A Proposal to Test the Efficacy and Tolerability of Bortezomib in Pulmonary Chronic GVHD
Status:
Terminated
Trial end date:
2015-09-09
Target enrollment:
Participant gender:
Summary
Approximately 10,000 allogeneic hematopoietic stem cell transplants (HSCT) are performed
annually in the US for various indications. Bronchiolitis obliterans (BO) is the most common
late noninfectious complication following allogeneic hematopoietic stem cell transplant.
Prognosis of BO in the allogeneic HSCT setting is dismal and there are no therapies proven to
be consistently effective. The exact incidence is not clear but may be as high as 30%2 . Risk
factors include new or ongoing chronic graft versus host disease (cGVHD), age, antecedent
obstructive airways disease and viral infections1. BO is characterized physiologically by
progressive irreversible airflow obstruction and pathologically by luminal occlusion of the
distal airways due to progressive scarring3. The pathogenesis is not completely understood
but the cytokine transforming growth factor-beta 1 (TGF-b1), important for both tissue repair
and fibrosis, is thought to play a pivotal role. Bortezomib, an FDA approved proteasomal
inhibitor inhibits TGF-b1 signaling in vitro and protects against lung injury/fibrosis in
bleomycin mouse model as well as in a mouse model for skin fibrosis. This is consistent with
other data in the literature that proteasomal inhibition can prevent the development of
fibrosis. Thus the investigators propose to test the safety, tolerability and efficacy of
bortezomib in chronic pulmonary GVHD (BO).