1. Integrating Emerging Evidence Into the Management of Patients With Chronic Lymphocytic Leukemia
From a symposium conducted on: Saturday, October 17, :45 AM – 7:45 AM San Francisco, California
This activity is supported by educational grants from AbbVie Inc.; Genentech; and Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc
Image: M. I. Walker/Copyright©2015 Science Source. All Rights Reserved

2. Integrating Emerging Evidence Into the Management of Patients With Chronic Lymphocytic Leukemia
William G. Wierda, MD, PhD The University of Texas MD Anderson Cancer Center Houston, Texas
Andrew D. Zelenetz, MD, PhD Memorial Sloan Kettering Cancer Center Weill-Cornell Medical College New York, New York

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4. Patient Cases and Management Questions
This resource includes patient cases and expert management recommendations for those cases
6 CLL experts were surveyed on October 1, 2015 and asked to provide recommendations for the patient cases based on their practice at that time

5. Additional CLL Experts Surveyed
Jacqueline Barrientos, MD Assistant Professor of Medicine Division of Hematology/Oncology Hofstra North Shore-LIJ School of Medicine Attending Physician Division of Hematology/Oncology North Shore-LIJ Health System Lake Success, New York Jennifer R. Brown, MD, PhD Director, Chronic Lymphocytic Leukemia Center Dana-Farber Cancer Institute Associate Professor of Medicine, Harvard Medical School Boston, Massachusetts
Steven E. Coutre, MD Professor of Medicine Department of Hematology Stanford University School of Medicine Stanford, California
Thomas J. Kipps, MD, PhD Evelyn and Edwin Tasch Chair in Cancer Research
Distinguished Professor
Moores UCSD Cancer Center
University of California, San Diego
La Jolla, California

6. Faculty Disclosures
Jacqueline Barrientos, MD, has disclosed that she has served on advisory boards for AbbVie, Gilead, and Pharmacyclics. Jennifer R. Brown, MD, PhD, has disclosed that she has received consulting fees from Celgene, Genentech/Roche, Gilead Sciences, Infinity, Janssen, Pharmacyclics, ProNai, and Sun BioPharma. Steven E. Coutre, MD, has disclosed that he has received consulting fees from Gilead Sciences and Janssen and funds for research support from AbbVie, Celgene, Gilead Sciences, Janssen, and Pharmacyclics. Thomas J. Kipps, MD, PhD, has disclosed that he has served on a speakers bureau for Gilead Sciences; has received honoraria from AbbVie, Celgene, Gilead Sciences, and Pharmacyclics; has received consulting fees from AbbVie, Celgene, Roche, and Pharmacyclics; and has received funds for research support from AbbVie, Celgene, and Roche.

7. Faculty Disclosures
William G. Wierda, MD, PhD, has disclosed the following: AbbVie: Consulting Fees, Honoraria; Grant/Research Support; Scientific Advisor; Ascerta: Consulting Fees, Honoraria; Grant/Research Support; Scientific Advisor; Celgene Corporation: Consulting Fees, Honoraria; Scientific Advisor; Emergent BioSolutions Inc.: Consulting Fees, Honoraria; Grant/Research Support; Scientific Advisor; Genentech, Inc.: Consulting Fees, Honoraria; Grant/Research Support; Scientific Advisor; Genzyme Corporation: Consulting Fees, Honoraria; Scientific Advisor; Gilead Sciences: Consulting Fees, Honoraria; Grant/Research Support; Scientific Advisor; GlaxoSmithKline: Consulting Fees, Honoraria; Grant/Research Support; Scientific Advisor; Juno Therapeutics: Grant/Research Support; Karyopharm: Consulting Fees, Honoraria; Grant/Research Support; Scientific Advisor; Kite Pharma: Grant/Research Support; Merck & Co., Inc.: Consulting Fees, Honoraria; Scientific Advisor; Novartis Pharmaceuticals Corporation: Consulting Fees, Honoraria; Grant/Research Support; Scientific Advisor; Pharmacyclics: Consulting Fees, Honoraria; Grant/Research Support; Scientific Advisor; Roche Laboratories, Inc.: Consulting Fees, Honoraria; Grant/Research Support; Scientific Advisor; sanofi-aventis U.S.: Consulting Fees, Honoraria; Scientific Advisor.

8. Faculty Disclosures
Andrew D. Zelenetz, MD, PhD, has disclosed the following: Amgen Inc.: Consulting Fees, Honoraria; Boehringer Ingelheim GmbH: Scientific Advisor; Bristol-Myers Squibb Company: Grant/Research Support; Celgene Corporation: Consulting Fees, Honoraria; Gilead Sciences, Inc.: Consulting Fees, Honoraria; Grant/Research Support; GlaxoSmithKline: Consulting Fees, Honoraria; Grant/Research Support; Hospira: Consulting Fees, Honoraria; Medscape: Consulting Fees, Honoraria; Roche Laboratories, Inc.: Consulting Fees, Honoraria; Grant/Research Support.

9. Agenda Case Discussion 1: Managing Otherwise Healthy Patients with CLL
Case Discussion 2: Treatment Considerations for a Frail Patient with CLL
Case Discussion 3: Managing Treatment-Related Symptoms
Case Discussion 4: An Elderly Patient with Relapsed CLL and Clonal Evolution

10. Managing Otherwise Healthy Patients with CLL
William G. Wierda, MD, PhD The University of Texas MD Anderson Cancer Center Houston, Texas

11. Case 1: Diagnosis and Evaluation at Progression
A 63-year-old man was diagnosed with CLL in September 2014
9/2014: Asymptomatic, observed for 1 yr
9/2015:
WBC 123, ANC 1.7, ALC 119
Hgb 10.1, Hct 30.2; Plts 99
Spleen tip 3 cm beneath the left costal margin
Reports “I am okay, it’s just that I am getting older”
ALC, absolute lymphocyte count; ANC, absolute neutrophil count; CLL, chronic lymphocytic leukemia; CT, computed tomography; FISH, fluorescent in situ hybridization; Hct, hematocrit; Hgb, hemoglobin; Plts, platelets.

12. Case 1: Diagnosis and Evaluation at Progression
When considering your current practice, which of the following assessments would you use to guide your choice of therapy?
β2-microglobulin
CT chest, abdomen, and pelvis
IgHV mutation testing
FISH for del(11q), del(13q), trisomy 12, del(17p)
Sequencing to detect TP53 mutations
Unsure
ALC, absolute lymphocyte count; ANC, absolute neutrophil count; CLL, chronic lymphocytic leukemia; CT, computed tomography; FISH, fluorescent in situ hybridization; Hct, hematocrit; Hgb, hemoglobin; Plts, platelets.

