Emerging Treatments and Evolving Pathways for the Management of - PowerPoint PPT Presentation

CLL10 Study: FCR vs BR in Frontline Adverse Events CTC °3-4 (1st cycle until end of study) Adverse event FCR (%) BR (%) P value N= 279 N=278 Neutropenia 84.2 59.0 <0.001 Anemia 13.6 10.4 0.20 Thrombocytopenia 21.5 14.4 0.03 Infection 39.1 26.8 <0.001 Sec Neoplasm* 6.1 3.6 0.244 *sAML/MDS: FCR=6, BR=1 TRM 4.6 2.1 0.107 Infections 2.5 2.1 - Sec Neoplasm 1.1 0 - Other 1.0 Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942.

CLL10 Study: FCR vs BR in Front-line Infections CTC 3-4 in detail Adverse event FCR BR P value (% of pt) (% of pt) All Infections 39.1 26.8 <0.001 Infections during therapy 22.6 17.3 0.1 only Infections during first 5 11.8 3.6 <0.001 months after therapy All infections 35.2 27.5 0.1 in patients ≤ 65years All infections 47.7 20.6 <0.001 in patients >65years Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942.

Predictors of PFS in Multivariable Analysis COX regression Univariate Hazard 95% Confidence P value PFS comparison ratio Interval Lower Upper Treatment arm BR vs. FCR 1.680 1.270 2.222 <0.001 S-TK (U/L) >10 vs. ≤ 10 1.581 1.104 2.265 0.012 Cytogenetic subgroup del (11q) vs no del(11q) 1.878 1.391 2.536 <0.001 IGHV MS Unmutated vs mutated 1.937 1.357 2.763 <0.001 Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942.

Predictors of OS in Multivariable Analysis COX regression Univariate Hazard 95% Confidence P value OS comparison ratio Interval Lower Upper Age at study entry >65 years vs ≤ 65 years 1.880 1.118 3.162 0.017 IGHV MS Unmutated vs mutated 3.739 1.832 7.630 <0.001 Eichhorst et al. Lancet Oncol. 2016 Jul;17(7):928-942.

CLL10: FCR vs BR • FCR more effective in CR, MRD, PFS – Most noticeable in patients <65 yo • FCR toxicity higher especially in those >65 yo – No growth factors or antibiotic prophylaxis • Young fit – FCR • Older fit or intermediate fitness – Role for BR

FCR300: PFS and OS Median Follow-up Time 1.0 All: 9.8 yrs Alive: 11.5 yrs Proportion Surviving 0.8 0.6 PFS OS 0.4 Events Total Median 0.2 186 300 6.5 yrs 113 300 11+ yrs 0 0 24 48 72 96 120 144 168 Mos Wierda WG, et al. iWCLL 2013 Abstracts.

FCR300: PFS by IGHV Mutation Status Group Events Total 1.0 IGHV- M 33 82 Proportion Progression Free IGHV -UM 114 131 0.8 Unknown 39 87 0.6 0.4 P < .0001 0.2 0 0 24 48 72 96 120 144 168 Mos Wierda WG, et al. iWCLL 2013 Abstracts.

First-line FCR300: PFS and OS Outcomes by MRD Status Overall Survival 1.0 1.0 MRD- MRD- 0.8 0.8 Proportion Not Progressed Proportion Alive MRD+ 0.6 0.6 MRD+ 0.4 0.4 n events n events MRD- 70 0 MRD- 70 1 0.2 0.2 MRD+ 91 11 MRD+ 91 23 p<0.001 p<0.006 0.0 0.0 0 10 20 30 40 50 0 10 20 30 40 50 Months Months Strati P, et al. Blood . 2014;123(24):3727-3732.

MRD-negative Status at EOT Strongly Associated with PFS but Modified by IGHV EOT = end of treatment. Thompson P, et al. MRD analysis after FCR.

First-line FCR: Rossi Data Overall Survival Mut IGHV , no 11 or 17 UM IGHV or 11q 17p Rossi D, et al. Blood . 2015;126:1921-1924.

