Efficacy of Bendamustine and rituximab in a real-world patient population Median follow-up 37,1 months Efficacy of bendamustine and rituximab as first salvage treatment in CLL and indirect comparison with ibrutinib: a GIMEMA, ERIC and UK CLL FORUM study Multivariable analysis median PFS: 25 m Parameters P Hazard Ratio 95% C.I. 17p- vs others 0.0004 2.92 1.631 5.296 237 pts treated with BR (2nd line) Median age 70 y IGVH mut/unmut 0.0299 0.53 0.299 0.94 Others vs Binet C 0.0192 0.536 0.319 0.903 Median OS: 74 m Parameters P Hazard Ratio 95% C.I. Stage A-B vs C 0,0276 0,547 0,320 0,935 CR+PR vs NR 0.0001 0.344 0.198 0.595 Cuneo A et al. Haematologica April 2018. Accepted
Indirect comparison of BR and ibrutinib in a real world patient population: patient selection 24 treated with chemo only in 1 line 66 pts UK CLL forum Ibrutinib 95 pts treated with ibrutinb as 1 salvage 29 pts NPP Italy (GIMEMA) BR 237 pts Italy (GIMEMA-ERIC) 100 treated with chemo only in 1 line excluded excluded 71 pts Matched adjusted indirect comparison 137 pts
Indirect comparison of BR and ibrutinib in a real-world population who received CIT in first line Baseline characteristics of the BR and the ibrutinib cohorts (UK + NPP GIMEMA) in patients treated with chemoimmunotherapy in first line Variable BR (n=137) Ibrutinib (n=71) p Median age years (range) 68.2 (39.4-84.6) 67.1 (27.5-85.3) 0.603 Age years (%) 65/>65 39 (34.5)/74 (65.5) 27 (38.6)/43 (61.4) 0.691 Gender (%) M/F 91 (66.4)/46 (33.6) 45 (63.4)/ 26 (36.6) 0.777 ECOG PS (%) 0-1/ 2 113 (91.9)/10 (8.1) 57 (82.6)/ 12 (17.4) 0.090 Months between 1 st line and 2 nd line median (range) n. <36/ 36 (%) 30.60 (0.40, 79.40) 81 (59.1)/56 (40.9) 19.40 (1.80, 77.60) 54 (76.1)/17 (23.9) 0.001 0.023 Response to 1 st line treatment (%) no/yes 28 (20.4)/109 (79.6) 8 (15.1)/45 (84.9) 0.524 IGHV (%)mutated/unmutated 17 (19.5)/70 (80.5) 8 (32.0)/17 (68.0) 0.295 17p- (%) yes/no 16 (14.8)/92 (85.2) 22 (36.1)/39 (63.9) 0.003 Cuneo A et a. Haematologica April 2018. Accepted
Indirect comparison of BR and ibrutinib in a real world patient population: patient selection Ibrutinib BR 66 pts UK CLL forum 29 pts NPP Italy (GIMEMA) 237 pts Italy (GIMEMA-ERIC) 100 treated with chemo only in 1 line 24 treated with chemo only in 1 line 95 pts treated with ibrutinb as 1 salvage 22 with 17p- 10 with 17p unkonown 71 pts Matched adjusted indirect comparison 137 pts 39 pts 92 pts 16 with 17p- 29 with 17p unkonown
OS in 39 patients treated with ibrutinib and in 92 patients treated with BR. All patients had intact 17p and received CIT front-line Subanalysis of the OS in patients with intact 17p and <36 month interval between 1 st and 2 nd line % alive at 3 yrs BR (n=55) 72,6 ibrutinib (n = 33) 59,8 ibrutinib (n = 33) BR (n=55) 0 50 100 72,6% [95% C.I. 60.1-87.7] 59.8% [95% C.I. 44.2-80.7)] (p=0.19) Cuneo A et a. Haematologica April 2018. Accepted
Conclusions BR is an efficacious first salvage regimen in CLL in a real life population, including elderly patients patients with 2 or more comorbidities patients with a creatinine clearance <70 ml/min The outcome was better in patients with favorable genetic features and with early/intermediate disease stage BR and ibrutinib may be equally effective in terms of OS (1 st salvage, excluding 17p-) data obtained in the real-life setting (possible bias)
