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.