Management of Chronic Lymphatic Leukemia Beyond conventional therapy

3 rd Young Hematologists Orientation Program SGPGI Lucknow August 18 th -19 th 218 Management of Chronic Lymphatic Leukemia Beyond conventional therapy Prof. Hari Menon. MD DM Department of Hemato-Oncology Cytecare Cancer Hospitals Bengaluru, Hari.menon@cytecare.com

Chronic Lymphocytic Leukemia The most prevalent type of adult leukemia Defined by CD5+, CD19+, CD2+dim, CD23, sig (dim)+ cells in blood; Monoclonal B-cell lymphocytosis (< 5 x 1 9 /l cells) Median age of diagnosis of CLL is ~ 72 yrs, (1% younger than 5 yrs of age) More common in men than women (2:1 ratio) Genetic predisposition (~ 1% of first-generation relative with CLL) Chromosomal translocations and genetic aberrations are seen in less than 3%

CLL - Reduces patients life expectancy For patients diagnosed with CLL before the age of 5 years, the median expected life span is only 12.3 years compared with 31.2 years in age-matched control. ADAPTED FROM SHANAFELT T, ET AL. CANCER 21;116:4777 87.

Consideration in Management of CLL Does the patient require therapy. What would be prognostic / predictive Should you do additional testing for prognostic /predictive markers? when should treatment start? Is watch and worry still appropriate for many patients? what is your goal of therapy? what type of therapy do we choose? Intensive or non intensive The one that will give us a low MRD status. Regimen will give the best pfs/ttnt How to best manage relapse and sustain a response?

Despite this impact of CLL on life expectancy we still have a good measure of patients who are kept under observation. Whom do we choose to treat and not to treat? When do you choose to treat?

CLINICAL STAGE AND OUTCOME OF CLL Rai Stage Clinical Features Cases, % Low risk Lymphocyte count > 5 x 1 9 /L Survival, Yrs 3 > 1 Intermediate risk High risk Enlarged LN or organomegaly Hemoglobin < 11 g/dl Platelets < 1 x 1 9 /L 6 6 1 2 Rai KR, et al. Blood. 1975;46:219-234.

Modified Indications For Treatment of Chronic Lymphatic Leukemia

Patients with CLL can be stratified into three subgroups according to age and comorbidities 1,2 1. Balducci L, Exterman M. Oncologist 2;5:224 37. 2. Eichhorst B, Et Al. Leuk Lymphoma 29;5:171. 3. Shanafelt T. Hematology Am Soc Hematol Educ Program 213;213:158 67.

The tight link between efficacy and toxicity with historical CLL therapy. Shanafelt T. Hematology Am Soc Hematol Educ Program 213;213:158 67.

Prognostic and predictive markers in CLL

CLL outcome from diagnosis: Interphase Chromosomal (FISH) Abnormalities Abnormality Pts, % Median Time to Treatment, Mos Median OS, Mos del(17)(p13.1) 7 9 32 del(11)(q22.3) 17 13 79 Trisomy 12 14 33 114 del(13)(q14) 55 49 133 None detected 18 92 111 Döhner H, et al. N Engl J Med. 2;343:191-1916.

Patients Surviving (%) CLL: Prognostic Value Of FISH FISH Abnormalities Present in 268/325 Patients (82%) Lesion % Median OS, Mos Del(13q) 55 133 Del(11q) 18 79 Trisomy 12 16 114 Del(17p) 7 32 Del(6q) 6 N/A Normal 18 111 FISH Lesion Dohner et al 1997 Patients with Abnormality (%) Oscier et al 1999 Jarosova et al 21 Dewald et al 23 Sindelarava et al 25 del(13q) 45 36 18 47 54 Trisomy 12 15 15 13 25 16 del(17p) 1 8 11 8 16 del(11q) 2 17 11 15 12 1 8 6 4 2 Probability of OS From Diagnosis, by Genetic Aberration 17p deletion 11q deletion 12q trisomy Normal 13q deletion as sole abnormality Dohner H, et al. N Engl J Med. 2;343:191-1916. Dohner H, et al. Leukemia. 1997;11(suppl 2):S19-24. Oscier DG. Haematologica. 1999;84(suppl EHA-4):88-91. Jarosova M, et al. Onkologie. 21;24:6-65. Dewald GW, et al. Br J Haematol. 23;121:287-295. Sindelárová L, et al, Cancer Genet Cytogenet. 25;16:27-34. Mos

