CLL: treatment goals and therapeutic approach

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University of Munich Clinic of Hematology, Oncology, Immunology, Palliative Care, Infectious

1 CLL: treatment goals and therapeutic approach Clemens Wendtner Professor of Medicine Secretary of GCLLSG University of Cologne and Director Klinikum Schwabing Academic Teaching Hospital of University of Munich Clinic of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Munich HEMO 2016, Janssen Symposium, Florianopolis/ Brazil, November 10 th, 2016

2 Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Disclosures Hoffmann-La Roche, Celgene, Janssen, Mundipharma, GSK, Servier, Morphosys, Abbvie NA Hoffmann-La Roche, Celgene, Mundipharma, GSK, Servier, Janssen, Gilead, Genentech, Morphosys, Abbvie NA NA Honoraria Scientific Advisory Board Hoffmann-La Roche, Celgene, Mundipharma, GSK, Servier, Janssen, Gilead, Genentech, Morphosys, Abbvie Hoffmann-La Roche, Celgene, Mundipharma, GSK, Servier, Janssen, Gilead, Genentech, Morphosys, Abbvie Presentation includes discussion of the off-label use of a drug or drugs

3 Chronic Lymphocytic Leukemia (CLL) Most common leukemia in adults Complex pathogenesis: - Microenvironment stimulation - Immunologic drive, receptor signaling - Genomic aberrations, mutations, epigenetics

4 The Mutanome of CLL Cancer Drivers: Whole Exome Sequencing (WES) Landau, Tausch, Taylor-Weiner et al. Nature 2015 (total n=538) *novel driver 44 cancer driver mutations in total 69.3% patients with 1 driver

5 Variables Baseline characteristics Clinical Staging Laboratory results Molecular cytogenetic Gene mutations Cell expressions Serum markers Age, time between diagnosis and study, gender, study, treatment Binet stage, Rai stage, B-symptoms, ECOG performance status Hemoglobin, leucocytes, lymphocytes, platelets, neutrophils del(17p), del(11q), trisomy 12, del(13q), del(6q) IGHV, TP53, NOTCH1, SF3B1 Expressions of ZAP-70 and CD38 Serum thymidine kinase, serum β 2 - microglobulin, serum lactate dehydrogenase

7 Final multivariable model Variable Adverse factor Coeff. HR Grading TP53 (17p) Deleted and/or mutated IGHV Status Unmutated B2M, mg/l > Age > 65 years Stage Binet B/C or Rai I-IV Total Score 0 10 B2M, Serum β 2 -microglobulin; N=1214 The International CLL-IPI working group The Lancet Oncology 2016

8 CLL-IPI risk groups Training Internal-validation Overall survival (%) Low Low Intermediate Intermediate Very high High 0 Very high High Time (months) Time (months) The International CLL-IPI working group The Lancet Oncology 2016

Chronic Lymphocytic Leukemia (CLL) Most common leukemia in adults Complex pathogenesis: - Microenvironment stimulation - Immunologic drive, receptor signaling - Genomic aberrations, mutations,

10 Chronic Lymphocytic Leukemia (CLL) Most common leukemia in adults Complex pathogenesis: - Microenvironment stimulation - Immunologic drive, receptor signaling - Genomic aberrations, mutations, epigenetics Variable clinical course: - Survival: months decades - Wide spectrum of therapeutic options: watch & wait stem cell transplantation (SCT) - Model system for therapeutic developments: BCL2, PI3K, chimeric antigen receptor (CAR)

12 Very low-risk group even cured by chemotherapy/ FCR! Events Total 5-years OS 95% CI , Pairwise comparisons of the OS curves p mut IGHV 11q 17pmut IGHV < q p- < age/sex matched general population Cumulative probability of OS ( Months low risk: mutated IGHV, no 11q-, no 17plow risk CLL Events 5-year N Observed Expected OS (%) relative OS (%) p < <.0001 Rossi et al. Blood 2015 pii: blood [Epub ahead of print]

