1. Chronic Lymphocytic Leukemia: Expert Insights and Strategies for Refining Patient Care
This activity is supported by educational grants from AbbVie, Inc.; Genentech; Pharmacyclics LLC; and Janssen Biotech, Inc.

2. Faculty Jeffrey A. Jones, MD, MPH Associate Professor of Medicine
Section Head for CLL/HCL
Division of Hematology
The Ohio State University
Columbus, Ohio
Jeffrey A. Jones, MD, MPH, has disclosed that he has received consulting fees and funds for research support from AbbVie, Genentech, Gilead Sciences, Janssen, and Pharmacyclics.
This slide lists the faculty who were involved in the production of these slides.

3. Agenda Using CCO’s Online Treatment Decision Tool
Pts without del(17p) abnormalities
Elderly pt
Younger, fit pts
Pts with del(17p) abnormalities
First-line treatment
Treatment after progression

4. Online Treatment Decision Aid for CLL
Developed by 5 CLL experts based on key factors they considered important to guide therapy
Enter specific pt characteristics using drop down menus
CLL, chronic lymphocytic leukemia.
Available at: clinicaloptions.com/CLLTool

5. Pt Case: Expert Recommendations
Treatment recommendations from 5 CLL experts for our pt scenario are shown
CLL, chronic lymphocytic leukemia.
Available at: clinicaloptions.com/CLLTool

6. Case 1: Elderly, Fit Patients

7. Pt Case 1: Elderly Pt With Standard-Risk Disease
86-yr-old female
Has type 2 diabetes (on oral agents), HTN, GERD with Barrett’s esophagus, macular degeneration, hyperlipidemia, and osteoarthritis
ECOG PS of 1 (still gardens on the farm where she and her husband live independently, cooks all meals, runs errands with her husband, attends church functions)
Presented to an outside hospital after falling while waiting in line at the post office
No LOC, but was lightheaded and noted rapid heartbeat after rising from the ground
In ED, noted to have a rapid, regular tachycardia with heart rate of 160, SBP in the 110s, no chest pain or other cardiac symptom; resolved spontaneously, echo was normal
ECOG, Eastern Cooperative Oncology Group; ED, emergency department; GERD, Gastroesophageal Reflux Disease; HTN hypertension; LOC, loss of consciousness; PS, performance status; SBP, systolic blood pressure.

8. Pt Case 1: Elderly Pt With Standard-Risk Disease
Routine lab work demonstrated a lymphocyte predominant peripheral blood leukocytosis
In hospital, workup included PB flow that confirmed a CLL immunophenotype without evidence of TLS, no symptoms of leukostasis
On follow-up, you find
WBC of 3.97 x 109/L, ALC of 3.93 x 109/L, Hb of 11.2 g/dL, platelet count of 256 x 109/L
Serum creatinine clearance was 33 ml/min
Flow cytometry: CD19+, CD20dim, CD23+, CD5+, CD43+; CD10-, CD79-, FMC7-
FISH was negative, normal stimulated karyotype, IGHV mutated, ZAP-70 unmethylated
ALC, absolute lymphocyte count; CLL, chronic lymphocytic leukemia; Hb, hemoglobin; PB, peripheral blood; TLS, tumor-lysis syndrome; WBC, white blood cell count.

9. Expert Recommendations: Online Interactive Decision Support Tool

10. RESONATE-2: Ibrutinib vs Chlorambucil in Pts ≥ 65 Yrs of Age With Tx-Naive CLL/SLL
An international, randomized phase III trial
Primary endpoint: PFS
Secondary endpoints: OS, ORR, EFS, rate of hematologic improvement, and safety
Ibrutinib
420 mg/day until progression
Pts 65 yrs of age or older with treatment-naive CLL/SLL; no warfarin use; no del(17p) (N = 269)
Crossover upon PD (n = 43)
Chlorambucil
0.5 mg/kg (up to maximum of 0.8 mg/kg)
on Days 1, 15 of 28-day cycle
for up to 12 cycles
CLL, chronic lymphocytic leukemia; EFS, event-free survival; PD, progressive disease; SLL, small lymphocytic lymphoma; Tx, treatment.
Slide credit: clinicaloptions.com
Burger JA, et al. N Engl J Med. 2015;373:

11. RESONATE-2: Superior Efficacy With Ibrutinib vs Chlorambucil for Elderly Pts
PFS OS
Ibrutinib
100
100
Ibrutinib 80 80
Chlorambucil 60
Chlorambucil 60
Pts With PFS (%)
Median
PFS, Mos
Pts Who Survived (%) 40 40
Ibrutinib NR
Median: not reached in either group
HR: 0.16 (95% CI: ; P = .001 by log-rank test) 20
Clb 18.9 20
HR: 0.16 (95% CI: ; P < .001)
AE, adverse event; Clb, chlorambucil; NR, not reached. 6 12 18 24 6 12 18 24
Mos
Mos
AEs Summary
Ibrutinib
Chlorambucil
Most frequent AEs
Diarrhea, fatigue, cough, and nausea
Nausea, fatigue, neutropenia, anemia, and vomiting
AEs leading to discontinuation, % 9 23
Slide credit: clinicaloptions.com
Burger JA, et al. N Engl J Med. 2015;373:

