuppressants and only 22.4% of all patients were on corticosteroids. Since anecdotally, myofascial and sclerodermatous cGVHD are treated effectively with rituximab, it is notable that only 1 patient had this subtype of cGVHD in contrast to the expected frequency of this manifestation of cGVHD in individuals not given rituximab. At 12 months from HSCT, relapse-free survival was 71.1% and overall survival was 88.6%. CD19+ B cells were very low during the first year post-HSCT, however patients without cGVHD demonstrated a trend toward enhanced B cell recovery at 6, 9 and 12 months from HSCT (6 months 0.58 vs. 0.28 × 106/L; 9 months 1.10 vs. 0.66 × 106/L; 12 months 1.09 vs. 0.76 × 106/L, all p=NS). Similarly, there was a trend for BAFF levels to be higher throughout the first year in patients without cGVHD (6 months 13.64 vs. 11.81; 9 months 12.30 vs. 9.57; 12 months 12.25 vs. 9.79, all p=NS). Among patients with cGVHD, there was a trend for BAFF levels to be higher in those who did not require systemic corticosteroids when compared to those that required steroids at 9 and 12 months (9 months 15.09 vs. 5.89 p=0.045; 12 months 11.86 vs. 7.14, p=0.25). 18 month B cell and BAFF data will be available at ASH.

Conclusions.
The use of rituximab at 3, 6, 9 and 12 months after allogeneic HSCT can reduce the rate of steroid-requiring cGVHD by up to 50% when compared with historical control data. The presence of enhanced B cell recovery, potentially related to higher BAFF levels found during the first year after HSCT, predicts freedom from cGVHD and a reduction in the severity of cGVHD among those affected. These data provide additional support for the hypothesis that B cells contribute to the development of cGVHD. A randomized trial should be performed to confirm these findings.

Disclosures:
No relevant conflicts of interest to declare.