CLL: Incidence Of Genetic Lesions Incidence of Genetic Lesion, % Treatment naïve CLL [1] (n = 452) CLL8 [2] Frontline FC vs FCR (n = 635) CLL3X [3,4] High-Risk AlloSCT (n = 8) CLL2H [5,6] F-Refractory Alemtuzumab (n = 97) TP53 mut 5.3 11.5 3. 39. NOTCH1 mut 12.6 1. 14. 13.4 SF3B1 mut 8.6 18.4 26. 17.5 IGHV UM 32.8 63. 96. 79. del(17p) 5.3 8.4 18.1 3.1 del(11q) 16. 24.6 36.1 19.4 1. Puente XS, et al. Nature. 215;526:519-524. 2. Stilgenbauer S, et al. Blood. 214;123:3247-3254. 3. Dreger P, et al. ASH 212. Abstract 966. 4. Dreger P, et al. Blood. 213;121:3284-3288. 5. Schnaiter A, et al. Blood. 213;122:1266-127. 6. Schneiter A, et al. ASH 212. Abstract 71.

% Surviving % Treatment Free % Surviving % Surviving IGHV Mutation and Prognosis in CLL 1 Degree Of Mutation Is Related To Prognosis [1] Mutation Threshold Of 98% Was Arbitrary N = 31 Patients 5 Analyzed For Survival By Degree Of Sequence Homology For IGHV Genes OS < 97% 97-97.9% 98-99.% 1% Homology, % Median OS, Mos 1 12 98-99.9 97-97.9 184 < 97 NR 1 5 Treatment Free < 97% 97-97.9% V H 3-21 Is A Special Case [2] CLL With Rearrangement Of V H 3-21 Has A Poor Prognosis Without Regard To The Mutation Status 98-99.9% 2 1% 1 2 3 4 5 1 2 3 4 5 2 4 6 8 1 12 14 16 18 2 Yrs 1. Hamblin TJ, et al. Brit J Haematol. 28;14:32-323. 2. Thorselius M, et al. Blood. 26;17:2889-2894. 1 8 6 4 1 8 6 4 2 Ig-unmutated V H 3-21 Ig-mutated V H 3-21 2 4 6 8 1 12 14 16 18 2 Yrs Homologous V H 3-21 HCDR3 (-1 deviation) Nonhomologous V H 3-21 HCDR3

TP53, NOTCH1, AND SF3B1 mutations on outcome in CLL PFS TP53 AND SF3B1 MUTATIONS ASSOCIATED WITH INFERIOR PFS AND OS NOTCH1 MUTATION PREDICTED FOR DIMINISHED BENEFIT FROM RITUXIMAB OS Stilgenbauer S, et al. Blood. 214;123:3247-3254. Slide credit: clinicaloptions.com

Cumulative Proportion Progressing Cumulative Proportion Progressing NOTCH1 mutations- Lack of benefit to Anti-cd2 Mab 123 CLL symptomatic patients homogeneously treated with first-line fludarabine followed by consolidation rituximab in responding patients NOTCH1 mut -Significant associations with trisomy 12 (p =.3) and unmutated IGHV (p =.1)2 of 123 pts (16.3%). ASSOCIATED WITH INFERIOR RESPONSE RATES, PFS 1..8.6 Response Duration by NOTCH1 Mutations P =.4 n = 13 NOTCH1 wild type NOTCH1 mutated 1..8.6 Response Duration by Unconsolidated vs NOTCH1 wt and NOTCH1 Mut Consolidated Pts n = 1 n = 49 Unconsolidated Consolidated NOTCH1 wt Consolidated NOTCH1 mut.4.2 n = 2.4.2 n = 21 P =.7 P =.4 24 48 72 96 12 144 168 24 48 72 96 12 144 168 Mos From the End of Induction Therapy Mos From the End of Induction Therapy Del Poeta G, et al. 213 EHA. Abstract P12

So where is this knowledge taking us with regards to management of CLL? Outcomes with CT/ CIT treatment for CLL?

Cumulative Survival CLL8 : PFS 1..9.8.7.6.5.4 Survival Functions FC FCR FC censored FCR censored N = 817 Median PFS, Mos FC: 32.9 FCR: 57.9.3.2 HR:.56 (95% CI:.465-.673; P <.1).1 6 12 16 24 3 36 42 48 54 6 66 72 78 Mos Fink A, et al. ASH 211. Abstract 977.