12. Phase III CLL11 Trial: Chlorambucil Alone vs With Obinutuzumab vs With Rituximab
0.5 mg/kg PO on Days 1, 15 x 6 cycles
(n = 118)
Previously untreated
CLL pts with
comorbidities;
CIRS score > 6
and/or
CrCl < 70 mL/min
(N = 781)
Obinutuzumab
1000 mg IV cycle 1 on Days 1, 8, 15; cycles 2-6 on Day 1 Chlorambucil
(n = 333)
CIRS, Cumulative Illness Rating Scale; CLL, chronic lymphocytic leukemia; CrCl, creatinine clearance.
Rituximab
375 mg/m2 IV cycle 1 on Day 1; 500 mg/m2 cycles 2-6 on Day 1 Chlorambucil
(n = 330)
Goede V, et al. ASH Abstract 6. Goede V, et al. N Engl J Med. 2014;370:
Slide credit: clinicaloptions.com

13. CLL11: Survival With Clb/Obinutuzumab vs Clb Alone or Clb/Rituximab in CLL
1.0
1.0
HR: 0.18 (95% CI: ; P < .001)
0.8
0.8
HR: 0.41 (95% CI: ; P < .002)
0.6
0.6
Probability of PFS
Probability of OS
0.4
0.4
O-Clb Clb
0.2
26.7
O-Clb Clb
0.2
11.1 6 12 18 24 30 36 6 12 18 24 30 36
1.0
1.0
HR: 0.39 (95% CI: ; P < .001)
0.8
0.8
Clb, chlorambucil; CLL, chronic lymphocytic leukemia; O, obinutuzumab; R, rituximab.
In contrast, treatment with GA101 in combination with chlorambucil resulted in an overall survival benefit - compared to chemotherapy only.
HR: 0.66 (95% CI: ; P = .08)
0.6
0.6
Probability of PFS
Probability of OS
0.4
0.4
O-Clb R-Clb
26.7
O-Clb R-Clb
0.2
0.2
15.2 6 12 18 24 30 36 39 6 12 18 24 30 36 39
Mos
Mos
Slide credit: clinicaloptions.com
Goede V, et al. N Engl J Med. 2014;370:

14. CLL11: Response With Clb/Obinutuzumab vs Clb Alone or Clb/Rituximab in CLL
O-Clb (n = 238)
Clb (n = 118)
R-Clb (n = 233)
ORR
77.3
31.4
75.7 CR
22.3
7.3 PR
55.0
58.4
Pts With MRD-Negative Test, %
O-Clb
R-Clb
P Value
Bone marrow
19.5
2.6
< .001
Blood
37.7
3.3
Clb, chlorambucil; CLL, chronic lymphocytic leukemia; O, obinutuzumab; MRD, minimal residual disease; R, rituximab.
Investigator-assessed PFS was the primary endpoint of the study. For the head-to-head comparison of the GA101 arm with the rituximab arm, the hazard ratio was The median PFS was 27 months in the GA101 arm compared to 15 months in the rituximab arm. Thus, GA101 is superior to rituximab - in combination with chlorambucil – with regard to PFS.
Overall survival data for the head-to-head comparison of the GA101 arm with the rituximab arm are still immature, but look promising. At present, the hazard ratio is 0.66 and the p-value 0.08.
Slide credit: clinicaloptions.com
Goede V, et al. N Engl J Med. 2014;370:

15. CLL11: Grade ≥ 3 AEs With Obinutuzumab + Clb, Rituximab + Clb, or Clb Alone
Grade ≥ 3 AE in ≥ 3% of Pts in Any Arm, %
O-Clb vs Clb
R-Clb vs Clb
O-Clb vs R-Clb
O-Clb
(n = 241)
Clb
(n = 116)
R-Clb
(n = 225)
(n = 336)
(n = 321)
Any grade ≥ 3 73 50 56 70 55
Infusion-related rxn 21 -- 4 20
Neutropenia 35 16 27 33 28
Anemia 5
Thrombocytopenia 11 10 3
Leukopenia 1
Infection 14 13 12
Pneumonia
Febrile neutropenia 2
AE, adverse event; Clb, chlorambucil; O, obinutuzumab; R, rituximab.
Slide credit: clinicaloptions.com
Goede V, et al. N Engl J Med. 2014;370:

16. Pt Case 1: Elderly Pt With Standard-Risk Disease
This pt is already receiving a number of daily medications, was concerned about adding another pill to her routine, and wanted a defined duration of therapy
Treatment with obinutuzumab + chlorambucil was initiated
Experienced infusion-related reaction (manageable) during first infusion, no recurrence
Chlorambucil discontinued after cycle 2 secondary to persisting nausea, poor tolerance of antiemetics
Pt achieved normalization of counts and peripheral blood findings
No marrow to assess response formally
Continuing to observe

