Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med 2017;377: DOI: /NEJMoa

2 Supplementary Appendix Supplement to: Le Gouill S., MD, PhD et al. : Rituximab after Autologous Stem Cell Transplantation in Mantle Cell Lymphoma The LyMa trial is a phase III international prospective trial sponsored by the GOELAMS group and performed by the GOELAMS and GELA centers, now LYSA (The Lymphoma Study Association) for lymphoma studies. Contents : List of investigators page 2 Inclusion and exclusion criteria page 3 Overall study design page 4 Tumor status according to page international working group criteria Mantle cell lymphoma page 7 International Prognostic Index (MIPI) Figures : S1 EFS per protocol analysis page 8 S2 OS calculated from time of inclusion page 9 S3 PFS calculated from time of inclusion page 10 S4 OS according to MIPI page 11 score calculated from time of inclusion S5 PFS according to MIPI page 12 score calculated from time of inclusion Supplementary Table S1 (toxicity) page 13 ITT analysis (Cox model) page 15 according to randomization and stratified by use or not of R- CHOP before ASCT. 1

3 List of LyMa trial investigators Araujo Carla, MD (CH Bayonne, France), Eric Deconinck, MD, PhD (CHU Besançon, France), Richard Delarue (Necker Paris, France), Joel Fleury, MD (Clermont- Ferrand PSR, France), Bernard Drenou, MD (CH Colmar, France), Bernard Christian, MD (CH de Metz- Thionville, France) Pierre Morel MD (CH Lens, France), emmanuelle nicolas- virelizier, MD (Centre Leon Berard, Lyon, France), Reda Bouabdallah, MD (Centre Paoli Calmette Marseille France), Jamile Frayfer, MD (CH Meaux, France), Eric Jourdan, MD, PhD (CHU Nimes, France), Laurence Sahnes, MD (CH Perpignan, France), Alain Delmer, MD, PhD (CHU Reims, France), Alain Saad, MD (CH Beziers, France), Bertrand Joly, MD (CH Corbeilles- Essone, France), Nicolas Albin, MD (CHM Grenoble, France), Mohamed Belkaid (CH Colmar, France), Arnaud Jaccard, MD, PhD (CHU Limoges, France), Bernard Drenou, MD (CH Mulhouse, France), Nadine Morineau, MD (Centre Catherine de Sienne, Reze, France), Magda Alexis, MD (CH Orleans, France), Henry Jardel, MD (CH Vannes, France), Marie- Pierre Molles, MD (CHU Angers, France), Bernadette Corron, MD (CH Annecy, France), abderrrazak El Yamani, MD (CH Blois, France), Christian Berthou, MD, PhD (CHU Brest, France), Margareth macro, MD (CHU Caen, France), Kamel Laribi, MD (CH Le Mans, France), Philippe Moreau, MD (CH Lorient, France), Didier Bouscary, MD, PhD (Paris Cochin, France), Sylvain Choquet, MD (La Pitié Salpetrière, Paris, France), Maud Janvier, MD (Paris Saint- cloud, France), Christiane Mounier, MD (CHU St- Etienne, France), Laurent Sutton, MD (CH Argenteil, France), Pierre Soubeyran, MD, PhD (Bordeaux Bergonnié, France), Olivier Fitoussi, MD (Polyclinique Bordeaux Nord Aquitaine, France), Bachra Choufi, MD (CH Boulogne, France), Eric Van Hoof, MD, PhD (CH Bruges, Belgique), Christophe Fruchart, MD (Centre Baclesse, Caen, France), Dr Alex Bellange (CH Morlaix, France), Abdelmalek Aoudjhane, MD (Saint- Antoine, Paris, France), Andre Bosly, MD, PhD (CH Yvoire, Belgique), Sylvie Cailleres, MD (CH Aix- en- Provence, France), E Macintyre (Necker, Paris, France), Marie- Helène Delfau- Larue (CHU Creteil, France) 2

4 - Inclusion and exclusion criteria Inclusion criteria: - MCL CD20 positive according to WHO 2008 classification Untreated MCL patients younger older than 18 and younger than 66 At least one measurable site ECOG performance status Ejection cardiac function >50% Signed informed consent Measurable disease that requires treatment Absolute neutrophil count >1.0 x 10 9 /L Platelets >50 x 10 9 /L AST and/or ALT <3xULN Calculated creatinine clearance >50mL/min Bilirubin < 2x normal No other cancer (except in situ or baso- cellular) Exclusion criteria Other entity of lymphoma Active HBV, HCV HIV- positive Active systemic infection requiring treatment Uncontrolled diabetes Patient unable to receive one drug in the treatment plan 3