OS CLL8 TRIAL: FIRST-LINE FC VS FCR 1..9.8 FCR (n = 48).7.6.5.4.3.2.1 Median follow-up: 7 mos HR:.7; P =.1 FC (n = 49) 12 24 36 48 6 72 84 96 Fischer K, et al. ASH 212. Abstract 435. Mos

Cumulative Survival CLL1: PFS (PRIMARY ENDPOINT) AND OS WITH FCR VS BR IN PTS WITH ADVANCED CLL 1..8 PFS Median PFS, Mos FCR 55.2 BR 41.7 1..8 OS.6.6 P =.897.4.4.2 P <.1 HR: 1.626 (> 1.388 non-inferiority cut-off) 12 24 36 48 Mos 6.2 OS at 36 Mos, % FCR 9.6 BR 92.2 12 24 36 48 Mos to Event (OS) 6 Eichhorst B, et al. ASH 214. Abstract 19.

Does CIT produce long term responses?

Pts (%) Pts Progression Free (%) FCR3 Phase II Trial: Plateau in PFS with FCR As Initial Therapy For CLL WITH EXTENDED FOLLOW-UP, PFS 1 75 SHOWS PLATEAU AT YRS 1-11 N Event Free OS 3 154 PFS 3 11 LAST RELAPSES OCCURRED AROUND YR 1, WITH A PLATEAU IN PFS FOR IGHV-MUTATED PTS 1 75 N IGHV mutated IGHV unmutated Progression Free 88 49 126 12 5 5 25 2 4 6 8 1 Yrs 12 14 16 25 P <.1 2 4 6 8 1 Yrs 12 14 16 Thompson PA, et al. Blood. 215 Oct 22.

Does the newer Anti CD2 mabb have an advantage?

Probability of PFS Probability of OS Probability of PFS Probability of OS CLL11: Survival with Clb/Obinutuzumab Vs Clb Alone or Clb/Rituximab in CLL 1..8.6.4.2 O-Clb 26.7 Clb 11.1 6 12 18 24 3 36 1..8.6 HR:.18 (95% CI:.13-.24; P <.1) HR:.39 (95% CI:.31-.49; P <.1).4 O-Clb.2 R-Clb 26.7 15.2 6 12 18 24 3 36 39 Mos Goede V, et al. N Engl J Med. 214;37:111-111. 1..8.6 HR:.41 (95% CI:.23-.74; P <.2).4.2 O-Clb Clb 6 12 18 24 3 36 1..8.6.4.2 HR:.66 (95% CI:.41-1.6; P =.8) O-Clb R-Clb 6 12 18 24 3 36 39 Mos

CLL11: Response with CLB/Obinutuzumab Vs CLB alone or CLB/Rituximab in CLL Response, % O-Clb (n = 238) Clb (n = 118) R-Clb (n = 233) ORR 77.3 31.4 75.7 CR 22.3 7.3 PR 55. 31.4 58.4 Pts With MRD-Negative Test, % O-Clb R-Clb P Value Bone marrow 19.5 2.6 <.1 Blood 37.7 3.3 <.1 Goede V, et al. N Engl J Med. 214;37:111-111.

Targeting specific pathways A paradigm change in the management of CLL

Critical signaling pathways and new targeted agents In B-cell Malignancies BCR BCR signaling is required for tumor expansion and proliferation BCR signaling up-regulated Ibrutinib BTK LYN SYK PI3K delta Idelalisib Duvelisib Pilaralisib in CLL New inhibitors targeting multiple components of BCR PKC PLCγ2 Everolimus GSK-3 AKT mtor NF-kβ pathway signaling including pi3k delta, BTK, and SYK p7s6k elf4e

Targeting Bruton Kinase Ibrutinib in CLL

Pts (%) Pts With Response (%) PHASE II (PCYC-112/PCYC-113) IBRUTINIB MONOTHERAPY TRIAL IN CLL/SLL 1 PTS WITH CLL/SLL: TX NAIVE (N = 31) AND R/R WITH PD < 24 MOS 8 6 4 2 AFTER CHEMOIMMUNOTHERAPY OR FAILURE TO RESPOND (N = 11) PTS RECEIVED IBRUTINIB 42 OR 84 MG/DAY PO ORR: 84% 23 55 6 1 Untreated 65 Yrs of Age (n = 31) Best response to ibrutinib improves over time ORR: 9% 7 8 3 R/R (n = 11) ORR: 8% 6 R/R del(17p) (n = 34) ORR: 89% 4 12 5 2 9 3 4 2 Byrd JC, et al. Blood. 215;125:2497-256. 65 11 74 Total (N = 132) CR PR PR-L SD PD 1 9 8 7 6 5 4 3 2 1 48 42 21 CR PR PR-L 56 63 69 71 73 76 77 76 74 42 29 2 15 12 1 8 8 9 11 1 2 4 5 5 5 5 4 4 3 6 9 12 15 18 24 3 36 42 Mos From Initiation of Study Treatment 4