17. Cases 2 and 3: Younger, Fit Patients

18. Pt Case 2: Younger, Fit Pt With Favorable Risk Features
55-yr-old male was treated for URTI and peripheral blood lymphocytosis was noted
Follow-up several mos later demonstrated persistence of peripheral blood lymphocytosis with otherwise normal counts
Pt has COPD (current smoker), OSA on CPAP
ECOG PS is 0, and he works full time
Peripheral blood immunophenotyping showed monoclonal population of B-cells, coexpressing CD19, CD5, CD20dim, and CD23, with a subpopulation expressing FMC-7 consistent with CLL
Physical exam showed small nodes (< 2 cm) in the cervical chain, with no other physical findings
CLL, chronic lymphocytic leukemia; COPD, chronic obstructive pulmonary disease; CPAP, continuous positive airway pressure; ECOG, Eastern Cooperative Oncology Group; OSA, obstructive sleep apnea; PS, performance status; URTI, upper respiratory tract infection.

19. Pt Case 2: Younger, Fit Pt With Favorable Risk Features
Pt is diagnosed with asymptomatic CLL, and is observed for 2 yrs
Now, he is complaining of progressive fatigue, night sweats most nights, and modest progression of lymphadenopathy is observed
Peripheral blood counts remain relatively persevered, but pt is interested to pursue treatment for symptomatic disease
Genetic risk features (sent before planning treatment): normal karyotype, FISH showing isolated del(13q), IGHV mutated
Physical exam reveals 2-cm cervical and axillary nodes bilaterally; no palpable organomegaly
CLL, chronic lymphocytic leukemia.

20. Expert Recommendations: Online Interactive Decision Support Tool
BR, bendamustine, rituximab; FCR, fludarabine, cyclophosphamide, rituximab.

21. Phase III CLL8: FC vs FCR in Pts With Active CLL
Fludarabine 25 mg/m2 IV Days Cyclophosphamide 250 mg/m2 Days 1-3
Pts with untreated, active CLL and good physical fitness (ECOG PS ≤ 1, CIRS ≤ 6, creatinine clearance ≥ 1.17 mL/s) (N = 817)
FCR
Fludarabine 25 mg/m2 IV Days Cyclophosphamide 250 mg/m2 Days Rituximab 375 mg/m2 IV Day 0, cycle 1 + Rituximab 500 mg/m2 IV Day 1, cycles 2-6
CIRS, Cumulative Illness Rating Scale; CLL, chronic lymphocytic leukemia; ECOG, Eastern Cooperative Oncology Group; FC, fludarabine, cyclophosphamide; FCR, fludarabine, cyclophosphamide, rituximab; PS, performance status.
Primary endpoint: PFS
Hallek M, Lancet. 2010;376:
Fischer K, et al. Blood. 2016;127:
Slide credit: clinicaloptions.com

22. CLL8: Efficacy of FC vs FCR in Pts With Active CLL
PFS OS
Median
PFS, Mos
1.0
1.0
FCR ( = 408) 56.8
FC (n = 409) 32.9
0.8
0.8
0.6
0.6
Median
PFS, Mos
Probability of PFS
Probability of OS
0.4
0.4
FCR (n = 408) NR
FC (n = 409)
FC, fludarabine, cyclophosphamide; FCR, fludarabine, cyclophosphamide, rituximab; NR, not reached.
0.2
0.2
HR: 0.59 (95% CI: ; P < .001)
HR: 0.68 (95% CI, ; P = .001)
0.0
0.0 12 24 36 48 60 72 84 96 12 24 36 48 60 72 84 96
Mos on Study
Mos on Study
Slide credit: clinicaloptions.com
Fischer K, et al. Blood. 2016;127:

23. CLL8: Safety of FC vs FCR in Pts With Active CLL
Most Common Grade 3/4 AEs, n (%)[1]
FC (n = 396)
FCR (n = 404)
P Value
Any grade 3/4 event
249 (63)
309 (76)
< .0001
Hematologic toxicity
157 (40)
225 (56)
Infections
85 (21)
103 (25)
.18
Neutropenia
83 (21)
136 (34)
Leukocytopenia
48 (12)
97 (24)
Thrombocytopenia
44 (11)
30 (7)
.07
Long-term Safety, n (%)[2]
Prolonged neutropenia
(2 mos after end of tx)
67 (17)
34 (9)
(12 mos after end of tx)
16 (4)
14 (4)
Secondary primary malignancies
53 (13)
69 (17)
AE, adverse event; CLL, chronic lymphocytic leukemia; FC, fludarabine, cyclophosphamide; FCR, fludarabine, cyclophosphamide, rituximab; tx, treatment.
1. Hallek M, et al. Lancet. 2010;376:
2. Fischer K, et al. Blood. 2016;127:
Slide credit: clinicaloptions.com

24. Phase III CLL10: Final Analysis of FCR vs BR in Pts With Advanced CLL
Fludarabine 25 mg/m2 IV Days Cyclophosphamide 250 mg/m2 Days Rituximab 375 mg/m2 IV Day 0, cycle 1; Rituximab 500 mg/m2 IV Day 1, cycles 2-6
Pts with untreated, active CLL without del(17p) and good physical fitness (CIRS ≤ 6, creatinine clearance ≥ 70 mL/min) (N = 564) BR
Bendamustine 90 mg/m2 IV Days Rituximab 375 mg/m2 Day 0, cycle 1; Rituximab 500 mg/m2 IV Day 1, cycles 2-6
BR, bendamustine, rituximab; CIRS, Cumulative Illness Rating Scale; CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab.
Primary endpoint: noninferiority of BR vs FCR for PFS with HR (λBR/FCR) < 1.388
Slide credit: clinicaloptions.com
Eichhorst B, et al. Lancet Oncol. 2016;17:

