Do NCI criteria for chronic GvHD improve outcome? No?

Transcription

1 Do NCI criteria for chronic GvHD improve outcome? No? Daniel Wolff Dept. of Medicine III, University Hospital Regensburg

2 Disclosures Research Support/P.I. Dr. Falk Pharma Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board No relevant conflicts of interest to declare Dr. Falk Pharma No relevant conflicts of interest to declare No relevant conflicts of interest to declare Novartis, Therakos, Fresenius No relevant conflicts of interest to declare

3 NIH consensus development project for clinical trials in cgvhd I. Diagnosis and staging working group report (Filipovich, A, B&BMT, 2005) II. Histopathologic Diagnosis of cgvhd: Pathology Working Group Report (Shulman, H, B&BMT 2006) III. Toward Biomarker of cgvhd: Biomarker Working Group Report (Schultz, K, B&BMT 2006) IV: Measuring Therapeutic Response in cgvhd: Response Criteria Working Group Report (Pavletic, S. B&BMT 2005) V: Ancillary Therapy and Supportive Care of cgvhd: Ancillary Therapy and Supportive Care Working Group Report (Couriel, D. B&BMT 2006) VI. Design of Clinical Trials Working Group Report (Martin, P. B&BMT 2006) No common guidelines for diagnosis and staging in clinical routine No common guidelines for treatment of chronic GVHD

4 Application of NIH consensus in clinical routine: diagnosis and grading NIH grading is applied by a minority of the Tx centers in clinical routine within the EBMT and US Duarte, R. BMT 2013

5 Application of NIH consensus in clinical routine: Diagnosis and grading B&BMT 2011

6 Application of NIH consensus in clinical routine: response assessment Response assessment in clinical routine is not performed according to the NIH consensus Possible explanations: Lack of differentiation between active and inactive disease Sclerotic lesions often does not resolve completely Lack of documentation of body surface involvement (Time consuming documentation) (Initial lack of validation)

7 Unsolved issues within the NIH consensus Definition of Overlap: Currently every type of chronic GVHD showing common symptoms of GVHD is regarded as Overlap-Syndrome (any liver manifestation, GI-manifestation or maculopapular erythema (absence of diagnostic (lichenoid, sclerotic) changes) Overlap probably consists of a heterogeneous group including patients with dominating agvhd with mild (but irrelevant) symptoms of cgvhd, patients with true Overlap-Syndrome and patients with classic GVHD lacking distinctive symptoms of cgvhd documentation of acute component? Definition by biology required

8 Unsolved issues within the NIH consensus BMT 2013 in revision

9 Unsolved issues within the NIH consensus How to categorize a patient with isolated symptoms of acute GVHD after chronic GVHD No diagnostic features of cgvhd of the eyes and liver Do sicca symptoms alone justify diagnosis of chronic GVHD Schirmer test does not cover the full spectrum of ocular GVHD (blepharitis component is not captured) Arthralgia and symptoms of rheumatoid arthritis are not captured in a adequate manner Grading of rare manifestations (nephrotic syndrome, polyneuropathia, myasthenia gravis, polymyositis) not well defined Grading of genital manifestations in male patients not defined

10 Lack of improvement of treatment Despite numerous trials applying the NIH consensus criteria only one randomized trial had significant impact on clinical routine in cgvhd Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease Martin, P. Blood 2009 Triple Agent regimen including MMF does not improve outcome of cgvhd primary endpoint: resolution of chronic GVHD and withdrawal of all systemic treatment within 2 years, without secondary treatment A number of trials applied the NIH consensus criteria but did not changed practice yet.

11 Lack of impact on treatment Documentation per se does not improve treatment automatically Most of the improvement in survival occurred already before implementation of NIH grading (supportive care, increased treatment options in acute and chronic GVHD) Gooley, T.A. et al N Engl J. Med 2010

12 Positive impact of cgvhd on overall survial A cgvhd p = 0 B Intensity of conditioning p = 0,105 C p = 0 D p = 0,077 without cgvhd with cgvhd MAC RIC In patients with high risk disease cgvhd is the only significant factor protecting from relapse (Hilgendorf et al 2012)

13 Progress in practice of chronic GVHD after the NIH consensus Most of the proposed tools for clinical trials have been validated by the US Chronic GVHD consortium and the German-Austrian-Swiss GVHD group no longer expert consensus International Consensus on clinical practice in chronic GVHD 2009 organized by the German-Austrian-Swiss Group in collaboration with the US consortium International Consensus on histopathology in GVHD in collaboration with the US consortium (are to be published in 2013) Histopathology on Liver GVHD (currently considered for publ.) Histopathology on cutaneous GVHD (currently prepared for publ.) Histopathology on intestinal GVHD (round robin test to validate the consensus ongoing)

14 Conclusions Do NCI criteria for cgvhd improve outcome? No yet Validation of impact in clinical routine required Clarification and adjustments of definitions are required Critical data for clinical routine versus trials are to defined Dissemination of knowledge required Phase IIb and Phase III trials evaluating existing treatment options required Diagnostic criteria (role of histopathology, biomarker) need to be validated New treatment options especially to separate the GVL-GVD effect required

15 Future Meetings of the German-Austrian-Swiss-GVHD group Workshop on Clinical Practice in cgvhd & Workshop on oral cgvhd Regensburg November