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M. Gooptu and J. Koreth
cess. Although the mechanism by which ECP improves GvHD is a matter of debate, its immunomodulatory effects include Treg upregulation, a change from Th1 to Th2 cytokine profile, as well as modulation of APC.97 Importantly ECP may not result in additional immuno- suppression in GvHD patients. In a RCT evaluating ECP in cGvHD therapy, there was no increased risk of infec- tion in the ECP arm,98 which, if also true in the aGvHD setting, would be a major benefit. Initially evaluated in pediatric cohorts, ECP resulted in a response rate of 67% in a small study of adult aGvHD.99 In another small ECP study (n=23), CR was achieved in 70%, 42% and 0% of patients with grades II, III and IV aGvHD respectively. With regards to end-organ based efficacy, complete responses were seen in 66%, 27% and 40% of patients with skin, liver and gut involvement, respectively.100 However, the data are limited to small non-randomized studies and effi- cacy needs to be confirmed.
Finally, another novel therapeutic intervention for aGvHD, fecal microbiota transplantation (FMT), is further discussed in the section on microbiome and the role of dys- biosis.
These therapeutic strategies, along with the level of evi- dence supporting them, are summarized in Table 2.
Future trends
Finally, we highlight the emerging role of early prognostic biomarkers as well as the potentially critical role of the intestinal microbiome in influencing aGvHD and transplant outcomes.
Novel biomarkers in acute graft-versus-host disease Identifying predictive biomarkers for aGvHD develop- ment and/or prognosis has been an important question in the field. Hypothesis-driven markers based on the patho- physiology of aGvHD include acute phase reactants (e.g., IL-6, C-reactive protein [CRP]), Th1 cytokines (e.g., IL-12, IL-18), anti-inflammatory cytokines (e.g., IL-10, TGF-β), other circulating markers (e.g., IL-8, HGF, cytokeratin-18, CD30), and lymphocyte trafficking molecules (e.g., CXCL10, CCL8) have been evaluated with limited success. In contrast, unbiased marker discovery typically involved proteomic screening of GvHD and non-GvHD samples. In a discovery study from Ann Arbor, IL-2Ra, TNFR1, HGF and IL-8 identified early after aGvHD onset demonstrated impressive accuracy confirmed in a larger validation set.101 Another panel comprising IL-2Ra, TNFR1 and elafin has
also been validated.102
The Mount Sinai Acute GvHD International Consortium
(MAGIC) was established to identify potential biomarkers to risk stratify GvHD. Investigators tested previously iden- tified biomarkers, namely suppressor of tumorigenicity-2 (ST2) and regenerating islet-derived protein 3-a (REG3a), in SR aGvHD and found that marker elevation 7 days after aGvHD was a better predictor of NRM than the Minnesota clinical risk score.103 Another approach has evaluated mark- ers of endothelial toxicity documenting follistatin and endoglin as being associated with higher rates of grade III- IV aGvHD and NRM.104
The appropriate clinical application of these biomarker panels is a complex issue, with the underlying principle that test results should change therapy and, ideally, outcome. Risk-adapted approaches have proposed using these panels
in two different ways: (i) early post-transplant prior to diag- nosis of aGvHD, with allocation of high-risk patients to novel GvHD trials; and (ii) after the diagnosis of aGvHD, to stratify patients at high NRM risk and risk-adapt therapy accordingly.
Future clinical trials that use biomarkers to risk stratify aGvHD patients for eligibility or therapy will be important to prospectively evaluate their utility as a first step to their broader use in clinical practice.
The microbiome in acute graft-versus-host disease
The many micro-organisms which constitute the human gut are collectively called the intestinal microbiota while their genetic make-up has often been referred to as the ‘microbiome’.105 Diversity is a hallmark of the healthy gut microbiome. There is a growing appreciation of the role of the microbiome in various health and disease states. In HSCT, the loss of microbiota diversity (dysbiosis) has been
associated with the risk of aGvHD.105
This association between aGvHD and gut dysbiosis
relates to immunologic and metabolic imbalances in the gut wrought by HSCT, with loss of diversity of the microbiome. Under normal circumstances, diverse gut commensals result in healthy tissue immune cells, including recruitment of Treg cells, secretion of TGF-β and IL-10, as well as TH17 cells secreting IL-17 and IL-22.106 Another protective immune response modulated by gut bacteria relates to their produc- tion of short chain fatty acids (SCFA), a nutritional source for intestinal epithelial cells. Disruption of the intestinal micro- biome triggered by conditioning chemoradiotherapy and antibiotic use during transplantation results in overgrowth of bacteria (e.g., enterococci, Proteus spp.), and reduction in firmicutes (e.g., Blautia spp.), which generally are producers of SCFA, is considered an inciting stimulus for GvHD.107
Further studies are needed to develop actionable targets in this arena. It is a complex endeavor given the variations in gut microbiome over different geographical areas, across transplant strategies, and inpatient and outpatient settings. It is heartening that a recent study from four international centers showed that the patterns of loss of microbiome diversity during HSCT was similar across countries, and that lower diversity at time of neutrophil engraftment was associated with higher mortality.108 A large biorepository of stool samples along with blood and other samples is being built as the correlative arm of the large BMT CTN RCT 1703 (Mi-immune) study in which the biology of the micro- biome and correlations with transplant outcomes will be interrogated.
Fecal microbiota transplant as an effort to repopulate the gut with normal gut flora has been proposed as a means to control aGvHD, based on data limited to pilot studies109 and limited case series.110 Infection with extended spectrum β- lactamase (ESBL) producing Escherichia coli bacteria has been reported in at least two transplant patients post allogeneic transplantation who underwent FMT, one of whom died.111 Hence the safety and efficacy of FMT in aGvHD remains an open question.
Conclusion
To summarize, aGvHD remains an important problem in HSCT. However, where effective treatment options had previously been very limited, there are now multiple excit- ing translational advances.
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