Second Malignancy Risks MDACC Italian Data 50% p=0.0500 19.0% (4/21) Prevalence of second tumors 40% 30% Probability 12.1% (21/173) 20% 3.9% (3/77) 10% 0% Low-risk Intermediate-risk High-risk Time (years) Rossi D, et al. Blood . 2015;126:1921-1924. Thompson PA, et al. Blood. 2016 Jan 21;127(3):303-9.

MRD Negativity Predicts Best PFS and OS Kwok M, et al. Blood . 2016;128(24):2770-2773.

MRD Negativity Does Not Overcome Poor Prognosis of Del(17p/11q) Kwok M, et al. Blood . 2016;128(24):2770-2773.

Better PFS and OS If MRD Negativity After First-line Therapy Kwok M, et al. Blood . 2016;128(24):2770-2773.

Summary: Fit Patients • FCR remains most effective upfront therapy • A subset of patients remain progression free more than 10 yrs: – Mutated IGHV , low risk FISH • Key predictors of outcome after therapy: – 17p / TP53 mutn – 11q deletion and IGHV mutation status – Response (CR) and MRD status

First-line Treatment of CLL • For physically fit patients, FCR prolongs survival • Until recently, no “standard” treatment in elderly population – Phase 3 CLL elderly trial: fludarabine vs chlorambucil OS PFS Fludarabine Fludarabine NOT superior Chlorambucil to chlorambucil Fludarabine in PFS or OS Chlorambucil – Chlor – Retrospective analysis of CALGB first-line CLL trials • No benefit of fludarabine over chlorambucil in patients age ≥ 70 yrs • Rituximab added benefit regardless of age CALGB = Cancer and Leukemia Group B Eichhorst BF, et al. Blood . 2011 Feb 10;117(6):1817-21.

Association of Age and Comorbidity in CLL: Meta-analysis of GCLLSG CLL4 and CLL5 Trials • Incidence of comorbidities increases with age – <20% of youngest patients had comorbidities – >60% of oldest patients had comorbidities • Number of comorbidities increases with age – ~5% of youngest patients had ≥ 2 comorbidities – >30% of oldest patients had ≥ 2 comorbidities Cramer P, et al. Blood . 2006;108:Abstract 2840.

CLL11: Study Design 590 patients R GA101 + chlorambucil Previously A x 6 cycles untreated CLL N G-Clb vs. Clb D O Total CIRS score >6 Primary analysis Chlorambucil M and/or creatinine data cut-off: 07/2012 x 6 cycles (control arm) clearance <70 I mL/min Z R-Clb vs. Clb E Primary analysis Rituximab + chlorambucil N=780 (planned) data cut-off: 08/2012 x 6 cycles 2:1:2 Goede V, et al. N Engl J Med. 2014 Mar 20;370(12):1101-10.

CLL11: Study Design (Cont’d) Additional 590 patients 190 patients R GA101 + chlorambucil Previously A x 6 cycles untreated CLL N D O Total CIRS score >6 Chlorambucil M and/or creatinine G-Clb vs. R-Clb x 6 cycles (control arm) clearance <70 I Primary analysis mL/min Z data cut-off: 05/2013 E Rituximab + chlorambucil N=780 (planned) x 6 cycles 2:1:2 Goede V, et al. N Engl J Med. 2014 Mar 20;370(12):1101-10.

Lymphocyte Counts After Obinutuzumab and CLB Goede V, et al. N Engl J Med . 2014 Mar 20;370(12):1101-10. Goede V, et al., Leukemia . 2013;27:1172-1174.

Baseline Patient Characteristics G-Clb (n=333) R-Clb (n=330) % % Male 61 62 Median age, years (range) 74 (39-89) 73 (40-90) Aged ≥ 65 years 81 78 Aged ≥ 75 years 46 42 1 (0-3) 1 (0-3) Median ECOG PS (range) Median CIRS score 8.0 8.0 CIRS score >6 78 75 Median CrCl 62.5 62.6 CrCl <70 mL/min 65 64 CrCl <50 mL/min 27 25 Goede V, et al. N Engl J Med . 2014 Mar 20;370(12):1101-10.