13 Long term remissions after FCR chemoimmunotherapy Overall survival (OS) in IGHV mutated/unmutated patients Median observation time 5.9 years Cumulative survival Median OS FCR IGHV mutated Not reached FC IGHV mutated Not reached FCR IGHV unmutated 86 months FC IGHV unmutated 75 months Fischer K et al. BLOOD 2016;127:208-15

14 CLL10 STUDY: FCR VS BR IN FRONT-LINE Infections CTC 3-4 in detail Adverse event FCR (% of pt) BR (% of pt) p value All Infections <0.001 Infections during therapy only Infections during first 5 months after therapy All infections in patients 65years All infections in patients > 65years < <0.001 Eichhorst BF et al., Lancet Oncol 2016 Jul;17(7):928-42

CLL10 STUDY: FCR VS BR IN FRONT-LINE FOR FIT PATIENTS Progression-free survival by age group Patients 65 years: P < 0.001 FCR 53.

15 CLL10 STUDY: FCR VS BR IN FRONT-LINE FOR FIT PATIENTS Progression-free survival by age group Patients 65 years: P < FCR 53.6 months BR 38.5 months Patients > 65 years: P = FCR not reached BR 48.5 months Eichhorst BF et al., Lancet Oncol 2016 Jul;17(7):928-42

001 Infections during therapy only Infections during first 5 months after therapy All infections in

16 CLL10 STUDY: FCR VS BR IN FRONT-LINE Infections CTC 3-4 in detail Adverse event FCR (% of pt) BR (% of pt) p value All Infections <0.001 Infections during therapy only Infections during first 5 months after therapy All infections in patients 65years All infections in patients > 65years < <0.001 Eichhorst BF et al., Lancet Oncol 2016 Jul;17(7):928-42

17 German guidelines for first-line treatment of CLL (Onkopedia) Update 2016 Asymptomatic Symptomatic All Fit (go go) Frail (no go) Without del(17p13) or TP53mut 65 years >65 years Watch and wait FCR BR Best supportive care Palliative approach Curative approach CR/PR Watch and wait SD/PD Secondline therapy Alem: alemtuzumab; Chl: chlorambucil; Obin: obinutuzamab; Ofat: ofatumumab Wendtner CM, et al. DGHO guidelines 2016

18 German guidelines for first-line treatment of CLL (Onkopedia) Update 2016 Asymptomatic Symptomatic All Fit (go go) Unfit (slow go) Frail (no go) Without del(17p13) or TP53mut Without del(17p13) or TP53mut Watch and wait 65 years FCR >65 years BR Chl + Obin or Chl + Ofa or B + Ritux Best supportive care CR/PR SD/PD CR/PR SD/PD Palliative approach Curative approach Watch and wait Secondline therapy Watch and wait Secondline therapy Alem: alemtuzumab; Chl: chlorambucil; Obin: obinutuzamab; Ofat: ofatumumab Wendtner CM, et al. DGHO guidelines 2016

19 CLL11 Trial of GCLLSG Previously untreated CLL Total CIRS score >6 and/or creatinine clearance <70 ml/min N=780 (planned) R A N D O M I Z E 2:1:2 GA101 + chlorambucil x 6 cycles Chlorambucil x 6 cycles (control arm) Rituximab + chlorambucil x 6 cycles GA101: 1000 mg days 1, 8, and 15 cycle 1; day 1 cycles 2 6, every 28 days Rituximab: 375 mg/m 2 day 1 cycle 1, 500 mg/m 2 day 1 cycles 2 6, every 28 days Chlorambucil: 0.5 mg/kg day 1 and day 15 cycle 1 6, every 28 days

20 Response Rates and Progression-free Survival with Obinutuzumab Chlorambucil or Rituximab Chlorambucil versus Chlorambucil Alone. Goede et al., N Engl J Med 2014;370: Goede V et al. N Engl J Med 2014;370:

21 CLL11: R-Clb versus G-Clb Progression-free survival Clb + rituximab Clb + obinutuzumab Time (months) 21 Goede et al., N Engl J Med 2014;370:

22 Adverse Events of Grade 3 or Higher, Safety Population. Goede V et al. N Engl J Med 2014;370:

23 FCR Chemotherapy = Pyrrhic victory BR idelalisib Targeted drugs = agony of choice ONO-4059 IPI-145 TGR-1202 ibrutinib FR MRD- BG CFAR GA101 venetoclax nivolumab CART lenalidomide The Land of Cockaigne

24 Pathogenic Mechanisms are complex BCR SIGNALING GENOMIC ABERRATIONS, MUTATIONS, EPIGENETICS T CELL FUNCTIONS BCL2 FAMILY MEMBERS MICROENVIRONMENT Zenz T, et al. Nat Rev Cancer 10(1):37-50, 2010

25 RESONATE-2: Study Design Phase 3, International, open-label, randomized, multicenter study Treatment naïve CLL or SLL requiring therapy; >65 years N=269 R A N D O M I Z E 1:1 Oral ibrutinib 420 mg once daily* n = 136 *until PD or unacceptable toxicity Oral Chlorambucil 0.5mg/kg d1 & 15 of 28d cycle for 12 cycles* n = 133 *dose increased to max of 0.8mg/kg, if tolerated. Treatment for 12 cycles, or PD, lack of efficacy or unacceptable toxicity E N D O F S T U D Y Patients with IRC-confirmed PD were enrolled into a separate extension study PCYC-1116-CA for follow-up and second-line treatment per investigator s choice (including ibrutinib for patients progressing on chlorambucil) Stratification according to: ECOG performance status (0,1 vs. 2) Presence of advanced-stage disease (Rai stage 3-4 vs. < 3) Geographic region: US vs. non-us IRC, independent review committee; PD, progressive disease. Burger J et al. N Engl J Med 2015; [epub] NCT

26 Burger JA et al. N Engl J Med DOI: /NEJMoa Progression-free Survival

27 German guidelines for first-line treatment of CLL (Onkopedia) Update 2016 Asymptomatic Symptomatic All Fit (go go) Unfit (slow go) Frail (no go) Without del(17p13) or TP53mut Without del(17p13) or TP53mut Watch and wait 65 years FCR >65 years BR Chl + Obi or Chl + Ofa or B + Ritux or Ibrutinib >65 yrs Best supportive care CR/PR SD/PD CR/PR SD/PD Palliative approach Curative approach Watch and wait Secondline therapy Watch and wait Secondline therapy Alem: alemtuzumab; Chl: chlorambucil; Obin: obinutuzamab; Ofat: ofatumumab Wendtner CM, et al. DGHO guidelines 2016

28 German guidelines for first-line treatment of CLL (Onkopedia) Update 2016 Asymptomatic Symptomatic All Fit (go go) Unfit (slow go) Frail (no go) Without del(17p13) or TP53mut With del(17p13) or TP53mut Without del(17p13) or TP53mut With del(17p13) or TP53mut Watch and wait 65 years FCR >65 years BR Ibrutinib (Idelalisib) Chl + Obi or Chl + Ofa or B + Ritux or Ibrutinib Ibrutinib (Idelalisib) Best supportive care CR/PR SD/PD CR/PR SD/PD Palliative approach Curative approach Watch and wait Secondline therapy Watch and wait Secondline therapy Alem: alemtuzumab; Chl: chlorambucil; Obin: obinutuzamab; Ofat: ofatumumab Wendtner CM, et al. DGHO guidelines 2016

29 Relapsed/ refractory CLL Vincent van Gogh, 1890 On the Treshold of Eternity

Ibrutinib treatment significantly lengthened PFS (median not reached vs. 8.1 mo, HR=0.106, 95% CI 0.073-0.

