1. Overview of Chronic GVHD Response Assessment
Steven Z. Pavletic, M.D.
National Cancer Institute
National Institutes of Health
Bethesda, MD

2. Chronic Graft-Versus Host Disease
A multi-system chronic alloimmune and autoimmune disorder that occurs after allogeneic hematopoietic stem cell transplantation, characterized by immunosuppression, immune dysregulation, decreased organ function, and causing impaired survival.

3. Increasing Incidence Older recipient age Peripheral blood
Unrelated donors
DLIs
Lower RR mortality
Treatment of infections
CIBMTR
All Images Are Copyright Protected
About 7000 allotransplants each year in North America

4. Infections Disability Quality of life Endocrine Metabolism Nutrition
Bronchiolitis obliterans
Ocular sicca
Loss of bile ducts
Oral ulcers
Nail dystrophy
Fasciitis
Infections
Disability
Quality of life
Endocrine
Metabolism
Nutrition
Pain
Skin sclerosis
Skin ulcers
Spectrum of
manifestations
in chronic GVHD
All Images Are Copyright Protected
Deep sclerosis

5. Organs Involved
All Images Are Copyright Protected
Flowers, 2002

6. Changing Concepts: GVHD Syndrome After AlloHCT
Acute GVHD: rash, GI, liver Chronic GVHD: skin, eyes, mouth, GI
liver, musculoskeletal, lungs, GU
Alloreactivity
Autoimmunity
Immunodeficiency
- Classic acute Late acute - Classic chronic
- Chronic overlap
All Images Are Copyright Protected
Day y 2 y y y
Activity Damage
(inflammation) i n j u r y r e p a i r (fibrosis)

7. Johns Hopkins Risk Classification
All Images Are Copyright Protected
Akpek, Blood, 2001

8. Experience and Perceived Success with 15 Most Common Therapies
All Images Are Copyright Protected
Lee et al., BBMT 2002

9. Fresh Attention Needed
Criteria for diagnosis and staging developed 25 years ago not adequate.
Current standard therapy developed in 1980s, no standard second line therapy.
There is no FDA approved indication for chronic GVHD.
No criteria for therapeutic trials exist .

10. Develop definitions and tools for conducting clinical trials.
NIH Chronic GVHD Consensus Development Project on Criteria for Clinical Trials
Develop definitions and tools for conducting clinical trials.
Outline standards of supportive care.
Identify directions for future research.

11. NIH Chronic GVHD Consensus Development Project on Criteria for Clinical Trials: Working Groups
Co-Chairs: S.Pavletic, NCI and G.Vogelsang, Johns Hopkins
1. Diagnosis and Staging: L. Filipovich et al., BBMT, 11: , 2005
2. Histopathology: H. Shulman et al., BBMT, 12:31-47, 2006
3. Biomarkers: K. Schultz et al., BBMT, 2006 (in press)
4. Response Criteria: S. Pavletic et al., BBMT, 2006 (in press)
5. Ancillary and Supportive Care: D. Couriel et al., BBMT, 2006
6. Clinical trials design: S. Lee and P. Martin et al., BBMT 2006

12. NIH Chronic GVHD Consensus Development Project on Criteria for Clinical Trials: Timeline
June 14, Determination to proceed
June-November Form working teams
Work on drafts
November Face to face, Breakouts
February First public presentation
June 6, Consensus Conference
Post-June Dissemination & training
Implementation in trials
Validation studies
Seek funding
Periodic reevaluation Meeting 2008

13. Endpoints for Treatment Trials Need for validated short term endpoints
Interpretation
Time to endpoint
Comment
CGVHD response
Response to treatment according to organ-specific or summary measures
Short (months)
No validated or accepted scales exist
Relapse-free Survival to permanent discontinuation of immunosuppre- ssion
Cure
Long (years)

14. Response to Therapy
Comparison of disease activity assessments at two different time points.
A judgment must be made whether the magnitude of any change qualifies as improvement or deterioration.

15. Response Criteria — Problems
There are no agreed upon or validated measures and definitions of response in chronic GVHD.
Current definitions of response qualitative, global and subjective.
It is impossible to compare responses among different clinical trials.
No distinction exists between disease activity (reversible) and damage (irreversible changes).

16. Response Criteria — Goals
Develop a consensus scoring system that will assess chronic GVHD disease activity for use in clinical trials, not for routine patient care.
Adults and children
Non-transplant providers
Key chronic GVHD manifestations
Quantitative measures
Domains should be assessed separately
Validated measures priority
Suitable for FDA approval trials

17. Challenges in Defining Quantitative Response Scales
Conversion of qualitative improvements in to quantitative scales due to the chronic nature of disease and the tendency to accumulate damage. Examples:
Extensive skin sclerosis
Bronchiolitis obliterans
Destruction of lacrimal function

18. Challenges in Defining Quantitative Response Scales
Absence of reproducible quantitative measures. Examples:
Skin sclerosis
Oral lesions

19. Disease Death Symptoms Remission Cure Function Quality of life
How to Measure Outcomes When Survival or Remission are Not Adequate Endpoints?
Disease
Death
Symptoms
Remission
Cure
Function
Quality of life

20. Proposed Measures (Forms A&B)
Measure Clinician assessed Patient reported
Core – Chronic GVHD Specific
Signs Organ specific measures N/A
Symptoms Clinician assessed Patient reported
Lee Symptom Scale
Global Rating 7 point change scale point change scale Mild-moderate-severe Mild-moderate-severe severity scale 0-10 severity scale
Ancillary - CGVHD Non-Specific
Function Grip Strength HAP
2 min walk time ASK (children)
Performance status Karnofsky/Lansky N/A
Quality of life N/A FACT-BMT
SF-36 v.2
CHRIs-HSCT (children)

21. Feasibility Evaluation of New Measures of Therapeutic Response
In terms of feasibility the raters offered a universally favorable evaluation of the training session, and felt that the clinician form (which you have in the appendix of your handout materials) was easy to complete
Mitchell et al., Blood vol.106; ASH 2005, abstract #3121

22. Measuring Therapeutic Response In Chronic GVHD NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease: IV. Response Criteria Working Group Report
Steven Pavletic, Paul Martin, Stephanie J. Lee, Sandra Mitchell, David Jacobsohn, Edward W. Cowen, Maria L. Turner, Gorgun Akpek, Andrew Gilman, George McDonald, Mark Schubert, Ann Berger, Peter Bross, Jason W. Chien, Daniel Couriel, JP Dunn, Jane Fall-Dickson, Ann Farrell, Mary E.D. Flowers, Hildegard Greinix, Steven Hirschfeld, Lynn Gerber, Stella Kim, Robert Knobler, Peter A. Lachenbruch, Frederick W. Miller, Barbara Mittleman, Esperanza Papadopoulos, Susan K. Parsons, Donna Przepiorka, Michael Robinson, Michael Ward, Bryce Reeve, Lisa G. Rider, Howard Shulman, Kirk R. Schultz, Daniel Weisdorf, and Georgia B. Vogelsang
Biology of Blood and Marrow Transplantation, In press, 2006