Proportion Achieving PFS Proportion Achieving OS Ibrutinib Monotherapy 3 Yrs Postinitiation In CLL/SLL: PFS, OS By Cytogenetics PFS OS 1. 1..8.8.6.6.4.2 del(17p) del(11q) No del(17p) or del(11q).4.2 del(17p) del(11q) No del(17p) or del(11q) Log-rank P =.31 Log-rank P =.327 6 12 18 24 3 36 42. 6 12 18 24 3 36 42 Mos From Initiation of Study Treatment Mos From Initiation of Study Treatment del(17p) R/R (n = 34) del(11p) R/R (n = 28) No del(17p/11q) R/R (n = 34) del(17p) R/R (n = 34) del(11p) R/R (n = 28) No del(17p/11q) R/R (n = 34) 3-mo PFS, % (95% CI) 48 (29-65) 74 (53-87) 87 (68-95) 3-mo OS, % (95% CI) 65 (46-79) 85 (65-94) 9 (73-97) Median PFS, mos (95% CI) 28 (18.2-NE) 38.7 (31.2-NE) NR (NE-NE) Median OS, mos (95% CI) NR (21.5-NE) NR (41.4-NE) NR (NE-NE) Byrd JC, et al. Blood. 215;125:2497-256.

RESONATE-2: Ibrutinib Vs Chlorambucil In Pts 65 Yrs Of Age With Tx-naive CLL/SLL AN INTERNATIONAL, RANDOMIZED PHASE III TRIAL Pts 65 yrs of age or older with treatmentnaive CLL/SLL; no warfarin use; no del(17p) (N = 269) Ibrutinib 42 mg/day until progression Chlorambucil.5 mg/kg (up to maximum of.8 mg/kg) on Days 1, 15 of 28-day cycle for up to 12 cycles Crossover upon PD (n = 43) Burger JA, et al. N Engl J Med. 215. PRIMARY ENDPOINT: PFS SECONDARY ENDPOINTS: OS, ORR, EFS, RATE OF HEMATOLOGIC IMPROVEMENT, AND SAFETY

Pts With PFS (%) Pts Who Survived (%) RESONATE-2: Superior Efficacy With Ibrutinib Vs Chlorambucil For Elderly Pts 1 PFS Ibrutinib 1 OS Ibrutinib 8 8 Chlorambucil 6 Chlorambucil 6 4 2 Median, mos Clb 18.9 Ibrutinib NR HR:.16 (95% CI:.9-.28; P <.1) 6 12 18 24 Mos AEs Summary Ibrutinib Chlorambucil Most frequent AEs Burger JA, et al. N Engl J Med. 215; Diarrhea, fatigue, cough and nausea Nausea, fatigue, neutropenia, anemia, and vomiting AEs leading to discontinuation, % 9 23 4 2 HR:.16 (95% CI:.5-.56; P <.1 by log-rank test) 6 12 18 24 Mos

Phase III RESONATE: Ibrutinib Vs Ofatumumab In Previously Treated CLL/SLL CLL/SLL diagnosis 1 prior therapy ECOG PS -1 Measurable nodal disease by CT Ibrutinib 42 mg/day PO until PD or unacceptable toxicity (n = 195) Ofatumumab IV starting dose of 3 mg followed by 2 mg x 11 doses for 24 wks (n = 196) Crossover = 122 pts To Ibrutinib 42 mg/day following PD Primary goal: updated efficacy results, with median treatment duration of 16 mos, relative to genetic features and prior treatment exposure, and updated AE data Brown JR, et al. ASH 214. Abstract 3331. Byrd JC, et al. N Engl J Med. 214;371:213-223.

PFS (%) RESONATE: Ibrutinib Vs Ofatumumab In Previously Treated CLL/SLL 1 8 6 HR:.215 (95% CI:.146-.317) 4 2 RICHTER S TRANSFORMATION CONFIRMED IN 2 PTS ON EACH ARM; Byrd JC, et al. N Engl J Med. 214;371:213-223. Log-rank P <.1 Ibrutinib Ofatumumab Median PFS, mos NR 8.8 3 6 9 12 15 Mos 1 ADDITIONAL PT ON IBRUTINIB EXPERIENCED DISEASE TRANSFORMATION TO PROLYMPHOCYTIC LEUKEMIA

PFS (%) 1 RESONATE: PFS By Del(17p) With Ibrutinib Vs Ofatumumab In CLL/SLL 8 Ibrutinib del(17p) ibrutinib no del(17p) Ofatumumab del(17p) Ofatumumab no del(17p) Median PFS, mos NR NR 5.9 8.2 HR: 1.314 (95% CI:.698-2.473; P =.396) HR: 1.413 (95% CI: 1.17-1.963; P =.39) 6 4 2 3 6 9 12 15 18 21 24 Mos For ibrutinib, no significant difference in PFS with or without del(17p) Brown JR, et al. ASH 214. Abstract 3331.