30 Ibrutinib: RESONATE (PCYC-1112) Update Progression free survical (PFS) All Patients modifiziert nach 1 Median follow-up was 16 months vs. 12 months for ibrutinib vs. ofatumumab. Ibrutinib treatment significantly lengthened PFS (median not reached vs. 8.1 mo, HR=0.106, 95% CI , P<0.001). 12-month PFS rate was significantly improved for ibrutinib vs. ofatumumab (84% vs. 18%, P<0.001). 1. Brown J, et al. ASH Abstract 2014 (#3331) 30

32 German guidelines for treatment of relapsed/ refractory CLL (Onkopedia) Fit (go go) Unfit (slow go) Frail (no go) SD/PD or early relapse a or del(17p13)/tp53m ut Late relapse SD/PD or Early relapse a or del(17p13)/tp53m ut Late relapse Ibrutinib or Idelalisib + R Followed by Allo SCT Ibrutinib or Idelalisib + R Repeat first-line therapy or Ibrutinib or Idelalisib + R or Other CIT (e.g. BR, B + Ofat) Ibrutinib or Idelalisib + R Repeat first-line therapy or Other CIT (BR, Chl + R, Chl + Obin, Chl + Ofat, B + Ofat) or Ibrutinib or Idelalisib + R Best supportive care Palliative approach Curative approach a Within 2 3 years; Alem: alemtuzumab; Allo SCT: allogeneic stem cell transplant; Chl: chlorambucil; CIT: chemoimmunotherapy; Obin: obinutuzamab; Ofat: ofatumumab Wendtner CM, et al. DGHO guidelines 2016

34 BTKi side effect: bleeding

Ristocetin-induced Platelet Aggregation for Monitoring of Bleeding Tendency in Ibrutinib-treated Patients with Chronic Lymphocytic Leukemia Lukas Kazianka 1,

Sabine Struve 4, MD, Manuela Bergmann, MD 4 Alexander Hauswirth, MD 1, Ingrid Pabinger, MD 1, Alexander Egle 3, MD, Clemens Wendtner 4, MD, Peter Quehenberger, MD

Paracelsus Medical University,Salzburg, 4 Klinikum Schwabing, Academic Teaching Hospital of the University of Munich, 5 Department of Laboratory Medicine and

37 Ristocetin-induced Platelet Aggregation for Monitoring of Bleeding Tendency in Ibrutinib-treated Patients with Chronic Lymphocytic Leukemia Lukas Kazianka 1, Christa Drucker 2, Cathrin Skrabs, MD 1, Philipp Staber, MD, PhD 1, Edit Porpaczy, MD, PhD 1, Christine Einberger 1, Marion Heinz 1, MSc, Thomas Melchardt 3, MD, Sabine Struve 4, MD, Manuela Bergmann, MD 4 Alexander Hauswirth, MD 1, Ingrid Pabinger, MD 1, Alexander Egle 3, MD, Clemens Wendtner 4, MD, Peter Quehenberger, MD 5, Bernd Jilma, MD 2, and Ulrich Jaeger, MD 1,6 1 Department of Medicine I, Division of Hematology and Hemostaseology; 2 Department of Clinical Pharmacology, 3 Paracelsus Medical University,Salzburg, 4 Klinikum Schwabing, Academic Teaching Hospital of the University of Munich, 5 Department of Laboratory Medicine and Clinical Chemistry, 6 Comprehensive Cancer Center, Medical University of Vienna. Vienna, Salzburg, Austria and Munich, Germany ulrich.jaeger@meduniwien.ac.at Leukemia, in press

38 Background: BTK and platelet function Bruton s tyrosine kinase (BTK) expresssed in platelets. 1 BTK downstream of GPIb and GPVI receptors. 2,3 Collagen and Von Willebrand Factor (vwf)-induced platelet aggregation impaired by ibrutinib. vwf-antigen and activity within normal range. 4-6 Aim: Quantitative assessment of platelet aggregation to optimize management of bleeding tendency during ibrutinib therapy References: 1. Berglöf A et al., Scand J Immunol 2015; 82:208-17; 2. Liu J et al., Blood 2014; 108: ; 3. Atkinson B et al., Blood 2003; 102: ; 4. Levade M et al., Blood 2014; 124:3991-5; 5. Kamel S et al., Leukemia 2015; 29:783-7; 6.Wiestner A et al., IWCLL 2015

39 Ristocetin-induced platelet aggregation and bleeding severity n = 31 patients, 202 measurements p = /24 (100%) CTC grade 2 or 3 events occurred at ristoinduced aggregation <36 U Events median (range) U No bleeding or CTC grade (0 199) CTC grade 2 & 3 12 (0 36) Leukemia, in press

