Supplementary appendix

Transcription

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Rummel M, Kaiser U, Balser C, et al, for the Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol 2015; published online Dec 4.

2 Appendix Fig. 1: PFS (A) and OS (B) for centres recruiting fewer vs. more than 3 patients / centre PFS (A) Probability Numbers at risk 1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 3 pat / ctr, n = 50, 37 events, median = 16.1 months (IQR ) > 3 pat / ctr, n = 169, 124 events, median = 22.9 months (IQR ) Time (months) p = pat. / centre > 3 pat. / centre OS (B) Probability 1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 3 pat / ctr, n = 50, 27 events, median = 61.9 months (IQR 16.7 nyr) > 3 pat / ctr, n = 169, 99 events, median = 57.6 months (IQR 24.8 nyr) Time (months) p = 0.92 Numbers at risk 3 pat. / centre > 3 pat. / centre

3 Appendix Fig. 2: PFS (A) and OS (B) for patients receiving R maintenance vs no maintenance PFS (A) Probability 1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 p = 0.01 R maintenance, n = 44, 20 ev., median = 72.1 months (IQR 34.3 nyr) No maintenance, n = 108, 75 ev., median = 30.4 months (IQR 14.4 nyr) Time (months) Numbers at risk R Maintenance No maintenance (B) 1 0,9 0,8 0,7 OS Probability 0,6 0,5 0,4 0,3 0,2 0,1 0 p = 0.03 R maintenance, n = 44, 14 events No maintenance, n = 108, 57 ev., median = 69.7 months (IQR 31.7 nyr) Time (months) Numbers at risk R maintenance No maintenance

4 Appendix table 1: Patient characteristics of primary refractory patients Age B-R (n = 8) F-R (n = 30) Median (range) years 66.6 (55 79) 66.4 (38 86) >70 years no. (%) 3 (37.5%) 12 (40.0%) Stage no. (%) IV 5 (62.5%) 16 (53.3%) Histology no. (%) Follicular 4 (50.0%) 15 (50.0%) Mantle cell 3 (37.5%) 11 (36.7%) Waldenströms 0 (0%) 1 (3.3%) Marginal zone 1 (12.5%) 2 (6.7%) Lymphocytic 0 (0%) 0 (0%) Low grade, unclassifiable 0 (0%) 1 (3.3%) B-symptoms no. (%) 1 (12.5%) 9 (30.0%) Bone marrow involved no. (%) 3 (37.5%) 12 (40.0%) LDH >240 U/L no. (%) 6 (75.0%) 14 (46.7%) Bulky disease no. (%) 2 (25.0%) 9 (30.0%) Prognostic groups for all patients IPI > 2 no. (%) 5 (62.5%) 9 (30.0%) Prognostic groups for follicular lymphoma patients Low risk FLIPI (0-1 risk factor) no. (%) 1 (25.0%) 2 (13.3%) Intermediate risk FLIPI (2 risk factors) no. (%) 1 (25.0%) 6 (40.0%) Poor risk FLIPI (3 5 risk factors) no. (%) 2 (50.0%) 6 (40.0%) 3

5 Appendix table 2: Patient characteristics and outcome for MCL Age B-R (n = 24) F-R (n = 23) Median (range) years 71.6 (49 79) 69.4 (51 82) >70 years no. (%) 13 (54.2%) 11 (47.8%) Stage no. (%) IV 17 (70.8%) 12 (52.2%) B-symptoms no. (%) 3 (12.5%) 5 (21.7%) Bone marrow involved no. (%) 13 (54.2%) 9 (39.1%) LDH >240 U/L no. (%) 13 (54.2%) 11 (47.8%) Bulky disease no. (%) 7 (29.2%) 5 (21.7%) Prognostic groups for all patients IPI > 2 no. (%) 10 (41.7%) 11 (47.8%) Previous treatments - no. 1 (%) 14 (58.3%) 10 (43.5%) 2 (%) 5 (20.8%) 10 (43.5%) >2 (%) 5 (20.8%) 3 (13.0%) Previous treatment regimens no. Bendamustine 3 4 Fludarabine 1 2 CHOP APBSCT 2 3 Prior Rituximab no. (%) 16 (66.7%) 19 (82.6%) 4

6 Response rates: ORR 17 (70.8%) 6 (26.1%) CR 9 (37.5%) 3 (13.0%) PR 8 (33.3%) 3 (13.0%) SD 2 (8.3%) 4 (17.4%) Progression 3 (12.5%) 11 (47.8%) n.e. 2 (8.3%) 2 (8.7%) Survival time: PFS - median (months) 17.6 ( ) 4.7 ( ) OS - median (months) 35.3 (14.9 nyr) 20.9 ( ) 5

7 Appendix table 3: Patient characteristics of patients with R-maintenance vs. no maintenance R maint. (n = 44) no R (n = 108) Age Median (range) years 67.4 (40 82) 67.6 (43 81) >70 years no. (%) 16 (36.4%) 38 (35.2%) Stage no. (%) IV 28 (63.6%) 70 (64.8%) Histology no. (%) Follicular 31 (70.5%) 55 (50.9%) Mantle cell 5 (11.4%) 19 (17.6%) Waldenströms 3 (6.8%) 14 (13.0%) Marginal zone 4 (9.1%) 10 (9.3%) Lymphocytic 1 (2.3%) 9 (8.3%) Low grade, unclassifiable 0 (0%) 1 (0.9%) B-symptoms no. (%) 9 (20.5%) 30 (27.8%) Bone marrow involved no. (%) 25 (56.8%) 52 (48.1%) LDH >240 U/L no. (%) 16 (36.4%) 36 (33.3%) Bulky disease no. (%) 13 (29.5%) 18 (16.7%) Prognostic groups for all patients IPI > 2 no. (%) 14 (31.8%) 37 (34.3%) Prognostic groups for follicular lymphoma patients Low risk FLIPI (0-1 risk factor) no. (%) 9 (29.0%) 13 (23.6%) Intermediate risk FLIPI (2 risk factors) no. (%) 7 (22.6%) 19 (34.5%) Poor risk FLIPI (3 5 risk factors) no. (%) 13 (41.9%) 21 (38.2%) 6