25. CLL10: Response With FCR vs BR in Pts With Advanced CLL
FCR (n = 282)
BR (n = 279)
P Value
CR (CR + CRi)
39.7
30.8
.034 CR
35.1
30.4
CRi
4.6
0.4 PR
55.7
64.9
ORR
95.4
95.7
1.0
MRD Negativity, %
FCR (n = 282)
BR (n = 279)
BM at final restaging 27 11
PB at final restaging 49 38
PB 12 mos after final restaging 17 7
PB 18 mos after final restaging 13 6
BM, bone marrow; BR, bendamustine, rituximab; CRi, complete remission with incomplete blood count recovery; FCR, fludarabine, cyclophosphamide, rituximab; MRD, minimal residual disease; PB, peripheral blood.
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. Lancet Oncol. 2016;17:
Eichhorst B, et al. ASH Abstract 19.
Slide credit: clinicaloptions.com

26. HR: 1.643 (> 1.388 non-inferiority cutoff)
CLL10: PFS (Primary Endpoint) and OS With FCR vs BR in Pts With Advanced CLL
PFS OS
1.0
Median
PFS, Mos
1.0
FCR BR
OS at
36 Mos, %
0.8
0.8
FCR BR
0.6
0.6
Cumulative Survival
0.4
0.4
BR, bendamustine, rituximab; CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab.
0.2
0.2
HR: (> non-inferiority cutoff)
P < .001
HR: 1.034
P = .897 12 24 36 48 60 12 24 36 48 60
Mos
Mos to Event (OS)
Slide credit: clinicaloptions.com
Eichhorst B, et al. Lancet Oncol. 2016;17:

27. CLL10: Adverse Events With FCR vs BR in Pts With Advanced CLL
P Value
Neutropenia
84.2
59.0
< .001
Anemia
13.6
10.4
.20
Thrombocytopenia
21.5
14.4
.03
Infection
39.1
26.8
Secondary neoplasm*
6.1
3.6
.244
Treatment-related mortality
4.6
2.1
.107
Infections
2.5 --
Secondary neoplasm
1.1
Other
1.0
BR, bendamustine, rituximab; CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab; MDS, myelodysplastic syndromes; sAML, secondary acute myeloid leukemia.
*sAML/MDS: FCR = 6, BR = 1.
Slide credit: clinicaloptions.com
Eichhorst B, et al. ASH Abstract 19

28. Expert Recommendations: Online Interactive Decision Support Tool
Treatment setting: newly diagnosed; no del(17p)
Age and fitness: younger than 65 yrs; fit with no renal impairment
IGHV mutation: yes
IGHV mutation: no
Expert
Recommendation
Expert 1
FCR
Expert 2
Ibrutinib
Expert 3
Expert 4
Expert 5
Expert
Recommendation
Expert 1
Ibrutinib
Expert 2
Expert 3
Expert 4 BR
Expert 5
BR, bendamustine, rituximab; FCR, fludarabine, cyclophosphamide, rituximab
Slide credit: clinicaloptions.com

29. Pts Progression Free (%)
FCR300 Phase II Trial: Plateau in PFS With FCR as Initial Therapy for CLL
With extended follow-up, PFS shows plateau at Yrs 10-11
Last relapses occurred around Yr 10, with a plateau in PFS for IGHV-mutated pts
Progression Free N
Event Free N OS
PFS
IGHV mutated IGHV unmutated
100
100 75 75
Pts (%) 50
Pts Progression Free (%) 50
CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab 25 25
P < .0001 2 4 6 8 10 12 14 16 2 4 6 8 10 12 14 16
Yrs
Yrs
Slide credit: clinicaloptions.com
Thompson PA, et al. Blood. 2016;127:

30. CLL8: Plateau in PFS and OS With FCR as Initial Therapy for CLL
FCR IGHV mut pts (n = 113)
FC IGHV mut pts (n = 117)
FCR IGHV unm pts (n = 197)
FC IGHV unm pts (n = 195)
1.0
1.0
0.8
0.8
0.6
0.6
Probability of PFS
Probability of OS
0.4
0.4
CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab; mut, mutated; unm, unmutated.
0.2
0.2
P < by log-rank test
P < by log-rank test 12 24 36 48 60 72 84 96 12 24 36 48 60 72 84 96
Mos on Study
Mos on Study
Slide credit: clinicaloptions.com
Fischer K, et al. Blood. 2016;127:

31. Assessing MRD Status to Determine Duration of Therapy
CLL8: MRD levels independently predict OS and PFS and may serve as a surrogate marker of efficacy[1]
Prospective MRD assessment in FCR-treated CLL pts showed MRD-negative pts had comparable PFS and OS, independent of number of cycles of therapy[2]
Early MRD eradication assessed by 4-color flow cytometry
may guide when to halt therapy[2]
1.0
P = NS
1.0
0.8
P = .05
0.8
P = NS
0.6
0.6
P < .001
P < .001
PFS (%)
OS (%)
0.4
0.4
MRD- after C3
MRD+ after C3
MRD- after C3, end of tx
MRD+ after C3, MRD- at end of tx
MRD+ after C3, end of tx
BM, bone marrow; CLL, chronic lymphocytic leukemia; FC, fludarabine, cyclophosphamide; FCR, fludarabine, cyclophosphamide, rituximab; MRD, minimal residual disease; NS, not significant; PB, peripheral blood; tx, treatment.
0.2
0.2 10 20 30 40 50 60 10 20 30 40 50 60
1. Böttcher S, et al. J Clin Oncol. 2012;30:
2. Strati P, et al. Blood. 2014;123:
Slide credit: clinicaloptions.com

32. Pt Case 2: Younger, Fit Pt With Favorable Risk Features
Pt begins treatment with FCR for up to 6 cycles
No treatment-related AEs aside from slow-to-recover blood cell counts after 4 cycles of therapy
After a 4-wk delay from planned start of cycle 5, BM biopsy performed and consistent with CR, MRD negative
Therapy was discontinued; counts recovered during follow-up
Last seen at 5 yrs after completing therapy; no evidence for disease recurrence
AE, adverse event; BM, bone marrow; MRD, minimal residual disease.

33. Pt Case 3: Younger, Fit Pt Who Prefers Non-Chemo Option
60-yr-old female with HTN, thyroid cancer 7 yrs prior (thyroidectomy, radioiodine) without recurrence, surgically hypothyroid
Routine evaluation during work-up for syncope found asymptomatic PB lymphocytosis
CBC showed WBC of 20.1 x 109/L, Hb of 14 g/dL, and platelets of x 109/L
Peripheral smear showed absolute lymphocytosis with atypia, which is concerning for chronic lymphoproliferative disorder
Peripheral blood immunophenotyping showed lymphoid cells demonstrate as a monoclonal B-cell population with presence of CD19, CD 20 (dim), kappa light chain (dim), CD23, FMC7, and CD5, but lacked expression of CD79b, CD10, and CD38
CBC, complete blood count; Hb, hemoglobin; HTN, hypertension; PB, peripheral blood; WBC, white blood cell count;

34. Pt Case 3: Younger, Fit Pt Who Prefers Non-Chemo Option
She was observed for 3 yrs without specific intervention before she progressed to Rai stage III disease and met indications for therapy
She remains largely asymptomatic save for notable progression of nontender lymphadenopathy
Palpable spleen about 2 cm below left costal margin
Genetic risk assessment: IGHV unmutated, with del(11q)
She is concerned about secondary cancers from treatment given her history of prior thyroid cancer

35. Expert Recommendations: Online Interactive Decision Support Tool
BR, bendamustine, rituximab.

36. Pt Preferences for Selecting Treatment for Pts Without del(17p)
Because there may be multiple reasonable options for first-line therapy for pts without del(17p), discussing the risks and benefits of each approach are important aspects of care
Additional considerations include pt preference:
Ongoing, indefinite treatment vs therapy with a defined period of time
Specific concerns regarding the adverse events of each appropriate agent
Concerns regarding development of acute vs chronic adverse events (eg, secondary malignancies) associated with each options
Cost of each treatment option

37. Treatment of R/R CLL in Patients Without del(17p)
CLL, chronic lymphocytic leukemia; R/R, relapsed or refractory.

38. Pt Case 6: R/R CLL With Poor Tolerance to Ibrutinib
84-yr-old female diagnosed with asymptomatic Rai stage 1 CLL after a fall
Peripheral blood lymphocytosis; otherwise normal CBC
Baseline risk assessment showed normal karyotype, del(13q) (18.7%), mutated phenotype (somatic mutation rate of the IGHV gene is 8.2%)
No specific intervention until she progressed to Rai stage III disease 4 yrs later
Progressive lymphadenopathy, constitutional symptoms, development of recurrent anemia and thrombocytopenia
CBC, complete blood count; CLL, chronic lymphocytic leukemia; R/R, relapsed or refractory.

39. Pt Case 6: R/R CLL With Poor Tolerance to Ibrutinib
She initiated ibrutinib 420 mg/day PO x 2 wks
Treatment was discontinued due to skin rash and mouth sores
Upon rechallenge, pt experienced swollen mouth and tongue 2 hrs after dose
After permanently discontinuing and resolving acute AEs, disease still required therapy
AE, adverse event; CLL, chronic lymphocytic leukemia; R/R, relapsed or refractory.

40. Expert Recommendations: Online Interactive Decision Support Tool
BR, bendamustine, rituximab; Clb, chlorambucil; CLL, chronic lymphocytic leukemia; R, rituximab.