40 Ristocetin-induced platelet aggregation improves after discontinuation of ibrutinib Time course n = 7 p = n = 5 Time median (range) U Variable time course after discontinuation: During therapy 13 (2 20) Quantitative RIPA valuable for monitoring. Therapy paused 47 (19 78) Median interval between measurements: 18 days Median increase of Risto-CoF: 369% from baseline Leukemia, in press

41 PI3K SIDE EFFECT: COLITIS

42 PI3K SIDE EFFECT: PNEUMONITIS

43 GS-US (Phase 3): IDL+BR vs PBO+BR in R/R CLL Infections Update ASCO/ EHA 2016 Patients, n (%) IDL+BR n=207 PBO+BR n=209 Infection-Related AEs in >10% of Patients Any Grade Grade 3 Any Grade Grade 3 Febrile neutropenia 45 (22) 42 (20) 14 (7) 12 (6) Pneumonia 36 (17) 23 (11) 23 (11) 13 (6) Upper respiratory tract infection 28 (14) 2 (1) 23 (11) 3 (1) Opportunistic Infections (Any Grade) PJP 4 (2) 0 On prophylaxis for PJP 0 0 On prophylaxis for PJP and developed PJP 0 0 Death due to PJP 0 0 CMV 13 (6) 3 (1) Death due to CMV 0 1 (<1) Infection-related AEs and opportunistic infections occurred more frequently in patients treated with IDL+BR compared to PBO+BR AE, adverse event; B, bendamustine; CMV, cytomegalovirus; IDL, idelalisib; PJP, Pneumocystis jirovecii pneumonia; R, rituximab 1. Adapted from: Barrientos, ASCO, 2016, Adapted from: Hillmen, EHA, 2016, E

44 Key recent updates for venetoclax Clemens-Martin Wendtner Venetoclax? Klinikum Schwabing, Academic Teaching Hospital of the Ludwig- Maximilians University of Munich, Germany

STUDY M13-982 A Phase 2 Open-Label Study of the

$Relapsed or Refractory Chronic Lymphocytic$

47 STUDY M A Phase 2 Open-Label Study of the Efficacy of ABT-199 (GDC-0199) in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion before 2 months after

48 Venetoclax (ABT-199/GDC-0199) Monotherapy Induces Deep Remissions, Including Complete Remission and Undetectable MRD, in Ultra-High Risk Relapsed/Refractory Chronic Lymphocytic Leukemia with 17p Deletion: Results of the Pivotal International Phase 2 Study Stephan Stilgenbauer 1, Barbara Eichhorst 2, Johannes Schetelig 3, Steven Coutre 4, John F Seymour 5, Talha Munir 6, Soham D Puvvada 7, Clemens-Martin Wendtner 8, Andrew W Roberts 9, Wojciech Jurczak 10, Stephen P Mulligan 11, Sebastian Böttcher 12, Mehrdad Mobasher 13, Ming Zhu 14, Brenda Chyla 14, Maria Verdugo 14, Sari Heitner Enschede 14, Elisa Cerri 14, Rod Humerickhouse 14, Gary Gordon 14, Michael Hallek 2, William G Wierda 15 1 University of Ulm, Germany; 2 Universitätsklinikum Köln, Germany; 3 University Hospital, Technische Universität Dresden, Germany; 4 Stanford University Medical Center, USA; 5 Peter MacCallum Cancer Centre, Australia; 6 St James's University Hospital, UK; 7 University of Arizona, USA; 8 Klinikum Schwabing, Munich, Germany; 9 Royal Melbourne Hospital, Australia; 10 Jagiellonian University, Poland; 11 Royal North Shore Hospital, Sydney, Australia; 12 University Hospital of Schleswig-Holstein, Campus Kiel, Germany 13 Genentech Inc, USA; 14 AbbVie Inc, USA; 15 UT MD Anderson Cancer Center, USA Lancet Oncol May 10 [Epub ahead of print] LBA #6, ASH 2015

