Managing the Otherwise Healthy Patient With CLL Susan M. O’Brien, MD Professor of Medicine Department of Leukemia University of Texas M. D. Anderson Cancer Center Houston, Texas This activity is supported by educational grants from Infinity Pharmaceuticals Inc.; Janssen Biotech Inc., Pharmacyclics Inc.; TG Therapeutics.

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Faculty Disclosures Susan M. O’Brien, MD, has disclosed that she has received consulting fees from Amgen, Celgene, Emergent, Genentech, Gilead Sciences, GlaxoSmithKline, Infinity, Pharmacyclics, and Spectrum; has received funds for research support from Emergent, Genentech, Gilead Sciences, Infinity, MorphoSys, Pharmacyclics, and Spectrum; and has served on the advisory board for CLL Global Research Foundation. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

Response to FCR (NCI-WG: N = 300) Patients, n Patients, % CR 156 70 Nodular PR 23 10 PR 34 15 No response 11 5 Early death 2 < 1 95% *Evaluated 6 mos after last course. Keating MJ, et al. J Clin Oncol. 2005;23:4079-4088.

CLL8 Study Design 817 patients with untreated, active CLL and good physical fitness (CIRS ≤ 6, creatinine clearance ≥ 70 mL/min) 6 courses FCR R Follow-up FC C1 C2 C3 C4 C5 C6 Demographics similar between 2 treatment arms CIRS, cumulative illness rating score; CLL, chronic lymphocytic leukemia; FC, fludarabine/cyclophosphamide; FCR, fludarabine/cyclophosphamide/rituximab. Updated results of the third analysis Median observation time: 5.9 yrs Hallek M, et al. Lancet. 2010;376:1164-1174.

FC vs FCR: Response Response FC,% FCR, % P Value CR 23 45 < .01 CRu .22 CRi 2 .52 nPR .15 PR 50 40 OR 85 93 CR, complete response; CRi, complete remission with incomplete blood count recovery; CRu, complete response unconfirmed; FC, fludarabine/cyclophosphamide; FCR, fludarabine/cyclophosphamide/rituximab; nPR, nodular partial response; OR, overall response; PR, partial response. Hallek M, et al. Lancet. 2010;376:1164-1174. FrontlineTherapyCase

CLL8 Update: PFS Survival Functions 1.0 FC FCR FC censored FCR censored 0.9 0.8 0.7 N = 817 0.6 Median PFS, Mos FC: 32.9 FCR: 57.9 Cumulative Survival 0.5 0.4 CI, confidence interval; FC, fludarabine/cyclophosphamide; FCR, fludarabine/cyclophosphamide/rituximab; HR, hazard ratio; nPR, nodular partial response; OR, overall response; PFS, progression-free survival; PR, partial response. 0.3 HR: 0.56 95% CI: 0.465-0.673 P < .0001 0.2 0.1 6 12 16 24 30 36 42 48 54 60 66 72 78 Mos Fink A, et al. ASH 2011. Abstract 977. FrontlineTherapyCase

CLL8 Trial: First-line FC vs FCR 1.0 0.9 FCR 0.8 0.7 FC 0.6 OS 0.5 0.4 0.3 FC, fludarabine/cyclophosphamide; FCR, fludarabine/cyclophosphamide/rituximab; HR, hazard ratio Median follow-up: 70 mos HR: 0.7; P = .001 0.2 0.1 12 24 36 48 60 72 84 96 Mos Fischer K, et al. ASH 2012. Abstract 435. FrontlineTherapyCase

CLL10, Phase III Interim Analysis: FCR vs BR in CLL Fludarabine 25 mg/m3 IV Days 1-3 Cyclophosphamide 250 mg/m2 Days 1-3 Rituximab 375 mg/m2 IV Day 0, cycle 1 Rituximab 500 mg/m3 IV Day 1, cycles 2-6 Patients with untreated, active CLL without del(17p) and good physical fitness (CIRS ≤ 6, creatinine clearance ≥ 70 mL/min) (N = 561) BR Bendamustine 90 mg/m3 IV Days 1-2 Rituximab 375 mg/m2 Day 0, cycle 1 Rituximab 500 mg/m2 IV Day 1, cycles 2-4 BR, bendamustine/rituximab; CIRS, Cumulative Illness Rating Scale; CLL, chronic lymphocytic leukemia; FCR, fludarabine/cyclophosphamide/rituximab; HR, hazard ratio; IV, intravenously; PFS, progression-free survival. Primary endpoint: noninferiority of BR vs FCR for PFS HR (λBR/FCR) < 1.388 Eichhorst B, et al. ASH 2013. Abstract 526.