41. Phase III Study 116/117: Rituximab ± Idelalisib in Relapsed CLL
Primary Study 116
Extension Study 117
Double blind
Blinded dose
Open label
Idelalisib 150 mg BID
Idelalisib 300 mg BID
Rituximab* (n = 110)
Pts with relapsed CLL, not appropriate for cytotoxic therapy; ≥ 1 prior anti-CD20 or ≥ 2 prior cytotoxic therapies PD
Placebo BID
Idelalisib 150 mg BID
CLL, chronic lymphocytic leukemia; PD, progressive disease.
Rituximab* (n = 110)
Interim analysis; unblinding
Independent review
Blinded, independent review
Primary endpoint: PFS, OS by subgroup analysis
*Rituximab given in 8 doses; first dose 375 mg/m2, then 500 mg/m2 every 2 wks x 4, then every 4 wks x 3.
Slide credit: clinicaloptions.com
Sharman JP, et al. ASH Abstract 330.

42. Phase III Study 116/117: PFS With Rituximab ± Idelalisib in Relapsed CLL
100 80 60
PFS (%) 40 20
Idelalisib + R (n = 110)
Placebo + R* (n = 110)
CLL, chronic lymphocytic leukemia; NR, not reached; R, rituximab. 2 4 6 8 10 12 14 16 18 20 22 24 26
Mos
Median PFS, Mos (95% CI)
HR (95% CI)
P Value
Idelalisib + R
19.4 (16.6-NR)
0.25 ( )
< .0001
Placebo + R
7.3 ( )
*Placebo + R includes those pts who received open-label idelalisib after unblinding without prior progression (n = 42).
Slide credit: clinicaloptions.com
Sharman JP, et al. ASH Abstract 330.

43. Idelalisib + Rituximab in Relapsed CLL: PFS Subgroup Analysis*
IGHV: Unmutated vs Mutated
del(17p)/TP53mut: Present vs Not Present
100
100 80 80 60 60
PFS (%)
PFS (%) 40 40 20 20
P = .75
P = .94
CLL, chronic lymphocytic leukemia; NR, not reached. 2 4 6 8 10 12 14 16 18 20 22 24 26 2 4 6 8 10 12 14 16 18 20 22 24 26
Mos
Mos
Median PFS,
Mos (95% CI)
NR (10.7-NR)
19.4 (16.6-NR)
Median PFS,
Mos (95% CI)
20.3 (19.4-NR)
16.6 (13.9-NR)
No del(17p)/TP53mut (n = 64)
Mutated (n = 19)
Unmutated (n = 91)
del(17p)/TP53mut
(n = 46)
*Including extension study.
Slide credit: clinicaloptions.com
Sharman JP, et al. ASH Abstract 330.

44. Idelalisib + R vs Placebo + R ➞ Idelalisib in Relapsed CLL: OS
All Pts
IGHV Unmutated
100 80 60 40 20
100 80 60 40 20
OS (%)
OS (%)
Idelalisib + R (n = 110) Placebo + R (n = 110)
P = .0001
Idelalisib + R (n = 91) Placebo + R (n = 93)
P = .0003 2 4 6 8 10 12 14 16 18 20 22 24 26 2 4 6 8 10 12 14 16 18 20 22 24 26
Mos
Mos
del(17p)/TP53 Mutation (Either)
del(11q) Positive
100 80 60 40 20
100 80 60 40 20
CLL, chronic lymphocytic leukemia; R, rituximab.
OS (%)
OS (%)
Idelalisib + R (n = 46) Placebo + R (n = 49)
P = .001
Idelalisib + R (n = 25) Placebo + R (n = 23)
P = .21 2 4 6 8 10 12 14 16 18 20 22 24 26 2 4 6 8 10 12 14 16 18 20 22 24 26
Mos
Mos
Slide credit: clinicaloptions.com
Sharman JP, et al. ASH Abstract 330.

45. Idelalisib: Notable AEs
Diarrhea:
Occurs in 2 Forms
Transaminase Elevations: Generally Reversible
Pneumonitis: Consistent With Reports With mTOR Inhibitors
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
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 > 20 x ULN
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
AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; mTOR, mechanistic target of rapamycin; ULN, upper limit of normal.
Slide credit: clinicaloptions.com
Coutre SE, et al. Leuk Lymphoma. 2015;56:

46. Pt Case 6: R/R CLL With Poor Tolerance to Ibrutinib
Pt initiated therapy with idelalisib + rituximab
Peripheral blood counts normalized within the first 8 wks of treatment, as did palpable lymphadenopathy
Scans (performed by her local oncologist) showed lymph nodes all below 2 cm
Continued treatment until discontinued secondary to persistent diarrhea
Workup negative for infection, no other etiologies, pt declined colonoscopy to evaluate
Diarrhea resolved off therapy with oral budesonide; counts remained stable and pt remains under observation
CLL, chronic lymphocytic leukemia; R/R, relapsed or refractory.

47. Patients With CLL and del(17p)
CLL, chronic lymphocytic leukemia.

48. Case 4: Frontline Treatment for Pts With High-Risk Cytogenetics (del[17p])
A 65-yr-old male was initially diagnosed with CLL when peripheral blood lymphocytosis was noted on routine CBC obtained as part of health maintenance examination
FISH detected del(17p)
CBC, complete blood count; CLL, chronic lymphocytic leukemia.