5 - Overall study design R- DHAP (One course every 21 days): rituximab 375 mg/m 2 intravenously on day 1, dexamethasone 40 mg intravenously on days 1 to 4, cytarabine 2 g/m 2 intravenously every 12 h on day 2 and platinium derivative (continuous infusion cisplatin 100 mg/m 2 over 24 h on day 1 or carboplatin with AUC = 5 mg/ml.min (target Area Under the concentration vs. time Curve using the Calvert formula) or oxaliplatin 130 mg/m² on day 1). According to local investigator decision one course of CVP was allowed before R- DHAP: cyclophosphamide 750 mg/m 2 intravenously on day 1, vincristine 1,4 mg/m 2 intravenously on day 1 (total dose 2 mg) and prednisolone 80 mg/m 2 on days 1 to 5. R- CHOP: rituximab 375 mg/m2 on day 1, cyclophosphamide 750 mg/m2 on day 1, vincristine (total dose 2 mg) 1.4 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1 and prednisolone 80 mg/m 2 on days 1 to 5, one course every 14 days. R- BEAM: Rituximab (500 mg/m2 on day - 8) and BEAM: carmustine [1,3- bis(2- chloroethyl)- 1- nitrosourea] 300 mg/m 2 on day - 7, etoposide 400 mg/m 2 on days - 6 to - 3, cytarabine 400 mg/m 2 on days - 6 to - 3 and melphalan 140 mg/m 2 on day - 2. Peripheral stem cells (PSC) were injected on day 0. PR: partial response (tumor reduced by less than 75% after induction) Disease was assessed before ASCT and 2 months after ASCT. 4

6 Follow- up after ASCT and for patients in both arms: - - physical examination every two months for 3 years, every six months for 3 years and then every year until progression CT/scan every 6 months for 3 years and then every year for 3 years. 5

7 Tumor status according to 1999 international working group criteria (Cheson et al., Journal of Clinical Oncology 17, no.4 (April 1999) ) 6

8 Mantle cell lymphoma International Prognostic Index (MIPI) (Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced- stage mantle cell lymphoma. Blood 2008 ; 111(2): ) Simplified prognostic index Points Age, y ECOG LDH, per ULN WBC, 10-6 L 0 < <0.67 < For each prognostic factor, 0 to 3 points were given to each patient and points were summed up to a maximum of 11. Patients with 0 to 3 points are classified as low risk patients with 4 to 5 points are classified as intermediate risk patients with 6 to 11 points are classified as high risk. ECOG performance status is weighted with 2 points if patients are unable to work or bedridden (ECOG 2-4). LDH is weighted according to the ratio to the ULN. 7

9 Figure S1 PER PROTOCOL ANALYSIS. We performed a per protocol analysis regarding the primary endpoint (EFS). This analysis included all randomized patients who received at least one dose of treatment and had no major protocol deviation. 8

10 Figure S2 Kaplan- Meier analysis of overall survival (OS) calculated from time of inclusion 9

11 Figure S3. Kaplan- Meier Analysis of Progression- free survival (PFS) calculated from time of inclusion 10

12 Figure S4 Kaplan- Meier Analysis of Overall survival (OS) according to MIPI (MCL international prognostic index) score calculated from time of inclusion 11

13 Figure S5. Kaplan- Meier Analysis of Progression free survival (PFS) according to MIPI score calculated from time of inclusion 12