13. CLL Patient Populations and “ 2015 Standards of Care”
Untreated, high-risk - watch and wait 
First-line therapy (consider age and FISH)
Fit CIT-eligible – FCR
Elderly – chlorambucil + CD20 mAb
Del(17p) - ibrutinib
Second-line treatments for active disease 
BTK inhibitor (ibrutinib)
PI3K inhibitor (idelalisib) + rituximab
Richter’s transformation – intensive CIT, SCT
CIT, chemoimmunotherapy; FCR, fludarabine, cyclophosphamide, rituximab; FISH, fluorescent in situ hybridization; mAb, monoclonal antibody; SCT, stem cell transplantation.

14. Case 1 Continued: Recommendation for Therapy
CLL FISH panel: sole del(11q) abnormality
IgHV mutation status: germline 4-34 (unmutated)
CT scan: confirmed splenomegaly and showed diffuse adenopathy including bilateral axillary, subcarinal, retroperitoneal, and right external iliac nodes, as well as an 8-cm mesenteric mass
CLL, chronic lymphocytic leukemia; CT, computed tomography; FISH, fluorescent in situ hybridization.

15. Case 1 Continued: Recommendation for Therapy
In your current practice, which of the following would you recommend for this patient?
Continued observation
Fludarabine, cyclophosphamide, and rituximab
Bendamustine and rituximab
Obinutuzumab and chlorambucil
Ibrutinib
Unsure
CLL, chronic lymphocytic leukemia; CT, computed tomography; FISH, fluorescent in situ hybridization.

16. Expert Recommendations for Therapy
Answer
Wierda
Zelenetz
Barrientos
Brown
Coutre
Kipps
Observation
FCR X BR
Obinutuzumab/ chlorambucil
Ibrutinib
CLL, chronic lymphocytic leukemia; CT, computed tomography; FISH, fluorescent in situ hybridization.

17. FCR Regimen for CLL Days of Therapy Drug Dose Cycle 1 Cycles 2-6
Rituximab
375 mg/m2 1
500 mg/m2
Fludarabine
25 mg/m2
2-4
1-3
Cyclophosphamide
250 mg/m2
Allopurinol 300 mg/day
Rituximab PI.
Keating et al. J Clin Oncol Jun 20;23(18): Epub 2005 Mar 14

18. CLL8 Trial: OS with Frontline FC vs FCR
Rationale
FCR 69.4% alive
Median not reached
FC 62.3% alive
Median 86 months
HR 0.68,
95% CI
p=0.001
FC, fludarabine/cyclophosphamide; FCR, fludarabine/cyclophosphamide/rituximab; OS, overall survival.
Fischer K, et al. ASH Abstract 435.
2014CCOASH

19. FCR300 in CLL: PFS and OS Proportion Surviving Months 1.0 0.8 0.9 0.6
0.7
0.4
0.5
0.2
0.3
0.1
0.0
Median follow up time
All yrs
Alive yrs
Proportion Surviving
CLL, chronic lymphocytic leukemia; OS, overall survival, PFS, progression-free survival.
Events Total Median
yrs
yrs 12 24 36 48 60 72 84
156 96
108
120
132
144
168
Months
Keating, et al. iwCLL Abstract MDACC Data, IWCLL 2013, Cologne

20. FCR300 in CLL: PFS by IgHV Mutation Status
1.0
Group Events Total
0.9
IGHV-M
0.8
IGHV-UM
0.7
Unknown
0.6
Proportion Progression-free
0.5
0.4
0.3
P < .0001
CLL, chronic lymphocytic leukemia; M, mutated; PFS, progression-free survival; UM, unmutated.
0.2
0.1
0.0 12 24 36 48 60 72 84
156 96
108
120
132
144
168
Months
Keating, et al. iwCLL Abstract MDACC Data, IWCLL 2013, Cologne

21. CLL10 (Phase III): Final Analysis of FCR vs BR in Pts With Advanced CLL
Randomization
Patients with untreated, active CLL without del(17p) and good physical fitness (CIRS ≤ 6, CrCl ≥ 70 ml/min)
FCR
Fludarabine 25 mg/m² i.v., days 1-3
Cyclophosphamide 250 mg/m², days 1-3,
Rituximab 375 mg/ m2i.v.day 0, cycle 1
Rituximab 500 mg/m² i.v. day 1, cycle 2-6 BR
Bendamustine 90mg/m² day 1-2
Rituximab 375 mg/m² day 0, cycle 1
Rituximab 500 mg/m² day 1, cycle 2-6
BR, bendamustine, rituximab; CIRS, Cumulative Illness Rating Scale; CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab; IV, intravenously; PFS, progression-free survival.
Non-Inferiority of BR in comparison to FCR for PFS: HR (λ BR/FCR) less than 1.388
Eichhorst B, et al. ASH Abstract 19

22. FCR vs BR in Pts With Advanced CLL (CLL10): PFS
Response
FCR
n=282 BR
n=279
P value
CR (CR + CRi) CR
CRi
39.7%
35.1%
4.6 %
30.8%
30.4%
0.4%
0.034 PR
55.7
64.9
ORR
95.4
95.7
1.0
BR, bendamustine, rituximab; CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab; ITT, intent to treat; NR, not reached; PFS, progression-free survival.
OS at 36 months:
FCR 90.6%
BR 92.2%
P = 0.897
Median PFS
FCR months
BR months
P < 0.001
HR = (> 1.388)
Eichhorst B, et al. ASH Abstract 19
No difference in overall survival

23. CLL10 Study: FCR VS BR in Front-line PFS by IGHV Mutation Status
Unmutated IGHV: P = 0.017
FCR months BR months
Mutated IGHV: P = 0.153
FCR not reached BR months
Eichhorst B, et al. ASH Abstract 19

24. CLL10 Study: FCR VS BR in Front-line PFS by Age
Patients ≤ 65 years: P < 0.001
FCR months BR months
Patients > 65 years: P = 0.170
FCR not reached BR months
Eichhorst B, et al. ASH Abstract 19

25. FCR vs BR in Pts With Advanced CLL (CLL10): Infections
CTC Grade 3/4 Adverse Event, %
FCR BR
P Value
All Infections
39.1
26.8
< .001
Infections during therapy only
22.6
17.3
.10
Infections during first 5 months after therapy
11.8
3.6
All infections
in patients ≤ 65 years
35.2
27.5
.10
in patients > 65 years
47.7
20.6
< .001
BR, bendamustine, rituximab; CLL, chronic lymphocytic leukemia; CTC, common toxicity criteria; FCR, fludarabine, cyclophosphamide, rituximab.
Eichhorst B, et al. ASH Abstract 19

26. CLL10 STUDY FCR VS BR IN FRONTLINE: Conclusions
Final analysis shows inferiority of BR versus FCR with regard to PFS and CRR.
BR is associated with lower rates of neutropenia and severe infections in elderly patients.
FCR remains standard therapy in fit patients.
BR may be considered in fit, but elderly patients as alternative.