49 Best Response IRC, n (%) Investigator, n (%) Overall Response 85 (79.4) 79 (73.8) CR or CRi 8 (7.5) 17 (15.9) npr 3 (2.8) 4 (3.7) PR 74 (69.2) 58 (54.2) No response 22 (20.6) 28 (26.2) Stable disease NA 24 (22.4) Disease progression NA 2 (1.9) Incomplete data NA 2 (1.9) 25 of 48 patients with no CLL in the bone marrow 18 of 45 patients assessed were MRD-negative in PB

Cumulative Incidence of Response iwcll Response MRD-Negativity Median time-to-first response: 0.8 months (0.1 8.

50 Cumulative Incidence of Response iwcll Response MRD-Negativity Median time-to-first response: 0.8 months ( ) Median time to CR/CRi: 8.2 months ( ) Of 45 patients tested, 18 achieved MRD-negativity in peripheral blood

51 M14-032: Venetoclax is active in CLL patients who have relapsed or are refractory to Ibrutinib or Idelalisib Phase 2 study Coutre S et al., Poster Presentation at EHA 21 st Congress, Copenhagen, June 9-12, 2016.

54 German guidelines for treatment of relapsed/ refractory CLL (Onkopedia) Update 2016/ 2017? Fit (go go) Unfit (slow go) Frail (no go) SD/PD or early relapse a or del(17p13)/tp53m ut Late relapse SD/PD or Early relapse a or del(17p13)/tp53m ut Late relapse Ibrutinib or Idelalisib + R Followed by Allo SCT Ibrutinib or Idelalisib + R Repeat first-line therapy or Ibrutinib or Idelalisib + R or Other CIT (e.g. BR, B + Ofat) Ibrutinib or Idelalisib + R Repeat first-line therapy or Other CIT (BR, Chl + R, Chl + Obin, Chl + Ofat, B + Ofat) or Ibrutinib or Idelalisib + R Best supportive care PD PD Palliative approach Venetoclax Venetoclax Curative approach a Within 2 3 years; Alem: alemtuzumab; Allo SCT: allogeneic stem cell transplant; Chl: chlorambucil; CIT: chemoimmunotherapy; Obin: obinutuzamab; Ofat: ofatumumab Wendtner CM, et al. DGHO guidelines

55 Study Design Two-Cohort Study Cohort A: MOR208+idelalisib Cohort B: MOR208+venetoclax Cycle 1-3 Cycle 4-6 Cycle 7-24 R/R CLL/SLL post-btki (e.g. Ibrutinib) Idela/Venetoclax d1-d28 MOR208 d1,8,15,22 +C1D4 * Idela/Venetoclax d1-d28 MOR208 d1,15 Idela/Venetoclax d1-d28 MOR208 d1 EOT Survival follow-up Initiation of MOR208 administration on C1D1 *Ramp-up/Titration of Venetoclax starting on C1D8 MorphoSys, German CLL Study Group Meeting, Prof. Dr. Wendtner 55

56 FOURTH GENERATION OF GCLLSG TRIALS RISK, STAGE AND FITNESS ADAPTED, USING TARGETED AGENTS Inactive Binet A CLL12 Comprehensive biological & genetic risk assessment Low, Inter-mediate, high, very high W&W W&W Ibrutinib Delay disease onset

57 IBRUTINIB IN EARLY STAGE CLL RECRUITMENT Screening (N=455) Risk Stratification (N=355) low (N=119) intermediate (N=176) high (N=54) very high (N=6) Randomization (N=236) watch&wait placebo Ibrutinib

58 IBRUTINIB IN EARLY STAGE CLL DISTRIBUTION OF RISK FACTORS Allocation to risk group (%) TP53 mutation N=20 (5.8%)

59 IBRUTINIB IN EARLY STAGE CLL SERIOUS ADVERSE EVENTS (N=60)

60 FOURTH GENERATION OF GCLLSG TRIALS RISK, STAGE AND FITNESS ADAPTED, USING TARGETED AGENTS Inactive Binet A Active disease CLL12 CLL14 Comprehensive biological & genetic risk assessment Slow go W&W Low, W&W Inter-mediate, high, very high Ibrutinib CLB-G AG Delay disease onset Long-term diseasecontrol with minimal side effects