Cumulative Incidence of Discontinuation of Ibrutinib Therapy (%) Retrospective Study: Time To Discontinuation of Ibrutinib SINGLE INSTITUTION RETROSPECTIVE ANALYSIS OF 38 PTS PARTICIPATING IN 4 SEQUENTIAL TRIALS OF IBRUTINIB 3 25 2 15 1 5 Cumulative Incidence, % (95% CI) 12 Mos 18 Mos Other event 13.5 (9.5-17.6) 15.6 (11.1-2.) Richter s transformation 4.5 (2.-7.) 6.5 (3.3-9.6) CLL progression.3 (-1.) 2.4 (.3-4.6) 6 12 18 24 3 36 42 Mos Maddocks KJ, et al. JAMA Oncol. 215;1:8-87. 48

PFS (%) OS (%) PFS (%) PFS (%) Ibrutinib vs Ofatumumab (Phase III RESONATE) [1] Single-agent Ibrutinib (5-year follow up from phase Ib/II study) [2] TP53 Status Affects Survival In Relapsed/Refractory CLL Treated With Ibrutinib Ibrutinib with del(17p) (n = 63) Ibrutinib without del(17p) (n = 132) Ofatumumab with del(17p) (n = 64) Ofatumumab without del(17p) (n = 132) 1 9 8 7 6 5 4 3 2 1 3 6 9 12 15 18 21 Mos 1 8 6 4 2 del(17p) del(11q) Trisomy 12 del(13q) No abnormality Ibrutinib without or with del17p HR: 1.421 (95% CI:.771-2.62) Log-rank P =.2575 1. Brown JR, et al. Leukemia. 218;32:83-91. 2. O Brien S, et al. Blood. 218;131:191-1919. 24 6 12 18 24 3 36 42 48 54 6 66 72 78 Mos From Initiation of Study Treatment 1 9 8 7 6 5 4 3 2 1 Log-rank P.1737 comparing del(17p) and TP53 vs del(17p) or TP53 mutation Log-rank P.381 comparing del(17p) and TP53 vs no del(17p) or TP53 mutation Log-rank P.522 comparing del(17p) or TP53 mutation vs no del 17p or TP53 mutation 3 6 9 12 15 18 21 Mos 1 8 6 4 2 No del(17p) or TP53 mutation (n = 68) del(17p) or TP53 mutation (n = 48) del(17p) and TP53 mutation (n = 38) del (17p) del (11q) Trisomy 12 del (13q) No Abnormality 24 6 12 18 24 3 36 42 48 54 6 66 72 78 Mos From Initiation of Study Treatment

IBRUTINIB: CONCLUSIONS Ibrutinib is very active in pts with Treatment naïve and R/R CLL produces ORR of 8% to 9%, with CR of 6% to 7%, and 53% of pts remain on ibrutinib at median 3-yr follow-up No significant difference in pfs, regardless of del(17p) status Ibrutinib can result in various AEs Rate of atrial fibrillation is less than 1% Increases bleeding risk, but most bleeding is mild and not serious Use caution when combining with anticoagulants or in pts with predisposing risk factors Slide credit: clinicaloptions.com

PI3K Signaling Pathway As A Target In B Cells BCR LYN SYK p85 p11 PI3K Delta AKT PTEN P PIP 2 P P Proliferation Cyclin-D p27 kip1 GSK-3ß Bad Cell survival FoxO mtor IKK ASK Protein synthesis NF-kB pathway SAPK/JNK pathway