Adverse Events of Interest G-Clb (n=336) a R-Clb (n=321) a % % Any AE grade ≥ 3 b 70 55 Infusion-related reaction 20 4 Neutropenia 33 28 Anemia 4 4 Thrombocytopenia 10 3 Infection 12 14 Pneumonia 4 5 a Safety population for G-Clb includes 5 patients randomized to R-Clb who received 1 infusion of GA101 in error b Incidence rate of  3% in any treatment arm AE = adverse event. Goede V, et al. N Engl J Med . 2014 Mar 20;370(12):1101-10.

Minimal Residual Disease As measured by central laboratory assessment (ASO-RQ-PCR) at 3 months after end of treatment; bone marrow samples were usually only taken from patients thought to be in CR. Goede V, et al. N Engl J Med . 2014 Mar 20;370(12):1101-10.

Progression-free Survival (Head-to-Head) 1.0 0.9 Progression-free survival 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (months) No. at risk G-Clb: 330 307 302 278 213 156 122 93 60 34 12 4 1 0 R-Clb: 330 317 309 259 163 114 72 49 31 14 5 2 0 0 Median observation time: G-Clb, 18.8 months; R-Clb, 18.6 months. Type 1 error controlled through closed test procedure; P value of the global test was <0.0001. Independent Review Committee- assessed progression-free survival (PFS) was consistent with investigator-assessed PFS. Goede V, et al. N Engl J Med . 2014 Mar 20;370(12):1101-10.

Overall Survival (GA101) 1.0 0.9 0.8 Overall survival 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (months) No. at risk G-Clb: 238 226 223 221 215 211 170 144 115 71 34 14 2 0 Clb: 118 109 105 103 102 94 70 56 44 29 15 5 0 0 Total number of deaths: G-Clb, 22 (9%); Clb, 24 (20%) Median observation time: G-Clb, 23.2 months; Clb, 20.4 months. No multiplicity adjustment was done for secondary endpoints. Goede V, et al. N Engl J Med . 2014 Mar 20;370(12):1101-10.

Overall Survival (Head-to-Head) 1.0 0.9 0.8 Overall survival 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (months) No. at risk G-Clb: 333 316 310 303 261 214 170 144 115 71 34 14 2 0 R-Clb: 330 320 314 305 255 203 169 138 105 61 27 8 0 0 Total number of deaths: G-Clb, 28 (8%); R-Clb, 41 (12%) Median observation time: G-Clb, 18.8 months; R-Clb, 18.6 months. No multiplicity adjustment was done for secondary endpoints. Goede V, et al. N Engl J Med . 2014 Mar 20;370(12):1101-10.

CLL11: TTNT G-Clb vs R-Clb 1.0 Stratified HR 0.57 G ‐ Clb 95% CI 0.44–0.74 0.9 P <0.0001 R ‐ Clb Time to new anti-leukemic 0.8 0.7 treatment 0.6 0.5 0.4 0.3 0.2 0.1 38.2 51.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Time (months) No. at risk GClb 333 291 282 274 267 253 238 232 218 209 189 173 139 102 72 54 26 17 5 2 0 RClb 330 313 303 276 243 225 208 177 160 142 126 112 87 62 42 33 18 10 0 0 0 Goede V, et al. Leukemia. 2015 Jul;29(7):1602-4.

Summary: Unfit Patients • Randomized phase 3 trials establish PFS benefit of adding anti-CD20 antibody to chlorambucil • Only obinutuzumab has been compared head-to-head with rituximab, with improved MRD negativity and PFS—but not improved OS • Time to next therapy quite good for 6 months of well- tolerated treatment VS • Kinase inhibitors likely to move into this space where resources permit – How should therapy be selected?

PCYC-1102/1103 Phase 2 Study Design Phase 2 (PCYC-1102) Extension Study N=132 (PCYC-1103) Treatment Naïve (TN) ≥ 65 years Patients with n=31 CLL/SLL treated with ≥ SD Long-Term oral, once-daily Follow-Up ibrutinib (420 or 840 mg/day) Relapsed/Refractory * (R/R) n=101 * R/R includes patients with high-risk CLL/SLL, defined as progression of disease <24 months after initiation of a chemoimmunotherapy regimen or failure to respond O’Brien SM, et al. American Society of Hematology 59 th Annual Meeting and Exposition. Atlanta, GA; December 9-12, 2016. Abstract 233.