Efficacy and tolerability of Bendamustine and Rituximab in first line and second line treatment in CLL An observational study proposed by the ERIC-GIMEMA groups Rationale for the study (first line) Bendamustine + Rituximab is the most widely employed regimen in first line in the young and in the elderly patient 1 In the published guidelines for the appropriate use of bendamustine in first-line therapy of CLL prepared on behalf of SIE, SIES, GITMO Group 2 the following unmet need was recognized: - efficacy and safety of BR in elderly/unfit patients 1 Green MR, ASH, 2014 abs # 4676; 2. Cuneo A, et al Leuk Res, 2014
Baseline characteristics of 157 unfit patients (Cr Cl <70) treated with BR in first line level Overall n 157 age (%) >65 years 128 (81.5) median [range] 72.64 [39.05, 88.91] stage (%) Binet B-C or Rai I-IV 77 (60.6) serum beta2 (%) >3.5 91 (84.3) ighv (%) Unmutated 34 (45.3) TP53 status (%) Deletion 17p and/or TP53 mutation 24 (18.8) FISH (%) 11q- 9 (8.3) sex (%) male 92 (58.6) ecog (%) 0-1 137 (90,7%) number_of_comorbidities (%) 2 or more 103 (66.0) wbc (median [range]) 70.00 [4.69, 113000.00] plts (median [range]) 148.00 [16.00, 310000.00] Hb (median [range]) 11.55 [4.00, 16.40]
Primary endpoint: PFS Median follow-up 26.5 months (range: 4.5-80.7) months %PFS estimate lower 95%CI Upper 95%CI 12 92.3 88.2 96.6 24 80.6 74.1 87.8 36 66.6 57.1 77.8
PFS: predictive/prognostic factors Parameters Pr > ChiSq Hazard Ratio 95% Lower Confidence Limit for Hazard Ratio 95% Upper Confidence Limit for Hazard Ratio >65yy vs <=65yy 0.0448 4.294 1.034 17.824 Binet B-C or Rai I-IV vs Binet A or Rai 0 0.0529 2.325 0.990 5.460 beta2 >3.5 vs <=3.5 0.3388 1.795 0.541 5.955 ighv Unmutated vs Mutated 0.4454 1.466 0.549 3.917 17p- and/or TP53 mutation vs No 0.0569 2.519 0.973 6.520 17p/TP53 mut CR/CRi/PR/nPR vs PD/SD/NR/Death/NE 0.0013 3.883 1.701 8.861
Overall survival months % alive estimate lower 95%CI Upper 95%CI 12 96.1 93.2 99.2 24 89.5 84.3 95 36 79.5 70.2 90
OS: predictive factors Pr > ChiSq Hazard Ratio 95% Lower Confidence Limit for Hazard Ratio 95% Upper Confidence Limit for Hazard Ratio Binet B-C or Rai I-IV vs Binet A or Rai 0 0.0719 3.143 0.903 10.942 beta2 >3.5 vs <=3.5 0.2870 3.005 0.396 22.782 ighv Unmutated vs Mutated 0.5233 0.612 0.135 2.769 Deletion 17p and/or TP53 mutation vs No Deletion 17p/TP53 mutation CR/CRi/PR/nPR/LPR vs PD/SD/NR/Death/Not evaluable 0.0042 5.624 1.722 18.364 0.0012 4.793 1.860 12.347 Age 17p-/TP53 mut
Efficacy and tolerability of Bendamustine and Rituximab in the first line treatment of unfit CLL patients An observational study proposed by the ERIC-GIMEMA groups Possible perspectives Analysis of predictive factors Comparison with the MABLE study 1 Indirect comparison with chlorambucil and Rituximab in the real life - GIMEMA data 2 (?) Indirect comparison with ibrutinib in a real world treatment-naive patient population (?) 1. Michellaet AS, et al. Haematologica 2018;103:698-7062. 2. Laurenti L et al, Haematologica. 2017 Sep;102(9):e352-e355