8 Appendix table 4: Response rates of patients previously treated with bendamustine and randomised into B-R Patients previously treated with bendamustine (n = 13) ORR 10 (76.9%) CR 2 (15.4)% PR 8 (61.5%) SD 3 (23.1%) Progression 0 (0%) n.e. 0 (0%) 7

9 Appendix table 5: Subsequent treatments for patients with progression (n=161) Treatment B-R F-R Bendamustine-based B-R 9 11 B mono - 5 BM-R - 2 Fludarabine-based F-R 2 - FC-R 2 - FM-R - 1 FC-Campath - 1 Other therapies Irradiation 9 9 HDT + APBSCT 5 5 CHOP-R 3 7 Zevalin 1 4 Rituximab 2 - GemOx-R 3 1 R-ICE - 1 DHAP - 1 MCP - 1 Chlorambucil 1 - CVP - 1 Cladribine 1 - Dexa, Bleo, Vinbl 1 - PAD 1 Unknown whether subsequent treatment or which kind of treatment was received after progression B-R: Bendamustine, Rituximab; BM-R: Bendamustine, Mitoxantrone, Rituximab; F-R: Fludarabine, Rituximab; FC-R: Fludarabine, Cyclophosphamide, Rituximab; FM-R: Fludarabine, Mitoxantrone, Rituximab; FC-Campath: Fludarabine, Cyclophosphamide, Alemtuzumab; HDT + APBSCT: High dose chemotherapy + Autologous Peripheral Blood Cell Transplantation; GemOx-R: Gemcitabine, Oxaliplatin, Rituximab; R-ICE: Rituximab, Ifosfamide, Carboplatin, Etoposide; DHAP: Dexamethasone, Cytarabine, Cisplatin; MCP: Mitoxantrone, Chlorambucil, Prednisolone; Dexa: Dexamethasone; Bleo: Bleomycin; Vinbl: Vinblastine; PAD: Bortezomib, Adriamycin, Dexamethasone. 8

10 Appendix table 6: Response rates of rituximab-naïve patients and patients pretreated with rituximab R prior treatment (n = 91) No prior treatment with R (n = 128) ORR 52 (57.1%) 96 (75.0%) CR 21 (23.1)% 43 (33.6)% PR 31 (34.1%) 53 (41.4%) SD 8 (8.8%) 15 (11.7%) Progression 25 (27.5%) 13 (10.2%) n.e. 6 (6.6%) 4 (3.1%) Appendix table 7: Haematologic toxic events of all grades in patients receiving at least one dose of study treatment. B-R F-R (n=114) (n=105) Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4 Leukocytopenia 81 (71%) 29 (25%) 9 (8%) 65 (62%) 23 (22%) 8 (8%) Neutropenia 46 (40%) 21 (18%) 12 (11%) 38 (36%) 11 (10%) 11 (10%) Thrombocytopenia 30 (26%) 7 (6%) 2 (2%) 22 (21%) 5 (5%) 5 (5%) Anemia 63 (41%) 5 (4%) 1 (1%) 39 (31%) 4 (4%) 2 (2%) 9

11 Bendamustine plus rituximab versus fludarabine plus rituximab in the treatment of patients with relapsed indolent and mantle cell lymphomas (StiL NHL ): Results of a multicentre, randomised, prospective, open-label non-inferiority phase III trial Study investigators M Hahn, S Mueller, Ansbach; M Klausmann, S Krüger, Aschaffenburg; C Aulmann, Augsburg; J Borghardt, Bad Münder; A Korfel, Berlin; M Goerner, M Just, E Schäfer, Bielefeld; U von Grünhagen, Cottbus; H Bernhard, G Kojouharoff, Darmstadt; J Schroeder, J Selbach, Duisburg; H-J Schütte, Düsseldorf; W Knauf, E. Jäger, L Bergmann, Frankfurt; I Wilke, Fürth; G Schliesser, A Kaebisch, W Blau, A Burchardt, M Rummel, Giessen; R Depenbusch, Gütersloh; R Rohrberg, U Neef, Halle; S Müller-Hagen, Hamburg; H Dürk, Hamm; G Lautenschläger, M Burk, Hanau; R Mao, D Kofahl-Krause, A Ganser, Hannover; L Hahn, Herne; U Kaiser, Hildesheim; H Link, S Mahlmann, Kaiserslautern; O Prümmer, Kempten; M Neise, Krefeld; M Stauch, Kronach; L Müller, Leer; N Niederle, A Heider, Leverkusen; T Neuhaus, Limburg; G Heil, Lüdenscheid; K Hünermund, Ludwigshafen; C Balser, F Weidenbach, Marburg; J Eggert, Moers; W Abenhardt, P Bojko, H Hitz, München; C Losem, D Plewe, Neuss; U Hutzschenreuter, Nordhorn; J Zimber, Nürnberg; H-E Balló, H- P Boeck, Offenbach; G Maschmeyer, F Rothmann, Potsdam; B Krammer-Steiner, Rostock; M Baldus, Rüsselsheim; A Matzdorff, Saarbrücken; H Fiechtner, Stuttgart; W Brugger, Villingen-Schwenningen; M Sandherr, M Perker, Weilheim; K-M Josten, Wiesbaden; U Schellenberger, Wilhelmshaven; R Schlag, Würzburg; all in Germany