CLL10 Study: FCR VS BR in Frontline Response to Therapy (Best Response) P Value CR (CR + CRi) 47.4 38.1 .031 CR 40.1 36.3 CRi 7.3 1.8 PR 50.4 59.7 ORR 97.8 1.0 BR, bendamustine/rituximab; CIRS, Cumulative Illness Rating Scale; CLL, chronic lymphocytic leukemia; CR, complete response; CRi, CR with incomplete blood count recovery; FCR, fludarabine/cyclophosphamide/rituximab; IV, intravenously; ORR, overall response rate; OS, overall survival; PR, partial response. Of the 14 patients not evaluable for response: 4 pts received a new treatment during the first three cycles and before Interim Staging 4 pts died before Interim Staging 4 pts withdrew consent before Interim Staging 1 pt is lost for FU before Interim Staging 1 pt was end-of-study before Interim Staging Eichhorst B, et al. ASH 2013. Abstract 526. FrontlineTherapyCase

CLL10 Study: FCR VS BR in Frontline Minimal Residual Disease 100 90 80 P = .02 70 P < .001 FCR BR 60 MRD-Negative Pts (%) in Relation to Pts With MRD Samples 50 P = .023 40 30 BR, bendamustine/rituximab; FCR, fludarabine/cyclophosphamide/rituximab; Final PB 74% vs 63%; BM 58 vs 31 % 20 10 Interim PB Final PB Final BM No. of Patients 72/180 44/156 137/185 107/170 75/129 31/98 Eichhorst B, et al. ASH 2013. Abstract 526. FrontlineTherapyCase

CLL10 Study: FCR VS BR in Frontline PFS (Primary Endpoint) Study Medication Survival Functions 1.0 BR FCR BR censored FCR censored 0.9 0.8 0.7 0.6 Median PFS, Mos FCR: not reached BR: 44.9 Cumulative Survival 0.5 0.4 BR, bendamustine/rituximab; FCR, fludarabine/cyclophosphamide/rituximab; PFS, progression-free survival; 0.3 P = .04 0.2 0.1 6 12 18 24 30 35 42 48 54 Mos Eichhorst B, et al. ASH 2013. Abstract 526.

CLL10: Adverse Events Interval first cycle until 3 mos after final staging Adverse event FCR, % of Pts BR, % of Pts P Value All 90.8 78.5 < .001 Hematological AEs 90.0 66.9 Neutropenia 81.7 56.8 Anemia 12.9 9.7 .28 Thrombocytopenia 21.5 14.4 .03 Infection 39.0 25.4 .001 TRM 3.9 2.1 .23 BR, bendamustine/rituximab; FCR, fludarabine/cyclophosphamide/rituximab; Eichhorst B, et al. ASH 2013. Abstract 526.

CLL11 Trial: Obinutuzumab + Chlorambucil vs Rituximab + Chlorambucil Randomized 1:2:2 28-day cycle Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles (n = 118) Previously untreated CLL patients with comorbidities (CIRS score > 6 and/or CrCl < 70 mL/min) (N = 780) Obinutuzumab 1000 mg IV cycle 1 on Days 1, 8, 15; cycles 2-6 on Day 1 + Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles (n = 333) CIRS, Cumulative Illness Rating Scale; CLL, chronic lymphocytic leukemia; CrCl, creatinine clearance; IV, intravenously; PO, orally. The rituximab arm vs. the chemotherapy only arm was the second pairwise comparison. Primary results of this comparison were presented at the 2013 Annual ASCO Meeting. Rituximab 375 mg/m2 IV cycle 1 on Day 1; 500 mg/m2 cycles 2-6 on Day 1 + Chlorambucil 0.5 mg/kg PO on Days 1, 15 x 6 cycles (n = 330) Patients who progress on chlorambucil alone allowed to crossover to obinutuzumab + chlorambucil arm. Goede V, et al. N Engl J Med. 2014;370:1101-1110. 

Obinutuzumab + Chlorambucil vs Rituximab + Chlorambucil: PFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Obinutuzumab-chlorambucil Chlorambucil Stratified HR: 0.18 (95% CI: 0.13-0.24; P < .0001) Probability of PFS PFS, progression-free survival. 11.1 26.7 3 6 9 12 15 18 21 24 27 30 33 36 39 Mos Goede V, et al. N Engl J Med. 2014;370:1101-1110. 

Phase III COMPLEMENT1: Ofatumumab + Chlorambucil vs Chlorambucil Alone Ofatumumab Cycle 1: 300 mg on Day 1, 1000 mg on Day 8 Cycle 2-12: 1000 mg on Day 1 every 28 days + Chlorambucil 10 mg/m2 on Days 1-7 every 28 days Patients with previously untreated CLL (N = 444) Follow-up: 1 mos past last dose, 3rd mos, then every 3 mos after Chlorambucil 10 mg/m2 on Days 1-7 every 28 days CLL, chronic lymphocytic leukemia; ORR, overall survival; PD, progressive disease; PFS, progression-free survival; q28d, every 28 days; q3m, every 3 months. *Minimum 3 cycles or until best response or PD; maximum 12 cycles; no crossover allowed. Dose rationale: highest PFS and ORR with the lowest toxicity compared with any other chlorambucil treatment Hillmen P, et al. ASH 2013. Abstract 528.