Ibrutinib Treatment Continued in 65% TN and 30% R/R Patients TN R/R Disposition (n=31) (n=101) 62 49 Median time on study, months (range) (1–67) (1–67) Duration of study treatment, n (%) ≤ 1 year 5 (16%) 24 (24%) >1–2 years 0 14 (14%) >2–3 years 1 (3%) 9 (9%) >3–4 years 1 (3%) 19 (19%) ≥ 4 years 24 (77%) 35 (35%) Patients remaining on ibrutinib therapy, n (%) 20 (65%) 30 (30%) After ~5 Primary reason for discontinuation, n (%) years Progressive disease 1 (3%) 33 (33%) of Adverse event 6 (19%) 21 (21%) follow- Consent withdrawal 3 (10%) 5 (5%) up Investigator decision 0 11 (11%) Lost to follow ‐ up 1 (3%) 1 (1%) O’Brien SM, et al. American Society of Hematology 59 th Annual Meeting and Exposition. Atlanta, GA; December 9-12, 2016. Abstract 233.

Survival Outcomes by Chromosomal Abnormalities Detected by FISH in R/R Patients Progression-Free Survival Overall Survival Median 5-year Median 5-year OS PFS PFS OS Del17p (n=34) 26 mo 19% Del17p (n=34) 57 mo 32% Del11q (n=28) 55 mo 33% Del11q (n=28) NR 61% Trisomy 12 (n=5) NR 80% Trisomy 12 (n=5) NR 80% Del13q (n=13) NR 91% Del13q (n=13) NR 91% No abnormality** No abnormality** NR 66% NR 83% (n=16) (n=16) O’Brien SM, et al. American Society of Hematology 59 th Annual Meeting and Exposition. Atlanta, GA; December 9-12, 2016. Abstract 233.

Survival by Complex Karyotype Progression-Free Survival Overall Survival Media 5-year Media 5-year n OS OS n PFS PFS Complex karyotype Complex karyotype 57 mo 46% 33 mo 36% (n=41) (n=41) No complex karyotype No complex karyotype NR 84% NR 69% (n=71) (n=71) The majority (90%) of patients with complex karyotype had R/R disease (median 4 prior therapies). NR = not reached. O’Brien SM, et al. American Society of Hematology 59 th Annual Meeting and Exposition. Atlanta, GA; December 9-12, 2016. Abstract 233.

PFS for Patients with Del17p CLL on Ibrutinib (n=243) Estimated 12- Estimated 24- Estimated 30- mo PFS, % mo PFS, % mo PFS, % (95% CI) (95% CI) (95% CI) 80% (74, 84) 63% (57, 69) 55% (48, 62) Median time on study = 28 months (range: 0.3-61 ) Jones J, et al. EHA Annual Meeting 2016. Copenhagen, Denmark; June 9-16, 2016. Abstract S429.

PFS of Del17p Patients +/- Complex Karyotype in the PCYC-1102/1103 Study Median Median OS, PFS, mo mo Del17p + CK (n=22) 25 Del17p + CK (n=22) 32 Del17p no CK Del17p no CK 52 NR (n=10) (n=10)  69% of del17p patients had CK vs 31% of del17p patients without CK – Median age (range): 65 y (49-79) vs 60 y (44-82) – Median prior therapies (range): 4 (1-9) vs 2.5 (0-12) – Median platelets (range): 72 × 10 9 /L (20-151) vs 110 × 10 9 /L (17-310) – Rai stage III-IV: 64% vs 40% CK = complex karyotype; NR = not reached. Jones J, et al. EHA Annual Meeting 2016. Copenhagen, Denmark; June 9-16, 2016. Abstract S429.

PCYC 1112 RESONATE: PFS by Del17p 100 90 Progression-Free Survival (%) 80 70 60 50 40 Ibrutinib with del17p (n=63) Ibrutinib without del17p (n=132) 30 Ofatumumab with del17p (n=64) Ofatumumab without del17p (n=132) 20 10 0 0 3 6 9 12 15 18 21 24 Months Brown, et al. Leukemia. 2017.

