1. 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.

2. About These Slides
Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options (
Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. 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.

5. 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:

6. 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:

7. 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:
FrontlineTherapyCase

8. 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: 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: % CI: 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 Abstract 977.
FrontlineTherapyCase

9. 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 Abstract 435.
FrontlineTherapyCase

10. 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 Abstract 526.

11. 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 Abstract 526.
FrontlineTherapyCase

12. 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 / / / / / /98
Eichhorst B, et al. ASH Abstract 526.
FrontlineTherapyCase

13. 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 Abstract 526.

14. 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 Abstract 526.

15. 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:  

16. 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: (95% CI: ; 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:  

17. 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 Abstract 528.

18. Ofatumumab + Chlorambucil vs Chlorambucil Alone: PFS*
Ofatumumab + chlorambucil mPFS: 22.4 mos HR: 0.57 (95% CI: ; P < .001)
1.0
9.0
8.0
Chlorambucil mPFS: 13.1 mos (95% CI: )
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 Abstract 528.

19. 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
Relapsed
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.

20. 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:

21. 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:

22. 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:

23. 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:

24. 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:

25. 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

26. PFS and OS With FCR in Relapsed CLL
Progressed or Died
Median, Mos
1.0
Patients
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:

27. 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:

28. 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

29. Go Online for More CCO Education in CLL!
ClinicalThought blog posts
Downloadable and CME-certified slidesets
Educational videos
Text modules
Interactive Virtual Presentations
Conference Coverage
CML, chronic myeloid leukemia; TKI, tyrosine kinase inhibitor.
clinicaloptions.com/oncology