asbmt online journal club 6.4.15 #bmtojc
TRANSCRIPT
![Page 1: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/1.jpg)
![Page 2: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/2.jpg)
• 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%)
![Page 3: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/3.jpg)
• Degree of HLA disparity
• Gender disparity
• Intensity of Conditioning
• PPX regimen
• Graft source
![Page 4: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/4.jpg)
• 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.
![Page 5: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/5.jpg)
Westin et al Advances in Hematology 2011 601953
![Page 6: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/6.jpg)
![Page 7: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/7.jpg)
• 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
![Page 8: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/8.jpg)
• 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
![Page 9: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/9.jpg)
Levine, Biol Blood Marrow Transplant. 2012 Jan; 18(1 Suppl): S116–S124.
Many case-control , training Multiple sites, test
Thousands,standardization
![Page 10: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/10.jpg)
• 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.
![Page 11: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/11.jpg)
• 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
![Page 12: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/12.jpg)
• 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)
![Page 13: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/13.jpg)
• 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).
![Page 14: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/14.jpg)
• 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
![Page 15: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/15.jpg)
• 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
![Page 16: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/16.jpg)
• 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
![Page 17: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/17.jpg)
This was consistent between Ann Arbor groups in the validation sets for overall survival at 6m and 1 year
![Page 18: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/18.jpg)
![Page 19: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/19.jpg)
![Page 20: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/20.jpg)
Courtesy of Dr. J.Levine
![Page 21: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/21.jpg)
Multivariate Comparison of AA and Glucksberg for NRM
![Page 22: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/22.jpg)
• 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?
![Page 23: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/23.jpg)
• 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.
![Page 24: ASBMT online journal club 6.4.15 #BMTOJC](https://reader034.vdocuments.us/reader034/viewer/2022051315/55c13cb6bb61eb8d1f8b4596/html5/thumbnails/24.jpg)