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predicting GVHD post-DLI. The ability to identify patients who will not
develop GVL early post-transplantation using a simple proteomics test has
important therapeutic consequences, including more stringent monitor-
ing of MRD and/or preventative care with DLI or tumor-specific vaccines.
Determining which patients will develop GVL with GVHD and those at high
risk for subsequent GVHD morbidity could lead to tailored treatment plans,
including specific immunosuppressive treatments that do not influence
GVL response. Equally important is the identification of patients who will
develop GVL without GVHD, potentially enabling more rapid tapering of
immunosuppressive regimens and thereby reducing long-term toxicity in
these patients. The cost-effective monitoring of MRD post-transplantation
via the detection of plasma proteins rather than through invasive methods
such as bone marrow aspiration, which is both painful and not amenable to
the frequent monitoring of patient status, will facilitate the development of
preemptive DLI and vaccines in patients with positive MRD.
Incorporating GVHD biomarkers in clinical trials
Given the progress being made in GVHD biomarker identification and vali-
dation, it is not surprising that clinical trial design will begin incorporating
biomarkers.
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Target-specific diagnostic biomarkers that can differentiate skin GVHD from
other rashes and GI GVHD from other forms of enteritis will allow replace-
ment of invasive biopsies. First, a simple observational trial during which
samples and biopsies will be taken at onset of GVHD should be performed.
During this trial, physicians will treat according to symptoms and perform
biopsies as usual. A retrospective analysis of the samples with different
thresholds of biomarkers will determine whether the biomarkers can replace
the invasive biopsies as well as the best threshold. If this study concludes that
the biomarker does as well as the biopsies, the next trial would be a random-
ized interventional trial; one-half of the patients will be treated according to
the biopsy results, and one-half will be treated according to the biomarker
results; the development of GVHD and other outcomes will then be evaluated.
Another potential clinical application of GVHD biomarkers is to use them
to stratify patients based on risk at the time of GVHD onset. GI GVHD is
considered a high-risk feature for mortality, but given the absence of fur-
ther risk stratification, the standard of care for all patients with GI GVHD
is the prompt initiation of systemic steroid treatment, with the addition of
second-line agents reserved for patients who fail initial therapy. Unfortu-
nately, most patients who require second-line therapy die, highlighting the
need for refinement of risk beyond what the current grading system pro-
vides. We have recently developed a risk stratification algorithm for patients
with new-onset GI GVHD that incorporates clinical stage, histologic grade,
and plasma levels of the newly discovered GI GVHD biomarker REG3α. This
easy-to-use algorithm assigns one equal-weight point to each of the three
individual risk factors: clinical stage >1, histologic grade >3, and REG3α
concentration >151 ng/ml. Patients with two or more risk factors at onset
were less likely to respond to treatment, which translates into highly signifi-
cant differences in NRM. Patients with two or three risk factors (i.e., high
risk) at the onset of clinical manifestations of GI GVHD experience 1-year
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