27. Case 1 Continued: Post-remission Therapy
The patient was treated with FCR for 6 cycles. During treatment the peripheral palpable adenopathy and splenomegaly rapidly resolved.
Post-treatment evaluation demonstrated a “good clinical response”
However, flow cytometry detected a kappa-restricted monoclonal B-cell population that was CD10-, CD19+, CD20 dim, CD23+, CD5+
Comprised 0.5% of the cells in the lymphocyte gate.

28. Case 1 Continued: Post-remission Therapy
In your current practice, which of the following would you recommend for this patient?
Observation
Maintenance rituximab
Maintenance ofatumumab
Bendamustine and rituximab
Allogeneic stem cell transplantation
Unsure

29. Expert Recommendations
Answer
Wierda
Zelenetz
Barrientos
Brown
Coutre
Kipps
Observation X
Maintenance rituximab
Maintenance ofatumumab
Bendamustine and rituximab
Allo-SCT
CLL, chronic lymphocytic leukemia; CT, computed tomography; FISH, fluorescent in situ hybridization.

30. PROLONG: Ofatumumab Maintenance vs Obs in Relapsed CLL- Design
300 mg - Week mg - Week 2, then every 8 weeks for 2 yrs*
(n = 238)
Relapsed CLL in 2nd/3rd remission (CR/PR) and within 3 months after response assessment after induction
(N = 474)
*Aimed at prolonged ofatumumab
plasma concentrations > 10 g/mL
OBSERVATION
(n = 236)
CLL, chronic lymphocytic leukemia; CR, complete response; PR, partial response.
F/U every 3 months for 5 yrs
van Oers MH, et al. Lancet Oncol. 2015;16:

31. PROLONG: Ofatumumab Maintenance vs Obs in Relapsed CLL- Adverse Events
Adverse Events, n (%)
OFA (n = 237)
Obs (n = 237)
AEs, any
205 (86)
170 (72)*
AEs related to study treatment
142 (60) NA
AEs leading to withdrawal from study
AEs ≥ Grade 3
108 (46)
67 (28)
Neutropenia
56 (24)
23 (10)*
Infections
30 (13)
20 (8) NS
Thrombocytopenia
4 (2)
8 (3)
Infusion-related reactions
3 (1)
Death
2 (<1)
5 (2)
Infections/sepsis
1 (<1)
Progressive disease
Secondary malignancy
Other
AE, adverse event; CLL, chronic lymphocytic leukemia; NA, not available; NS, not significant; Obs, observation; OFA, ofatumumab.
*P < (Stratified Cochran-Mantel-Haenszel)
van Oers MH, et al. ASH Abstract 21.

32. PROLONG: Ofatumumab Maintenance vs Obs in Relapsed CLL- PFS
OFA mPFS: 29.4 months
(95% CI: )
HR 0.50, P < .0001*
obs mPFS: 15.2 months
(95% CI: )
CLL, chronic lymphocytic leukemia; mPFS, median progression-free survival; Obs, observation; OFA, ofatumumab; PFS, progression-free survival.
Median follow-up: 19.1 months
*Stratified log-rank test
van Oers MH, et al. Lancet Oncol. 2015;16:

33. Ofatumumab Maintenance vs Obs in Relapsed CLL (PROLONG): Overall Survival
Median OS not reached for either arm
HR:0.85; P = .4877*
CLL, chronic lymphocytic leukemia; Obs, observation; OS, overall survival.
*Stratified log-rank test
van Oers MH, et al. Lancet Oncol. 2015;16:

34. Phase III Mabtenance Trial (CLL AGMT 8a): R Maint After Chemoimmunotherapy Induction
International, open label trial
N = 263 (1st and 2nd line)
Recruitment: Sep – Dec. 2013
Rituximab-containing Chemoimmunotherapy
RANDOMIZATION
8 x rituximab 375 mg/m²
every 3 months for 24 months
Observation
every 3 months for 24 months
CZ: 102
SL: 35
RO: 3
A: 105
CLL, chronic lymphocytic leukemia; Maint, maintenance; MRD, minimal residual disease; PB, peripheral blood; R, rituximab.
BUL: 18
Follow-up for 24 months
MRD (PB) every 3 months
(done centrally at Salzburg and Brno; method [PBL] according to Rawstron1)
Participating Centers: 30
1Rawstron A, et al. Leukemia. 2007;21:
Greil R, et al. ASH Abstract 20.

35. R Maint After Chemoimmunotherapy Induction in CLL (Mabtenance): PFS
PFS at 17.3 mo
Rituximab: 85.1%
Observation: 75.5%
P = .007
1.0
0.8
0.6
0.4
0.2
0.0
250
500
750
1000
1250
1500 days
Rituximab
Control
CLL, chronic lymphocytic leukemia; Maint, maintenance; PFS, progression-free survivval; R, rituximab.
Median observation time 525 days (17.3m)
Greil R, et al. ASH Abstract 20.

36. Anti-CD20 Maintenance in CLL
Two trials show efficacy of ofatumumab and rituximab maintenance in extending PFS in relapsed CLL
PROLONG (ofatumumab) was restricted to relapsed patients
Mabtenance had some first line patients
No unexpected toxicity with maintenance
Increased incidence of neutropenia and infections
Follow up is short for impact of hypogammaglobulinemia
No survival advantage with maintenance
Greil et al., ASH 2014, Abstract 20; van Oers et al., ASH 2014, Abstract 21

37. Treatment Considerations for Elderly or Frail Patients with CLL
Andrew D. Zelenetz, MD, PhD Memorial Sloan Kettering Cancer Center Weill-Cornell Medical College New York, New York

38. Case 2: Approaching the “Slow Go” Patient
A 78-year-old woman with multiple medical problems presents for evaluation of progressive fatigue and weight loss of 4 kg.
PMH remarkable for chronic degenerative back disease necessitating use of a walker
Osteoporosis
CRI (CrCl: 32 mL/min)
Hypertension.
She lives alone and can take care of her ADLs with the aid of a companion.
Diagnosed with CLL
CBC: WBC 43.2, ANC 1.3 , ALC 39.7 ;
Hgb 8.9, HCT 26.4; PLTS 89.
Exam reveals
Thin woman, height 155 cm, weight 43.6 kg with small volume axillary and inguinal adenopathy.
The spleen is palpable 4 cm beneath the left costal margin.
Evaluation reveals IgHV germline mutation, FISH reveals trisomy 12.

