Looking toward the future: an individualized approach to allogeneic transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 488

FIGURE 21.1
Personalized risk management of relapse and GVHD following allogeneic transplantation. Risk analysis for relapse will begin with minimal residual disease (MRD)
evaluation prior to transplantation. For significant MRD, additional consolidative chemotherapy will be considered. The conditioning regimen should be disease-specific
(e.g., clofarabine for active acute myeloid leukemia) and some agents, such as suberoylanilide hydroxamic acid (SAHA), may provide both anti-tumor and anti-GVHD effi-
cacy. Maintenance therapy will begin shortly after transplant in patients at highest risk for relapse. Scheduled MRD analysis post-transplant will assess relapse status and
may trigger the addition of disease specific immunotherapies (e.g., haploidentical NK cells). A panel of biomarkers will help predict the risk of GVHD and guide therapy
for patients at high risk of severe GVHD. Biomarkers will also monitor the response to GVHD treatment and indicate the need for intensification. The end result of these
interventions will be a personalized, risk-adapted approach to management of both GVHD and GVL.

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The future of GVHD: diagnosis, prognosis

Consider this common clinical scenario: 1 month after allogeneic BMT,
a patient develops a new onset skin rash following a platelet transfusion,
soon after starting voriconazole. In the differential diagnosis, the physician
considers a reaction to the platelets, an allergic reaction, a nonallergic drug
reaction (e.g., voriconazole-induced photosensitivity), infection, or the
onset of GVHD. A skin biopsy is performed and steroid treatment is initi-
ated. The final diagnosis relies heavily upon the subjective interpretation of
the pathologist. If the same patient presents with abdominal pain and new-
onset diarrhea, the differential expands to include acute gastrointestinal
(GI) GVHD. The GI biopsy requires subspecialty consultation and an addi-
tional procedural risk; again, the final diagnosis requires an experienced
pathologist. Moreover, the severity of pathologic disease does not uniformly
correlate with the extent of clinical disease and borderline histology is not
uncommon, reducing the overall utility of a diagnostic biopsy. The advent
of a GVHD-specific biomarker could reduce much of this uncertainty.

The next decade will probably see a widespread increase in the use of vali-
dated, GVHD-specific biomarkers. In 2010, the Michigan group used pro-
teomic methods to identify elafin, the first plasma biomarker specific for
GVHD of the skin [4] . A twofold rise in elafin levels was seen in patients
with biopsy-proven skin GVHD, but not in BMT patients with nonspecific
rashes. In 2011, the same group identified a serum biomarker for GI GVHD,
regenerating islet-derived 3α (REG3α) [5] . Evaluation of >1000 patients from
three separate transplant centers showed REG3α to be threefold higher in
patients with biopsy-proven GI GVHD than in patients with GI infection.
Four other diagnostic plasma biomarkers have been validated in a similar
fashion in large data sets [6] .