Improved Survival using Dual Monoclonal Antibody Therapy with Aggressive Anti-Microbial Prophylaxis In Steroid-Refractory Acute Graft-Versus-Host Disease

Abstract 1262

Steroid-refractory acute graft versus host disease (aGVHD) is associated with a poor prognosis. Although clinical responses occur to second line therapy they are associated with high rates of infection and dismal long-term survival. Blockade at 2 different points in the cytokine cascade with infliximab and daclizumab (double antibody therapy, DAT), along with aggressive infection prophylaxis may improve outcomes. We retrospectively reviewed our experience using DAT in steroid-refractory aGVHD. Between December 2005 and December 2009, 22 patients were treated of which 20 are evaluable. All patients had persistent or progressive aGVHD despite 1–2 mg/kg/d steroids for a median of 9 days (range 2–55). Five patients had failed 2^nd line systemic aGVHD therapy and 1 patient failed 3^rd line therapy prior to DAT. Combination therapy was given for aGVHD grade 2 (n=3), 3 (n=13), or 4 (n=4). GVHD involved the skin in 7 patients, the liver in 9 patients and GI tract in 16 patients. The median age at time of therapy was 55 years (range 29–69). Grafts were from HLA identical siblings (9), 10 locus matched unrelated donors (5), 9/10 locus matched unrelated donors (3), cord blood (2) or 5/10 haploidentical donor (1). The conditioning regimen was myeloablative in 10 patients, and either nonmyeloablative or reduced intensity in 10 patients. Indications for stem cell transplant were acute leukemia (7), chronic myelogenous leukemia (2), chronic lymphocytic leukemia (1), myelodysplastic syndrome (4), non-Hodgkins lymphoma (5), and multiple myeloma (1). Most patients received methotrexate (MTX) with tacrolimus (FK)(14) or mycophenolate (MMF) (4) for GVHD prophylaxis; one patient received MTX with FK and MMF and one FK alone. Fifteen patients developed aGVHD after the primary transplant and five after donor lymphocyte infusion. Daclizumab was given (1mg/kg) day 1,4,8,15, and 22, and infliximab (10mg/kg) days 1,8,15, and 22. Steroid therapy was aggressively tapered upon commencement of DAT. Maximal response achieved by day 60 post initiation of therapy was assessed. Five pts (25%) attained a CR (resolution of all symptoms), 10 (50%) PR (improvement in ≥ 1 organ & no progression in others), 2(10%) MR (improvement in ≥ 1 organ & deterioration or new symptoms in others) and 3 (15%) no response. Five patients received 1–2 additional courses of DAT at a median of 60 days. Three patients (15%) were concurrently on an investigational protocol utilizing mesenchymal stem cells. All patients received antifungal (azole with mold coverage or echinocandin), anti-Herpes virus, and Pneumocystis prophylaxis. Patients with gastrointestinal GVHD also received antibacterial prophylaxis irrespective of neutropenia. Patients were monitored once or twice weekly for CMV reactivation and received preemptive therapy upon reactivation. Only two patients had documented fungal infections: Mucormycosis in 1 and Candida parapsilosis in 1. Sixteen (80%) of patients had bacterial infections, including 21 gram-positive infections and 13 gram-negative infections. Viral infections, primarily CMV reactivation, occurred in 16 patients (80%). As of August 2010, 12 patients have died after a median of 102 days from initiation of DAT (range 14–658) (5 from relapsed or progressive disease, 3 from aGVHD, 2 from cGVHD, and 2 from organ failure). With a median follow up of 511 days for living patients, the estimated probability of survival at 6 months and 12 months is 55% and 50%, respectively. DAT is an effective therapy for steroid-refractory aGVHD. Survival beyond 6 months can be achieved in approximately half the patients using this strategy. Aggressive antifungal and antiviral prophylaxis may have contributed to this outcome.