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of events many weeks or months later. After various biomarker combina-
tions were tested, a final panel consisting of IL2Rα, TNFR1, and REG3α
was found to have a strong predictive value. Patients can be categorized as
being high risk for GVHD occurring within the first 2 months post-HSCT on
a weekly basis up until day 28. As with any screening test, improvements in
sensitivity come at the expense of specificity and vice versa; which aspect to
emphasize is a matter of clinical judgment. The experience with post-HSCT
cytomegalovirus (CMV) disease offers an instructive example in how the
transplant community approaches this sort of problem. Prior to the devel-
opment of CMV predictive tests, the incidence of CMV disease was approxi-
mately 35%, with high mortality rates. The introduction of CMV-preemptive
strategies guided by polymerase chain reaction or antigenemia studies
reduced CMV disease to approximately 5-15%
[91]
. Extrapolating from
published data on the number of positive CMV screening tests compared to
the expected number of cases of CMV disease, it appears that around 50%
of positive CMV screens, if untreated, would not result in CMV disease. The
sensitivity of CMV screening tests is very high, in the range of 90%, meaning
that relatively few cases of CMV disease develop in the absence of a posi-
tive screening test. Thus, it has become common practice to administer
preemptive therapy to patients who are not likely to develop CMV disease
to effectively prevent cases of CMV disease. If we apply a similar standard
to GVHD-preemptive therapy (1:1 true positive to false positive), the sen-
sitivity of the biomarker GVHD prediction panel is 67%. While not yet as
accurate as the gold standard, CMV screening, we believe that these results
are sufficient to design a clinical trial to test whether a preemptive strategy
would prevent GVHD. The toxicity of the intervention is an important con-
sideration in trial design, as excess toxicity from preemption will dampen
acceptance of the strategy. A short course of corticosteroid therapy at the
time during which markers of alloreactivity are increasing may be a reason-
able therapy to test. The success of preemption must include a reduction
not only in the incidence of GVHD, but also in infectious complications and
relapse. Ultimately, a randomized trial will be needed to assess the effec-
tiveness of GVHD preemption as described previously
[84]
.
473
Preemptive strategies for cGVHD, similar to those discussed for aGVHD, are
also being designed. Given the correlation between B-cell-related biomarkers
and the development of cGVHD, together with clinical data supporting the
use of rituximab to prevent cGVHD
[92]
, at the time of publication a Canadian
trial is being designed that will administer rituximab to children identified as
at high risk for the development of cGVHD based on biomarker assays
[84]
.
Future research on biomarkers: from diagnosis to
therapy
Future directions include a blinded evaluation of these biomarkers with
samples collected in a multicenter prospective study. Ideally, this requires a
multicenter cohort, indispensible to the reduction of center effects and to the
successful design of subsequent trials, which is ideally performed through
an institution such as the Blood and Marrow Transplant Clinical Trial Net-
work to both establish a unique resource for bone marrow transplantation
(BMT) clinicians and further a national resource for investigators to explore
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