• Initially known as “secondary

disease” in mice seen in the 60’s amongst lethally radiated mice who underwent allogenic transplants

• GVHD is the major cause of

non-relapse morbidity and mortality post allogeneic transplant

• Incidence of aGVHD is about 50% (range of 10%-80%)

• Degree of HLA disparity

• Gender disparity

• Intensity of Conditioning

• PPX regimen

• Graft source

• Corticosteroids are the standard initial therapy

for aGVHD • Problem: Only 50% of these patients respond to

this initial therapy

• If they fail initial therapy have mortality rates as high as 95% - important to try and identify.

Westin et al Advances in Hematology 2011 601953

• None of the patient demographic or transplant

characteristics independently predicted response to steroids

• Hence good opportunity for the use of biomarkers to help stratify those patients who may be at risk for not only development of GVHD but indicate refractoriness

• WHO- any substance, structure, or process or its products that can be measured in the body and influence or predict the incidence/outcome of disease

• What we need: A test which has

the potential to define new risk strata to help guide management and predict response to treatment

• Need to be reliable, reproducible

while maintaining adequate sensitivity and specificity.

Madu CO, Lu Y. J Cancer 2010; 1:150-177

Levine, Biol Blood Marrow Transplant. 2012 Jan; 18(1 Suppl): S116–S124.

Many case-control , training Multiple sites, test

Thousands,standardization

• 12 Biomarkers evaluated prospectively sampled (discover set, response to treatment set, stratification set) n=673 patients

• Biomarker called ST2- single best biomarker non-response to initial therapy, and NRM of the biomarkers tested.

• Part of IL-1 receptor family and IL-33 is it’s ligand.

• Cellular receptor which binds to IL-33 and is involved in immune response and tissue repair

• Soluble form acts as a decoy receptor downregulating IL33 function

• Prospective Collection-

• Random assignment into an training set or validation set

• Algorithm utilizing biomarkers which would predict NRM at 6 months post

transplant and non-response to initial therapy for aGVHD

• Traditional grading systems correlate maximal severity with response and hence survival but diagnostic grade does not always correlate with treatment outcomes

• Also each center and physician may differ in the method of when and how much

in regards to therapy and initiation- goal is to overcome this

• Purpose is to come up with a scoring system that is consistent amongst different training and validation groups (patients,diseases,transplants etc)

• Study consists of training set and then a test set for validation. TNFR1, ST2, REG3α, IL2Rα, elafin measured by ELISA

• 492 patients (360 from UM, 132 from Germany) randomized into

training (n=328) and test (n=164) sets. Separate group of 300 patients who provided blood upon enrolling on BMT-CTN studies GVHD therapy provided a independent validation set. • Prospective collection of blood samples collected at the onset of

grade I-IV aGVHD (within 48 hours of starting steroids for GVHD therapy).

• Competing risks regression modeling was used to create algorithms that predicted 6 mo NRM with relapse treated as the competing risk

• Likelihood ratio testing to develop the most optimal

predictive algorithm (up to 5 biomarkers) • The best algorithm included TNFR1, ST2, REG3α

• This algorithm was used to create a predicted probability on patients in the training set.

• The probabilities were then ranked from lowest

to highest to identify thresholds to determine 3 different scores. (NRM-15% difference btwn each score)

• The higher threshold would be used for Ann Arbor-1= NRM of <10%. The lower thresholds for Ann Arbor 3 with a NRM of >40%.

• This approach basically defined 3 scores in which NRM increased with grade at both the 6 and 12 month mark.

• Algorithm and thresholds then evaluated twice Independent test set: UM/Ger(n=164) Multicenter validation set (n=300)

Levine Lancet Hematology 2015

• Algorithm was applied to the test set as well as the independent validation set with very similar differences between the three groups in regards to NRM

This was consistent between Ann Arbor groups in the validation sets for overall survival at 6m and 1 year

Courtesy of Dr. J.Levine

Multivariate Comparison of AA and Glucksberg for NRM

• Biomarkers can be used to create scores to predict NRM at the time of GVHD diagnosis

• Reproducible in multiple validation groups • Higher scores vs lower re: treatment • Further investigate if possible to predict risk of GI GVHD before clinical

symptoms develop Where can Ann Arbor Score be helpful? • clinical grade I GVHD who need tx and response in grade II • GVHD bx equivocal Future Investigations • Ann Arbor 3 pts: clinical trials of intensive primary therapy • Correlation rapid steroid tapers or tapering of IS?

• Validate the scores’ prognostic

quality in large multicenter cohorts including various patients, diseases and transplant methods.

• Standardize the threshold for the

cutoff value of ST2- difference by condition regimen and by the assay format?

• Can we follow biomarkers for monitoring the response to aGVHD treatment ?

• Combine with other clinical GVHD risk scores.