61 CLL14 Recruitment

62 CLL14 Participating Countries

63 CLL14 Serious Adverse Events As of September 2016 CTC grade Total N (%) 200* 1 10 (5.0) 2 28 (14.0) (59.0) 4 35 (17.5) 5 9** (4.5) *in 432 patients ** in 7 patients

FOURTH GENERATION OF GCLLSG TRIALS RISK, STAGE AND FITNESS ADAPTED, USING TARGETED AGENTS Inactive Binet A Active disease CLL12 CLL13 CLL14 Comprehensive biological & genetic risk assessment Go go

64 FOURTH GENERATION OF GCLLSG TRIALS RISK, STAGE AND FITNESS ADAPTED, USING TARGETED AGENTS Inactive Binet A Active disease CLL12 CLL13 CLL14 Comprehensive biological & genetic risk assessment Go go Slow go W&W Low, W&W Inter-mediate, high, very high Ibrutinib FCR/ BR AR AG AIG CLB-G AG Delay disease onset Disease (MRD) eradication and longer survival Long-term diseasecontrol with minimal side effects

CLL13 PROTOCOL Treatment schedule Rituximab 375 (500) mg/m² iv c 1-6 d 0 Fludarabine 25 mg/m² iv c 1-6 d 1-3 Cyclophosphamide 250 mg/m² iv c 1-6 d 1-3 (or) Bendamustine 90 mg/m² c 1-6 d1,2 [Age

65 CLL13 PROTOCOL Treatment schedule Rituximab 375 (500) mg/m² iv c 1-6 d 0 Fludarabine 25 mg/m² iv c 1-6 d 1-3 Cyclophosphamide 250 mg/m² iv c 1-6 d 1-3 (or) Bendamustine 90 mg/m² c 1-6 d1,2 [Age stratification] RANDOMIZATION Rituximab 375 (500) mg/m² iv (c1 6, d1) Venetoclax c1 d22 c 12 d mg po daily (ramp-up) Obinutuzumab 1000 mg iv (c1 d1(2)/8/15, c2-6 d1) Venetoclax c1 d 22 c 12 d mg po daily (ramp-up) Obinutuzumab 1000 mg iv (c1 d1(2)/8/15, c2-6 d1) Ibrutinib d 1-MRD-/PD 420 mg po daily until MRD negativity is achieved Venetoclax c1 d 22- c12 d mg po daily (ramp-up) month evaluation of MRD (month 0, 2, 9, 12, 15)

67 SUMMARY Chemoimmunotherapy remains a reasonable option for the frontline setting while it has to be adapted according to patients fitness (FCR, Clb-Obi etc.). For ultra-high risk pts (17p-, TP53mut) ibrutinib is the first choice in firstline. Recently, ibrutinib received FDA and EMA approval for the frontline treatment regardless of age, fitness and cytogenetic risk category. Nevertheless, the definitive role compared to CIT has to be shown. Both ibrutinib and idelalisib have shown high efficacy combined with manageable toxicity in relapsed/ refractory CLL. BCL-2 inhibition by venetoclax is a new FDA-approved treatment option for ultra-high risk CLL (17p-) after at least one prior treatment. Combination studies of one or more of the new drugs (ibrutinib, idelalisib, venetoclax etc.) with antibodies (GA101 etc.) and/ or chemoimmunotherapy will show whether deeper and even longer remissions can be achieved. In pts with deep remissions discontinuation of TKIs should be explored within clinical trials.

69 Thanks for your attention!

BENDAMUSTINE + RITUXIMAB IN CLL

BENDAMUSTINE + RITUXIMAB IN CLL Barbara Eichhorst Bologna 13. November 2017 CONFLICT OF INTERESTS 1. Advisory Boards Janssen, Gilead, Roche, Abbvie, GSK 2. Honoraria Roche, GSK, Gilead, Janssen, Abbvie,