PFS (%) OS (%) Screen Arm A n = 11 Arm B n = 11 Randomization/ Stratification Idelalisib, A Pi3kd Inhibitor, Overcomes Adverse Effect Of TP53 Aberration Population: Relapsed CLL warranting treatment (iwcll); progression < 24 mos since last treatment Primary Study 116 Extension Study 117 Double-Blind Initial Therapy Rituximab (6 mos) Rituximab (6 mos) Double- Blind Continuous Therapy Idelalisib (15 mg BID) Placebo (BID) Blinded, Independent Review Sharman JP, et al. ASH 214. Abstract 33. Disease Progression Blinded Dose Open Label Idelalisib (3 mg BID) Idelalisib (3 mg BID) Interim Analyses and Unblinding Independent Review PFS in TP53-Aberrant Patients With Idelalisib + Rituximab 1 8 6 4 No del del del(17p)/tp53mut: Present vs Not Present 2 No del(17p)/tp53mut (n = 64) Del(17p)/TP53mut (n = 46) 2 4 6 8 1 12 14 1618 2 22 24 26 Mos 64 46 61 41 59 59 36 36 52 37 33 3 21 14 11 22 12 8 8 4 Median PFS (95% CI) No del 2.3 mos (19.4, - ) del 16.6 mos (13.9, - ) 4 3 1 1 1 P Value.94 OS in TP53-Aberrant Patients With Idelalisib + Rituximab vs Control 1 8 6 4 IDELA + R PBO + R del(17p)/tp53mut: Mutation (Either) 2 Idelalisib + R (n = 46) Placebo + R (n = 49) 2 4 6 8 1 12 14 1618 2 22 24 26 Mos 46 49 45 41 41 41 39 37 4 39 33 25 Median OS (95% CI) IDELA + R NR (18.8,- ) PBO + R 14.8 mos (8.4, - ) 3 23 17 11 16 12 8 4 5 4 HR (95% CI) 2 2.31 (.15-.65) 1 P Value.1

IDELALISIB: TOXICITIES Diarrhea: occurs in 2 forms Self-limiting: usually mild; early onset (median 1.5 mos); responds to common antidiarrheal agents Severe diarrhea: late onset (median 7 mos); responds poorly to antimotility agents but appears to be responsive to budesonide and/or systemic corticosteroids Transaminase elevations: generally reversible Usually occurs within first 12 wks 74% of pts with treatment interruption able to resume idelalisib at a lower dose without recurrence Permanently discontinue idelalisib if ALT/AST > 2 x ULN Pneumonitis: consistent with reports with mtor inhibitors Any pt who presents with pulmonary symptoms should be evaluated for pneumonitis Hold idelalisib with any symptomatic pneumonitis Often treated with corticosteroids in addition to continuing antibiotics and holding idelalisib if no improvement Coutre SE, et al. Leuk Lymphoma. 215;56:2779-2786.

Targeting the BCL2 receptor. Venetoclax the new star for CLL management

Targeting BCL 2 Venetoclax: Mechanism Of Action 1 Proapoptotic proteins (BAX, BAK) An Increase in BCL-2 Expression Allows the Cancer Cell to Survive Antiapoptotic proteins (BCL-2) 2 Venetoclax Binds to and Inhibits Overexpressed BCL-2 BH3-only Venetoclax 3 Apoptosis is Initiated Active caspase Apoptosome APAF-1 Cytochrome C Procaspase BAK BAX BCL-2 BCL-2 Mitochondria Mitochondria Mitochondria Kumar S, et al. ASCO 215. Abstract 8576.

Venetoclax + Rituximab In R/R CLL: Phase Ib Dose-escalation Strategy Wk 1 Wk 1 Wk 2 Wk 3 Wk 4 Mo 1 Mos 2-6 Day 1 Days 2-7 2 mg 5 mg 1 Cohort Cohort Cohort 2 mg mg Dose Dose Dose Mo 7 and ongoing Venetoclax monotherapy Rituximab: Day 1 Day 1 of Mos 2-6 375 mg/m 2 5 mg/m 2 Protocol-defined option to stop venetoclax after achieving CR or MRD-negative PR Dose-escalation phase: 2, 3, 4, 5, 6-mg/day cohorts (n = 41) Safety expansion phase: 4-mg/day cohort (n = 8) Data pooled for safety and efficacy analyses Seymour JF, et al. Lancet Oncol. 217;18:23-24.