Ofatumumab + Chlorambucil vs Chlorambucil Alone: PFS* Ofatumumab + chlorambucil mPFS: 22.4 mos HR: 0.57 (95% CI: 19.0-25.2; P < .001) 1.0 9.0 8.0 Chlorambucil mPFS: 13.1 mos (95% CI: 10.6-13.8) 7.0 6.0 Probability of PFS 5.0 4.0 3.0 CI, confidence interval; HR, hazard ratio; M, median; PFS, progression-free survival. 2.0 1.0 Median follow-up: 28.9 mos 4 8 12 16 20 24 28 32 36 40 44 48 52 Mos Since Randomization *As assessed by an Independent Review Committee, Hillmen P, et al. ASH 2013. Abstract 528.

Time to Progression FCR by Response 1.0 0.8 0.6 Proportion 0.4 CR, complete response; FCR, fludarabine/cyclophosphamide/rituximab; nPR, nodular partial response; PR, partial response. Pts 216 32 37 Relapsed 62 12 24 Response CR nCR PR 0.2 12 24 36 48 60 72 84 96 Mos Tam CS, et al. J Clin Oncol. 2007;25:Abstract 7008.

CLL8 Trial: FCR vs FC MRD Levels in Peripheral Blood * * * *P < .0001 100 10-1 10-2 10-3 10-4 FC, fludarabine/cyclophosphamide; FCR, fludarabine/cyclophosphamide/rituximab; MRD, mimimal residual disease FC FCR FC FCR FC FCR FC FCR Baseline Cycle 3 Cycle 6 2 Mos Posttherapy Bottcher S, et al. J Clin Oncol. 2012;30:980-988.

MRD in Peripheral Blood—All Patients 2 Mos Posttreatment: PFS 1.0 Frequency (n = 280) < 10-4 0.8 50% 0.6 36% PFS 0.4 ≥ 10-4 to < 10-2 MRD, mimimal residual disease; PFS, progression-free survival; 14% 0.2 ≥ 10-2 P < .0001 12 24 36 48 ≥ 10-4 to < 10-2 < 10-4 ≥ 10-2 Mos MRD Level Bottcher S, et al. J Clin Oncol. 2012;30:980-988.

MRD in Bone Marrow—All Patients 2 Mos Posttreatment: PFS 1.0 Frequency (n = 193) < 10-2 0.8 88% 0.6 PFS 0.4 MRD, mimimal residual disease; PFS, progression-free survival; ≥ 10-2 0.2 12% P < .0001 10 20 30 40 50 < 10-2 ≥ 10-2 Mos MRD Level Bottcher S, et al. J Clin Oncol. 2012;30:980-988.

MRD in Peripheral Blood 2 Mos Posttreatment: Cumulative Survival 1.0 0.8 0.6 MRD Level < 10-4 ≥ 10-4 to < 10-2 ≥ 10-2 Cumulative Survial 0.4 MRD, mimimal residual disease; OS, overall survival 0.2 6 12 18 24 30 36 42 48 54 60 66 72 78 Mos Bottcher S, et al. J Clin Oncol. 2012;30:980-988.

MRD in Bone Marrow 2 Mos Posttreatment 1.0 0.8 0.6 MRD Level < 10-4 ≥ 10-4 to < 10-2 ≥ 10-2 Cumulative Survial 0.4 MRD, mimimal residual disease; OS, overall survival 0.2 6 12 18 24 30 36 42 48 54 60 66 72 78 Mos Bottcher S, et al. J Clin Oncol. 2012;30:980-988.

Case Study Discussion 1 The patient completes 6 cycles of FCR 3 yrs later ALC 27,000, Hb 11.6 Platelets 141,000 No palpable nodes/spleen 4 yrs later ALC 142,000, Hb 10.8 Platelets 104,000 4 cm cervical and axillary nodes 3 cm spleen FISH: negative

PFS and OS With FCR in Relapsed CLL Progressed or Died 192 223 Median, Mos 46.7 20.9 1.0 Patients 284 284 OS PFS 0.9 0.8 0.7 0.6 Proportion Progression Free or Alive 0.5 0.4 0.3 0.2 0.1 12 24 36 48 60 72 84 96 108 120 Mos Badoux XC, et al. Blood. 2011;117:3016-3024.

BR in Relapsed CLL: EFS 1.0 0.9 0.8 0.7 0.6 Proportion of EFS 0.5 0.4 0.3 0.2 0.1 0.0 6 12 18 24 30 36 42 48 Mos to Event Fischer K, et al. J Clin Oncol. 2011;29:3559-3566.

Duration of Response in R/R or TN CLL Patients Median DOR was not reached for either TN or R/R responders achieving PR or better, after a median follow-up of 28.1 and 23.9 mos, respectively At 30 mos, 95.8% and 69.7% of R/R responders were alive without disease progression 1.0 RR TN 0.8 0.6 Event-Free Probability (%) DOR defined as the number of months from first documented PR with lymphocytosis or better to disease progression or death or date of last adequate disease assessment for patients who achieved PR or better 0.4 + Censored Pts at Risk, n 0.2 98 25 90 24 87 23 8223 67 23 62 23 53 23 39 19 31 14 24 6 10 2 3 0 1 RR TN 3 6 9 12 15 18 21 24 27 30 33 36 39 Mos From First Dose Date Byrd J, et al. ASH. 2012; Abstract 189. FDAWebinar

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