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

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.

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

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

Organs Involved All Images Are Copyright Protected Flowers, 2002

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 0 50 100 180 1 y 2 y 3 y 5 y Activity Damage (inflammation) i n j u r y r e p a i r (fibrosis)

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

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

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 .

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.

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, 11:945-955, 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

NIH Chronic GVHD Consensus Development Project on Criteria for Clinical Trials: Timeline June 14, 04 Determination to proceed June-November 04 Form working teams Work on drafts November 04 Face to face, Breakouts February 05 First public presentation June 6, 05 Consensus Conference Post-June 05 Dissemination & training Implementation in trials Validation studies Seek funding Periodic reevaluation Meeting 2008

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)

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.

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).

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

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

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

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

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 7 point change scale Mild-moderate-severe Mild-moderate-severe 0-10 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)

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

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