Differential Gene Expression Analysis Predicts For Response To Bortezomib In The Treatment Of Steroid Refractory Chronic Graft-Versus-Host Disease (cGVHD)

We conducted a trial of bortezomib in patients with steroid-refractory cGVHD. Patients received 1.6 mg/m² q wk x 4 followed by one week of rest, for up to six cycles, with some going on to a maintenance phase of treatment every other week for an additional 6 months. Twenty-one patients were registered on trial two patients withdrew before beginning treatment. Nineteen patients received between two and twelve months of treatment. The treatment was well tolerated with no grade 3 or higher adverse events (AE). Six patients had either CR or near CR. Average Rodnan scores on the 8 patients with sclerosis completing 2 or more cycles of therapy decreased from 22.6 ± 12.8 to 5.9 ± 6.2, p<0.005. One patient with non-healing suppurating lesions of his lower extremities had marked healing, another had significant decrease in chronic diarrhea. Weekly bortezomib for cGVHD was well tolerated and resulted in early improvement in a subset of patients with long standing refractory disease.

Differential gene expression analysis was performed on the blood of patients prior to starting therapy, after two cycles and after their final cycle of therapy. All samples were run simultaneously at the end of the trial. Patients were classified as High (CR or near CR), intermediate (PR or stable disease), or poor responders (progression or not evaluable) based on clinical response. At baseline cGVHD patients express an overall decrease in T cell markers such as lineage (CD4), chemokine receptors (CCR6, CXCR3 and CCR7), and co-stimulatory molecules (CD40L, ICOS, CD28, and CD27), as well as decreases in IL23 and Granzyme K message compared to healthy controls. Increases were seen in myeloid/macrophage markers (CD163 and OSCAR). Baseline profiles of good responders were closer to those of healthy controls as compared to poor responders (figure below). Inflammation, cell death and apoptosis modules are up regulated and immune response modules are down-regulated in low and medium responders

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HC – Healthy Control; DC – Disease Control (allogeneic BMT recipients without cGVHD)

Weekly bortezomib for cGVHD appears to be well tolerated and results in early improvement in long standing refractory disease in a subset of patients. Gene expression profiles at the initiation of treatment correlated with response and may be useful in predicting which patients will respond to bortezomib.