39. Case 2: Approaching the “Slow Go” Patient
In your current practice, which of the following treatment approaches would you recommend?
Hospice
Chlorambucil
Ibrutinib
Bendamustine and rituximab
Idelalisib and rituximab
Obinutuzumab and chlorambucil
Rituximab and chlorambucil
Unsure

40. Expert Recommendations
Answer
Wierda
Zelenetz
Barrientos
Brown
Coutre
Kipps
Hospice
Chlorambucil
Ibrutinib X
Bendamustine/rituximab
Idelalisib/ rituximab
Obinutuzumab/ chlorambucil
Rituximab/ chlorambucil
CLL, chronic lymphocytic leukemia; CT, computed tomography; FISH, fluorescent in situ hybridization.

41. Approaching the Patient with CLL: Cumulative Index Rating Scale [CIRS]
Frailty
NO GO: supportive therapy
CIRS > 12
SLOW GO: reduced-intensity treatment
CIRS 7-12
GO GO: standard treatment
CIRS 0-6
Physically fit
No significant comorbidities [CIRS 3/4]
Excellent renal function
Regardless of age
Frailty: multisystem reduction in physiological capacity
Miller MD, et al. Psychiatry Res. 1992;41: Online tool: eforms.moffitt.org/cirsgScore.aspx

42. Approaching the Slow Go patient
Multiple chronic issues or
One or more significant comorbidities
May have impaired renal function
Increases toxicity of fludarabine-based regimens
Chlorambucil has been a straw man in many trials for this group of patients
FR has been used to reduce hematologic toxicity
CLL11 and COMPLEMENT studies evaluated anti-CD20 antibodies combined with chlorambucil

43. Comparison of FDA-approved Anti-CD20 Antibodies
Rituximab
Ofatumumab
Obinutuzumab
Type I II
Apoptosis +
-/+ ++
ADCC
+/-
+++
Complement fixation
Obinutuzumab
binding site
Rituximab
Cheson BD, et al. J Clin Oncol. 2010;28: Niederfellner G, et al. Blood. 2011;118:

44. GCLLSG CLL11 Untreated CLL Elderly/Comorbid Pts[1] Chlorambucil
Rituximab-Chlorambucil
Obinutuzumab-Chlorambucil
Obinutuzumab
Novel type II anti-CD20 antibody
Increased direct cell killing and ADCC
Phase 1 study in 13 relapsed/refractory CLL pts[2]
ORR 62%, with 69% grade 3-4 ANC
Very rapid B cell depletion
Safety run-in to CLL11 enrolled 6 pts, did not meet toxicity criteria for stopping
CLL11 opened to enrollment in April 2010
1. Goede V, et al. N Engl J Med. 2014;370: Cartron G, et al. Blood. 2014;124:  

45. Obinutuzumab/Chlorambucil vs Rituximab/Chlorambucil in CLL: Adverse Events
Goede V, et al. N Engl J Med. 2014;370:

46. Obinutuzumab/Chlorambucil vs Rituximab/Chlorambucil in CLL: Updated PFS and OS Results
Goede V, et al. Leukemia. 2015;29:

47. COMPLEMENT 1: Chlorambucil ± Ofatumumab In Elderly or Unfit CLL Patients, Study Schema
Key eligibility criteria
Untreated CLL patients with active disease (N = 447)
Inappropriate for F-based therapy
ECOG ≤ 2
Ofatumumab + Chlorambucil
(O+CHL; (n = 221)
Primary: PFS by IRC
Secondary: ORR*, OS, safety
1:1
CHL alone (n = 226)
Chlorambucil: 10 mg/m2 PO d1-7 q28d; maximum 12 cycles
Ofatumumab: 300 mg IV d1 cycle 1, 1000 mg d8 cycle 1; 1000 mg d1 cycle 2-12; q28d
Phase III comparison of frontline chlorambucil alone vs chlorambucil + ofatumumab
*Response measured per IWCLL 2008 criteria.
Hillmen P, et al. Lancet. 2015;385:

48. Chlorambucil ± Ofatumumab In Elderly or Unfit CLL Patients: Efficacy
Response
CHL
(n = 226)
O+CHL
(n = 221)
ORR
69%
82% CR 1%
14% PR
67%
68% SD
23%
12% PD 4% 2%
Hillmen P, et al. ASH Abstract 528. Hillmen P, et al. Lancet. 2015;385:

49. Chlorambucil ± Ofatumumab In Elderly or Unfit CLL Patients: PFS, OS, and Forest Plot for PFS
Hillmen P, et al. Lancet. 2015;385:

50. Chlorambucil ± Ofatumumab In Elderly or Unfit CLL Patients: Safety
AEs*
CHL
(n = 227)
O+CHL
(n = 217)
Any AE
87%
94%
Related to study treatment
65%
84%
Leading to treatment withdrawal
13%
Grade ≥ 3 AEs
43%
50%
Infusion-related reactions
N/A
10%
Neutropenia
14%
26%
Thrombocytopenia 5%
Anemia
Infections
12% 9%
Deaths (including due to PD 3% 4%
Patients received an median of 6 cycles in each arm
Dose reductions of chlorambucil occurred in 19% of patients in each arm
*Includes only patients who received treatment.
Hillmen P, et al. Lancet. 2015;385:

51. Chlorambucil ± Ofatumumab In Elderly or Unfit CLL Patients: Summary and Conclusions
Ofa+CHL showed improved efficacy over CHL including
71% improvement in PFS (22.4 vs 13.1 months)
Extended treatment-free period of 15 months (TTNT: 39.8 vs 24.7 months; P < 0.001)
Increased response rates with combination Ofa+CHL vs CHL alone
82% vs 69% ORR (P < 0.001)
14% vs 1% CR
Improved and durable MRD negativity: 38% vs 0% in CR patients
Improved efficacy irrespective of age or fitness
Elevated grade 3/4 AEs were shown with Ofa-CHL, including mild infusion-related reactions and neutropenia, but was not reflected in withdrawals or infections
First-line Ofa+CHL demonstrated clinical improvements over CHL with a manageable side effect profile in CLL patients unfit for fludarabine-based therapy
No overall survival advantage to date
Hillmen P, et al. Lancet. 2015;385:

52. Additional options Bendamustine-rituximab
This is a very frail patient, the risk of cytopenias and increased nausea and vomiting make this a less attractive option
Lenalidomide
Phase II data demonstrated an overall response rate of 65% with 6% CR
However, phase III was stopped secondary to possible increase in second cancers
Ibrutinib
Phase II data suggest excellent results but follow up is short
Phase III vs chlorambucil: this is a very weak comparator, and therapy is continuous
Rituximab-Idelalisib
Phase II data with excellent benefit
High rate of toxicity in the treatment naïve patient

53. Case 2 Continued: Management at Relapse
The patient was treated with obinutuzumab and chlorambucil and tolerated 4 cycles of treatment before she developed prolonged cytopenias
On exam there is no adenopathy or splenomegaly. The CBC reveals WBC 2.3, ANC 1.7, ALC 0.1; Hgb 9.2, HCT 27.4; PLTS 100
Peripheral blood flow shows a persistent CLL clone in about 5% of her lymphocytes and you choose to observe
Initially in follow up the cytopenias gradually resolve. 6 months after therapy: WBC 5.1, ANC 2.5, ALC 2.1; Hgb 10.9, HCT 32.9; PLTS 132
However, over the next 12 months the patient has a rising ALC and develops progressive anemia and thrombocytopenia
The current CBC is WBC 32.1, ANC 1.3, ALC 29.1; Hgb 9.1, HCT 27.4; PLTS 97. Repeat FISH demonstrates only trisomy (12). She develops atrial fibrillation and is started on apixaban.

