G. Socié, MD, PhD Hematology Transplantation Hospital Saint Louis Paris University Paris Denis Diderot & INSERM U728 16:00-17:30 Session 7 GvHD Prevention by T-Cell Modulation Is photopheresis treatment of choice for chronic GvHD? Chair: H.J. Deeg, USA 16:45-17:00 Yes: H. Greinix, Austria 17:00-17:15 No: G. Socié, France 17:15-17:30 Discussion?
Chronic GvHD I. Prophylaxis Prophylactic treatment Randomized Trials of acute GvHD prophylaxis with CSA CSA+MTX vs. CSA No difference CSA+MTX vs. MTX No difference CSA high vs. Low dose No difference CSA duration (24 vs. 6 mo.) No difference CSA duration (6 mo. vs. 60 days) No difference Randomized Trials of acute GvHD prophylaxis with tacrolimus No difference
T-cell depletion and chronic GVHD? I. Prophylaxis 45 40 35 30 25 20 15 10 5 0 32 26 14 agvhd IIII-IV 41 36 21 extens. cgvhd no ATG ATG 7,5 ATG 15 BB & MT 8:656-661 (2002) Blood. 2005;106:3308-3313
I. Prophylaxis Socié et al. Blood, 2011
Effect of ATG-F on treatment duration and time to stop immunosuppressive therapy I. Prophylaxis Probability of being alive and free of IST Socié et al Blood, 2011 HRs (ATG-F vs. control) Receiving IST = 0.31, p<0.0001 Stop IST= 2.02, p=0.0001
Treatment Intensity II. Treatment Symptom Threshold Symptoms Waning Clinical Tolerance Symptoms Waxing Time Courtesy of PJ Martin
II. Treatment CSp +PDN + MMF Courtesy of Paul Martin, MD + MMF - MMF CSA + PDN is the standard Blood, 2009; 113: 5074-5082
CTN Protocol 0801 Study Schema Non-ECP Centers Phase II ECP Centers Randomize 1:1 Randomize 1:1 P+SRL P+SRL+CNI P+SRL+CNI P+SRL+ECP N=50 N=50 N=50 N=50 Phase III Continued accrual: All Centers Randomize 1:1 Phase II Winner Phase III Winner Test Phase III P+SRL+CNI Phase II Control 50 +150 +150 50 N=200 GS / N=200 GvHD / 2011 / COSTEM
Secondary treatments II. Treatment Consensus conference on clinical practice in chronic GVHD: Second-Line Treatment of chronic Graft-versus-Host Disease D. Wolff, M. Schleuning, S. von Harsdorf, U. Bacher, A. Gerbitz, M. Stadler, F. Ayuk, A. Kiani, R. Schwerdtfeger, G.B. Vogelsang, G. Kobbe, M. Gramatzki, A. Lawitschka, M. Mohty, S.Z. Pavletic, H. Greinix, E. Holler Biology of Blood and Marrow Transplantation 2010
Secondary treatments II. Treatment Subjectively: 4 major 2 nd or subsequent treatment lines ECP Rituximab Sirolimus Imatinib (?)
Issues with ECP: Practical - Need to go back to center for treatment - Need central venous access - Associated (increased?) infectious risk Methodological - Lessons from the randomized study
ECP Cutaneous c.gvhd not controlled by steroid Blood. 2008;112:2667-2674
ECP Involved Site at Baseline Improvement, n (%) ECP Control p value Oral Mucosa 16/30 (53) 8/30 (27) 0.064 Liver 3/14 (21) 6/14 (43) 0.420 Lungs 1/9 (11) 2/7 (29) 0.550 Eye 8/27 (30) 2/28 (7) 0.040 Joint 4/18 (22) 2/16 (12) 0.660 Gastrointestinal Tract 1/2 (50) 3/9 (33) 0.999 Blood. 2008;112:2667-2674
The only proof of efficacy in this disease is Being alive without immunosuppressive therapy (tolerance) CI of IST discontinuation Blood. 2004;104:3501-3506
Endpoint Interpretation Time Patient-reported outcomes Self-assessed morbidity Short GVHD response organ-specific or summary Short Time to GVHD progression GVHD-specific mortality Similar to progression of malignant disease Similar to transplantrelated mortality Variable Long Overall survival Survival Long RFS to resolution of GVHD Complete response Long RFS to discontinuation of IST Cure Long NIH Consensus; Chronic GvHD June 2005
Outcome Improvement Worsening CR PR Minor response Resolution of all chronic GVHD disease N A activity 50%-99% improvement in at least one organ system 25-49% improvement in at least one organ system Mixed response > 25% improvement in 1 organ > 25% worsening in other organ Stable < 25% improvement No worsening in other organ Progression No > 25% in at least 1 organ NIH Consensus; Chronic GvHD June 2005 N A N A
Summary of recommendations: Inclusion and exclusion criteria +++ Baseline evaluations Guidance regarding the dosing and dose adjustment of IST drugs Calendar-driven, standardized measures of response Primary and secondary endpoints +++ Competing events