Disclosure for Ralf Trappe, MD

Transcription

1 Disclosure for Ralf Trappe, MD In compliance with ACCME policy, ASH requires the following disclosures to the session audience: Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Hoffmann La Roche Ltd., AMGEN GmbH No relevant conflicts of interest to declare Hoffmann La Roche Ltd. No relevant conflicts of interest to declare No relevant conflicts of interest to declare Hoffmann La Roche Ltd. Genzyme GmbH Presentation includes discussion of the following off-label use of a drug or medical device: No disclosures 51 st ASH Annual Meeting New Orleans, Loisianna

2 Sequential Treatment with Rituximab and CHOP Chemotherapy in B-Cell PTLD Moving Forward to a First Standard of Care: Results From a Prospective International Multicenter Trial Ralf Trappe 1, Sylvain Choquet 2, Stephan Oertel 3, Veronique LeBlond 2, Daan Dierickx 4, Peter Mollee 5, Monica Sender 6, Tor Ekman 6, Jan Maciej Zaucha 7, Petra Reinke 1, Ruth Neuhaus 1, Hans Lehmkuhl 8, Martin Dreyling 9, Ulrich Dührsen 10, Gilles Salles 11, Franck Morschhauser 12, Arnaud Jaccard 13, Thierry Lamy 14, Ioannis Anagnostopoulos 1, Martine Raphael 15, Bernd Dörken 1 and Hanno Riess 1 1 Charité-Universitätsmedizin Berlin, Berlin, Germany; 2 Hôpital Pitié-Salpétrière, Paris, France; 3 Pharmaceutical Division (PBNO), F. Hoffmann - LaRoche Ltd., Basel, Switzerland; 4 Hospital Gasthuisberg, Leuven, Belgium; 5 Princess Alexandra Hospital, Brisbane, Australia; 5 Sahlgrens Hospital, Gothenburg, Sweden; 7 Medical University of Gdansk and Polish Lymphoma Research Group, Gdynia, Poland; 8 German Heart Center Berlin, Germany; 9 University of Munich - Campus Großhadern, Munich, Germany; 10 University Hospital, University of Duisburg-Essen, Essen, Germany; 11 Centre Hospitalier Lyon Sud, Lyon, France; 12 Hôpital Claude Huriez, Lille, France; 13 Hôpital Dupuytren, Limoges, France; 14 CHU Rennes, Rennes, France; 95 Hôpital du Kremlin Bicêtre, Le Kremlin Bicêtre, France

3 Introduction to PTLD Post-transplant lymphoproliferative disorder (PTLD) is the second most frequent malignancy following solid organ transplantation (SOT) Incidence of PTLD is dependent on: type of transplant intensity of immunosuppression PTLD is associated with the Epstein Barr virus (EBV): transplant patients who are EBV-negative are at high risk of PTLD

4 Treatment options in PTLD Treatment options include: reduction of immunosuppression chemotherapy rituximab monotherapy antiviral therapy immunomodulation surgery radiation therapy

5 Chemotherapy in PTLD: Overview Group Study format Chemo Regimen CR Treatment-related mortality Mamzer-Bruneel (2000) 1 retrospective CHOP (7) other (4)* 6/10 5/10 Norin (2004) 1 retrospective CHOP 5/12 2/12 Elstrom (2006) 2 retrospective CHOP (10), R- CHOP (9), other (4)* 13/23 6/23 Fohrer (2006) 3 prospective ACVBP (20), R-ACVBP (1)* 22/24 3/24 Choquet (2007) 4 retrospective CHOP 13/26 8/26 *all ± radiotherapy 1.Mamzer-Bruneel MF, et al. J Clin Oncol 2000; 18: Norin S, et al. Med Oncol 2004; 21: Elstrom RL, et al. Am J Transplant 2006; 6: Fohrer C, et al. Br J Haematol 2006; 134: Choquet S, et al. Haematologica 2007; 92:

6 Rituximab monotherapy in PTLD: Overview Three prospective, multicenter phase II trials Included adults with PTLD after SOT who did not respond to prior reduction of immunosuppression N Response rate Median PFS/TTF (months) Infections (WHO Grade III/IV) Treatmentrelated mortality Oertel (2005) 1 17 CR: 53% PR: 6% 8.9 none none Choquet (2006) 2 43 CR: 28% PR: 16% 3.3 none none González Barca (2007) 3* 38 CR: 61% PR: 18% 34% early progression or therapy failure none none *in case of initial response 4 additional doses of rituximab were administered 1. Oertel SH, et al. Am J Transplant 2005; 5: Choquet S, et al. Blood 2006; 107: González-Barca, et al. Haematologica 2007; 92:

7 Sequential treatment (ST) with rituximab and CHOP in PTLD: Study design Design: Phase II day 1 day 8 day 15 day 22 day 50 day 72 day 94 day 116 Rituximab (375mg/m²) I Rituximab (375mg/m²) II Rituximab (375mg/m²) III Rituximab (375mg/m²) IV CHOP-21 + G-CSF I CHOP-21 + G-CSF II CHOP-21 + G-CSF III CHOP-21 + G-CSF IV Recruiting centers in: Germany France Belgium Poland Sweden Australia Start of recruitment: January 2003 Planned recruitment: 150 patients Recruitment: ongoing The European Study Group on PTLD

8 Response to rituximab treatment was a significant predictor of overall survival (OS) 100 Log-Rank Test: p = Percent OS months CR or PR after 4 cycles of rituximab (n=35) SD or PD after 4 cycles of rituximab (n=23)

9 Risk stratified sequential treatment (RSST) with rituximab and CHOP in PTLD High risk Low risk

10 Patient recruitment Median follow (ST): 34.0 months Median follow up (RSST): 9.1 months Number of patients ST RSST

11 Patient characteristics (ST/RSST) Protocol ST / RSST Number of pts Age at diagosis (years) Median 53.2 / 60.0 Transplantat type Kidney 42% / 58% Kidney + pancreas 5% / 0% Liver 23% / 20% Heart 20% / 15% Lung+Heart/Lung 9% / 8% Time from transplant to PTLD < 1 Jahr 25% / 25% > 1 Jahr 75% / 75% Histology (WHO, 2001) Polymorphic PTLD 5% / 13% Monomorphic PTLD 95% / 87% Burkitt 3% / 2% DLBCL 75% / 78% Plasma cell myeloma 3% / 0% Others 13% / 8% Stage of disease I + II 41% / 42% III + IV 59% / 58% LDH Elevated 71% / 64% Normal 29% / 36% EBV-association Yes 49% / 47% No 51% / 53%

12 Response rates and safety data 100% 80% 60% 40% 20% 0% PR CR PR PR CR CR 4xR ST RSST ORR ST: 89%, RSST: 93% CR ST: 69%, RSST: 74% Treatment Related Mortality ST: 9% (6/64) - 1 due to CMV-infection - 1 due to PcP-pneumonia - 1 due to hepatitis - 3 due to sepsis RSST: 2.5% (1/40) - 1 due to sepsis secondary to intestinal perforation

13 Survival data Time to progression by study in all patients (n=104) in low risk patients only having received rituximab treatment (n=32) ST RSST RSST ST RSST: without progression at 1 year: 93% ST: without progression at 1 year: 81% RSST: without relapse after CR: 94% ST: without relapse after CR: 94%

14 Survival data High risk patients (n=72) RSST ST RSST: OS at 1 year: 75% ST: OS at 1 year: 64%

15 Conclusion Sequential treatment (ST) of PTLD with rituximab followed by 4 cycles of CHOP + G-CSF is: highly effective well tolerated superior to rituximab alone superior to CHOP alone as compared to historical controls Risk stratified sequential treatment (RSST): shows a lower toxicity than sequential treatment (ST) 32% of patients that can effectively be treated by rituximab monotherapy