54. Case 2: Management at Relapse
Which of the following would you recommend for this patient?
Continued observation
Hospice
Ibrutinib
Idelalisib with rituximab
Unsure

55. Expert Recommendations
Answer
Wierda
Zelenetz
Barrientos
Brown
Coutre
Kipps
Continued observation
Hospice
Ibrutinib X
Idelalisib with rituximab
CLL, chronic lymphocytic leukemia; CT, computed tomography; FISH, fluorescent in situ hybridization.

56. RESONATE Phase 3 Study Design
Oral ibrutinib 420 mg once daily until PD or unacceptable toxicity
n=195
Enrollment Dates:
June 2012 – April 2013
Patients with previously treated CLL/SLL
1:1 R
ANDOM I Z E
IV ofatumumab initial dose of 300 mg followed by 2000 mg × 11 doses over 24 weeks
n=196
Crossover to ibrutinib 420 mg once daily after IRC-confirmed PD (n=57)
(August 2013)
Stratification according to:
Disease refractory to purine analog chemoimmunotherapy (no response or relapsed within 12 months)
Presence or absence of 17p13.1 (17p del)
At time of interim analysis, median time on study was 9.4 months
Protocol amended for crossover with support of Data Monitoring Committee and discussion with health authorities.
PD, progressive disease. 
Byrd JC, et al. N Engl J Med. 2014;371:

57. RESONATE: Responses and Outcomes
Byrd JC, et al. N Engl J Med. 2014;371:

58. Ibrutinib: Toxicities
Hemorrhage
Fatal bleeding events have occurred; Grade 3 or higher bleeding events 6% (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage); bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with ibrutinib.
Hold for 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.
Cytopenias, Grade 3/4
Neutropenia (range, 19 to 29%)
Thrombocytopenia (range, 5 to 17%)
Anemia (range, 0 to 9%)
Atrial Fibrillation 6-9%
Increased in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation.
Tumor Lysis Syndrome
Tumor lysis syndrome has been reported, monitor closely particularly in patients with high tumor burden.
ADVERSE REACTIONS (any grade)
Most common adverse reactions (≥25%) in patients with B-cell malignancies were: thrombocytopenia (43-57%), neutropenia (44-51%), diarrhea (37-51%), anemia (13-41%), fatigue (21-41%), musculoskeletal pain (28-37%), bruising (12-30%), nausea (21-31%), URI (16-34%), and rash (22-25%).
Ibrutinib prescribing information

59. R+Idelalisib vs R+Placebo: Second Interim Analysis with Crossover
Population:
Relapsed CLL warranting treatment (iwCLL); progression < 24 mo since last treatment
Primary Study 116
Extension Study 117
Double-Blind Initial Therapy
Double-Blind Continuous Therapy
Blinded Dose
Open-Label
Arm A N=110
Rituximab (6 mo)
Idelalisib (150 mg BID)
Idelalisib (300 mg BID)
Disease Progression
Screen
Placebo (BID)
Idelalisib (150 mg BID)
Arm B N=110
Rituximab (6 mo)
BID, twice daily; CLL, chronic lymphocytic leukemia; DMC, data monitoring committee; IA, interim analysis; iwCLL, International Workshop on Chronic Lymphocytic Leukemia; mo, months.
Randomization/ Stratification
Blinded, Independent Review
Interim Analyses and Unblinding
Independent Review
Median Follow-up, months
IDELA + R
PBO + R
1st Interim Analysis 4
DMC halted trial (Furman NEJM 2014) 50% events
2nd Interim Analysis 6 5
Blind ended (Coutre ASCO 2014) 63% events
Arm A continues (amendment to be all 150mg)
Arm B crosses over
Update 13 11
PFS, OS by subgroup analysis
Sharman J, et al. ASH Abstract 330.

60. R+Idelalisib v R+Placebo: PFS including crossover
All Patients
Placebo + R includes those patients who received open-label idelalisib after unblinding without prior progression (n=42).
Idelalisib + R (N=110)
Placebo + R (N=110)
HR, hazard ratio; CI, confidence interval; IDELA, idelalisib; PBO, placebo; R, rituximab.
N at risk
IDELA + R
110
102 95 92 83 64 43 26 19 12 7 1
PBO + R 86 66 58 51 33 15 5 -
Median PFS (95% CI)
HR (95% CI)
p-value
IDELA + R
19.4 mo (16.6, ‒ )
0.25 (0.16, 0.39)
<0.0001
PBO + R
7.3 mo (5.5, 8.5)
Sharman J, et al. ASH Abstract 330.

61. Overall Survival, Including Extension Study
Overall Survival, Including Extension Study* Idelalisib + R vs Placebo + R ➞ Idelalisib
All Patients
IGHV Unmutated
Idelalisib + R (N=110)
Placebo + R (N=110)
Idelalisib + R (n=91)
Placebo + R (n=93)
N at risk
IDELA + R
110
107
101
100 93 85 60 41 30 23 13 7 3
PBO + R 99 90 84 66 42 27 20 8 4 1
CI, confidence interval; HR, hazard ratio; IDELA, idelalisib; OS, overall survival; PBO, placebo; R, rituximab. 91 88 82 81 75 70 48 33 25 19 10 6 2 93 83 79 77 72 55 35 22 15 3
Median OS (95% CI)
HR (95% CI)
p-value
IDELA + R
NR ( ‒, ‒ )
0.34 (0.19, 0.6)
0.0001
PBO + R
20.8 mo (14.8, ‒ )
Median OS (95% CI)
HR (95% CI)
p-value
NR (19.0, ‒ )
0.35 (0.19, 0.6)
0.0003
18.1 mo (14.8, ‒ )
*As randomized, including cross-over
Sharman J, et al. ASH Abstract 330.

62. Adverse Events in ≥ 15% of Patients Idelalisib + R vs Placebo + R → Idelalisib
IDELA + R (N=110)
PBO + R → IDELA (N=108)
Any Grade, %
Grade ≥3, %
AE by Preferred Term
2nd IA
Update
Any AE 96 98 64 80
100 52 78
Pyrexia 35 44 3 6 17 32 1
Diarrhea/colitis 21 42 16 ̶ 13
Fatigue 26 36 5 28 43
Cough 34 2
Nausea 31
Chills 22
Infusion reaction 19 20 30 4
Constipation 11
Decreased appetite 12 10
Pneumonia 18 8 9
Dyspnea 25
Rash
Vomiting
Upper respiratory infection 7 15 24
Edema, peripheral
Night sweats 14
Asthenia
Abdominal pain
AE, adverse event; R, rituximab.
Sharman J, et al. ASH Abstract 330.

