Treatment of Patients with Steroid Refractory Acute Graft Vs Host Disease (SR-GvHD): A Matched Paired Analysis of Anti-CD26 (Begelomab) Compared to Other Treatment

Background. CD26 is a multifunctional glycoprotein expressed both as a soluble form and on the cell surface of various tissues, including activated T lymphocytes and intestinal epithelial cells. CD26 has enzymatic activity (DPP IV) and cleaves N-terminal dipeptides of hormones, cytokines and chemokines . Inhibition of CD26 impairs T cells migration across the endothelial barrier (Trends in Immunology 2008; 29:295). We have used a monoclonal antibody directed against CD26 , to treat SR-GvHD, and showed response rates and long term survival in 50% of patients (Acta Haematologica 1985; 73:185). This anti-CD26 antibody has been recently made available for clinical use (Begelomab) and we have tested the antibody in patients with SR-GvHD .

Begelomab. Begelomab is a murine IgG2B monoclonal antibody against CD26 , produced by a P3X63 hybridoma (ADIENNE SA, Lugano, Switzerland). Twenty eight patients with SR-GvHD, over 18 years of age, were enrolled in two prospective trials testing safety and efficacy of Begelomab at different doses : the first 12 patients, in a pilot study, received 2 mg/day for 5 days. The second group of 16 patients entered a dose finding study with 2 mg/m^2/day x5, 3 mg/dayx5, 4.5 mg/m^2day5 , or 3 mg/m^2/dayx5 followed by 6 additional biweekly doses.

There were no adverse events attributable to Begelomab, and several consecutive infusions, including the additional 6 doses in 3 weeks, were gien without any allergic reaction,

Controls. 82 patients were randomly matched to the 28 Begelomab patients (maximum possible matches, Optimal Match, NCSS 10), from a group of 91 SR-aGvHD patients treated in Genova (n=36), Seattle, USA (n=22) and Salamanca ,Spain (n=33). Matching was performed on GvHD grading, age, disease phase and donor type. The 82 matched Controls were composed of 36 patients from Genova , 17 from Seattle and 27 from Salamanca. Controls received best available treatment, which included anti-thymocyte globulin, extracorporeal photopheresis , mycophenolate , sirolimus , etanercept , high dose steroids high dose cyclophosphamide , alfa1 anti-tripsin.

Clinical characteristics of the patients. The median age of the 2 groups was 44 vs 42 years in Controls vs Begelomab (p=0.2); proportion of donors other than HLA identicall sibling 65% vs 79% (p=0.2), patients with active disease at transplant 51% vs 46% (p=0.6); day of acute GvHD from transplant 17 vs 22 days (p=0.04). Overall grading of acute GvHD , at the time the patient was considered steroid refractory, was comparable in the 2 groups : grade III-IV was 77% vs 74% in Controls and Begelomab respectively (p=0.7); stage 3-4 skin was 50% vs 57% (p=0.5), stage 3-4 liver was 5% vs 21% in Begelomab (p=0.008) and stage 3-4 gut was seen in 30% and 28% respectively (p=0.8).

Response to Begelomab. Response data were available for 55 Controls and 28 Begelomab patients: day 28 responders were 41% in controls vs 75% for Begelomab (p=0.004). In patients with grade 2-4 gut GvHD it was 34% vs 82% (p=0.001).

Outcome. Survival data was available for all 110 patients. The cumulative incidence of non relapse mortality (NRM) at 180 days, was 50% in Controls and 25% in Begelomab (p=0.008) (Fig.1), and the cumulative incidence of relapse related mortality (RRD) at 3 years was 15% vs 25% respectively (p=0.1) The overall survival at 1 year was 31% vs 50% in Controls and Begelomab patients (p=0.06).

Conclusions. Begelomab induces a high remission rate on day+28, in patients with steroid refractory acute GvHD, including a proportion of severe gut and liver GvHD. Non relapse mortality at 6 months was significantly lower in Begelomab patients, as compared to a group of 82 matched controls: this was seen despite a significantly greater proportion of patients with liver stage 3-4 GvHD in the Begelomab group. There was a borderline survival advantage at 1 year for Begelomab patients. To confirm these results, a multicenter prospective randomized trial is ongoing, in patients with SR-aGvHD , comparing Begelomab versus best standard therapy