PCYC 1112 RESONATE: PFS by TP53 / Del17p Brown, et al. Leukemia. 2017.

Front-line Ibrutinib in del(17p) Overall Survival 100 Overall Survival (%) 80 Previously Relapsed Untreated Refractory 60 N 35 16 40 Median 15 months 26 months Relapsed/Refractory Follow-up Previously Untreated 20 Rai Stage III/IV 63% 75% P = 0.42 0 Bulky 23% 50% adenopathy 0 6 12 18 24 30 IGHV 63% 75% Months unmutated PFS 82%, OS 80% at 24 mos Farooqui MZ, et al. Lancet Oncol. 2015;16(2):169-176.

Ibrutinib for Upfront Therapy of 17p Deleted CLL: • Clearly the drug of choice given current data – But unsatisfying as a single agent given the continuous relapse and Richter’s seen in any trial with reasonably long follow-up…. • BUT still no combination data in an upfront setting • 17p remains an unmet need not yet adequately addressed… • SCT still needs to be considered

RESONATE-2 (PCYC-1115/1116) Study Design PCYC- R Patients (N=269) ibrutinib 420 mg ibrutinib 420 mg 1116 A • Treatment-naïve once daily until once daily until Extension N CLL/SLL with progression progression CLL PD Study* D active disease or 1115 O • Age ≥ 65 years In clb arm, study M n=55 • For patients 65-69 closure I chlorambucil 0.5 mg/kg crossed years, comorbidity Z (to maximum 0.8 over to that may preclude E mg/kg) days 1, 15 of 28- ibrutinib FCR following day cycle up to 12 • del17p excluded 1:1 PD cycles Stratification factors Efficacy (PFS, OS, ORR) determined by • ECOG status (0-1 vs. 2) investigator-assessment. • Rai stage (III-IV vs. ≤ II) *Patients could enroll in separate extension study PCYC-1116 after independent review committee- confirmed PD or at study PCYC-1115 closure for continuing treatment and follow-up. Barr, et al. Blood . 2016.

Patient Characteristics Ibrutinib Chlorambucil Characteristic (n=136) (n=133) Median age, years (range) 73 (65–89) 72 (65–90) ≥ 70 years, % 71 70 ECOG performance status, % 1 48 50 2 8 9 Rai stage III or IV, % 44 47 CIRS score >6, % 31 33 Creatinine clearance <60 mL/min, 44 50 % Bulky disease ≥ 5 cm, % 40 30 β 2-microglobulin >3.5 mg/L, % 63 67 Hemoglobin ≤ 11 g/dL, % 38 41 Platelet count ≤ 100 x 10 9 /L, % 26 21 Del11q, % 21 19 Barr et al, Blood . Unmutated IGHV, % 43 45 2016.

RESONATE 2: PFS and OS by Investigator Assessment • 24-month OS rate: 98% with • 18-month PFS rate: 90% with ibrutinib vs. 52% with ibrutinib and 85% with chlorambucil chlorambucil • AEs: 14% hypertension, 6% • 3 deaths on ibrutinib arm vs 17 atrial fibrillation, 4% major deaths on chlorambucil arm hemorrhage, 2 sudden deaths Burger JA, et al. N Engl J Med . 2015 Dec 17;373(25):2425-37

Ibrutinib Significantly Improved PFS in Patients Regardless of IGHV Status (n=40) (n=58) (n=42) (n=60) 79% of patients continue on ibrutinib treatment on study with 83% of patients receiving at least 2 years of treatment Barr, et al. Blood . 2016.

ORR in the Ibrutinib Arm PR-L PR nPR CR/CRi 100% 95% 100% 92% 90% 88% 14% 90% 21% Best Response 18% 80% 20% 20% 1% 70% 1% 3% 60% 50% 86% 40% 74% 71% 67% 65% (%) 30% 20% 10% 1% 2% 0% All Patients With Del11q Without Unmutated Mutated IGHV (N=136) (n=29) Del11q IGHV (n=58) (n=40) (n=101) Ibrutinib CR rates continue to improve over time: increasing from 7% at 12 months to 15% at 24 months to 18% with median follow-up of 29 months 1 *Response rates with chlorambucil are the same as in the original report 2 1. Barr, et al. Blood . 2016; 2. Burger, et al. NEJM . 2015.

