Presentation on theme: "Overview of Chronic GVHD Response Assessment"— Presentation transcript:
1 Overview of Chronic GVHD Response Assessment Steven Z. Pavletic, M.D.National Cancer InstituteNational Institutes of HealthBethesda, 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 donorsDLIsLower RR mortalityTreatment of infectionsCIBMTRAll Images Are Copyright ProtectedAbout 7000 allotransplants each year in North America
4 Infections Disability Quality of life Endocrine Metabolism Nutrition Bronchiolitis obliteransOcular siccaLoss of bile ductsOral ulcersNail dystrophyFasciitisInfectionsDisabilityQuality of lifeEndocrineMetabolismNutritionPainSkin sclerosisSkin ulcersSpectrum ofmanifestationsin chronic GVHDAll Images Are Copyright ProtectedDeep sclerosis
5 Organs InvolvedAll Images Are Copyright ProtectedFlowers, 2002
6 Changing Concepts: GVHD Syndrome After AlloHCT Acute GVHD: rash, GI, liver Chronic GVHD: skin, eyes, mouth, GIliver, musculoskeletal, lungs, GUAlloreactivityAutoimmunityImmunodeficiency- Classic acute Late acute - Classic chronic- Chronic overlapAll Images Are Copyright ProtectedDay y 2 y y yActivity Damage(inflammation) i n j u r y r e p a i r (fibrosis)
7 Johns Hopkins Risk Classification All Images Are Copyright ProtectedAkpek, Blood, 2001
8 Experience and Perceived Success with 15 Most Common Therapies All Images Are Copyright ProtectedLee 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 TrialsDevelop 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 Hopkins1. Diagnosis and Staging: L. Filipovich et al., BBMT, 11: , 20052. Histopathology: H. Shulman et al., BBMT, 12:31-47, 20063. 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, 20066. 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 proceedJune-November Form working teamsWork on draftsNovember Face to face, BreakoutsFebruary First public presentationJune 6, Consensus ConferencePost-June Dissemination & trainingImplementation in trialsValidation studiesSeek fundingPeriodic reevaluation Meeting 2008
13 Endpoints for Treatment Trials Need for validated short term endpoints InterpretationTime to endpointCommentCGVHD responseResponse to treatment according to organ-specific or summary measuresShort (months)No validated or accepted scales existRelapse-free Survival to permanent discontinuation of immunosuppre- ssionCureLong (years)
14 Response to TherapyComparison 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 childrenNon-transplant providersKey chronic GVHD manifestationsQuantitative measuresDomains should be assessed separatelyValidated measures prioritySuitable 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 sclerosisBronchiolitis obliteransDestruction of lacrimal function
18 Challenges in Defining Quantitative Response Scales Absence of reproducible quantitative measures. Examples:Skin sclerosisOral lesions
19 Disease Death Symptoms Remission Cure Function Quality of life How to Measure Outcomes When Survival or Remission are Not Adequate Endpoints?DiseaseDeathSymptomsRemissionCureFunctionQuality of life
20 Proposed Measures (Forms A&B) Measure Clinician assessed Patient reportedCore – Chronic GVHD SpecificSigns Organ specific measures N/ASymptoms Clinician assessed Patient reportedLee Symptom ScaleGlobal Rating 7 point change scale point change scale Mild-moderate-severe Mild-moderate-severe severity scale 0-10 severity scaleAncillary - CGVHD Non-SpecificFunction Grip Strength HAP2 min walk time ASK (children)Performance status Karnofsky/Lansky N/AQuality of life N/A FACT-BMTSF-36 v.2CHRIs-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 completeMitchell 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 ReportSteven 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. VogelsangBiology of Blood and Marrow Transplantation, In press, 2006