Proteomics in graft-versushost disease and graftversus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 462

cell signaling. We are currently validating these candidate biomarkers for
response to treatment in approximately 1200 samples taken at the initia-
tion of systemic steroid therapy, at day 14, and at day 28 post-therapy [41] .
The candidates include six markers that were discovered with in-depth pro-
teomic analysis along with the biomarkers that we previously identified as
diagnostic markers. Interestingly, several of these novel biomarkers offer
important insights into the biology of GVHD and are potential therapeutic
targets (unpublished observations).

Identification and validation of chronic GVHD
biomarkers

Chronic GVHD (cGVHD) is the most common long-term complication
of allo-HSCT and is a leading cause of mortality in patients that survive 2
years without relapse [72] , limiting the wider application of this therapeu-
tic approach to patients with hematologic malignancies and bone marrow
failures. In contrast to aGVHD, cGVHD often presents with clinical manifes-
tations that resemble those of autoimmune diseases, such as scleroderma,
Sjogren's syndrome, and systemic lupus erythematosus. Traditionally,
a cut-off of 100 days post-HSCT was used to differentiate between acute
(before) and chronic (after) GVHD. However, it is now recognized that
earlier chronic disease onset could occur, as well as clinical syndromes
with features of aGVHD, beyond 100 days post-HSCT, particularly after
reduced-intensity conditioning regimens [73] . The median onset of cGVHD
is between 4 and 5 months post-HSCT. There are many risk factors for the
development of cGVHD, including age at transplantation, donor source
and HLA disparity, peripheral blood grafts, and a history of prior aGVHD
[74] . Depending on the presence or absence of these risk factors, the rates
of cGVHD can be as high as 40-70% [75] . Despite the high incidence of this
complication, the pathophysiology of this disorder remains poorly under-
stood. Its diagnosis is based on clinical symptoms (i.e., inflammatory and
fibrotic components) of several target organs (e.g., skin, nails, mouth, eyes,
genitalia, musculoskeletal, GI tract, liver, and lung) that can be confirmed
by biopsies. At present, no simple diagnostic or prognostic test for cGVHD
exists. In 2006, the National Institutes of Health cGVHD Biomarker Con-
sensus Group defined the ideal cGVHD biomarker [76] . Blood biomarkers
(both cellular and protein) have been evaluated. Earlier studies have shown
low platelet counts (<100,000/mm 3 ) to be a negative survival predictor in
cGVHD [77] . High eosinophil counts (>500/mm 3 ) have been correlated with
the presence or development of cGVHD [78] . However, these two markers
have not been investigated in clinical trials. Furthermore, eosinophil counts
did not significantly differ between patients with and without cGVHD in the
Children's Oncology Group study [79] . With the advent of new therapeu-
tic agents, microangiopathic thrombocytopenia, hypersplenism, infection,
and platelet count may vary independent of the pathology of cGVHD [77] ,
suggesting that the measurement of platelet count may be unreliable in
some patients. Another study has shown a correlation between high levels
of transforming growth factor-β1 in the sera of HSCT patients with cGVHD
[80] , but this has not been confirmed in a large-scale study. Biomarkers have
been identified that are associated with active cGVHD, such as high levels

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