63. Select Lab Abnormalities: Idelalisib + R vs Placebo + R → Idelalisib
Idelalisib + R (N=110)
Placebo + R → Idelalisib (N=108)
Any Grade, %
Grade ≥3, %
2nd IA
Update
ALT/AST elevation 40 49 8 10 20 53 1 6
Neutropenia 60 66 37 41 51 68 27 43
Anemia 29 33 7 32 50 17 24
Thrombocytopenia 19 11 14 18
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CLL, chronic lymphocytic leukemia; OS, overall survival; R, rituximab.
Sharman J, et al. ASH Abstract 330.

64. Conclusions
Phase 3 demonstrates comparable efficacy of idelalisib + rituximab in the presence or absence of high-risk genomic alterations
OS is higher for patients on idelalisib + rituximab despite cross-over in extension design
Idelalisib + rituximab has an acceptable safety profile in patients with relapsed/refractory CLL
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CLL, chronic lymphocytic leukemia; OS, overall survival; R, rituximab.
Sharman J, et al. ASH Abstract 330.

65. Case 2: Comments on Relapse Management
Continued observation
The patient meets iwCLL criteria for treatment
Hospice
Reasonable treatment options with acceptable toxicity
Ibrutinib
The pre-existing atrial fibrillation and anti-coagulation make this less desirable
Idelalisib with rituximab
This would be my choice given the comorbid conditions
Clinical trial with venetoclax
With excellent non-trial options available and the risk of tumor lysis, I would not offer this frail patient a clinical trial

66. Case 2 Continued: Management of Complications
You choose to treat with rituximab and idelalisib
You closely monitor the AST and ALT
The AST rises to 112 (ULN 37) and ALT to 154 (ULN 37).

67. Case 2 Continued: Management of Complications
What is your recommendation?
Hold idelalisib until AST/ALT < 37, restart at full dose 150 mg orally twice daily
Hold idelalisib until AST/ALT < 37, restart at 100 mg orally twice daily
Reduce dose of idelalisib to 100 mg orally twice daily
Continue full-dose idelalisib, continue to monitor AST/ALT

68. Expert Recommendations
Answer
Wierda
Zelenetz
Barrientos
Brown
Coutre
Kipps
Hold idelalisib until AST/ALT < 37, restart at full dose 150 mg oral twice daily X
Hold idelalisib until AST/ALT < 37, restart at 100 mg oral twice daily
Reduce dose of idelalisib to 100 mg oral twice daily
Continue full dose idelalisib, continue to monitor AST/ALT
CLL, chronic lymphocytic leukemia; CT, computed tomography; FISH, fluorescent in situ hybridization.

69. Expert panel opinion on managing idelalisib adverse events
Recently e-published in Leukemia & Lymphoma
Reports consensus adverse event management recommendations developed by an expert panel of hematologists and a gastroenterologist
Available as a free open-access download
Coutre S, et al. Leuk Lymphoma. 2015;May 19:1-8  [Epub ahead of print].

70. Diarrhea and Colitis

71. Characteristics of Diarrhea in Patients Taking Idelalisib
Two types of diarrhea were observed in idelalisib clinical trials
Generally occurs within first 8 weeks
Typically mild or moderate (grade 1/2)
Often responsive to common antidiarrheal agents
Self-limiting diarrhea
Tends to occur relatively late
Responds poorly to antidiarrheal or empiric antimicrobial therapy
Considered most likely to be idelalisib related
Severe diarrhea
Severity of Diarrhea
Median Onset (range), months
Any grade
1.9 ( )
Grade 1/2
1.5 ( )
Grade 3/4
7.1 ( )
Coutre S, et al. Leuk Lymphoma. 2015;May 19:1-8  [Epub ahead of print].

72. Budesonide Dosing and Administration
Mean time to resolution of diarrhea with budesonide was 12.1 days vs approximately 1 month with idelalisib interruption alone
Budesonide may speed resolution of diarrhea
The recommended dose is 9 mg once daily (3 × 3-mg capsules), per the package insert
Budesonide dosing
Duration of budesonide treatment should be based on individual clinical response
Continue budesonide until complete resolution of diarrhea
Budesonide should not be used for chronic suppression of symptoms associated with ongoing use of idelalisib
Treatment should be individualized based on a patient’s age, comorbidities, and social/family support
Budesonide administration for managing diarrhea
Coutre S, et al. Leuk Lymphoma. 2015;May 19:1-8  [Epub ahead of print].

73. Transaminase Elevations

74. Characteristics of Transaminitis in Patients Taking Idelalisib
Elevations in ALT or AST > 5 × ULN have been observed with idelalisib treatment
Usually occur within the first 12 weeks of idelalisib treatment
Most elevations were reversible with idelalisib dose interruption
74% of patients with ALT or AST elevations who had treatment interruption were able to resume idelalisib treatment at a lower dose without recurrence
Coutre S, et al. Leuk Lymphoma. 2015;May 19:1-8  [Epub ahead of print].

75. Monitoring and Management of Transaminase Elevations
Monitoring for ALT, AST, and Total Bilirubin Elevations
First 3 Months
After 3 Months
If > 3 × ULN
Monitor in all patients every 2 weeks
Monitor every 4 weeks for the next 3 months and every 1-3 months thereafter
Monitor weekly until resolved
Avoid administering other hepatotoxic drugs concurrently with idelalisib
Idelalisib treatment should be withheld for grade 3/4 transaminase elevations (ALT/AST > 5 × ULN)
Monitor weekly until resolved
Once transaminase elevations have resolved (ALT/AST ≤ 1 × ULN), resume idelalisib at 100 mg BID and monitor as clinically indicated
Permanently discontinue idelalisib if ALT/AST > 20 × ULN
Management of ALT/AST Elevations
Coutre S, et al. Leuk Lymphoma. 2015;May 19:1-8  [Epub ahead of print].

76. Pneumonitis

77. Characteristics of Pneumonitis in Patients Taking Idelalisib
There are no data on the MOA of pneumonitis with idelalisib, although it is consistent with the reports of pneumonitis seen with mTOR inhibitors
Any patient taking idelalisib who presents with pulmonary symptoms (cough, dyspnea, hypoxia, interstitial infiltrates, or > 5% decline in oxygen saturation) should be evaluated for pneumonitis
If pneumonitis is suspected, idelalisib treatment should be interrupted until the cause is determined
Evaluations should be performed for infectious etiologies of pneumonitis, including testing for Pneumocystis jirovecii
If pneumonitis is symptomatic (any severity), idelalisib treatment should be discontinued
In clinical trials, some patients were treated with corticosteroids in addition to continuing antibiotics if pneumonitis did not improve
Coutre S, et al. Leuk Lymphoma. 2015;May 19:1-8  [Epub ahead of print].

