Phase II Clinical Trial of Abatacept for Steroid-Refractory Chronic Graft Versus Host Disease
Authors: Koshy Anita G. , Kim Haesook T. , Stroopinsky Dina , Liegel Jessica J. , Arnason Jon E. , Ho Vincent T. , Antin Joseph H. , Joyce Robin M. , Cutler Corey , Gooptu Mahasweta , Nikiforow Sarah , Logan Emma K. , Elavalakanar Pavania , Stephenson Susan , El Banna Hassan , Bindal Poorva , Cheloni Giulia , Avigan David , Soiffer Robert J. , Rosenblatt Jacalyn 
Published: November 2021

Abstract
Background: Chronic graft versus host disease (cGVHD) remains a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HCT), with a cumulative incidence of 50% (Arora et al, Biol Blood Marrow Transplant 2016). Systemic corticosteroids are considered first-line therapy, and best approach to managing steroid-refractory cGVHD is lacking. Abatacept is a recombinant fusion protein consisting of the extracellular domain of human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc portion of human immunoglobulin G1 (IgG1) to prevent complement fixation and antibody-dependent cellular cytotoxicity. Abatacept is a selective costimulation modulator that binds specifically to CD80 and CD86 on antigen presenting cells, thus attenuating CD28-mediated T cell activation. We previously reported results from a Phase I clinical trial evaluating the safety and clinical efficacy of abatacept in patients with steroid-refractory cGVHD (Nahas et al, Blood 2018 #NCT01954979). Here we report results of the phase II study evaluating the overall clinical response rate of abatacept in patients with steroid-refractory cGVHD.
Methods: Allogeneic bone marrow or stem cell transplantation recipients were eligible if they developed cGVHD as defined by NIH consensus criteria and were treated with prednisone ≥ 0.25 mg/kg/day for at least 4 weeks without complete resolution of signs and symptoms. Peripheral blood was drawn prior to each dose of abatacept and following completion of therapy to assess the effect of treatment on circulating T cells. Abatacept was administered at 10mg/kg for a total of 6 doses. Doses 1-3 were administered at two-week intervals. One month after administration of Dose 3, abatacept was given at four-week intervals for Doses 4-6. Patients who completed 6 doses of abatacept and continued to demonstrate response were eligible to receive extended duration therapy with monthly abatacept at a dose of 10mg/kg for up to a total of 12 additional doses. Primary study endpoint was overall response rate (ORR) of using abatacept in treating cGVHD. Complete response (CR) was defined as resolution of all manifestations in each organ or site, and partial response (PR) was defined as improvement in at least one organ or site without progression in any other organ or site as per the 2014 NIH Chronic GVHD Consensus Response Criteria (Lee et al Biol Blood Marrow Transplant 2015).
Results: 39 subjects with median age of 62 years (range 25-77 years) had undergone HCT a median of 43 months (range 6-173 months) prior to study entry. Patients were treated with abatacept and received a median of 8 doses (range 2-18). 17 patients had moderate cGVHD and 22 patients had severe cGVHD at baseline. Baseline cGVHD assessment of the 39 evaluable patients showed involvement of the skin in 85% (n=33), mouth in 44% (n=17), eyes in 69% (n=27), gastrointestinal tract (GI) in 18% (n=7), liver in 23% (n=9), lung in 54% (n=21), joints in 82% (n=32), and genital tract in 8% (n=3). The ORR was 49% (19/39 patients) with CR 0% and PR 49%. The organ sites with greatest improvement included lung (33%), eyes (23%), mouth (21%), and joints (21%). Progression of disease occurred in 26% of patients (n=10), with sites of involvement including skin (8%), mouth (10%), eyes (5%), lung (3%), and joints (5%). Baseline median daily dose of prednisone was 20mg with a 27.5% reduction at 1-month follow-up to 14.5mg (p &lt;0.01) and 50% reduction at 5-month follow-up to 10mg (p=0.02). The most common adverse events were neutropenia, fatigue, headache, and upper respiratory infection (URI). No infusional reactions were observed. Nine events of neutropenia (5 Grade 2 , 2 Grade 3, 2 Grade 4) were reported in four patients. Infections were uncommon and included 1 Grade 2 eye infection, 2 Grade 2 lung infections, 1 Grade 3 lung infection, and 1 Grade 3 urinary tract infection. One patient died within 30 days from receiving the 6 th dose of abatacept due to concurrent HSV hepatitis.
Conclusions: Abatacept is associated with a 49% ORR in steroid refractory cGVHD and leads to durable reduction in prednisone dosing over time. Severe infections are uncommon and the infusions are well tolerated. Abatacept represents a promising novel therapeutic agent for patients with steroid-refractory cGVHD.

Disclosures
Stroopinsky: The Blackstone Group: Consultancy. Arnason: Juno/BMS: Honoraria. Cutler: Cimeio: Consultancy; Editas: Consultancy; Kadmon: Consultancy; Pfizer: Consultancy; Mallinckrodt: Consultancy; CareDx: Consultancy; Incyte: Consultancy; Omeros: Consultancy; Syndax: Consultancy; Mesoblast: Consultancy; Deciphera: Consultancy; Jazz: Consultancy. Nikiforow: Kite/Gilead: Other: ad HOC Advisory Boards; Novartis: Other: ad Hoc Advisory Boards; Iovance: Other: ad Hoc Advisory Boards; Glaxo Smith Kline (GSK): Other: ad Hoc Advisory Boards. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Soiffer: Rheos Therapeutics, USA: Consultancy; Kiadis, Netherlands: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, USA: Other: Data Safety Monitoring Board; Precision Biosciences, USA: Consultancy; Jazz Pharmaceuticals, USA: Consultancy; Takeda: Consultancy; Jasper: Consultancy; Gilead, USA: Other: Career Development Award Committee; NMPD - Be the Match, USA: Membership on an entity's Board of Directors or advisory committees. Rosenblatt: Attivare Therapeutics: Consultancy; Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Wolters Kluwer Health: Consultancy, Patents & Royalties; Bristol-Myers Squibb: Research Funding.