Treatment-emergent AEs ( ≥ Grade 3) Over Time in First-line Ibrutinib Patients ( ≥ 4% Over 29 Months Median Follow-Up) Ibrutinib Arm 0- ≤ 12 months >12-24 months >24-36 months (n=135), % (n=123), % (n=112), % Neutropenia 8 4 0 Pneumonia* 5 2 1 Anemia 6 1 1 Hypertension 4 2 0 Hyponatremia 2 2 0 Atrial fibrillation 1 0 4 • Grade ≥ 3 AEs in ≥ 4% of patients over the 29 mo follow-up: neutropenia (12%), pneumonia (7%), anemia (7%), hypertension (5%), hyponatremia (4%), and atrial fibrillation (4%) • Major hemorrhage occurred in 7% of ibrutinib-treated patients (1 Grade 2, 7 Grade 3, 1 Grade 4; 5 in first 12 months and 4 between 1-2 years) • Atrial fibrillation occurred in 10% of ibrutinib-treated patients (1 Grade 1, 7 Grade 2, 6 Grade 3) Barr et al, Blood 2016. Barr et al. Blood . 2016.

Ibrutinib for Upfront Therapy: What Are the Issues? • Only data in a non-representative population of very healthy older patients with low disease burden and disease risk, short follow-up, and a very poor comparator arm • Patients all 65 or over—but low comorbidity • Toxicity is not negligible even in this population (afib, hemorrhage, arthralgia)

OSU Experience: Long-term Ibrutinib Cumulative Incidence Estimates At 2 Years At 3 Years At 4 Years CLL progression 5.0% 10.8% 19.1% Transformation 7.3% 9.1% 9.6% Other event 18.7% 23.9% 25.0% Woyach JA, et al. J Clin Oncol . 2017 May 1;35(13):1437-1443.

Predictors of Ibrutinib Discontinuation: OSU Experience Transformation Progressive Other Event CLL Variable HR HR HR P P P Complex karyotype (yes v no) 5.00 .008 2.81 .006 - - MYC abnormality (yes v no) 2.15 .051 - - - - Del17p (yes v no) - - 2.14 .016 - - Age (  v <65 years) - - 0.49 .023 2.02 .004 Prior therapies > 3 (yes v no) - - - - 1.99 .005 Woyach JA, et al. J Clin Oncol . 2017 May 1;35(13):1437-1443.

OSU: Discontinuation for Non-PD by Age Maddocks et al. JAMA Oncology. 2015

Real World KI Use: Reasons for Discontinuation Most Common Reasons for Ibrutinib Discontinuation Ibrutinib Toxicity 51% CLL progression 28% Richter’s transformation 8% SCT / CAR-T 2% Unrelated death or other 11% 5 Most Common Toxicities as a Reason Others: for Discontinuation • Arthralgia Atrial fibrillation 20% • Edema Infection 12% • Diarrhea/GI Hematologic 9% Bleeding 9% Pneumonitis 8% KI = ____. Mato et al, Blood . 2016.

PFS for Alternate KI by Discontinuation Reason Mato et al, Blood . 2016. RT excluded from analysis

Retrospective Analysis of Toxicities and Outcomes for Ibrutinib-treated Patients: Design and Patient Characteristics Retrospective analysis: 621 ibrutinib-treated patients at 9 US cancer centers or Connect Ⓡ CLL Registry Characteristics, n Ibrutinib in Frontline (n=80) Ibrutinib in Relapse (n= 536) Median age at diagnosis, years (range) 62 (37-88) (N=78) 60 (22-95) (n=532) Prior therapies, median (range) 0 2 (1-10) del(17p), % 37% (n=76) 26% (n=368) del(11q), % 19% (n=75) 35% (n=367) TP53 mutation, % 12% (n=42) 13% (n=142) Complex karyotype ( ≥ 3 40% (n=60) 34% (n=214) abnormalities), % Median time from diagnosis to 26 (1-232) 78 (1-660) Ibrutinib, months (range) Median ibrutinib starting dose, mg 420 420 Ibrutinib as monotherapy, % 68% (n=80) 89% (n=536) Ibrutinib hold required, % 30% (n=79) 37% (n=310) Ibrutinib dose adjustment required, % 15% (n=79) 20% (n=309) 546 patients (88%) were treated with commercial drug; Clinical trial patients were younger (median age 57 vs 61 years), had longer time from diagnosis to ibrutinib (median 85 vs 72 Mato et al, Blood . 2016. months), and were more consistently initiated at 420 mg (100% vs 89%).