78. Summary Diarrhea occurs in two forms: self-limiting and severe
Self-limiting diarrhea usually has an early onset and responds to common antidiarrheal agents
Severe diarrhea responds poorly to anti-motility agents, but appears to be responsive to budesonide and/or systemic corticosteroids
ALT/AST elevations are generally reversible with idelalisib dose interruptions
74% of patients were able to be retreated with idelalisib without recurrence
Any patient taking idelalisib who presents with pulmonary symptoms should be evaluated for pneumonitis
Discontinue idelalisib with any severity of symptomatic pneumonitis
Some patients were treated with discontinuation of corticosteroids in addition to continuing antibiotics if pneumonitis did not improve
Coutre S, et al. Leuk Lymphoma. 2015;May 19:1-8  [Epub ahead of print].

79. Case 3: Clonal evolution
74-year-old woman presents for a second opinion for management of recurrent CLL. She is relatively fit and is independent in her ADLs
She was originally diagnosed at age 62 with Rai stage 0 disease
She was monitored for 5 years. She developed diffuse adenopathy and has a lymphocyte doubling time of 5 months
IGHV was mutated and FISH revealed del(13q)
She was treated with bendamustine and rituximab x 6 with an excellent clinical response
There was evidence of recurrent lymphocytosis after 24 months. She was treated with fludarabine and rituximab for 4 cycles. There was a good response and the patient asked to stop treatment
Very shortly after the completion of therapy the patient had a rapidly rising ALC
She was offered treatment with obinutuzumab and chlorambucil and wants a second opinion. You repeat the FISH which now shows del(13q) and del(17p).

80. Case 3: Clonal evolution
If this patient came to you for a second opinion, what would you recommend?
Obinutuzumab and chlorambucil
Repeat bendamustine and rituximab
Start ibrutinib
Start idelalisib + rituximab
Start lenalidomide + rituximab
Clinical trial with venetoclax
Unsure

81. Expert Recommendations
Answer
Wierda
Zelenetz
Barrientos
Brown
Coutre
Kipps
Obinutuzumab/chlorambucil
Bendamustine and rituximab
Ibrutinib X
Idelalisib/ rituximab
Lenalidomide/ rituximab
Clinical trial
CLL, chronic lymphocytic leukemia; CT, computed tomography; FISH, fluorescent in situ hybridization.

82. PCYC-1117 (RESONATE-17) Study Design
Key eligibility criteria
CLL/SLL
Documentation of del17p13.1 in peripheral blood by FISH analysis*
R/R disease after 1-4 prior lines of therapy
ECOG PS 0-1
Measurable nodal disease
Single-agent ibrutinib in del17p CLL/SLL
Ibrutinib 420 mg PO daily
until unacceptable toxicity or disease progression
(N = 144)
Primary analysis
12 months after last patient enrolled
*Cut-off for del17p was >7% positive cells.
Phase 2, open-label, single-arm, multicenter, international study
Primary endpoint: ORR as evaluated by IRC (2008 IWCLL criteria)1,2
Secondary endpoints: DOR, safety, tolerability
Exploratory endpoints: PFS, OS
1. Hallek et al. Blood. 2008;111: ; 2. Hallek et al, Blood. 2012; e-letter, June 04, 2012
O’Brien S, et al. ASH Abstract 327.

83. RESONATE-17: Overall Response - Investigator and IRC Assessment
ibrutinib
(N=144)
Investigator Assessment CR
CRi
PR-L PR
60%
ibrutinib (N=144)
PR-L PR
IRC Assessment
65%
Percent of Responders
Median follow-up: 11.5 months
Best response (ORR+PR-L) by IRC without second confirmatory CT scan: 74% (95% CI: 66-80)
Median DOR was not reached; 12-month DOR rate: 88.3%
O’Brien S, et al. ASH Abstract 327.
28/05/ :09

84. Progression-Free Survival
Median PFS not reached
Median follow-up months N
12-month PFS rate
Overall
144
79.3%
Del17p quartiles*
<25%
25-50%
50-75%
≥75% 35 37 33 39
85%
81%
83%
69%
*Based on % of CLL cells with del17p at baseline
O’Brien S, et al. ASH Abstract 327.
28/05/ :09

85. Overall Survival Median OS not reached Median follow-up 11.5 months N
12-month OS rate
Overall
144
83.5 %
Del17p quartiles*
<25%
25-50%
50-75%
≥75% 35 37 33 39
85%
89%
86%
76%
*Based on % of CLL cells with del17p at baseline
O’Brien S, et al. ASH Abstract 327.
28/05/ :09

86. Conclusions
Ibrutinib is efficacious with a favorable risk-benefit profile in largest prospective study in del17p CLL/SLL
Best response (ORR including PR-L): 83% (investigator assessed)
Median PFS and DOR: not reached at median follow up 11.5 months
12-month PFS: 79%, consistent with previously-observed efficacy1
PFS outcomes favorable compared to that of front-line del17p CLL treated with FCR or alemtuzumab (median PFS: 11 months)2,3
Safety profile consistent with previous reports for ibrutinib1
Ibrutinib effective in patients with del17p CLL/SLL
1. Byrd et al. NEJM. 2013;369:32-42; 2. Hallek et al. Lancet. 2010;376: ; 3. Hillmen et al. J Clin Oncol. 2007;10: ; O’Brien S, et al. ASH Abstract 327.
28/05/ :09

87. Del17p/TP53 Mutation (Either)
Overall Survival, Including Extension Study* Idelalisib + R vs Placebo + R ➞ Idelalisib
Del17p/TP53 Mutation (Either)
Del11q Positive
Idelalisib + R (n=46)
Placebo + R (n=49)
Idelalisib + R (n=25)
Placebo + R (n=23)
CI, confidence interval; HR, hazard ratio; IDELA, idelalisib; OS, overall survival; PBO, placebo; R, rituximab.
N at risk
IDELA + R 46 45 41 40 39 30 23 16 12 5 2
PBO + R 49 37 33 25 17 11 8 4 1
N at risk 25 24 23 22 20 17 12 8 7 6 5 3 1 21 16 11 2
Median OS (95% CI)
HR (95% CI)
p-value
IDELA + R
NR (18.8, ‒ )
0.31 (0.15, 0.65)
0.001
PBO + R
14.8 mo (8.4, ‒ )
Median OS (95% CI)
HR (95% CI)
p-value
NR ( ‒, ‒ ) NA
0.21
18.1 (11.1, ‒ )
*As randomized, including cross-over
Sharman J, et al. ASH Abstract 330.