49. Expert Recommendations: Online Interactive Decision Support Tool
CLL, chronic lymphocytic leukemia.

50. Phase III RESONATE: Ibrutinib vs Ofatumumab in Previously Treated CLL/SLL
Ibrutinib 420 mg/day PO until PD or unacceptable toxicity (n = 195)
CLL/SLL diagnosis
≥ 1 prior therapy; ECOG PS 0-1; measurable nodal disease by CT
Ofatumumab IV starting dose of 300 mg followed by 2000 mg x 11 doses for 24 wks (n = 196)
Crossover = 122 pts
To Ibrutinib 420 mg/day following PD
AE, adverse event; CLL, chronic lymphocytic leukemia; ECOG, Eastern Cooperative Oncology Group; PD, progressive disease; PS, performance status; SLL, small lymphocytic lymphoma.
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 Abstract Byrd JC, et al. N Engl J Med. 2014;371:  
Slide credit: clinicaloptions.com

51. RESONATE: PFS by del(17p) With Ibrutinib vs Ofatumumab in CLL/SLL
Ibrutinib del(17p) Ibrutinib no del(17p)
Ofatumumab del(17p)
Ofatumumab no del(17p)
Median
PFS, mos NR
5.9
8.2
HR: (95% CI:
; P = .396)
HR: (95% CI:
; P = .039)
100 80 60
PFS (%) 40
CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma. 20 3 6 9 12 15 18 21 24
Mos
For ibrutinib, no significant difference in PFS with or without del(17p)
Slide credit: clinicaloptions.com
Brown JR, et al. ASH Abstract 3331.

52. Ibrutinib: Toxicities
Hemorrhage: fatal bleeding events have occurred
Grade ≥ 3: 6% of pts
Any grade, including bruising and petechiae: ~ 50% of pts
Recommendation: hold tx for days presurgery/ postsurgery depending on the type of surgery and the risk of bleeding
Atrial fibrillation: 6% to 9% of pts
Increased in pts with cardiac risk factors, acute infections, and history of atrial fibrillation
Cytopenias, grade 3/4
Neutropenia (19% to 29%); thrombocytopenia (5% to 17%); anemia (0% to 9%)
Tumor lysis syndrome
Monitor closely, particularly pts with high tumor burden
Most common AEs (≥ 25%): thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, URI, and rash
AE, adverse event; tx, treatment; URI, upper respiratory infection.
Slide credit: clinicaloptions.com
Ibrutinib [package insert]

53. Case 4: Pts With High-Risk Cytogenetics (del[17p]) at Relapse
Pt began ibrutinib and responded well
Best response was PR but he never normalized his platelet count during therapy
After 3 yrs on therapy, he begins developing worsening cytopenias, marked splenomegaly, and new lymphadenopathy
Exam reveals palpable spleen 15 cm below left costal margin; 2 cm inguinal LN bilaterally; shotty cervical nodes
Labs show WBC of 131.6x109/L, Hb of 12.5 g/dL, platelet count of 50x109/L, ALC of 110x109/L, ANC of 9.2x109/L, and serum creatinine of 1.55 mg/dL
NGS for known ibrutinib resistance mutations showed C481S mutation in 85%, PLCg2 29%
ALC, absolute lymphocyte count; ANC, absolute neutrophil count; Hb, hemoglobin; LN, lymph node; NGS, next-generation sequencing; PLT, platelet; WBC, whole blood count.

54. Expert Recommendations: Online Interactive Decision Support Tool
CLL, chronic lymphocytic leukemia; LDH, lactate dehydrogenase; R/R, relapsed/refractory.

55. Venetoclax: Mechanism of Action1 2 3
An increase in BCL-2 expression allows the cancer cell to survive
Venetoclax binds to and inhibits overexpressed BCL-2
Apoptosis is initiated
Active caspase
Apoptosome
Venetoclax
Proapoptotic
proteins
(BAX, BAK)
Antiapoptotic
proteins
(BCL-2)
APAF-1
BH3 only
Cytochrome C
Procaspase
BAK
BAX
BCL-2
BCL-2
Mitochondria
Mitochondria
Mitochondria
Kumar S, et al. ASCO Abstract 8576.
Reproduced with permission.
Slide credit: clinicaloptions.com

56. Venetoclax Monotherapy: Phase II Trial in Ultrahigh-Risk R/R CLL With del(17p)
Phase II trial in pts with R/R CLL with del(17p) confirmed by central lab
ECOG PS ≤ 2; creatinine clearance ≥ 50 mL/min; no major organ dysfunction
PO, QD dosing increasing weekly with risk-based prophylaxis to mitigate tumor lysis syndrome
CLL, chronic lymphocytic leukemia; ECOG, Eastern Cooperative Oncology Group; PS, performance status; R/R, relapsed or refractory.
20 mg
50 mg
100 mg
200 mg
400 mg
Wk 1
Wk 2
Wk 3
Wk 4
Wk 5
Slide credit: clinicaloptions.com
Stilgenbauer S, et al. Lancet Oncol. 2016;17:

57. Venetoclax Monotherapy: Phase II Trial in Ultrahigh-Risk R/R CLL With del(17p)
Outcome
Pts (N = 107)
Overall response, %
CR or CRi
nPR PR 79 8 3 69
Pts with PB MRD: test, %
16.8
Time to first response,
mos (range)
0.8 ( )
Time to CR/CRi,
8.2 ( )
1-yr PFS, % (95% CI)
72.0 ( )
1-yr OS, % (95% CI)
86.7 ( )
Tx-Emergent AE,* %
Any Grade
Grade ≥ 3
Any 97 76
Neutropenia 43 40
Diarrhea 29
Nausea 1
Anemia 27 18
Fatigue 22
Pyrexia 20
Thrombocytopenia 19 15
Hyperphosphatemia 16
Vomiting
Upper respiratory Infection 2
AE, adverse event; CLL, chronic lymphocytic leukemia; CRi, complete remission with incomplete blood count recovery; MRD, minimal residual disease; nPR, near PR; PB, peripheral blood; R/R, relapsed or refractory; tx, treatment.
*Most common tx-emergent AEs in ≥ 15% of pts.
Slide credit: clinicaloptions.com
Stilgenbauer S, et al. Lancet Oncol. 2016;17:

58. Venetoclax Monotherapy: Phase II Trial in Ultrahigh-Risk R/R CLL With del(17p)
PFS
12-mo PFS: 72% (95% CI: 61.8% to 79.8%) OS
12-mo OS: 86.7% (95% CI: 78.6% to 91.9%)
100
Pts (%)
100 75 50 25 6 12 18
Pts at Risk, n
107 97 70 5 75
Pts (%) 50 25
CLL, chronic lymphocytic leukemia; R/R, relapsed/refractory. 6 12 18
Pts at Risk, n
107 86 34 2
Slide credit: clinicaloptions.com
Stilgenbauer S, et al. Lancet Oncol. 2016;17:

59. Case 4: Pts With High-Risk Cytogenetics (del[17p]) at Relapse
Pt began venetoclax (current standard of care)
Admitted to hospital for 20 mg and 50 mg dose ramp-up per package insert directions
No TLS was observed and continued dose ramp-up over the following 3 wks on an outpatient basis without TLS
Pt experienced another treatment-related toxicity, neutropenia, which was complicated by hospital admission for febrile neutropenia (resolved without sequelae)
Pt is currently maintaining a normal ANC on pegfilgrastim every 2 wks
ANC, absolute neutrophil count; TLS, tumor lysis syndrome.

60. Allogeneic Stem Cell Transplantation in CLL
Allo-SCT offers durable disease control in pts with poor prognosis[1]
Reduced-intensity conditioning decreases nonrelapse mortality, graft- vs-host disease, relapse[1]
EBMT issued 2007 consensus recommendations to consider allo-SCT for younger poor-risk pts with CLL[1]:
Refractory to or early relapse (≤ 12 mos) after purine analogs
Relapse (≤ 24 mos) after responding to purine analog therapy or autologous transplantation
p53 abnormalities needing treatment
Criteria supported by improved 2-yr OS for poor-risk CLL pts with compatible donor vs no donor match (78% vs 55%, respectively; HR: 0.38; P = .014)[2]
Allo-SCT, allogeneic stem cell transplantation; CLL, chronic lymphocytic leukemia; EBMT, European Group for Blood and Marrow Transplantation.
1. Dreger P, et al. Leukemia. 2007;21:12-17.
2. Herth I, et al. Ann Oncol. 2014;25:
Slide credit: clinicaloptions.com

61. CAR T-Cell Therapy in CLL
CAR T-cells targeting CD19 may offer durable activity in CLL
CD19 expressed on B-cells and B-cell malignancies, not hematopoietic stem cells
Limited clinical data available on anti-CD19 CAR T-cell therapy
Study N
ORR CR
University of Pennsylvania 2010 3 2
University of Pennsylvania 2014 24 10 5
National Cancer Institute 2012 4 1
National Cancer Institute 2015
Memorial Sloan Kettering 2011 8
CLL, chronic lymphocytic leukemia.
Slide credit: clinicaloptions.com
Mato A, et al. Blood. 2015;126:

62. Summary
Routine testing for genetic characteristics in CLL is essential to most effectively use current treatment options
Pts without del(17p) or other TP53 mutations have multiple treatment options
Chemoimmunotherapy: pts with favorable risk disease in the first-line setting; pts who prefer defined duration of therapy
Ibrutinib: first-line therapy for pts who have multiple comorbidities or are concerned with adverse events associated with chemoimmunotherapy; second-line therapy after progression
Idelalisib + rituximab: consider for pts who progress after or intolerant to ibrutinib
Pts with del(17p) or other TP53 mutations should receive ibrutinib as first-line therapy and venetoclax after progression

63. Go Online for More CCO Programs on CLL!
Online, Interactive Treatment Decision Aide with expert recommendations ClinicalThought Commentaries on specific clinical issues regarding management of CLL Additional downloadable slidesets with expert insights on management of CLL
clinicaloptions.com/oncology