Retrospective Analysis of Toxicities and Outcomes for Ibrutinib-Treated Patients: Discontinuations With a median follow-up of 14.5 months, estimated discontinuation rate was 42%; median time to discontinuation was 7 months Ibrutinib in Front Line Ibrutinib in Relapse Reasons for Commercial Clinical Trial Commercial Clinical Trial Discontinuation, % use (n=10) (n=9) Use (n=200) (n=31) Toxicity 50 78 53 39 CLL progression 10 22 19 36 Other/unrelated death 10 0 12 13 Physician or patient 20 0 6 10 preference RT DLBCL 0 0 5 0 SCT/CAR-T cells 0 0 4 3 Financial concerns 0 0 1 0 Secondary malignancy 10 0 1 0 RT Hodgkin lymphoma 0 0 1 0 Mato et al, Blood . 2016.

Retrospective Analysis of Toxicities and Outcomes for Ibrutinib-treated Patients • Median PFS and OS for entire cohort were 36 months and NR, respectively (median follow-up 17 months) • PFS was not significantly different based on use in front-line vs relapsed ( P =0.27) or commercial use vs clinical trial ( P =0.14) • In multivariable model, complex karyotype validated as independent predictor of PFS (HR 1.6, CI 1.1-2.5, P =0.04) but not OS (HR 1.6, CI 0.9-3.1, P =0.1) Mato et al. American Society of Hematology 58 th Annual Meeting. San Diego, CA; December 3-6, 2016. Abstract #3222.

Bleeding Events by Time to New Event Onset in PCYC-1102 • In PCYC-1102, major bleeding occurred in 5% of patients – Most bleeding events occurred early, during the first 3-6 months of therapy Jones JA et al . Br J Haematol . 2017 Jul;178(2):286-291.

AF Incidence Over Time on Ibrutinib 100 Patients with Event (%) 80 60 40 20 0 0 ‐ 4 4 ‐ 8 8 ‐ 12 12 ‐ 18 0 ‐ 4 4 ‐ 8 8 ‐ 12 12 ‐ 18 Months from Study Initiation Ibrutinib (n=49) Comparator (n = 12)    Prior history De novo Prior history De novo 45 Prior History 40 De Novo 35 Patients with Event 30 25 (%) 20 15 10 5 0 0 ‐ 4 4 ‐ 8 8 ‐ 12 12 ‐ 18 18 ‐ 24 24 ‐ 30 30 ‐ 36 >36 Months from Study Initiation Brown JR et al, Haematologica .

Risk Factors for AF in Ibrutinib RCTs Brown JR et al, Haematologica 2017.

Conclusions: Ibrutinib in R/R CLL • Ibrutinib in R/R CLL has excellent results, mostly PRs (not a cure) – Median PFS 52 mos on clinical trial  Worse for 17p, complex karyotype, 11q • BUT: outside trials, 40% stop in 14 mos, mostly due to adverse events, and median PFS is 36 mos – Real-world outcomes are not aligning with trials – Better management strategies for toxicity, and/or less toxic BTK inhibitors, may be needed • Those patients who progress on drug have been difficult to salvage – RT about 30-50% of the time in the relapsed setting, although randomized trials are balanced so far – Frequent BTK Cys481 mutations • Next-generation drugs: more specific; target BTK Cys mutation

Ibrutinib for Upfront Therapy: What Are the Issues? • NO data in young fit patients to whom RESONATE-2 data are being generalized – Who often do not want indefinite therapy – Who do not achieve CR much less MRD negativity – Who if maintained on ibrutinib may be hard to salvage on relapse • No data that CIT can be used later – Cost and compliance are huge issues

PCYC 1112 RESONATE: PFS by Line of Therapy Brown et al. American Society of Hematology 56 th Annual Meeting. San Francisco, CA; December 6-9, 2014.