88. Venetoclax is a Second Generation BCL-2 inhibitor
Navitoclax
Venetoclax
Platelet
Survival
Bcl-XL
Thrombocytopenia
Combination efficacy in solid tumors
Mono- /combination
Efficacy in lymphoid malignancies
Bcl-2
Lymphocyte
Survival
Lymphopenia
Dual Bcl-2 / Bcl-xL inhibition dictates therapeutic index (Efficacy / Toxicity) of navitoclax
Venetoclax is specific Bcl-2 inhibitor
Leverson JD, et al. Sci Transl Med. 2015;7:279ra40.

89. Venetoclax Monotherapy in Rel / Ref CLL: Schema
Daily Venetoclax doses increased weekly to the designated cohort dose (DCD)
Initial Ramp-Up Schema: Dose Escalation
Ramp-Up Schema: Expanded Safety Cohort
  * 3 patients (1 each in cohorts 2, 3, & 5) received Venetoclax 20 mg as initial dose
** Step-up doses range from 100 to 400 mg
# DCD ranges from 150 to 1200 mg
Seymour JF, et al. EHA Abstract S702.

90. Venetoclax Monotherapy in Rel / Ref CLL: Objective Responses of Venetoclax Treated Patients
All
n (%), n = 78
del (17p)
n (%), n = 19
F-Refractory
n (%), n = 41
IGHV Unmutated
n (%), n = 24
Overall response
60 (77)
15 (79)
31 (76)
18 (75)
Complete response (CR/CRi)#
18 (23)
5 (26)
9 (22)
7 (29)
Partial response*
42 (54)
10 (53)
22 (54)
11 (46)
Stable disease
10 (13)
2 (11)
7 (17)
2 (8)
Disease progression
2 (3)
1 (5)
1 (3)
D/C Prior to assessment+
6 (8)
2 (5)
Some patients may have more than one high risk marker.
#4 patients have CRi; +D/C = discontinued, first assessment at 6 weeks
*3 patients had confirmatory CT imaging assessments at less than an 8 week interval (5, 6, and 7 weeks)
As of April 9, evaluable patients (n=78) had 2 CT scans, performed approximately 8 weeks apart, n=55 from dose escalation and n=23 from the safety expansion cohort
A total of 26 patients are not yet evaluable in the SE cohort (12 patients had a PR at their first scan, 14 patients have not yet reached their first assessment)
The median duration of response has not yet been reached based on current patient enrollment numbers.
Seymour JF, et al. EHA Abstract S702.

91. Best Percent Change from Baseline in Bone Marrow Infiltrate (n=51)
Anti-tumor activity of Venetoclax was observed in all tumor compartments.
# ^
# Patient had 70% infiltrate at baseline and at Week 24
^Patient did not have CLL infiltrate at baseline.
Median time to 50% reduction: 5.5 months, range [1.9 – 17.4]*
46/51 (90%) evaluable patients have had at least a 50% reduction.
Seymour JF, et al. EHA Abstract S702.

92. Minimal Residual Disease (MRD): Preliminary Analyses
11/18 patients with CR/CRi were assessed for MRD
Quantification by 4 color flow cytometry using local lab methods
Per bone marrow (BM) assessment:
No detectable MRD was found in 6 patients (of these, 3 with suboptimal cell numbers analyzed, not 10-4 sensitivity)
Low level MRD was found in 4 (0.17%, 0.7%, 0.75%, 1.5%)
Per Peripheral Blood (PB) Assessment
1 patient had no detectable MRD in PB (no BM assessed)
Of the patients who had no detectable MRD per BM, 1 patient was fludarabine refractory and del(17p), 3 patients were fludarabine refractory and 1 patient was del (17p)
Seymour JF, et al. EHA Abstract S702.

93. Progression Free Survival (PFS) at 400 mg or Higher
Median PFS for patients treated at or above 400 mg has not yet been reached, (median follow-up of 5.3 months, range [0.03 – 22])
As of April 9, 2014, the median PFS for all patients is approximately 18 months
Seymour JF, et al. EHA Abstract S702.

94. Progression Free Survival (PFS) at 400 mg or Higher in High Risk Patients
Median PFS for fludarabine refractory and/or del(17p) patients treated at or above 400 mg has not yet been reached (median follow-up 5.3 months, range [0.03 – 22])
Seymour JF, et al. EHA Abstract S702.

95. Adverse Events All Grades ≥20% of pts N=105 n (%) Diarrhea 42 (40)
Neutropenia
38 (36)
Nausea
37 (35)
Upper respiratory tract infection
35 (33)
Fatigue
27 (27)
Cough
21 (20)
Grades 3/4
≥ 5% pts
Anemia
10 (10)
Febrile neutropenia
7 (7)
Thrombocytopenia
Hyperglycemia
Tumor lysis syndrome (TLS)
7 (7) 
Hypokalemia
5 (5)
Seymour JF, et al. EHA Abstract S702.

96. Venetoclax + Rituximab for R/R CLL, Phase 1b: Dosing Schedule Cohorts 3 - 6
400mg, 500mg, 600mg and safety expansion cohorts dosed with this schedule
OR: if one or more electrolytes meet Cairo-Bishop criteria and/or
if there is ≥ 30% decrease in ALC with first dose
Roberts AW, et al. EHA Abstract S703.

97. R/R CLL, Rituximab + Venetoclax: Responses
Roberts A, et al. ASH Abstract 325.

98. Adverse Events (AEs) AEs in ≥ 20% of Pts Pts (N = 49), % Any AE 100
Neutropenia 49
Nausea 47
Diarrhea 45
Pyrexia 37
Upper respiratory infection
Cough 33
Fatigue
Headache 31
Anemia 22
Thrombocytopenia
Grade 3/4 AEs in ≥ 3 Pts
Pts
(N = 49), %
Any grade 3/4 AE 71
Neutropenia 47
Anemia 14
Leukopenia 10
Febrile neutropenia 6
Serious AEs in ≥ 2 Pts
Pts
(N = 49), %
Pyrexia 8
Febrile neutropenia 4
Infusion-related reaction
Tumor lysis syndrome
Roberts A, et al. ASH Abstract 325. 98

99. Venetoclax Oral Bcl-2 inhibitor with potent therapeutic activity
Complete remissions in rel/ref CLL
MRD-negative CRs reported
Active in very high-risk CLL: rel/ref del(17p) CLL and fludarabine-refractory CLL
Additional combinations under study
FDA-approval strategy in development

100. Go Online for More CCO Education on CLL!
Expert Commentaries on Evolving Data
Additional Downloadable Slidesets
Comprehensive inPractice Chapter on NHL: available for point-of-care credit
clinicaloptions.com/oncology