14 - TABLE S1- Grade 3 and 4 toxicities in RM and Observation Arm TREATMENT ARM OBSERVATION < months months months RITUXIMAB Maintenance < months months months N=118 N=110 N=104 N=112 N=102 N=99 Hematology (All) 44 (37.3%) 14 (12.7%) 26 (25.0%) 51 (45.5%) 25 (24.5%) 22 (22.2%) Neutropenia 31 (26.3%) 1 (0.9%) 3 (2.9%) 46 (41.1%) 16 (15.7%) 12 (12.1%) Thrombocytopenia 5 (4.2%) 2 (1.8%) 4 (3.8%) 6 (5.4%) 4 (3.9%) 5 (5.1%) Infections classified 1 (0.8%) 1 (0.9%) 2 (1.9%) 1 (0.9%) 1 (1.0%) 2 (2.0%) as an event Infections 4 (3.4%) 2 (1.8%) 3 (2.9%) 7 (6.3%) 2 (2.0%) 3 (3.0%) Cutaneous 1 (0.8%) 0 (0.0%) 1 (1.0%) 0 (0.0%) 0 (0.0%) 2 (2.0%) GI function 1 (0.8%) 0 (0.0%) 0 (0.0%) 1 (0.9%) 1 (1.0%) 1 (1.0%) Pulmonary function 3 (2.5%) 1 (0.9%) 4 (3.8%) 1 (0.9%) 1 (1.0%) 2 (2.0%) Cardiac function 0 (0.0%) 0 (0.0%) 1 (1.0%) 0 (0.0%) 0 (0.0%) 1 (1.0%) Neurology 0 (0.0%) 2 (1.8%) 1 (1.0%) 4 (3.6%) 2 (2.0%) 4 (4.0%) Transaminases 0 (0.0%) 0 (0.0%) 0 (0.0%) 5 (4.5%) 4 (4.0%) 1 (1.0%) Bilirubin 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.9%) 1 (1.0%) 0 (0.0%) Creatinine 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (1.8%) 0 (0.0%) 1 (1.0%) 13

15 Grade 1-2 toxicities after transplantation: - Infection: there were 67 events (in 54 patients) in the observation arm versus 126 events (in 80 patients) in the Rituximab arm. - Neutropenia: there were 45 events (in 29 patients) in the observation arm versus 92 events (in 35 patients) in the Rituximab arm. 14

16 ITT analysis (Cox model) according to randomization and stratified by use or not of R- CHOP before ASCT. - Regarding the primary endpoint (EFS): Table Cox Model : EFS From Randomization According to Treatment Arm and Stratified by R- CHOP - ITT Parameter Modality Hazard 95% Hazard Ratio Confidence Limits Pr > Tested Ratio Lower Upper ChiSq Treatment RITUXIMAB arm Model is performed on 240 patients (72 events and 168 censoring). - Regarding the secondary endpoint PFS: Table Cox Model : PFS From Randomization According to Treatment Arm and Stratified by R- CHOP - ITT Parameter Modality Hazard 95% Hazard Ratio Confidence Limits Pr > Tested Ratio Lower Upper ChiSq Treatment RITUXIMAB arm Model is performed on 240 patients (63 events and 177 censoring). - Regarding the secondary endpoints OS: Table Cox Model : OS From Randomization According to Treatment Arm and Stratified by R- CHOP - ITT Parameter Modality Hazard 95% Hazard Ratio Confidence Limits Pr > Tested Ratio Lower Upper ChiSq Treatment RITUXIMAB arm Model is performed on 240 patients (37 events and 203 censoring). 15

17 Sensitivity ITT analysis (Cox model) on modified ITT population defined as all patients from ITT population with an event different from lost to follow- up. Three patients were lost to follow up (1 in the Rituximab arm and two in the observation arm). - Regarding the primary endpoint (EFS): Table Cox Model : EFS From Randomization According to Treatment Arm - ITT (Lost to Follow- Up Excluded) Parameter Modality Tested Treatment arm Hazard Ratio Lower 95% Hazard Ratio Confidence Limits Pr > Upper ChiSq RITUXIMAB Model is performed on 237 patients (72 events and 165 censoring). - Regarding the secondary endpoint PFS: Table Cox Model : PFS From Randomization According to Treatment Arm - ITT (Lost to Follow- Up Excluded) Parameter Modality Tested Treatment arm Hazard Ratio Lower 95% Hazard Ratio Confidence Limits Pr > Upper ChiSq RITUXIMAB Model is performed on 237 patients (63 events and 174 censoring). - Regarding the secondary endpoint OS: Table Cox Model : OS From Randomization According to Treatment Arm - ITT (Lost to Follow- Up Excluded) Parameter Modality Tested Treatment arm Hazard Ratio Lower 95% Hazard Ratio Confidence Limits Pr > Upper ChiSq RITUXIMAB Model is performed on 237 patients (37 events and 200 censoring). 16