PFS by Prior Lines of Therapy: RESONATE and RESONATE-2 O’Brien et al. American Society of Clinical Oncology Annual Meeting. Chicago, IL; June 3-7, 2016.

OSU Experience: Long-Term Ibrutinib Cumulative Incidence Estimates At 2 Years At 3 Years At 4 Years (95 % Cl) CLL progression 5.0% 10.8% 19.1% Transformation 7.3% 9.1% 9.6% Other event 18.7% 23.9% 25.0% Woyach JA, et al. J Clin Oncol . 2017 May 1;35(13):1437-1443.

Venetoclax (ABT-199) Response in Relapsed/Refractory CLL/SLL Response All del(17p) F- IGHV (n = 116) (n = 31) Refractory Unmutated (n = 70) (n = 46) Overall 79% 71% 79% 76% response CR 20% 16% 16% 17% PR 59% 55% 63% 59% Bulky nodes (>5 cm) N CR/CRi % (95% CI) ORR % (95% CI) Yes 67 6 (2, 15) 78 (66, 87) No 48 38 (24, 53) 83 (70, 93) Roberts AW, et al. N Engl J Med. 2015. 374(4):311-322.

Venetoclax (ABT-199) in Relapsed/Refractory CLL/SLL Roberts AW, et al. N Engl J Med. 2015. 374(4):311-322.

Adverse Events All Grades N=105 ≥ 20% of pts n (%) Diarrhea 42 (40) Neutropenia 38 (36) Nausea 37 (35) 35 (33) Upper respiratory tract infection Fatigue 27 (27) 21 (20) Cough Grades 3/4 ≥ 5% pts n (%) Neutropenia 35 (33) Anemia 10 (10) Febrile neutropenia 7 (7) Roberts AW, et al. N Thrombocytopenia 7 (7) Engl J Med. 2015. 374(4):311-322. 7 (7) Hyperglycemia Tumor lysis syndrome (TLS) 7 (7) 5 (5) Hypokalemia

Detailed Risk Stratification of Patients for Tumor Lysis 19 th Congress of the European Hematology Association. Milan, Italy; June 12-15, 2014. Poster 868.

Venetoclax Dosing Schedule • To mitigate TLS risk, patients received prophylaxis with uric acid lowering agents and hydration starting at least 72 hours before first venetoclax dose • Patients with high tumor burden were hospitalized for first dose at 20 and 50 mg and received IV hydration and rasburicase • Laboratory values were monitored at first dose and each subsequent dose increase High tumor burden: any lymph node ≥ 10 cm; or both lymph node ≥ 5 cm and ALC ≥ 25x10 9 /L Stilgenbauer S et al, Lancet Oncol . 2016 Jun;17(6):768-778.

Venetoclax in High-risk R/R CLL with del17p: Baseline Characteristics Characteristic, n N=107 a (%) (%) Age, years Median, range 67, 37–85 Sex Male 70 (65) Prior therapies Median, range 2, 1–10 Prior bendamustine / 54 (50) / 38 (70) refractory Prior fludarabine / 78 (73) / 34 (44) refractory One or more Bulky nodes 57 (53) nodes ≥ 5 cm Low 19 (18) Stilgenbauer S et al, Lancet Oncol . 2016 TLS risk category Medium 43 (40) Jun;17(6):768-778. High 45 (42) Rai stage III or IV 51(48) Unmutated 30 (81) IGHV

Venetoclax in High-risk R/R CLL with 17p del iwCLL Response (74%) MRD-negativity  Median time-to-first response:  Of 45 patients tested, 18 0.8 months (0.1–8.1) achieved MRD-negativity in  Median time to CR/Cri (16%): peripheral blood 8.2 months (3.0–16.3) Stilgenbauer S, et al. Blood . 2015; 126(23):LBA-6. Stilgenbauer S et al, Lancet Oncol . 2016 Jun;17(6):768-778.