Venetoclax + Rituximab In R/R CLL: Outcomes After Discontinuing Therapy MRD-positive CR/CRi MRD-negative CR/CRi MRD-negative PR Seymour JF, et al. Lancet Oncol. 217;18:23-24. * * Time on venetoclax Time off venetoclax Asymptomatic progression Best iwcll and MRD response Discontinued from study Lost to follow-up 4 8 12 16 2 16 18 32 36 48 42 Mos *

Venetoclax Monotherapy: Phase II Trial In Ultrahigh-risk R/R CLL With Del(17p) PFS and OS (N=17) Week 1* D1 Week 1 D2 7 Week 2 Week 3 Week 4 and following Venetoclax 2 mg test 5 mg 1 mg 2 mg 4 mg Objectives: Primary: ORR by IRC assessment Secondary: CR/PR rates, time to first response, DoR, PFS, OS, safety Exploratory: MRD (flow cytometry, sensitivity <1-4 ) Key Inclusion: Rel/ref CLL, del(17p) confirmed by central laboratory ECOG score 2 ANC 1K/µL; Plt 4K/µL; Hgb 8 g/dl Creatinine clearance 5 ml/min Key Exclusion: AlloBMT, Richter s, uncontrolled autoimmune cytopenia, other malignancy, major organ dysfuction Risk-based tumor lysis monitoring Weekly step-wise weekly ramp-up Response assessment (iwcll 28): CBC, PE monthly CT scan to confirm clinical response (prespecified at week 36) Bone marrow biopsy to confirm CR 12-MO OS: 86.7% (95% CI: 78.6% TO 91.9%) Stilgenbauer S, et al. ASH 215. Abstract LBA-6. Stilgenbauer S, et al. Lancet Oncol. 216;17:768-778. 12-MO PFS: 72% (95% CI: 61.8% TO 79.8%)

MURANO Interim Analysis: Study Design MULTICENTER, RANDOMIZED, OPEN-LABEL PHASE III TRIAL Stratified by del(17p), prior tx response*, geographic region 28-day cycles Adult patients with R/R CLL, 1-3 prior tx lines (with 1 CTcontaining regimen), prior bendamustine permitted if DoR 24 mos (N = 389) Venetoclax dose ramp-up 2-4 mg PO QD for 5 wks then 4 mg PO QD for C1-6 + Rituximab 375 mg/m 2 on Day 1 of C1, then 5 mg/m 2 Day 1 of C2-6 (n = 194) Bendamustine 7 mg/m 2 on Days 1, 2 of C1-6 + Rituximab 375 mg/m 2 on Day 1 of C1, then 5 mg/m 2 Day 1 of C2-6 (n = 195) Venetoclax monotherapy until PD, unacceptable toxicity, or maximum of 2 yrs from Day 1 of C1 *High-risk CLL defined as: del(17p); no response to first-line CT-containing tx; or relapsed in 12 mos after CT or in 24 mos after chemoimmunotherapy. Primary endpoint: investigator-assessed PFS Secondary endpoints: IRC-assessed PFS and MRD negativity, IRC-assessed CR ORR OS (hierarchical testing), safety Seymour JF, et al. ASH 217. Abstract LBA-2. ClinicalTrials.gov. NCT25471.

PFS (%) MURANO Interim Analysis: Investigator-assessed PFS 1 8 6 4 2 Pts at Risk, n VEN + R BR HR:.17 (95% CI:.11-.25); P <.1 Pts, n mpfs, Mos 1-yr PFS, % 2-yr PFS, % VEN + R 194 NR 92.7 84.9 BR 195 17 72.5 36.3 Censored 3 6 9 12 15 18 21 24 27 3 33 36 39 Mos 194 19 185 179 176 173 157 115 76 33 14 5 3 195 177 163 141 127 12 81 57 35 12 3 3 MEDIAN F/U: 23.8 MOS (-37.4) COMPLETED 2-YRS WITHOUT PROGRESSION, N = 65; PTS WITH 3-MO F/U, N = 12 IRC-ASSESSED PFS CONCORDANT WITH INVESTIGATOR ASSESSMENT MPFS FOR VEN + R VS BR: NR VS 18.1 MOS (HR:.19; 95% CI:.13-.28; P <.1) Seymour JF, et al. ASH 217. Abstract LBA-2. Reprinted with permission.

PFS (%) MURANO Interim Analysis: Investigator-assessed PFS By Del(17p) Status 1 8 6 4 2 Pts at Risk, n VEN + R with del(17p) VEN + R without del(17p) BR with del(17p) BR without del(17p) HR for VEN + R vs BR (95% CI) With del(17p).13 (.5-.29) Without del(17p).19 (.12-.32) 46 127 46 123 VEN + R with del(17p) (n = 46) VEN + R without del(17p) (n = 127) BR with del(17p) (n = 46) BR without del(17p) (n = 123) Censored 3 6 9 12 15 18 21 24 27 3 33 36 39 Mos 44 43 43 43 42 36 25 17 7 2 127 124 118 116 114 15 76 48 2 1 4 3 4 34 27 25 2 14 8 5 1 114 18 99 88 7 6 44 26 1 3 1 Venetoclax + rituximab consistently favored across subgroups stratified by del(17p) status, TP53 status, baseline IGHV status, no. prior tx, refractory vs relapse to last tx Seymour JF, et al. ASH 217. Abstract LBA-2. Reprinted with permission.

