Introduction
Corticosteroids remain first-line therapy for GVHD1. Although several salvage therapeutic options for SR and SD GVHD exist, there is no consensus6. Consequences of prolonged steroid use is severe non-specific immunosuppression, potential loss of graft-versus-tumor (GVT) effect in patients with malignancy, and increased infection risk1. Salvage therapy is often selected based on adverse effect profile, patient’s unique characteristics, drug availability, or institutional experience1.
Bortezomib is a first-generation reversible proteasome inhibitor that has shown efficacy in murine aGVHD models leading to clinical trials and use in adult HSCT. Bortezomib inhibits nuclear factor-kappa B (NF-κB) 1, resulting in inhibition of T- and B-cell activation and pro-inflammatory cytokine transcription1,2. It increases T-cell apoptosis, decreases expression of activation markers and receptors on T-cells, and decreases T-cell proliferation. Additionally, bortezomib aids in treating GVHD by preventing activation of DCs which mediate antigen presentation and cytokine transcription that ultimately causes organ damage in GVHD1,2.
Basic science studies demonstrated that bortezomib has the effect of preserving GVT effect by allowing for persistence of T-regulatory cells thus promoting recipient T-cell reconstitution.2
Continuous administration of bortezomib after HSCT in pre-clinical studies resulted in cutaneous aGVHD reduction, associated with decreased IL-6 level14. Bortezomib administration resulted in the specific downregulation of CXCR3, a skin-homing chemokine receptor, on donor CD8+ T cells in a murine aGVHD model.14
Koreth et al reported on 45 adult patients with mMUD donors who received GVHD prophylaxis with bortezomib in addition to methotrexate and tacrolimus2. Grade 2-4 aGVHD was present in 22% and 29% developed cGVHD, with a 2-year OS of 64%2. Additionally, T-cell reconstitution was deemed favorable when compared with matched patients who received standard GVHD prophylaxis without bortezomib2.
Miller et al demonstrated patients with SD and SR cGVHD while on bortezomib was able to wean from prednisone2. Paiet al evaluated SR cGVHD patients treated with bortezomib, documenting favorable responses including decreased sclerotic non-healing skin lesions and reduced diarrhea2.
Herrera et al evaluated a combination of bortezomib and prednisone treatment of cGVHD 2. A positive response reported in 80%, with 10% a complete response (CR) and the remainder had a partial response (PR). Best results were seen in the skin and gastrointestinal tract2.
Further studies of bortezomib are needed in children and young adults to delineate its potential benefits and toxicities in this age group in terms of GVHD prophylaxis and treatment. Over a period of five years, five pediatric BMT patients at Sylvester Comprehensive Cancer Center at the University of Miami and Holtz Children’s Hospital were treated with bortezomib as part of their treatment for SR and SD GVHD post-HSCT. We review these to provide proof of principle for potential future trials of this agent for SR and SD GVHD in pediatric HSCT.