WHAT IS THE BEST Front-Line REGIMEN for Patients With CLL <60 YEARS OF AGE WHO MEET TREATMENT CRITERIA? Bendamustine and Rituximab (BR) Alessandra Ferrajoli, M.D. Department of Leukemia The University of Texas MD Anderson Cancer Center

Bendamustine Hydrochloride (Synthesized in East Germany in 1963) Alkylating group Benzimidazole ring (shares the antimetabolic properties of purine analogues) Butyric acid side-chain single agent (Knauf WU , J Clin Oncol, 2009) in combination with anthracyclines (Weide R, Leuk Lymph, 2002) in combination with rituximab (Fischer K, J Clin Oncol, 2011) Ferrajoli A. Haematologica 10:1300, 2005

Bendamustine Bifunctional Antineoplastic Agent CH3 N ClH2C N N CO2H Purine-like Benzimidazole Ring ClH2C Alkylating Group Available in Germany, 1971-1992 Unique in vitro anti-tumor profile Rummel M, et al. J Clin Oncol. 2005;23:3383-3389. 3

BENDAMUSTINE COMBINED WITH RITUXIMAB IN FIRST-LINE THERAPY OF CLL: TREATMENT SCHEDULE R = Rituximab 375 mg/m2 day 0, cycle 1, 500 mg/m2 cycle 2-6, q4wks B = Bendamustine 90 mg/m2 day 1-2, cycle 1-6, q4wks Fischer et al. J Clin Oncol 30:3209-16, 2012 4

BENDAMUSTINE COMBINED WITH RITUXIMAB IN FIRST-LINE THERAPY OF CLL: RESPONSE RATE % ORR 103 88 CR 27 23.1 PR 74 64.9 SD 11 9.4 Fischer et al. J Clin Oncol 30:3209-16, 2012

CLL10 Study: FCR VS BR in Front-line Design Patients with untreated, active CLL without del(17p) and good physical fitness (CIRS ≤ 6, creatinine clearance ≥ 70 ml/min) Randomization FCR Fludarabine 25 mg/m² i.v., days 1-3 Cyclophosphamide 250 mg/m², days 1-3, Rituximab 375 mg/ m2 i.v. day 0, cycle 1 Rituximab 500 mg/m² i.v. day 1, cycle 2-6 BR Bendamustine 90mg/m² day 1-2 Rituximab 375 mg/m² day 0, cycle 1 Rituximab 500 mg/m² day 1, cycle 2-6 Non-Inferiority of BR in comparison to FCR for PFS: HR (λ BR/FCR) less than 1.388 Eichhorst et al. ASH 2013, Abstract 526.

CLL10 Study: FCR VS BR in Front-line Consort Diagram 688 CLL patients screened centrally for: immunophenotype CIRS genomic aberrations (FISH) GFR IGHV sequencing 564 underwent 1:1 randomization FCR n = 284 BR n = 280 1 treatment before randomization 1 patient decision 1 misdiagnosis (MCL) ITT: FCR n = 282 ITT: BR n = 279 Median observation time: 27.5 months Eichhorst B. et al, ASH 2013

CLL10 Study: FCR VS BR in Front-line Patients´ characteristics Baseline characteristics FCR n=282 BR n=279 p value Median age (y) 61.0 62.1 0.131 Age ≥ 65 33.7% 40.5% 0.098 Age ≥ 70 13.8% 21.5% 0.020 Male 71.3% 74.2% 0.450 Median time since diagnosis (months) 21.2 24.4 0.811 ECOG = 0 63.2% 64.1% 0.207 CIRS, median 2 0.689 Mean number of cycles 5.27 5.41 0.022 Eichhorst et al. ASH 2013, Abstract 526.

CLL10 Study: FCR VS BR in Front-Line Patients´ characteristics: prognostic factors Baseline prognostic factors FCR n=282 BR n=279 p value Binet stage A 22.4% 22.2% 0.970 Binet stage B 37.4% 38.4% Binet stage C 40.2% 39.4% IGHV Unmutated 55.3% 67.8% 0.003 11q deletion 24.1% 22.6% 0.691 Trisomy 12 12.4% 12.2% 1.000 13q deletion 55.0% 52.7% 0.612 s- TK (U/L) ≥ 10.0 73.9% 74.3% 0.921 s- β2m (mg/l) ≥ 3.5 31.6% 39.5% 0.059 Eichhorst et al. ASH 2013, Abstract 526.

CLL10 Study: FCR VS BR in FrontLine Response to therapy (Best response) Response FCR n=274 BR n=273 p value CR (CR + CRi) 47.4% 38.1% 0.031 CR 40.1% 36.3% CRi 7.3% 1.8% PR 50.4% 59.7% ORR 97.8% 1.0 Eichhorst et al. ASH 2013, Abstract 526.