Pts (%) Pts (%) MURANO Interim Analysis: MRD Negativity Higher rates of blood MRD negativity achieved and maintained with VEN + R vs BR MRD Negativity,* (n) % VEN + R (n = 194) Seymour JF, et al. ASH 217. Abstract LBA-2. BR (n = 195) BL 4 mos 88 (45) 11 (6) 9 mos 121 (62) 26 (13) 12 mos 117 (6) 2 (1) 15 mos 11 (57) 19 (9) 18 mos 116 (6) 1 (5) *MRD negative: < 1 CLL cell/1, leukocytes (1-4 ). Centrally assessed every 3 mos after end of combination therapy or at response by multicolor flow cytometry and/or ASO-PCR; only 1 positive assay needed to report as MRD positive. ITT analysis with missing MRD data or failed assay reported as MRD positive. End of combination therapy. 1 8 6 4 2 1 8 6 4 2 VEN + R (n = 194) 4 9 12 15 18 Mos BR (n = 195) 4 9 12 15 18 Mos MRD negative MRD positive Assay failure PD/death/withdrew Sample missing

Venetoclax + Ibrutinib In CLL: Study Design Investigator-initiated, single-arm, multicohort phase ii (n=116) Adult pts with CLL/SLL meeting IWCLL 28 criteria with either R/R disease (cohort 1, n = 37) or untreated high-risk* disease (cohort 2, n = 4), adequate organ function, no prior IBR, no prior VEN Ibrutinib 42 mg QD in 28-d cycles Primary endpoint: CR/CRi per IWCLL 28 criteria Jain N, et al. ASH 217. Abstract 429. ClinicalTrials.gov. NCT2756897. Cycle 3 Ibrutinib 42 mg QD + Venetoclax dose escalation to 4 mg QD Other endpoints: OS, TLS risk categorization at BL vs post-ibr, safety IBR: until PD VEN: for 2 yrs * 1 of following high-risk characteristics: 65 yrs of age; del(11q); del(17p) or mutated TP53; unmutated IGHV. Venetoclax weekly dose escalation (all doses QD): 2 mg, 5 mg, 1 mg, 2 mg, 4 mg. Response assessment by blood, BM, CT every 3 mos during Yr 1, every 6 mos during Yr 2, then every 6-12 mos thereafter.

Pts (%) Venetoclax + Ibrutinib In CLL: Response In R/R Disease (Cohort 1) 1 9 3 8 7 6 42 69 77 8 CR/CRi PR (any LN > 1.5 cm by CT) BM MRD negative (by 4-color flow cytometry; sensitivity 1-4 ) 5 4 91 3 58 2 1 3 Mo IBR (n = 34) 8 3 Mo VEN + IBR (n = 26) 31 6 Mo VEN + IBR (n = 16) 23 13 15 2 9 Mo VEN + IBR (n = 13) 46 12 Mo VEN + IBR (n = 5) Jain N, et al. ASH 217. Abstract 429. Reprinted with permission.

Pts (%) Venetoclax + Ibrutinib In CLL: Response In Untreated High-risk Disease (Cohort 2) 1 9 3 8 7 6 5 4 97 61 75 8 8 1 1 CR/CRi PR (any LN > 1.5 cm by CT) BM MRD negative (by 4-color flow cytometry; sensitivity 1-4 ) 3 2 1 3 Mo IBR (n = 36) 39 21 3 Mo VEN + IBR (n = 33) 25 45 6 Mo VEN + IBR (n = 2) 2 9 Mo VEN + IBR (n = 1) 12 Mo VEN + IBR (n = 3) Jain N, et al. ASH 217. Abstract 429. Reprinted with permission.

How can we look at approaching a CLL patient requiring treatment today?

Population Initial Therapy Relapsed Therapy Younger, fit pts with low risk Older pts with comorbidities Pts with del(17p) or TP53 mutation *Not currently approved by the FDA. FCR (especially mutated IGHV) Bendamustine/rituximab Chlorambucil/obinutuzumab Chlorambucil/ofatumumab Ibrutinib Ibrutinib AlloSCT? Ibrutinib Idelalisib + R Ibrutinib + BR* Idelalisib + BR* Venetoclax* Ibrutinib Idelalisib + R Venetoclax Ibrutinib Idelalisib + R AlloSCT?