CLL10 Study: FCR VS BR in FrontLine Minimal residual disease (MRD) p=0.024 No. of patients: 72/180 44/156 137/185 107/170 75/129 31/98 Eichhorst et al. ASH 2013, Abstract 526.

CLL10 Study: FCR VS BR in Front-Line Progression-free survival = Primary endpoint Median PFS FCR not reached BR 44.9 months P = 0.041 Eichhorst B. et al, ASH 2013

CLL10 Study: FCR VS BR in FrontLine Multivariate Analysis Prognostic factor Overall Survival Progression-free Survival HR CI p-value Treatment arm 1.649 0.831-3.272 0.153 0.704 0.505-0.981 0.038 No del(11q) 0.551 0.227-1.340 0.189 0.447 0.291-0.685 <0.001 Age ≥ 65 2.095 1.057-4.150 0.034 0.800 0.566-1.129 0.204 CIRS item score >1 2.267 1.146-4.484 0.019 1.256 0.879-1.794 0.210 Beta2-MG 2.546 1.294-5.009 0.007 1.425 1.074-2.072 IGHV unmutated 4.017 1.552-10.395 0.004 2.645 1.712-4.086 Eichhorst B. et al, ASH 2013

WHAT IS THE BEST Front-Line REGIMEN for Patients With CLL <60 YEARS OF AGE WHO MEET TREATMENT CRITERIA? FCR: End of the debate not quite, let’s look at details

CLL10 Study: FCR VS BR in Front-line Overall survival OS at 24 months: FCR 94.2% BR 95.8% P = 0.593 Eichhorst B. et al, ASH 2013

CLL10 Study: FCR VS BR in FrontLine Adverse Events CTC °3-5 (Interval 1st cycle until 3 months after Final staging) Adverse event FCR (% of pt) BR p value All 90.8 78.5 <0.001 Hematological AEs 90.0 66.9 Neutropenia 81.7 56.8 Anemia 12.9 9.7 0.28 Thrombocytopenia 21.5 14.4 0.036 Infection 39.0 25.4 0.001 TRM 3.9 2.1 0.23 Eichhorst et al. ASH 2013, Abstract 526.

WHAT IS THE BEST Front-Line REGIMEN for Patients With CLL <60 YEARS OF AGE WHO MEET TREATMENT CRITERIA? BR: older patients no difference in PFS and OS has less infection less mylosuppressive easier to administer easier to add new agents

GA101 + Bendamustine x 6 cycles GALTON: Study Design GA101 + FC x 6 cycles n=21 Previously untreated CLL (N=41) Non-randomized US, multicenter Each center selects one arm GA101 + Bendamustine x 6 cycles n=20 Cycle 1, Day Cycles 2–6, Day GA101 + FC GA101 1000 mg IV 1 (100 mg), 2 (900 mg) 8 (1000 mg), 15 (1000 mg) 1 Fludarabine 25 mg/m2 IV 2, 3, 4 1, 2, 3 Cyclophosphamide 250 mg/m2 IV GA101 + Bendamustine Bendamustine 90 mg/m2 2, 3 1, 2 Brown et al. ASH 2013, Abstract 523.

PCYC 1108 A Phase 1b Study of Ibrutinib With BR or FCR in Patients With Relapsed/Refractory CLL/SLL Ibrutinib 420 mg orally, once daily in 28d cycles + BR (70 mg/m2 d1-d2 [B]; 375 mg/m2 cycle 1, 500 mg/m2 cycles 2-6 [R]) for 6 cycles N = 30 Ibrutinib 420 mg orally, once daily in 28d cycles + FCR (25 mg/m2 d1-3 [F]; 250 mg/m2 d1-3 [C]; 375 mg/m2 cycle 1, 500 mg/m2 cycles 2-6 [R]) for 6 cycles N = 3 Investigator Choice Primary endpoint Safety Secondary endpoints ORR PFS 12/11/2018 00:47

PCYC 1108 Overall Response Rate (ORR) Median treatment duration on this study was 16 months, with an ORR of 93.4% (28 responding patients [5 CR, 3 nPR]) 1 patient achieved a PR with lymphocytosis (not included in ORR)

PCYC 1108 Progression-Free Survival 18/21 patients who continued on ibrutinib within the extension study are still on treatment ~1 year after the data-cut off without evidence of progression 12/11/2018 00:47

PCYC 1108 TEAEs Grade ≥ 3 Occurring in ≥ 2 Patients 40% 7% 10%